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MHRA PAR – Max Strength Cold & Flu Capsules, hard PL 12063/0066 - 1 – Max Strength Sinus Relief Capsules, hard PL 12063/0067

MAX STRENGTH COLD & FLU CAPSULES, HARD (PARACETAMOL, CAFFEINE, PHENYLEPHRINE HYDROCHLORIDE)

PL 12063/0066

MAX STRENGTH SINUS RELIEF CAPSULES, HARD (PARACETAMOL, CAFFEINE, PHENYLEPHRINE HYDROCHLORIDE)

PL 12063/0067

UKPAR

TABLE OF CONTENTS Lay Summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 21

Steps taken after authorisation – summary

Page 22

Summary of Product Characteristics

Page 23

Product Information Leaflet

Page 39

Labelling Page 43


PL 12063/0066


PL 12063/0067

LAY SUMMARY

The MHRA granted Wrafton Laboratories Limited Marketing Authorisations (licences) for the medicinal products Max Strength Cold & Flu Capsules, hard (PL 12063/0066) and Max Strength Sinus Relief Capsules, hard (PL 12063/0067) on 9th June 2006. These General Sales List medicines (GSL) are used for the relief of the symptoms of sinusitis, colds and flu, including blocked nose, aches and pains, sore throat, headache, fatigue, drowsiness and fever. Max Strength Cold & Flu Capsules and Max Strength Sinus Relief Capsules contain the active ingredients:

- paracetamol, which is a pain reliever and reduces temperature/fever - caffeine, which increases the pain relief effect - phenylephrine hydrochloride, which is a decongestant

The data presented to the MHRA, pre licensing, demonstrated that Max Strength Cold & Flu Capsule and Max Strength Sinus Relief Capsules are equivalent to the approved product, Beechams Powders Capsules but with a higher strength of paracetamol and phenylephrine hydrochloride. These capsules can therefore be used instead of Beechams Powders capsules, when a higher dose is required. No new or unexpected safety concerns arose from these applications. It was, therefore, judged that the benefits of taking Max Strength Cold & Flu Capsules and Max Strength Sinus Relief Capsules outweigh the risks. Hence, Marketing Authorisations have been granted.



PL 12063/0066


PL 12063/0067

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 17

Clinical assessment

Page 18

Overall conclusions and risk benefit assessment Page 20


INTRODUCTION

Based on the review of the data on quality, safety and efficacy the UK granted marketing authorisations for the medicinal products Max Strength Cold & Flu Capsules, hard (PL 12063/0066) and Max Strength Sinus Relief Capsules, hard (PL 12063/0067) to Wrafton Laboratories Limited on 9th June 2006. The products are General Sales List (GSL) medicines. The applications were submitted as abridged applications according to article 10.1 [formerly article 10.1(a)(iii)] of Directive 2001/83/EC, claiming essential similarity to the original product Beechams Powders Capsules. The applicant’s products contain higher strength paracetamol and phenylephrine hydrochloride than the original product and, as such, the applicant has also referenced Lemsip Max Strength Capsules which have the same quantitative composition of paracetamol, caffeine and phenylephrine hydrochloride. The products contain the active ingredients paracetamol (an analgesic and antipyretic), caffeine (an analgesia adjunct) and phenylephrine (a decongestant). The products are indicated for the relief of symptoms of the common cold, influenza and sinusitis, including relief of aches and pains, headache, nasal congestion, headaches, sore throat, fatigue, drowsiness and lowering of temperature. These applications for Max Strength Cold & Flu Capsules and Max Strength Sinus Relief Capsules were assessed concurrently. Consequently, all sections of this Scientific Discussion refer to both products.


PHARMACEUTICAL ASSESSMENT

1. INTRODUCTION These are abridged applications for Marketing Authorisations in the UK submitted under Article 10.1 [formerly article 10.1 (a)(iii)] of Directive 2001/83 (as amended) with the difference compared to the original product listed as a different strength. The original product is listed as Beechams Powders Capsules, PL 00079/0205 granted 1st July 1982. The original product contains lower strengths of paracetamol and phenylephrine hydrochloride. The reference products are listed as Lemsip Max Strength Cold and Flu Capsules, PL 00063/0104 granted 9th October 1998 and Lemsip Max Strength Sinus Relief Capsules, PL 0063/0120 granted 12th March 2002. 2. ACTIVE SUBSTANCE 2.1 PARACETAMOL 2.1.1 General information The active substance supplier has been named. A valid Certificate of Suitability has been supplied. The re-test date on the certificate of suitability is 5 years if stored in either LDPE bags in cardboard drums or flexible containers lined with polyethylene.

Structure: Description: White odourless crystalline powder Chemical name: N-(4-hydroxyphenyl)acetamide Molecular formula: C8H9NO2 Relative molecular mass: 151.2 2.1.2 Manufacture 2.1.2.1 Manufacturing process The manufacturing process is referenced to the certificate of suitability.


