Co-Codamol 8mg-500mg and 30mg-500mg … Co-codamol 8/500mg and 30/500mg Effervescent Tablets PL 36390/0005-6 5 lead to any increase in environmental exposure concentrations of the

UKPAR Co-codamol 8/500mg and 30/500mg Effervescent Tablets PL 36390/0005-6

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Co-codamol 8/500mg Effervescent Tablets Co-codamol 30/500mg Effervescent Tablets

(paracetmol, codeine phosphate hemihydrate)

PL 36390/0005-6

UKPAR

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 Leaflets

Page 26

Labelling

Page 34


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Co-codamol 8/500mg and 30/500mg Effervescent Tablets


PL 36390/0005-6

LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted STD Chemicals Limited Marketing Authorisations (licences) for the medicinal products Co-codamol 8/500mg Effervescent Tablets and Co-codamol 30/500mg Effervescent Tablets (PL 36390/0005-6) on 6th October 2011. Co-Codamol 8/500mg Effervescent Tablets is a P licensed medicine, available only from pharmacies, under the supervision of a pharmacist. Co-Codamol 30/500mg Effervescent Tablets is a prescription-only medicine (POM). The active ingredients, paracetamol and codeine phosphate, belong to a group of medicines called analgesics, which act as painkillers. Paracetamol is also an antipyretic which means that it helps to reduce fever and lower your temperature. Co-codamol 8/500mg Effervescent Tablets are used for the short-term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone. They can be used for the symptomatic relief of muscular and rheumatic pains, headache, migraine, toothache, period pains and neuralgia (severe burning or stabbing pain following the line of a nerve). Co-codamol 30/500mg Effervescent Tablets are used for the relief of severe pain. Co-codamol 8/500mg and 30/500mg Effervescent Tablets are not suitable for use in children under 12 years of age. These Marketing Authorisations for Co-codamol 8/500mg and 30/500mg Effervescent Tablets are considered to be identical to the previously granted licences for Co-codamol Effervescent Tablets 8/500mg and Co-codamol 30/500mg Effervescent Tablets (PL 20417/0028 and 0025), authorised to Fannin (UK) Limited on 11th August 2011 and 29th July 2011, respectively. No new or unexpected safety concerns arose from these simple applications. It was judged that the benefits of Co-codamol 8/500mg and 30/500mg Effervescent Tablets outweigh the risk; hence Marketing Authorisations have been granted.


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PL 36390/0005-6

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 6

Non-clinical assessment

Page 9

Clinical assessment

Page 10

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 STD Chemicals Limited Marketing Authorisations (MAs) for the medicinal products Co-codamol 8/500mg Effervescent Tablets and Co-codamol 30/500mg Effervescent Tablets (PL 36390/0005-6) on 6th October 2011. Co-Codamol 8/500mg Effervescent Tablets is a P licensed medicine. Co-Codamol 30/500mg Effervescent Tablets is a prescription-only medicine (POM). These are simple, abridged, ‘informed consent’ applications, submitted according to Article 10c of EC Directive 2001/83 (as amended). The applications cross-reference the Marketing Authorisations for Co-codamol Effervescent Tablets 8/500mg and Co-codamol 30/500mg Effervescent Tablets (PL 20417/0028 and 0025), authorised to Fannin (UK) Limited on 11th August 2011 and 29th July 2011, respectively. The cross-referenced products were originally authorised to Neolab Limited (PL 08137/0042 and 0048) in June 2000 and October 2002, respectively. These two MAs underwent Change of Ownership (CoA) procedures to the current Fannin (UK) Limited licences. Co-codamol 8/500mg Effervescent Tablets are used in adults and children aged 12 years and over for the short-term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone. They are indicated for the symptomatic relief of muscular and rheumatic pains, headache, migraine, toothache, period pains and neuralgia. Co-codamol 30/500mg Effervescent Tablets are indicated in adults and children aged 12 years and over for the relief of severe pain. Paracetamol has analgesic and antipyretic actions. Codeine phosphate is an opioid analgesic. It has similar uses to morphine but is much less potent as an analgesic and has only mild sedative effects. The MHRA considers that the pharmacovigilance system 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). As the applications are for products that are identical to already authorised reference products, for which safety concerns requiring additional risk minimisation have been identified, a risk minimisation system is not considered necessary. The reference products have been in use for many years and the safety profiles of the actives are well-established. The MAH has provided adequate justification for not submitting an Environmental Risk Assessment (ERA). It is not considered that these medicinal products represent any risk to the environment. There is no reason to conclude that marketing of these products will change the overall use pattern of the existing market. The availability of these medicinal products, which are identical to the cited reference products, will not


