Paracetamol-Parasolve Max 1000mg soluble tablets PL-08137 … · 2010-09-15 · UKPAR Paracetamol 1000mg Soluble Tablets PL 08137/0230 Parasolve Max 1000mg Soluble Tablets 4 INTRODUCTION

UKPAR Paracetamol 1000mg Soluble Tablets PL 08137/0230 Parasolve Max 1000mg Soluble Tablets

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Paracetamol 1000mg Soluble Tablets / Parasolve Max 1000mg Soluble Tablets

(paracetamol)

PL 08137/0230

UK Public Assessment Report

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 12

Steps taken after authorisation

Page 13

Summary of Product Characteristics

Page 14

Product Information Leaflet

Page 18

Labelling

Page 20


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PL 08137/0230

LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted Neolab Limited a Marketing Authorisation (licence) for the medicinal product Paracetamol 1000mg Soluble Tablets / Parasolve Max 1000mg Soluble Tablets (PL 08137/0230) on 16th July 2010. The product is licensed under the two stated names but will be referred to as Paracetamol 1000mg Soluble Tablets in the remainder of this report. This is a P licensed medicine available only from pharmacies, under the supervision of a pharmacist. Paracetamol 1000mg Soluble Tablets are used to relieve pain, including muscular and rheumatic pains, headache, migraine, neuralgia (severe burning or stabbing pain following the line of a nerve), toothache, sore throat, period pains, aches and pains, discomfort associated with influenza (flu), feverishness and feverish colds. No new or unexpected safety concerns arose from this application and it was therefore judged that the benefits of Paracetamol 1000mg Soluble Tablets outweigh the risks; hence a Marketing Authorisation (MA) has been granted.


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PL 08137/0230

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusion and benefit- risk assessment

Page 11


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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 1000mg Soluble Tablets / Parasolve Max 1000mg Soluble Tablets (PL 08137/0230) on 16th July 2010. The product is a P licensed medicine. This is an abridged, bibliographic application for Paracetamol 1000mg Soluble Tablets / Parasolve Max 1000mg Soluble Tablets, submitted under Article 10a (well-established use) of Directive 2001/83 EC, as amended. The applicant already has two licences for an existing product, Paracetamol Soluble 500mg Tablets (PL 08137/0055 and 08137/0119, granted 21/11/2002 and 21/08/2003 respectively). The proposed product is formulated as a scaled-up presentation, containing twice the quantity of the active ingredient, of the currently licensed 500mg strength soluble tablets. Since the normal adult single recommended dose of paracetamol is 1000mg (usually taken as two 500mg tablets), the proposed dosage per soluble tablet is equivalent to the recommended single dose. Paracetamol 1000mg Soluble Tablets are indicated for the relief of headache (including migraine), neuralgia, toothache, period pain, and rheumatic aches and pains, as well as for the symptomatic relief of colds and influenza, and sore throats. Paracetamol is an effective analgesic and antipyretic agent. The drug has no effect on the cardiovascular and respiratory systems, and it does not cause gastric irritation or bleeding like salicylates. No new non-clinical or clinical studies were conducted, which is acceptable given that this is a bibliographic application for an active of well-established use. Bioequivalence studies are not necessary to support this application for a product that is administered as an oral solution. The pharmacovigilance system (PhVS), as described by the Marketing Authorisation Holder (MAH), fulfils the requirements and provides adequate evidence that the MAH has the services of a Qualified Person (QP) 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). The risk management for paracetamol is adequately controlled by the product information and through the pharmacovigilance activities detailed in the PhVS. There are no ongoing safety concerns with this well-established active that require additional risk-management activities. The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). It is not considered that this medicinal product represents any risk to the environment. There is no reason to conclude that marketing of this product will change the overall use pattern of the existing market.