2.1.2.2 Impurities The impurities are controlled by the levels in the European Pharmacopoeia monograph and certificates of suitability. Residual solvents used during the process are controlled in the active substance specification with the loss on drying test. 2.1.3 Control of active substance 2.1.3.1 Specification The specification used by the active substance manufacturer is that in the European Pharmacopoeia as covered by the certificate of suitability, with an additional in-house test. The finished product manufacturer specification provided for the active substance is in compliance with the European Pharmacopoeia monograph with additional in-house tests. 2.1.3.2 Analytical test methods The test methods used are those described in the pharmacopoeia. Consequently, no validation data has been presented for the pharmacopoeia methods. 2.1.3.3 Batch analyses Certificates of analysis for several batches, by the active substance manufacturer, demonstrate compliance to the specifications and inter-batch conformity. The impurity levels in the batches are well below specification. The raw material analysis reports from the finished product manufacturer have been provided. 2.1.3.4 Reference standards The certificate of suitability has been referenced for the reference standards. 2.1.3.5 Container closure system The certificate of suitability has been referenced for the container closure system. 2.1.3.6 Stability The certificate of suitability has been referenced for the stability of the active substance. 2.2 CAFFEINE 2.2.1 General information The active substance manufacturer has supplied a valid, current Certificate of Suitability with a re-test period of 4 years if stored in a container consisting of fibre drums or big bags lined with a low density polyethylene bag.


Structure: Description: Odourless silky, white crystals, usually matted together, or a white

crystalline powder. Chemical name: 1,3,7-Trimethylpurine-2,6 (3H,1H)-dione Molecular formula: C8H10N4O2 Relative molecular mass: 194.2 2.2.2 Manufacture 2.2.2.1 Manufacturing process The manufacturing process is referenced to the certificate of suitability. 2.2.2.2 Impurities The impurities are controlled by the levels in the European Pharmacopoeia monograph and certificate of suitability. 2.2.3 Control of active substance 2.2.3.1 Specification The specification used by the active substance manufacturer is that in the European Pharmacopoeia as covered by the certificate of suitability with an additional in-house test. The finished product manufacturer specification provided for the active substance is in compliance with the European Pharmacopoeia monograph with an additional in-house test. 2.2.3.2 Analytical test methods The test methods used are those described in the pharmacopoeia. Consequently, no validation data has been presented for the pharmacopoeia methods. Particle size is determined by air jet sieving which does not require validation data. 2.2.3.3 Batch analyses Certificates of analysis for several batches, by the active substance manufacturer, demonstrate compliance to the specifications and inter-batch conformity. The raw material analysis reports from the finished product manufacturer have been provided. 2.2.3.4 Reference standards The certificate of suitability has been referenced for the reference standards. 2.2.3.5 Container closure system


The certificate of suitability has been referenced for the container closure system. 2.2.3.6 Stability The certificate of suitability has been referenced for the stability of the active substance. The certificate of suitability has a re-test date of 4 years if stored in a container consisting of fibre drums or big bags lined with a low density polyethylene bag. 2.3 PHENYLEPHRINE HYDROCHLORIDE 2.3.1 General information The active substance is to be supplied by a named supplier. A valid, current certificate of suitability has been supplied. The re-test period for the active substance is 3 years if stored at room temperature not exceeding 25°C in a container consisting of two polyethylene bags placed in a fibre drum or in a polyethylene bottle.

Structure: Description: White or almost white crystalline powder Chemical name: (S)-1-(3-Hydroxyphenyl)-2-methylaminoethanol hydrochloride Molecular formula: C9H14ClNO2 Relative molecular mass: 203.7 2.3.2 Manufacture 2.3.2.1 Manufacturing process The manufacturing process is referenced to the certificate of suitability. 2.3.2.2 Impurities The impurities are controlled by the levels in the European Pharmacopoeia monograph and certificates of suitability. The certificates of suitability include additional tests for related substances and residual solvents 2.3.3 Control of active substance 2.3.3.1 Specification The specification used by the active substance manufacturer is that in the European Pharmacopoeia as covered by the certificate of suitability with an additional in-house test.


The finished product manufacturer specification provided for the active substance is in compliance with the European Pharmacopoeia monograph with an additional in-house test. 2.3.3.2 Analytical test methods The test methods used are those described in the pharmacopoeia. Consequently, no validation data has been presented for the pharmacopoeia methods. 2.3.3.3 Batch analyses Certificates of analysis for several batches, by the active substance manufacturer, demonstrate compliance to the specifications and inter-batch conformity. The raw material analysis reports have been provided from the finished product manufacturer. 2.3.3.4 Reference standards The certificate of suitability has been referenced for the reference standards. 2.3.3.5 Container closure system The certificate of suitability has been referenced for the container closure system. 2.3.3.6 Stability The certificate of suitability has been referenced for the stability of the active substance. The re-test period for the active substance is 3 years if stored at room temperature not exceeding 25°C in a container consisting of two polyethylene bags placed in a fibre drum or in a polyethylene bottle. It has been confirmed that the finished product manufacturer stores the active substance in a controlled environment with the temperature not exceeding 25°C as specified in the certificate of suitability. 3. DRUG PRODUCT 3.1 Composition The composition of the products are summarised in table 1. The products are red capped, yellow bodied (PL 12063/0066) or red capped/blue bodied (PL 12063/0067) hard gelatin capsules containing the drug product, an off-white powder. The products are packed in blisters comprising white opaque PVC lidded with aluminium foil. The pack has been approved as BS8404 compliant in line with current child resistant closure regulations. Table 1