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lead to any increase in environmental exposure concentrations of the active ingredients. No new data were submitted nor was it necessary for these simple applications, as the data are identical to those of the previously granted cross-reference products. As the cross-reference products were granted prior to the introduction of current legislation, no Public Assessment Report (PAR) was generated for them.


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PHARMACEUTICAL ASSESSMENT LICENCE NUMBERS: PL 36390/0005-6 PROPRIETARY NAME: Co-codamol 8/500mg and 30/500mg Effervescent

Tablets ACTIVE INGREDIENTS: Paracetamol, codeine phosphate COMPANY NAME: STD Chemicals Limited E.C. ARTICLE: Article 10c of Directive 2001/83/EC (as amended) LEGAL STATUS: Co-Codamol 8/500mg Effervescent Tablets - P

Co-Codamol 30/500mg Effervescent Tablets - POM 1. INTRODUCTION

These are simple abridged applications, submitted under Article 10c of Directive 2001/83/EC (as amended) for Co-codamol 8/500mg and 30/500mg Effervescent Tablets. The proposed MAH is STD Chemicals Limited. The reference products are Co-codamol Effervescent Tablets 8/500mg and Co-codamol 30/500mg Effervescent Tablets (PL 20417/0028 and 0025), authorised to Fannin (UK) Limited on 11th August 2011 and 29th July 2011, respectively. The proposed and reference products are considered identical. 2. MARKETING AUTHORISATION APPLICATION FORM

2.1 Name(s)

The approved names of the products are Co-codamol 8/500mg Effervescent Tablets and Co-codamol 30/500mg Effervescent Tablets. The products have been named in line with current requirements and the product names are acceptable. 2.2 Strength, pharmaceutical form, route of administration, container and pack sizes

Each Co-codamol 8/500mg Effervescent Tablet contains 8 mg of codeine phosphate and 500 mg of paracetamol. Each Co-codamol 30/500mg Effervescent Tablet contains 30 mg of codeine phosphate and 500 mg of paracetamol. Co-codamol 8/500mg Effervescent Tablets are licensed for marketing in 4 layer paper-polyethylene (PE)-aluminium foil-PE blister strips, which are packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 7, 10, 14, 20, 28, 30 or 32 effervescent tablets. Co-codamol 30/500mg Effervescent Tablets are licensed for marketing in aluminium-aluminium foil blister strips, which are packaged with the Patient Information Leaflet (PIL) into cardboard outer cartons in pack sizes of 30, 32, 56, 60, 84, 90 and 100 effervescent tablets. The MAH has stated that not all pack sizes may be marketed. The container closure systems and pack sizes are identical to those for the respective reference products.


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The approved shelf-life (3 years) and storage conditions (‘Do not store above 25°C. Store in a dry place and protect from light’ for the 8/500mg strength tablets and ‘Do not store above 25°C. Store in the original package’ for the 30/500mg strength tablets) are identical to the details registered for the respective reference products. 2.3 Legal status

P - Co-Codamol 8/500mg Effervescent Tablets is a P licensed medicine available only from pharmacies, under the supervision of a pharmacist. POM - Co-Codamol 30mg/500mg Effervescent Tablets are subject to a medical prescription. 2.4 Marketing Authorisation Holder / Contact Persons/Company