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PHARMACEUTICAL ASSESSMENT ACTIVE SUBSTANCE

Paracetamol

Nomenclature:

INN: Paracetamol

Chemical names: N-(4-hydroxyphenyl)acetamide

Structure:

Molecular formula: C8H9NO2

Molecular weight: 151.2 g/mol

CAS No: 103-90-2

Physical form: A white, crystalline powder

Solubility: Sparingly soluble in water, freely soluble in alcohol and very slightly soluble in dichloromethane

The active substance, paracetamol, is the subject of a European Pharmacopeia (Ph. Eur.) monograph. All aspects of the manufacture and control of paracetamol are supported by European Directorate for the Quality of Medicines (EDQM) Certificates of Suitability (CEP). The certificates are accepted as confirmation of the suitability of paracetamol for inclusion in this medicinal product.


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MEDICINAL PRODUCT

Description and Composition

Paracetamol 1000mg Soluble Tablets are presented as white to off-white coloured, circular, flat, bevelled, uncoated tablets with no markings. Each tablet contains 1000mg of paracetamol. Other ingredients consist of pharmaceutical excipients, namely citric acid (anhydrous) (E330), povidone, sodium bicarbonate (E500), sodium saccharin, sodium carbonate (anhydrous), simeticone (E900), polysorbate 80 (E433) and aspartame (E951). Appropriate justification for the inclusion of each excipient has been provided. All excipients used comply with their respective European Pharmacopoeia monographs. Satisfactory Certificates of Analysis have been provided for all excipients. There were no novel excipients used. There are no materials of human or animal origin contained in, or used in the manufacturing process for, 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 pharmaceutical development was aimed at producing an effervescent tablet with double the quantity of active of the approved product Paracetamol 500mg Soluble Tablets, PL 08137/0055. Manufacture

A description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation studies were conducted and the results were satisfactory. Finished product specification

The finished product specifications are provided for both release and shelf-life and are 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 accepted. Certificates of Analysis have been provided for any reference standards used. Container Closure System

The finished product is licensed for marketing in 4-layer blister strips that are laminated on both sides. The four layers are paper, low density polyethylene (LDPE), aluminium and a second LDPE layer. The blister strips are packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 8, 12, 16, 24, 30 and 50 tablets. The MAH has stated that not all pack sizes may be marketed.


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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. Stability

Finished product stability studies have been conducted in accordance with current guidelines, using product stored in the packaging proposed for marketing. Based on the results, a shelf-life of 2 years has been set, which is satisfactory. Storage instructions are ‘Do not store above 25°C. Store in the original package. Protect from moisture’. Bioequivalence Study

Bioequivalence studies are not necessary to support this application for a product that is administered as an oral solution. Quality Overall Summary

A satisfactory quality overview is provided, and has been prepared by an appropriately qualified expert. The CV of the expert has been supplied. Product Information

The approved Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL), and labelling are satisfactory. Mock-ups of the labelling and PIL have been provided for the product name ‘Paracetamol 1000mg Soluble Tablets’. The labelling fulfils the statutory requirements for Braille. The MAH has stated that not all licensed pack sizes may be marketed. They have committed to submitting mock-up labelling for unmarketed pack sizes, as well as livery for the product name ‘Parasolve Max 1000mg Soluble Tablets’, to the relevant regulatory authorities for approval before those packs are commercially marketed. Conclusion

All pharmaceutical issues have been resolved and the quality grounds for this application are considered adequate. There are no objections to approval of Paracetamol 1000mg Soluble Tablets from a pharmaceutical point of view.


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PRE-CLINICAL ASSESSMENT This is an abridged, bibliographic application for Paracetamol 1000mg Soluble Tablets, submitted under Article 10a of Directive 2001/83 EC, as amended. No new pre-clinical data have been supplied with this application and none are required for applications of this type. A pre-clinical overview has been written by a suitably qualified expert, whose CV has been supplied. The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). There are no objections to approval of this product from a pre-clinical point of view.