Name Reference Paracetamol Ph. Eur. & in house Phenylephrine hydrochloride Ph. Eur. & in house


Caffeine Ph. Eur. & in house Maize starch Ph. Eur. Croscarmellose sodium Ph. Eur. Sodium laurilsulfate Ph. Eur. Magnesium stearate Ph. Eur. Purified talc Ph. Eur. Gelatin Ph. Eur Erythrosine 95/45/EC Titanium dioxide Ph. Eur. Quinoline yellow 95/45/EC Patent blue V 95/45/EC Indigo carmine E132* 95/45/EC

* Only in PL 12063/0067 3.2 Pharmaceutical Development 3.2.1 Formulation development The qualitative and quantitative composition of the finished product has been designed to be equivalent to Lemsip Max Strength Cold & Flu capsules (PL 00063/0104) for PL 12063/0066 and Lemsip Max Strength Sinus Relief Capsules (PL 00063/0120) for PL 12063/0067. The formulation was based on Wrafton Laboratories Cold Relief capsules, a product containing Paracetamol (300mg), Phenylephrine hydrochloride (5mg) and caffeine (25mg) with maize starch, croscarmellose sodium, sodium laurilsulfate and magnesium stearate. Full details on the formulations manufactured with a quantitative assessment of the quality that determined the development of the product and the final proposed formulation have been provided. The quantitative data of the parameters assessed has been provided and demonstrates the development of the formulation. It has been stated that dissolution analyses were performed and showed equivalence to the Wrafton Cold Relief capsules. Single point data has been provided at 15 minutes demonstrating complete release of all the actives. Only a single point has been provided on the basis that more than 85% was released in 15 minutes in line with the guidelines. The dissolution parameters are stated as being standard parameters as specified in the European Pharmacopoeia. It has been stated that the discriminatory nature of the method has been demonstrated with the stability batches with the samples at accelerated conditions having a marginally lower value than those at long-term conditions. 3.2.2 Clinical trial formula No clinical studies have been performed. 3.2.4 Physicochemical and biological properties The finished product has been developed to ensure rapid dissolution. 3.2.5 Manufacturing development The development of the proposed manufacturing process has been adequately described.


3.2.6 Container closure system The packaging materials are opaque white PVC and aluminium foil. The combination complies with BS8404, the child resistant packaging regulations covering paracetamol containing products in blister packs. 3.3 Manufacture 3.3.1 Manufacturer A valid Manufacturers Licence and Wholesale Dealers Licence has been provided for the finished product manufacturer. 3.3.2 Batch formula The batch formula has been presented for the pilot scale batch and the maximum proposed full-scale production batch. It has been stated that other suitably validated batch sizes will be used up to the proposed maximum batch size. 3.3.3 Manufacturing process and process controls A flow diagram detailing the manufacturing process and in-process control testing has been provided. A written summary of the process has been included. The mixing and processing times for full-scale manufacture will be defined during full scale manufacturing trials. It has been confirmed that the equipment intended to be used for full-scale manufacture will utilise the equivalent mixing process to the stability batches and process evaluation batches presented. For the pilot scale batches the manufacturing process times have been stated and have been shown to be acceptable on the basis of the initial and subsequent stability data. The estimated time lines for the production scale batches have been stated and the suitability of these parameters will be assessed as part of the process validation on the production scale batches. This is acceptable. It has been confirmed that the hold time for the validation of the main blend for one month will be demonstrated by full testing after manufacture and then prior to encapsulation to justify this time period. This is acceptable. It has been confirmed that the shelf-life will be set from the beginning of the manufacturing process with the preparation of the materials. 3.3.4 Reprocessing No reprocessing will be undertaken. 3.3.5 Control of critical steps (in-process controls)


The in-process controls are limited. The manufacturing process is considered by the applicant to be suitably validated on a pilot scale. It is assumed that this is the justification for having minimal in-process controls. 3.3.6 Process validation or evaluation Three batches have been manufactured, at batch sizes representing more than 10% of the proposed maximum batch size. Satisfactory details of process validation and evaluation have been provided. Samples from each batch tested to the finished product specification demonstrated compliance to the specification with reasonable comparability. The validation protocol has been provided for the full-scale manufacture of the finished product, which is basically the same as that used for the pilot scale batches. It has been stated that the equipment to be used does not have specific validation documents, with its suitability based on its use for the manufacture of other products. The scale-up protocol has been provided and will cover the robustness of the process to compensate for the absence of formal validation documents for the equipment being used in the manufacture of the finished product. This is acceptable. 3.4 Control of excipients 3.4.1 Specification Maize starch, croscarmellose sodium, sodium laurilsulfate, magnesium stearate and purified talc have monographs in the European Pharmacopoeia. Certificates of analysis have been provided for these excipients, from the excipient manufacturers, accompanied by raw material analysis sheets from the finished product manufacturer. Identification and appearance tests are performed on the excipients upon receipt. Reduced testing is also performed on a rolling basis when supplied with a certificate of analysis from the excipient manufacturer so that all tests on the certificate of analysis are performed over 10 batches. Gelatin and titanium dioxide present in the capsule shell have monographs in the European Pharmacopoeia. The colours erythrosine, quinoline yellow, patent blue V and indigo carmine comply with commission directive 95/45/EC. Relevant certificates of conformance have been provided from the capsule manufacturer. Certificates of suitability have been provided from gelatin suppliers. The validity of the certificates of suitability for the gelatin as a consequence of the re-classification of countries listed as origin of source materials has been provided. The only product used derived from human or animal sources in the finished product is gelatin, which has been covered by the certificates of suitability. Relevant certification has been provided covering the TSE status and residual solvents for all the other materials present in the finished product.