The proposed Marketing Authorisation Holder is ‘STD Chemicals Limited, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW’. The Qualified Person (QP) responsible for pharmacovigilance was stated and their CV included. 2.5 Manufacturers

The proposed manufacturing sites are consistent with those registered for the cross-reference products and evidence of GMP compliance has been provided. 2.6 Qualitative and quantitative composition

The proposed compositions are consistent with the details registered for the cross-reference products. 2.7 Manufacturing process

The proposed manufacturing process is consistent with the details registered for the cross-reference products and the maximum batch sizes are stated. 2.8 Finished product / shelf-life specification

The proposed finished product specifications are consistent with the details registered for the cross-reference products. 2.9 Drug substance specification The proposed drug substance specifications are consistent with the details registered for the cross-reference products. 2.10 TSE Compliance

There are no materials of human or animal origin contained in or used in the manufacturing process for the proposed products. None of the excipients are sourced from genetically modified organisms. 3. EXPERT REPORT

A satisfactory quality overall summary has been prepared by an appropriately qualified expert. The CV of the expert was provided.


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4. PRODUCT NAME & APPEARANCE

See 2.1 for details of the proposed product names. Co-codamol 8/500mg and 30/500mg Effervescent Tablets are white, circular, flat, bevelled-edge tablets, plain on both sides. The appearance of the products is identical to that of the cross-reference products. 5. SUMMARY OF PRODUCT CHARACTERISTICS

The approved SmPCs are consistent with the details registered for the cross-reference products. 6. PATIENT INFORMATION LEAFLET (PIL) / LABELLING

The approved PILs are satisfactory and in line with the approved SmPCs. They have been prepared according to the Quality Review of Documents (QRD) template. PIL user-testing has been accepted based on bridging to the successful user-testing of the PILs for the reference products, Co-codamol Effervescent Tablets 8/500mg and Co-codamol 30/500mg Effervescent Tablets (PL 20417/0028 and 0025, Fannin (UK) Limited). The text, content and layout of the proposed PILs are identical to that of the approved PILs for the reference products. The bridging is accepted. Mock-ups of the labelling have been provided and are satisfactory. The approved artwork is comparable to the artwork registered for the cross-reference products and complies with statutory requirements. The MAH has stated that not all licensed pack sizes may be marketed. They have committed to submitting mock-ups for currently unmarketed pack sizes to the MHRA for approval before those packs are commercially marketed. 7. CONCLUSIONS

The grounds for these applications are considered adequate. Marketing Authorisations were therefore granted.


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NON-CLINICAL ASSESSMENT

These are simple, abridged, ‘informed consent’ applications made under Article 10c of EC Directive 2001/83 (as amended). No new non-clinical data have been supplied with these applications and none are required for applications of this type. A non-clinical overview has been written by a suitably qualified person and is satisfactory. The CV of the non-clinical expert has been supplied. The Marketing Authorisation Holder has provided adequate justification for not submitting an Environmental Risk Assessment (ERA).


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CLINICAL ASSESSMENT These are simple, abridged, ‘informed consent’ applications made under Article 10c of EC Directive 2001/83 (as amended), cross-referring to the Marketing Authorisations for Co-codamol Effervescent Tablets 8/500mg and Co-codamol 30/500mg Effervescent Tablets (PL 20417/0028 and 0025, Fannin (UK) Limited). No new clinical data have been supplied with the applications, and none are required for applications of this type. A clinical overview has been written by a suitably qualified person and is satisfactory. The CV of the clinical expert has been supplied.