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CLINICAL ASSESSMENT INDICATIONS

Paracetamol 1000mg Soluble Tablets are indicated for the relief of headache (including migraine), neuralgia, toothache, period pain, and rheumatic aches and pains, as well as for the symptomatic relief of colds and influenza, and sore throats. POSOLOGY AND METHOD OF ADMINISTRATION

Full details concerning the posology are provided in the SmPC. TOXICOLOGY

The toxicology of paracetamol is well known. No new data have been submitted and none are required for applications of this type. CLINICAL PHARMACOLOGY

Pharmacodynamics

The pharmacodynamics of paracetamol are well-characterised and have been adequately reviewed. No new pharmacodynamic data have been supplied and none are required for this type of application. The proposed product is a scaled-up presentation of an existing, licensed product and represents the standard adult dose in a single, soluble tablet formulation. Pharmacokinetics

The pharmacokinetics of paracetamol are well-characterised and have been adequately reviewed. No new pharmacodynamic data have been supplied and none are required for this type of application. This formulation is designed to be dissolved in water and administered as an oral solution. Clinical efficacy

The clinical efficacy of paracetamol is well-established and has been adequately reviewed. No new data have been submitted and none are required for applications of this type. SAFETY

The safety profile of paracetamol has been well-characterised and has been adequately reviewed. There are no current ongoing safety issues with this active. No new data have been submitted and none are required for applications of this type. PRODUCT INFORMATION:

Summary of Product Characteristics (SmPC)

The approved SmPC is acceptable. Patient Information Leaflet

The final PIL is in line with the approved SmPC and is satisfactory.


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PIL user testing has been accepted, based on a bridging report provided by the applicant making reference to the successful user-testing of the PIL for Paracetamol & Caffeine 500/65 mg Soluble Tablets. The visual presentation and textual content of the daughter PIL (Paracetamol 1000mg Soluble Tablets) is comparable to that of the parent PIL and the key safety messages have been considered. The bridging report is accepted. Labelling

The labelling is satisfactory. Clinical overview

A satisfactory clinical overview is provided, and has been prepared by an appropriately qualified expert. The CV of the clinical expert has been supplied. DISCUSSION AND CONCLUSION

Sufficient clinical information has been submitted to support this application. The grant of a Marketing Authorisation was recommended on medical grounds.


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OVERALL CONCLUSION AND BENEFIT- RISK ASSESSMENT QUALITY

The important quality characteristics of Paracetamol 1000mg 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. PRE-CLINICAL

No new pre-clinical data were submitted and none are required for an application of this type. EFFICACY

Medicinal products containing paracetamol have been available in the UK for more than ten years. Its use is well-established with recognised efficacy and acceptable safety. No new or unexpected safety concerns arise from this application. PRODUCT LITERATURE

The approved SmPC, PIL and labelling are satisfactory. Mock-ups of the labelling and PIL have been provided for the product name ‘Paracetamol 1000mg Soluble Tablets’. PIL user testing has been accepted, based on a bridging report provided by the applicant making reference to the successful user-testing of the PIL for Paracetamol & Caffeine 500/65 mg Soluble Tablets. The bridging report is accepted. Mock-ups of the labelling have been provided and are satisfactory. The approved labelling artwork complies with statutory requirements. The MAH has committed to submitting mock-ups for unmarketed packs, including livery for the product name ‘Parasolve Max 1000mg Soluble Tablets’, to the relevant regulatory authorities for approval before those packs are marketed. BENEFIT-RISK ASSESSMENT

The quality of the product is acceptable and no new pre-clinical or clinical safety concerns have been identified. Extensive clinical experience with paracetamol is considered to have demonstrated the therapeutic value of the active substance. The benefit: risk ratio is considered to be positive.


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PL 08137/0230

STEPS TAKEN FOR ASSESMENT

1 The MHRA received the Marketing Authorisation application on 6th March

2009

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 16th March 2009

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 13th August 2009

4 The applicant responded to the MHRA’s request, providing further information for the quality sections on 9th March 2010

5 The application was determined on 16th July 2010


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PL 08137/0230

STEPS TAKEN AFTER AUTHORISATION Not applicable


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SUMMARY OF PRODUCT CHARACTERISTICS

The UK Summary of Product Characteristics (SPC) for Paracetamol 1000mg Soluble Tablets / Parasolve Max 1000mg Soluble Tablets is as follows: 1 NAME OF THE MEDICINAL PRODUCT

Paracetamol 1000mg Soluble Tablets. Parasolve Max 1000mg Soluble Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 1000mg of the active ingredient paracetamol. For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM Effervescent tablet. Paracetamol 1000mg Soluble Tablets are white to off white coloured, circular, flat bevelled tablets, plain on both sides.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications For the relief of headache including migraine, neuralgia, toothache, period pain, and rheumatic aches and pains. Symptomatic relief of colds and influenza, and sore throats.