The analytical methods used to test the excipients are those provided in the European Pharmacopoeia. Consequently no validation data has been supplied. 3.5 Control of drug product 3.5.1 Specification All physical and chemical parameters have been shown to comply with the relevant legislations. The limits of unknown impurities have been set on the basis of the limits accepted for the active substances which are in compliance with the certificates of suitability. The applicant has justified the inclusion of uniformity of weight and content uniformity tests, rather than uniformity of dosage unit tests. It has been stated that the products are well known active substances with good safety profiles and there are no anticipated safety issues associated with the proposed tests. In line with the European Pharmacopoeia this is considered reasonable. 3.5.2 Analytical procedures All the details have been provided for the pharmacopoeia and non-pharmacopoeia methods. The assay methods and related substances methods for the active substances are all HPLC methods. 3.5.3 Validation The methods for dissolution, assay of the active substances and related substances have been adequately validated. Relevant validation data has been supplied for the microbiology methods in line with the European Pharmacopoeia. 3.5.4 Reference standards Suitable information on the reference standards for the active ingredients and related substances has been provided. The assay value of the reference standards used has been provided. Relevant data has been provided in relation to the standardisation of the reference standards against relevant pharmacopoeia monographs. 3.5.5 Batch analyses Batch analyses have been provided for the pilot scale validation batches. These are all within specification and show a reasonable degree of comparability. The certificates of analysis have been supplied. 3.5.6 Characterisation of impurities


The impurities in the active substances are stated as being covered by the certificates of suitability. The potential impurities of the finished product have been identified in relation to each of the active substances used and are suitably controlled. 3.6 Container closure system The packaging consists of opaque white PVC blisters lidded with aluminium foil. Relevant specifications have been supplied accompanied by certificates of conformity from the packaging material manufacturers. Adequate testing is performed on the packaging components, when received by the finished product manufacturer. Relevant certification of compliance to the EU directives on food contact materials has been provided from the suppliers of the PVC and the aluminium foil. The packaging material is in compliance with the child resistant closure regulations. Relevant confirmation has been supplied that the aluminium foil is listed as being compliant with the German standard DIN 55559 (B.Anz No./Date: 117, 01/07/81). To be compliant with BS8404 (for non-re-closable containers) additional testing is required to demonstrate adult accessibility. Acceptable testing has been supplied for a senior adult panel test section of BS 8404. 3.7 Stability Stability data has been presented for the validation batches. The active substances used in the batches are from different lots. The capsules were packed in the proposed commercial packaging. The storage conditions are long-term and accelerated ICH conditions. Stability tests performed are based on those in the finished product specification. Data has been presented for samples stored at both long-term and accelerated conditions. All samples remain in specification with the exception of appearance under accelerated conditions and show a reasonable degree of conformity across the batches. There were differences seen in appearance on storage under accelerated conditions, the powder showed evidence of agglomeration though broke up easily to form a free flowing powder and the capsule was softer to touch with a slightly greasy feel and there was some pitting on the capsule body. The current stability study will continue to 36 months. The first three production batches will be placed on to stability. This is a reasonable post approval stability commitment. A commitment has been made to put one batch a year on to stability there after. The applicant is proposing a shelf life of 24 months when stored below 25ºC. This is acceptable on the basis of the data presented. 3.8 Other information 3.8.1 Clinical work No clinical work has been conducted. See medical assessment for further comment. 3.8.2 Essential similarity


Comparative dissolution has been conducted with the original product rather than the reference product. Samples were analysed and shown to be comparable for the active substances. The dissolution profiles have not been provided due to the rapid release, in line with the guidelines. Comparative impurity profiles of the finished product with the reference product have been provided. 4. PRODUCT LITERATURE 4.1 SPC Satisfactory 4.2 PIL Satisfactory 4.3 LABEL Satisfactory 5. ADMINISTRATIVE 5.1 MAA form The MAA forms are in compliance with the SPC and current guidelines. 5.2 Quality Overall Summary The summary has been done by a suitably qualified person. The report is a summary of the module. 6. CONCLUSIONS AND ADVICE Marketing authorisations can be granted.


PRECLINICAL ASSESSMENT No new preclinical data have been supplied with these applications and none are required for applications of this type.


