PARACETAMOL & CAFFEINE 500/65MG SOLUBLE … · UKPAR Paracetamol & Caffeine 500/65mg Soluble...

UKPAR Paracetamol & Caffeine 500/65mg Soluble Tablets PL 08137/0157-31

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PARACETAMOL & CAFFEINE 500/65MG SOLUBLE TABLETS PL 08137/0157

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

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Steps taken after authorisation – summary

Summary of Product Characteristics Page 12

Product Information Leaflet

Page 16

Labelling Page 18


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LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Neolab Limited a Marketing Authorisation for the medicinal product Paracetamol & Caffeine 500/65mg Soluble Tablets (PL 08137/0157) on 02 July 2010. This is a General Sales List (GSL) medicine used to treat headache, migraine, backache, rheumatic and muscle pain, toothache and period pain. They also relieve discomfort in colds, influenza, sore throats and help reduce temperature. The tablets contain the active ingredients paracetamol and caffeine. Paracetamol is an analgesic and an antipyretic: it works by relieving pain and reducing body temperature when you have a fever. Caffeine acts to further help the effectiveness of paracetamol. No new or unexpected safety concerns arose from this application and it was, therefore, judged that the benefits of taking Paracetamol & Caffeine 500/65mg Soluble Tablets outweigh the risks; hence a Marketing Authorisation has been granted.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk assessment Page 10


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INTRODUCTION Based on the review of the data on quality, safety and efficacy, the MHRA granted Neolab Limited a marketing authorisation for the medicinal product Paracetamol & Caffeine 500/65mg Soluble Tablets (PL 08137/0157) on 02 July 2010. The product is a General Sales List (GSL) medicine and is indicated as a mild analgesic and antipyretic formulated to give extra pain relief. The tablets are recommended for the treatment of most painful and febrile conditions, for example, headache, including migraine, backache, toothache, rheumatic pain and dysmenorrhoea, and relief of the symptoms of colds, influenza and sore throat. The product contains the active ingredients paracetamol and caffeine. Paracetamol is a centrally acting analgesic (a pain killer that acts on pain centres in the brain), which is used to relieve mild to moderate pain in the body and also acts as an antipyretic to help reduce body temperature; caffeine is a mild stimulant. The application was submitted as a well-established use application, according to Article 10a of Directive 2001/83/EC, as amended. No new data were submitted nor were they necessary for this application, as the combination of paracetamol and caffeine is well-established. No new or unexpected safety concerns arose during review of information provided by the Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking Paracetamol & Caffeine 500/65mg Soluble Tablets outweigh the risks, hence a Marketing Authorisation has been granted.


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PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE - PARACETAMOL INN: Paracetamol Chemical Name: N-(4-hydroxyphenyl)acetamide. Molecular Formula: C8H9NO2 Structure:

Molecular weight: 151.2 Appearance: A white, crystalline powder, sparingly soluble in water,

freely soluble in alcohol and very slightly soluble in dichloromethane.

Paracetamol is the subject of a European Pharmacopoeia monograph. Manufacture All aspects of the manufacture and control of the active substance paracetamol are covered by European Directorate for the Quality of Medicines (EDQM) Certificates of Suitability. ACTIVE SUBSTANCE - CAFFEINE INN: Caffeine Chemical Name: 1,3,7-trimethyl-1,3-dihydro-1H-purine-2,5-dione

1,3,7-trimethylxanthine Molecular Formula: C8H10N4O2 Structure:

Molecular weight: 194.2 Appearance: A white or almost white, crystalline powder. It is

sparingly soluble in water, freely soluble in boiling water, and slightly soluble in ethanol.

Caffeine is the subject of a European Pharmacopoeia monograph. Manufacture All aspects of the manufacture and control of the active substance caffeine are covered by a European Directorate for the Quality of Medicines (EDQM) Certificate of Suitability.


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DRUG PRODUCT Other Ingredients Other ingredients consist of the pharmaceutical excipients citric acid (anhydrous) (E330), povidone, saccharin sodium, sodium hydrogen carbonate (E500), sodium carbonate anhydrous, simeticone, polysorbate 80 (E433), and aspartame (E951). All excipients comply with their respective European Pharmacopoeia monographs. Suitable certificates of analysis have been provided for all excipients, showing compliance with the proposed specifications. None of the excipients are sourced from materials of animal or human origin. No genetically modified organisms (GMO) have been used in the preparation of these excipients. Pharmaceutical Development The objective of the pharmaceutical development programme was to formulate an effervescent tablet containing paracetamol and caffeine, which could be considered to have the same properties as other products on the market (such as Panadol Extra Soluble, marketed by SmithKline Beecham Limited). A satisfactory account of the pharmaceutical development has been provided. Manufacture A description and flow-chart of the manufacturing method have been provided. In-process controls are satisfactory based on process validation data and controls on the finished product. Process validation has been carried out on batches of the product. The results appear satisfactory. Finished Product Specification The finished product specification is satisfactory. Test methods have been described and adequately validated, as appropriate. Batch data have been provided and comply with the release specification. Certificates of analysis have been provided for any working standards used. Container Closure System The finished product is packaged in a 4-ply (glassine paper/low-density polypropylene/low-density polyethylene/aluminium foil) laminate strip pack and then packed with the leaflet with the Patient Information Leaflet (PIL) into an outer cardboard carton. The tablets are available in a pack size of 24. Specifications and certificates of analysis for the primary packaging material have been provided. These are satisfactory. All primary packaging complies with EU legislation regarding contact with food. Stability Finished product stability studies were performed in accordance with current guidelines on batches of finished product packed in the packaging proposed for