4.2 Posology and method of administration For oral administration. Dissolve the tablets in water (about 200 ml) before swallowing. Adults and the elderly: One tablet to be taken up to four times daily. Maximum dose of 4 tablets in 24 hours. Children under 12 years of age: Not recommended. The dose should not be repeated more frequently than every 4 hours, and not more than 4 doses should be taken in any 24 hour period. Dosage should not be continued for more than 3 days without consulting a doctor.

4.3 Contraindications Hypersensitivity to paracetamol and/or any of the other ingredients.

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 hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Each tablet contains 586.11mg of sodium and may be harmful to people on a low sodium diet.


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The tablets also contain aspartame (a source of phenylalanine) and so should not be taken by people with phenylketonuria. 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. Do not take with any other paracetamol containing products. Do not exceed the recommended dose. If symptoms persist consult your doctor. Keep out of the reach of children.

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 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 used in recommended dosage, but patients should follow the advice of their doctor regarding its use. Paracetamol is 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 known.

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

4.9 Overdose 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 patient has risk factors (see below). Risk Factors: If the patient: a) Is on long term treatment with carbamazepine, phenobarbitone, 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 infective, starvation, cachexia.


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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, coma 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 It is considered that excess quantities of a toxic metabolite (usually adequately detoxified by glutathione when normal doses of paracetamol are employed), become irreversibly bound to liver tissue. 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 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 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 24 hours from ingestion should be discussed with the NPIS or a liver unit.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Paracetamol is an effective analgesic and antipyretic agent. The drug has no effect on the cardiovascular and respiratory systems, and it does not cause gastric irritation or bleeding like salicylates.

5.2 Pharmacokinetic properties Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring 30 minutes to 2 hours after ingestion. It is distributed in most body tissues; it crosses the placenta and is present in breast milk. Plasma protein binding is negligible at usual therapeutic concentrations but increases with increasing concentration. The elimination half life varies from about 1 to 3 hours. Paracetamol is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted unchanged as paracetamol. A minor hydroxylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver glutathione, may accumulate following paracetamol overdosage and cause liver damage.

5.3 Preclinical safety data No data of relevance which is additional to that already included in other sections of the SPC.


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6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Citric Acid (anhydrous) (E330) Povidone Sodium Bicarbonate (E500) Sodium Saccharin Sodium Carbonate (anhydrous) Simeticone (E900) Polysorbate 80 (E433) Aspartame (E951).

6.2 Incompatibilities Not applicable.

6.3 Shelf life 2 years.

6.4 Special precautions for storage Do not store above 25°C. Store in the original package. Protect from moisture.

6.5 Nature and contents of container

Strip (4 layer - paper/LDPE/aluminium/LDPE), laminate on both sides of strip. Pack sizes 8, 12, 16, 24, 30 and 50 tablets. Not all packs may be marketed

6.6 Special precautions for disposal Not applicable.

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

8 MARKETING AUTHORISATION NUMBER(S) PL 08137/0230

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 16/07/2010

10 DATE OF REVISION OF THE TEXT 16/07/2010


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PATIENT INFORMATION LEAFLET


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LABELLING

Carton for blisters, with Braille, pack size 8


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Carton for blisters, with Braille, pack size 12


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Braille

Blister foil

Documents

Paracetamol-Parasolve Max 1000mg soluble tablets PL-08137 … · 2010-09-15 · UKPAR Paracetamol 1000mg Soluble Tablets PL 08137/0230 Parasolve Max 1000mg Soluble Tablets 4 INTRODUCTION