CLINICAL ASSESSMENT

The applications have been submitted under Article 10.1 [formerly article 10.1(a)(iii)] of Directive 2001/83, (‘application for a product referring to a so-called original product’) with the difference compared to the original product listed as a different strength. The applicant has also referred to a reference medicinal product for each to justify the change in strength. 1. Introduction The three active ingredients are well known and have been approved singly or in combination for the indications claimed. An excellent 16-page Clinical Overview and Clinical Summary covering the rationale of product development, biopharmaceutics, clinical pharmacology, efficacy, safety and risk/benefit analysis in respect of both the products has been provided, by a suitably qualified person. 2. Assessment The following assessment of the SPCs of the two products is based on SPCs of other authorised similar products rather than on any one reference SPC. The assessment also taken into account the Agency guidance on individual active ingredients for GSL use 2.1. Therapeutic indications Satisfactory and acceptable. 2.2. Posology and method of administration Satisfactory and acceptable. 2.3. Contraindications Satisfactory and acceptable. 2.4. Special warnings and precautions for use Satisfactory and acceptable. 2.5. Interactions with other medicinal products and other forms of interaction Satisfactory and acceptable. 2.6. Pregnancy and lactation


Satisfactory and acceptable.

2.7. Effects on ability to drive and use machines Satisfactory and acceptable. 2.8. Undesirable effects Satisfactory and acceptable. 2.9. Overdose Satisfactory and acceptable. 2.10. Pharmacodynamic properties Satisfactory and acceptable. 2.11 Pharmacokinetic properties Satisfactory and acceptable. 3. Bioequivalence The applications have been submitted under Article 10.1 [formerly article 10.1(a)(iii)] of Directive 2001/83, (‘application for a product referring to a so-called original product’) with the difference compared to the original product listed as a different strength. The applicant has also referred to a reference medicinal product for each to justify the change in strength. The applicant submitted a justification for not performing bioequivalence studies. This has been discussed extensively within the Agency for its legal validity as well as scientific and safety merits. The Agency is content that the applicant has justified exemption from the need to demonstrate bioequivalence by referring to, and meeting, the inclusion and exemption criteria in the bioequivalence guideline. 4. Carton Clinically, these are satisfactory in terms of safety information. 5. Recommendations There are no clinical public health issues and the recommendation is to grant marketing authorisations for these preparations.


OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT QUALITY The important quality characteristics of Max Strength Cold & Flu Capsules and Max Strength Sinus Relief Capsules 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 have been supplied with these applications and none are required for applications of this type. EFFICACY Paracetamol, caffeine and phenylephrine are well-known drugs and have been used in the treatment of the common cold, influenza and sinusitis for many years. It has been demonstrated that the applicant’s products are comparable to the originator product, Beechams Powders Capsules and the reference product, Lemsip Max Strength Capsules. No new or unexpected safety concerns arise from these applications. The SPC, PIL and labelling are satisfactory. RISK BENEFIT ASSESSMENT The quality of the products is acceptable and no new preclinical or clinical safety concerns have been identified. The data supplied supports the claim that the applicant’s products and the innovator products are interchangeable, with the applicant’s products containing a higher dose of paracetamol and phenylephrine hydrochloride. Clinical experience with paracetamol, caffeine and phenylephrine hydrochloride is considered to have demonstrated the therapeutic value of the compounds. The risk benefit is therefore considered to be positive.



PL 12063/0066


PL 12063/0067

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the marketing authorisation applications on 20/10/2004 and 16/11/2004

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 10/11/2004 and 18/11/2004.

3 Following assessment of the application the MHRA requested further information relating to the dossier on 10/06/2005, 28/11/2005, 07/12/2005, 12/01/2006 and 15/03/2006.

4 The applicant responded to the MHRA’s requests, providing further information relating to the dossier on 28/11/2005, 07/12/2005, 01/03/2006 and 27/04/2006 and 23/05/2006.

5 The application was determined on 09/06/2006



PL 12063/0066


PL 12063/0067

STEPS TAKEN AFTER ASSESSMENT

Date submitted

Application type

Scope Outcome



PL 12063/0066

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Asda Max Strength Cold & Flu Capsules, hard Benylin Cold & Flu Max Strength Capsules, hard Boots Max Strength Cold & Flu Capsules, hard Lloydspharmacy Max Strength Cold & Flu Capsules, hard Morrisons Max Strength Cold & Flu Capsules, hard Sainsbury’s Max Strength Cold & Flu Capsules, hard Superdrug Max Strength Cold & Flu Capsules, hard Tesco Max Strength Cold & Flu Capsules, hard Wilko Max Strength Cold & Flu Capsules, hard

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Ingredient Mg/Capsule Paracetamol Caffeine Phenylephrine Hydrochloride

500 25 6.1

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Hard capsule. Red/yellow hard gelatin capsules containing the drug product, an off-white powder.

4. CLINICAL PARTICULARS 4.1. Therapeutic indications

For the relief of symptoms associated with the common cold and influenza, including relief of aches and pains, sore throat, headaches, fatigue and drowsiness, nasal congestion and lowering of temperature.


4.2. Posology and method of administration For oral use. Swallow whole with water. Do not chew. Adults and Children over 12 years 2 capsules every 4 hours as required to a maximum of four doses in any 24 hours. Do not exceed eight capsules in any 24 hours. Children 6-12 years 1 capsule every 4 hours as required to a maximum of four doses in any 24 hours. Do not exceed four capsules in any 24 hours. Not recommended for children under 6 years of age.

4.3. Contraindications

Paracetamol: Hypersensitivity to paracetamol or any of the

other constituents. Caffeine: Should be given with care to patients with a

history of peptic ulcer. Phenylephrine Hydrochloride: Severe coronary heart disease and cardiovascular

disorders. Hypertension. Hyperthyroidism. Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors.