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marketing. The data from these studies support a shelf-life of 3 years, with the storage conditions, “Store in the original package and protect from moisture.” Suitable post approval stability commitments have been provided to continue stability testing on batches of finished product. Summary of Product Characteristics (SPC), Patient Information Leaflet (PIL) and Labelling The SPC, PIL and labelling are pharmaceutically satisfactory. A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC, as amended. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains. MAA Form All aspects of the MAA form are pharmaceutically satisfactory. Expert Report The pharmaceutical expert report is written by an appropriately qualified person and is a suitable summary of the pharmaceutical aspects of the dossier. Conclusion It is recommended that a Marketing Authorisation is granted for this application.


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PRECLINICAL ASSESSMENT

PHARMACODYNAMICS, PHARMACOKINETICS AND TOXICOLOGY As the pharmacodynamic, pharmacokinetic and toxicological properties of paracetamol and caffeine are well-known, no further studies are required and none have been provided. PRECLINICAL EXPERT REPORT The preclinical expert report has been written by an appropriately qualified person and is a suitable summary of the preclinical aspects of the dossier. ENVIRONMENTAL RISK ASSESSMENT A suitable justification has been provided for non-submission of an Environmental Risk Assessment (ERA). CONCLUSION There are no objections to the approval of this product from a preclinical point of view.


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CLINICAL ASSESSMENT

CLINICAL PHARMACOLOGY The clinical pharmacology of paracetamol and caffeine is well-known. No new pharmacodynamic or pharmacokinetic data are provided or required for this application. EFFICACY The efficacy of paracetamol and caffeine is well-known. No new efficacy data are provided or required for this application. SAFETY The safety profile of paracetamol and caffeine is well-known. No new safety data are provided or required for this application. PHARMACOVIGILANCE SYSTEM AND RISK MANAGEMENT PLAN The Pharmacovigilance System, as described by the applicant, fulfils the requirements and provides adequate evidence that the applicant 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. A suitable justification has been provided for not submitting a risk management plan for this product. CLINICAL EXPERT REPORT The clinical expert report is written by an appropriately qualified physician and is a suitable summary of the clinical aspects of the dossier. SUMMARY OF PRODUCT CHARACTERISTICS (SPC), PATIENT INFORMATION LEAFLET (PIL) AND LABELLING The SPC, PIL and labelling are medically acceptable. The SPC and PIL are consistent with those for other similar products currently being marketed. CONCLUSION The grant of a Marketing Authorisation is recommended.


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OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT QUALITY The important quality characteristics of Paracetamol & Caffeine 500/65mg Soluble 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. As the pharmacokinetics, pharmacodynamics and toxicology of paracetamol and caffeine are well-known, no additional data were required. EFFICACY No new clinical pharmacology or efficacy data have been submitted. As the clinical pharmacology and efficacy of paracetamol and caffeine are well-known, no additional data were required. No new safety data have been submitted. As the safety profile of paracetamol and caffeine are well-known, no additional data were required. The SPC, PIL and labelling are satisfactory and consistent with those for other similar products on the market. BENEFIT/RISK ASSESSMENT The quality of the product is acceptable, and no new preclinical or clinical safety concerns have been identified. Extensive clinical experience with paracetamol and caffeine is considered to have demonstrated the therapeutic value of the compound. The benefit/risk is, therefore, considered to be positive.


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STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the marketing authorisation application on 16 January 2009.

2 Following standard checks and communication with the applicant the MHRA considered the applications valid on 20 January 2009.

3 Following assessment of the application the MHRA requested further information relating to the dossier on 11 August 2009.

4 The applicant responded to the MHRA’s requests, providing further information on 18 May 2010.

5 The applications were determined on 02 July 2010.


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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT Paracetamol & Caffeine 500/65 mg Soluble Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains Paracetamol 500 mg and Caffeine 65 mg. For a full list of excipients, see Section 6.1.