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. Use with caution in patients with Raynaud’s Phenomenon and diabetes mellitus. The following warnings will appear on the pack:- CONTAINS PARACETAMOL

- If symptoms persist consult your doctor. - Do not exceed the stated dose. - Keep all medicines out of the reach and sight of children. - Do not take with any other paracetamol-containing products. The Label shall say:


Immediate medical advice should be sought in the event of an overdose, even if you feel well. The Leaflet shall say: 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. If you are pregnant or being prescribed medicine by your doctor, seek your doctor’s advice before taking this product.

4.5. Interactions with other medicinal products and other forms of interaction

Paracetamol 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. Drugs which induce hepatic microsomal enzymes, such as alcohol, barbiturates, monoamine oxidase inhibitors and tricyclic antidepressants, may increase the hepatotoxicity of paracetamol, particularly after overdosage. Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors because of a risk of hypertensive crisis. Phenylephrine Hydrochloride Phenylephrine may adversely interact with other sympathomimetics, vasodilators and beta blockers.

4.6. Pregnancy and lactation

Paracetamol Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the 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. Caffeine Taken during pregnancy, it appears that the half-life of caffeine is prolonged. This is a possible contributing factor in hyperemesis gravidarum (morning sickness). Caffeine appears in breast milk. Irritability and poor sleeping pattern in the infant have been reported.


Phenylephrine Hydrochloride Due to the vasoconstrictive properties of phenylephrine the product should be used with caution in patients with a history of pre-eclampsia. Phenylephrine may reduce placental perfusion and the product should be used in pregnancy only if the benefits outweigh this risk. There is no information on use in lactation.

4.7. Effects on ability to drive and use machines

None known.

4.8. Undesirable effects

Paracetamol 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. Caffeine Nausea and insomnia have been noted. Phenylephrine Hydrochloride Phenylephrine hydrochloride may elevate blood pressure with headache, vomiting and rarely palpitations; tachycardia or reflex bradycardia; tingling and coolness of the skin. There have been rare reports of allergic reactions.

4.9. Overdose

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, 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 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. 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 British National Formulary (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 24 hours from ingestion should be discussed with the National Poisons Information Service (NPIS) or a liver unit.

Caffeine Doses over 1g are probably necessary to induce toxicity, 2-5g to produce severe toxicity and 5-10g is likely to be lethal. Symptoms include: epigastric pain, vomiting, diuresis, tachycardia. CNS stimulation (insomnia, restlessness, excitement, agitation, jitteriness, tremors, convulsions). No specific antidote is available, reduce or stop dosage and avoid excessive intake of coffee or tea. Phenylephrine Hydrochloride Severe overdosage may produce hypertension and associated reflex bradycardia. Treatment measures include early gastric lavage and symptomatic and supportive measures. The hypertensive effects may be treated with an alpha-receptor blocking agent (such as phentolamine mesylate 6-10mg) given intravenously, and the bradycardia treated with atropine, preferably only after the pressure has been controlled.


5. PHARMACOLOGICAL PROPERTIES 5.1. Pharmacodynamic properties

Pharmacotherapeutic Group: Other analgesics and antipyretics & Other cold combination preparations ATC code: N02BE51 PARACETAMOL Analgesic: The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting a prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation. Antipyretic: Paracetamol probably produces antipyresis by acting on the hypothalamic heat-regulating centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus. CAFFEINE Central nervous system stimulant – Caffeine stimulates all levels of the CNS, although its cortical effects are milder and of shorter duration than those of amfetamines. Analgesia Adjunct: Caffeine constricts cerebral vasculature with an accompanying decrease in cerebral blood flow and in the oxygen tension of the brain. It is believed that caffeine helps to relieve headaches by providing a more rapid onset of action and/or enhanced pain relief with lower doses of analgesic. Recent studies with ergotamine indicate that the enhancement of effect by the addition of caffeine may also be due to improved gastrointestinal absorption of ergotamine when administered with caffeine. PHENYLEPHRINE HYDROCHLORIDE Sympathomimetic amines, such as phenylephrine, act on alpha-adrenergic receptors of the respiratory tract to produce vasoconstriction, which temporarily reduces the swelling associated with inflammation of the mucous membranes lining the nasal and sinus passages. This allows the free drainage of the sinusoidal fluid from the sinuses. In addition to reducing mucosal lining swelling, decongestants also suppress the production of mucus, therefore preventing a build up of fluid within the cavities which could otherwise lead to pressure and pain.

5.2. Pharmacokinetic properties

PARACETAMOL


Absorption and Fate Paracetamol is rapidly absorbed from the gastro-intestinal tract with peak plasma concentrations occurring between 10 and 120 minutes after oral administration. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations. 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 overdose and cause liver damage. CAFFEINE Absorption and Fate Caffeine is absorbed readily after oral administration and is widely distributed throughout the body. Caffeine is metabolised almost completely via oxidation, demethylation, and acetylation, and is excreted in the urine as 1-methyluric acid, 1-methylxanthine, 7-methylxanthine, 1,7-dimethylxanthine (paraxanthine), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), and other metabolites with only about 1% unchanged. PHENYLEPHRINE HYDROCHLORIDE Absorption and Fate Phenylephrine has reduced bioavailability from the gastro-intestinal tract owing to irregular absorption and first-pass metabolism by monoamine oxidase in the gut and liver.

5.3. Preclinical safety data

There are no preclinical data of relevance to the prescriber additional to that already covered in other sections of the SPC.

6. PHARMACEUTICAL PARTICULARS 6.1. List of excipients

Maize Starch Croscarmellose Sodium Sodium Laurilsulfate Magnesium Stearate Talc


Gelatin Titanium Dioxide E171 Quinoline Yellow E104 Patent Blue V E131 Erythrosine E127

6.2. Incompatibilities

None known.

6.3. Shelf life

2 years.

6.4. Special precautions for storage

Do not store above 25°C.

6.5. Nature and contents of container

250 micron white opaque PVC/30 micron hard temper pyramidal aluminium foil, heat-seal coated, contained in an outer cardboard carton. Pack size: 8 or 16 capsules.

6.6 Special precautions for disposal None

7. MARKETING AUTHORISATION HOLDER Wrafton Laboratories Limited Wrafton Braunton North Devon EX33 2DL

8. MARKETING AUTHORISATION NUMBER PL 12063/0066


9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/06/2006 10 DATE OF REVISION OF THE TEXT

09/06/2006


MAX STRENGTH SINUS RELIEF CAPSULES, HARD

(PARACETAMOL, CAFFEINE, PHENYLEPHRINE HYDROCHLORIDE) PL 12063/0067

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Asda Max Strength Sinus Relief Capsules, Hard Boots Max Strength Sinus Relief Capsules, Hard Superdrug Max Strength Sinus Relief Capsules, Hard Wilko Max Strength Sinus Relief Capsules, Hard

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Ingredient mg/CapsuleParacetamol 500 Caffeine 25 Phenylephrine Hydrochloride 6.1 For a full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM Hard capsule. Red/blue hard gelatin capsules containing the drug product, an off-white powder.

4. CLINICAL PARTICULARS 4.1. Therapeutic indications

For the relief of symptoms associated with the pain and congestion of sinusitis, including relief of aches and pains, headache, nasal congestion and lowering of temperature.

4.2. Posology and method of administration

For oral use. Swallow whole with water. Do not chew.


Adults and Children over 12 years2 capsules every 4 hours as required to a maximum of four doses in any 24 hours. Do not exceed eight capsules in any 24 hours. Children 6 – 12 years1 capsule every 4 hours as required to a maximum of four doses in any 24 hours. Do not exceed four capsules in any 24 hours. Not recommended for children under 6 years of age.

4.3. Contraindications

Paracetamol: Hypersensitivity to paracetamol or any of the other constituents. Caffeine: Should be given with care to patients with a history of peptic ulcer. Phenylephrine Hydrochloride: Severe coronary heart disease and cardiovascular disorders. Hypertension. Hyperthyroidism. Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors.

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. Use with caution in patients with Raynaud’s Phenomenon and diabetes mellitus. The following warnings will appear on the pack:-

CONTAINS PARACETAMOL

- If symptoms persist consult your doctor. - Do not exceed the stated dose. - Keep all medicines out of the reach and sight of children. Do not take with any other paracetamol-containing products. The Label shall say: Immediate medical advice should be sought in the event of an overdose, even if you feel well. The Leaflet shall say:


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. If you are pregnant or being prescribed medicine by your doctor, seek your doctor’s advice before taking this product.

4.5. Interactions with other medicinal products and other forms of interaction

Paracetamol 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. Drugs which induce hepatic microsomal enzymes, such as alcohol, barbiturates, monoamine oxidase inhibitors and tricyclic antidepressants, may increase the hepatotoxicity of paracetamol, particularly after overdosage. Contraindicated in patients currently receiving or within two weeks of stopping therapy with monoamine oxidase inhibitors because of a risk of hypertensive crisis. Phenylephrine Hydrochloride Phenylephrine may adversely interact with other sympathomimetics, vasodilators and beta blockers.

4.6. Pregnancy and lactation

Paracetamol Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the 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. Caffeine Taken during pregnancy, it appears that the half-life of caffeine is prolonged. This is a possible contributing factor in hyperemesis gravidarum (morning sickness). Caffeine appears in breast milk. Irritability and poor sleeping pattern in the infant have been reported. Phenylephrine Hydrochloride Due to the vasoconstrictive properties of phenylephrine the product should be used with caution in patients with a history of pre-eclampsia. Phenylephrine may reduce placental perfusion and the product should be used in pregnancy only if the benefits outweigh this risk. There is no information on use in lactation.


4.7. Effects on ability to drive and use machines

None known

4.8. Undesirable effects

Paracetamol 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. Caffeine Nausea and insomnia have been noted. Phenylephrine Hydrochloride Phenylephrine hydrochloride may elevate blood pressure with headache, vomiting and rarely palpitations; tachycardia or reflex bradycardia; tingling and coolness of the skin. There have been rare reports of allergic reactions.

4.9. Overdose

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, 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 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. 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 British National Formulary (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 24 hours from ingestion should be discussed with the National Poisons Information Service (NPIS) or a liver unit.