3 PHARMACEUTICAL FORM Effervescent Tablet. Paracetamol & Caffeine 500/65 mg Soluble Tablets are white to off white coloured circular flat bevelled tablets plain on both sides.

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

Paracetamol & Caffeine Soluble Tablets are a mild analgesic and antipyretic formulated to give extra pain relief. The tablets are recommended for the treatment of most painful and febrile conditions, for example, headache, including migraine, backache, toothache, rheumatic pain and dysmenorrhoea, and relief of the symptoms of colds, influenza and sore throat.

4.2 Posology and method of administration Paracetamol & Caffeine Soluble Tablets should be dissolved in at least half a tumbler of water. Adults: Two tablets up to four times daily. Do not exceed 8 tablets in 24 hours. Elderly: As for adults. Children: Not recommended for children under 12 years. Method of Administration Paracetamol & Caffeine Soluble Tablets are for oral administration only.

4.3 Contraindications Hypersensitivity to paracetamol, caffeine or any of the other constituents.

4.4 Special warnings and precautions for use Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease. Excessive intake of tea or coffee should be avoided while taking this product. Do not exceed the stated dose. Patients should be advised to consult their doctor if their headaches become persistent. Patients should be advised not to take other paracetamol-containing products concurrently. If symptoms persist consult your doctor. Keep out of the reach and sight of children. Pack Label: Immediate medical advice should be sought in the event of an overdose, even if you feel well. Do not take with any other paracetamol-containing products.


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Patient Information Leaflet: Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage. This product contains aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria. Each of these tablets contains 409 mg of sodium. This may interfere if you are on a low sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction 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 daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

4.6 Pregnancy and lactation Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol and caffeine used in the recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol and caffeine are excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast feeding.

4.7 Effects on ability to drive and use machines None.

4.8 Undesirable effects Adverse effects of paracetamol are rare but hypersensitivity including skin rash may occur. There have been very rare reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessarily causally related to paracetamol.

4.9 Overdose Paracetamol Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g or more of paracetamol may lead to liver damage if the patient has risk factors (see below). Risk Factors: If the patient • Is on long term treatment with carbamazepine, phenobarbitone, phenytoin,

primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes. Or • Regularly consumes ethanol in excess of recommended amounts. Or • Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV

infection, starvation, cachexia. Symptoms Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. Management Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the


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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 serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit. Caffeine Symptoms Overdose of caffeine may produce nervousness, restlessness, insomnia, excitement, diuresis, facial flushing, muscle twitching, GI disturbance, tachycardia or cardiac arrhythmia, "rambling" flow of thought and speech, psychomotor agitation, or periods of inexhaustibility. Management Patients should receive general supportive care (e.g. hydration and maintenance of vital signs). The administration of activated charcoal may be beneficial when performed within one hour of the overdose, but can be considered for up to four hours after the overdose. The CNS effects of overdose may be treated with intravenous sedatives. Summary Treatment of overdose with Cope Sachets requires assessment of plasma paracetamol levels for antidote treatment, with signs and symptoms of codeine and caffeine toxicity being managed symptomatically.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

The combination of paracetamol and caffeine is a well established analgesic combination.

5.2 Pharmacokinetic properties Paracetamol is rapidly and almost completely absorbed from the gastro-intestinal tract, it is relatively uniformly distributed throughout most body fluids and exhibits variable protein binding. Excretion is almost exclusively renal, in the form of conjugated metabolites. Caffeine is absorbed readily after oral administration, maximal plasma concentrations are achieved within one hour and the plasma half-life is about 3.5 hours. 65 - 80% of administered caffeine is excreted in the urine as 1-methyluric acid and 1-methylxanthine.

5.3 Preclinical safety data There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Citric Acid (anhydrous) (E330), Povidone, Saccharin Sodium, Sodium Hydrogen Carbonate (E500) , Sodium Carbonate Anhydrous, Simeticone, Polysorbate 80 (E433), and Aspartame (E951).

6.2 Incompatibilities Not applicable.


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6.3 Shelf life 3 years.

6.4 Special precautions for storage Store in the original package and protect from moisture.

6.5 Nature and contents of container 4- Ply laminate strip pack These tablets are available in a pack size of 24.

6.6 Special precautions for disposal No special requirements.

7 MARKETING AUTHORISATION HOLDER Neolab Limited 57 High Street Odiham Hants RG29 1LF UK

8 MARKETING AUTHORISATION NUMBER(S) PL 08137/0157

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 02/07/2010 10 DATE OF REVISION OF THE TEXT

02/07/2010


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LABELLING


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PARACETAMOL & CAFFEINE 500/65MG SOLUBLE … · UKPAR Paracetamol & Caffeine 500/65mg Soluble...

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