Caffeine Doses over 1g are probably necessary to induce toxicity, 2 – 5g to produce severe toxicity and 5 – 10g is likely to be lethal. Symptoms include: epigastric pain, vomiting, diuresis, tachycardia, CNS stimulation (insomnia, restlessness, excitement, agitation, jitteriness, tremors, convulsions). No specific antidote is available, reduce or stop dosage and avoid excessive intake of coffee or tea. Phenylephrine Hydrochloride Severe overdosage may produce hypertension and associated reflex bradycardia. Treatment measures include early gastric lavage and symptomatic and supportive measures. The hypertensive effects may be treated with an alpha-receptor blocking agent (such as phentolamine mesylate 6 – 10 mg) given intravenously, and the bradycardia treated with atropine, preferably only after the pressure has been controlled.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic Group: Other analgesics and antipyretics & Other cold combination preparations


ATC code: N02BE51

5.1. Pharmacodynamic properties

PARACETAMOL Analgesic: The mechanism of analgesic action has not been fully determined. Paracetamol may act predominantly by inhibiting a prostaglandin synthesis in the central nervous system (CNS) and to a lesser extent through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of prostaglandin synthesis or to inhibition of the synthesis or actions of other substances that sensitise pain receptors to mechanical or chemical stimulation. Antipyretic: Paracetamol probably produces antipyresis by acting on the hypothalamic heat-regulating centre to produce peripheral vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves inhibition of prostaglandin synthesis in the hypothalamus. CAFFEINE Central nervous system stimulant – Caffeine stimulates all levels of the CNS, although its cortical effects are milder and of shorter duration than those of amfetamines. Analgesia Adjunct: Caffeine constricts cerebral vasculature with an accompanying decrease in cerebral blood flow and in the oxygen tension of the brain. It is believed that caffeine helps to relieve headache by providing a more rapid onset of action and/or enhanced pain relief with lower doses of analgesic. Recent studies with ergotamine indicate that the enhancement of effect by the addition of caffeine may also be due to improved gastrointestinal absorption of ergotamine when administered with caffeine. PHENYLEPHRINE HYDROCHLORIDE Sympathomimetic amines, such as phenylephrine, act on alpha-adrenergic receptors of the respiratory tract to produce vasoconstriction, which temporarily reduces the swelling associated with inflammation of the mucous membranes lining the nasal and sinus passages. This allows the free drainage of the sinusoidal fluid from the sinuses. In addition to reducing mucosal lining swelling, decongestants also suppress the production of mucus, therefore preventing a build up of fluid within the cavities which could otherwise lead to pressure and pain.

5.2. Pharmacokinetic properties

PARACETAMOL Absorption and Fate


Paracetamol is rapidly absorbed from the gastro-intestinal tract with peak plasma concentrations occurring between 10 and 120 minutes after oral administration. It is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations. 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 overdose and cause liver damage. CAFFEINE Absorption and Fate Caffeine is absorbed readily after oral administration and is widely distributed throughout the body. Caffeine is metabolised almost completely via oxidation, demethylation, and acetylation, and is excreted in the urine as 1-methyluric acid, 1-methylxanthine, 7-methylxanthine, 1,7-dimethylxanthine (paraxanthine), 5-acetylamino-6-formylamino-3-methyluracil (AFMU), and other metabolites with only about 1% unchanged. PHENYLEPHRINE HYDROCHLORIDE Absorption and Fate Phenylephrine has reduced bioavailability from the gastro-intestinal tract owing to irregular absorption and first-pass metabolism by monoamine oxidase in the gut and liver.

5.3. Preclinical safety data

There are no preclinical data of relevance to the prescriber additional to that already covered in other sections of the SPC.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Maize Starch Croscarmellose Sodium Sodium Laurilsulfate Magnesium Stearate Talc Gelatin Titanium Dioxide E171 Quinoline Yellow E104


Patent Blue V E131 Erythrosine E127 Indigo Carmine E132

6.2. Incompatibilities None known.

6.3. Shelf life

2 years

6.4. Special precautions for storage

Do not store above 25°C.

6.5. Nature and contents of container

250 micron white opaque PVC/30 micron hard temper pyramidal aluminium foil, heat-seal coated, contained in an outer cardboard carton. Pack sizes: 16 capsules.

6.6 Special precautions for disposal

None

7. MARKETING AUTHORISATION HOLDER Wrafton Laboratories Limited Wrafton Braunton North Devon EX33 2DL

8. MARKETING AUTHORISATION NUMBER PL 12063/0067

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION


09/06/2006 10 DATE OF REVISION OF THE TEXT

09/06/2006



PL 12063/0066

PRODUCT INFORMATION LEAFLET

Please note that the leaflet and labelling below is representative of that produced by the individual distributors of these products. The content will be the same although the layout is different.



MAX STRENGTH SINUS RELIEF CAPSULES, HARD

(PARACETAMOL, CAFFEINE, PHENYLEPHRINE HYDROCHLORIDE) PL 12063/0067

PRODUCT INFORMATION LEAFLET




PL 12063/0066

LABELLING CARTON


FOIL



PL 12063/0067

LABELLING

CARTON

FOIL


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