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OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT QUALITY

The data for these applications are consistent with those previously assessed for the cross-reference products and as such have been judged to be satisfactory. NON-CLINICAL

No new non-clinical data were submitted and none are required for applications of this type. EFFICACY

These applications are considered identical to the previously granted licences for Co-codamol Effervescent Tablets 8/500mg and Co-codamol 30/500mg Effervescent Tablets (PL 20417/0028 and 0025, Fannin (UK) Limited). No new or unexpected safety concerns arise from these applications. PRODUCT LITERATURE

The approved SmPCs, PILs and labelling are satisfactory and consistent with the details registered for the cross-reference products. PIL user-testing has been accepted based on bridging to the successful user-testing of the PILs for the reference products, Co-codamol Effervescent Tablets 8/500mg and Co-codamol 30/500mg Effervescent Tablets (PL 20417/0028 and 0025, Fannin (UK) Limited.). Mock-ups of the labelling have been provided and are satisfactory. The approved labelling artwork complies with statutory requirements. In line with current legislation, the name of the product in Braille appears on the outer packaging. The MAH has stated that not all licensed pack sizes may be marketed. They have committed to submitting mock-ups for currently unmarketed pack sizes to the MHRA for approval before those packs are commercially marketed. BENEFIT-RISK ASSESSMENT

The quality of the products is acceptable and no new non-clinical or clinical safety concerns have been identified. The applicant’s products are identical to the cross-reference products. The benefit: risk ratio is considered to be positive.


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PL 36390/0005-6

STEPS TAKEN FOR ASSESMENT 1 The MHRA received the marketing authorisation applications on 12th April

2011.

2 Following standard checks and communication with the applicant the MHRA considered the applications valid on 19th May 2011.

3 Following assessment of the applications the MHRA requested further information relating to the quality dossier on 28th June 2011.

4 The applicant responded to the MHRA’s requests, providing further information for the quality sections on 7th July 2011.

5 The applications were determined on 6th October 2011.


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PL 36390/0005-6

STEPS TAKEN AFTER AUTHORISATION Not applicable


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SUMMARY OF PRODUCT CHARACTERISTICS The UK Summary of Product Characteristics (SmPC) for Co-codamol 8/500mg Effervescent Tablets (PL 36390/0005) is as follows: 1 NAME OF THE MEDICINAL PRODUCT

Co-codamol 8/500mg Effervescent Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 8mg codeine phosphate hemihydrate and 500mg paracetamol Also contains aspartame and sodium. For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Effervescent tablet White circular, flat bevelled edge tablet, plain on both sides.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone. For the treatment of muscular and rheumatic pains, headache, migraine, neuralgia, toothache and period pains.

4.2 Posology and method of administration

For oral administration only. The tablets should be dissolved in at least half a tumbler of water before taking.

Adults and children over 12 years One to two tablets dissolved in water every 4 to 6 hours as required, to a maximum of 8 tablets daily. Elderly There is no current evidence for the alteration of the adult dose except where there is impaired hepatic function when dosage reduction may be necessary. Do not take more than 3 days continuously without medical review

4.3 Contraindications

Conditions where morphine and opioids are contra-indicated e.g. acute alcoholism and where risk of paralytic ileus, acute respiratory depression, raised intracranial pressure or head injury (affects pupillary responses vital for neurological assessment). Sensitivity to codeine or paracetamol or any of the constituents of the tablets.

4.4 Special warnings and precautions for use

Other paracetamol containing medication should be avoided when taking co-codamol effervescent tablets. These tablets contain sodium and should be avoided by patients on a low sodium diet. The tablets contain aspartame and so should not be taken by patients with phenylketonuria. Care should be taken when prescribing these tablets to patients with liver or renal impairment.


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The hazards of paracetamol overdose are greater in those with non-cirrhotic alcoholic liver disease. The label will state: Front of Pack • Can cause addiction • For three days use only

Back of Pack • For the short term treatment of acute moderate pain when other painkillers have not

worked. Do not take less than four hours after taking other painkillers. • For the treatment of pain, including muscular and rheumatic pains, headache, migraine,

neuralgia, toothache and period pains. • If you need to take this medicine continuously for more than three days you should see

your doctor or pharmacist • This medicine contains codeine which can cause addiction if you take it continuously for

more than three days. If you take this medicine for headaches for more than three days it can make them worse

The leaflet will state: Headlines section (to be prominently displayed) • This medicine can only be used for the short term treatment of acute moderate pain which

is not relieved by paracetamol, ibuprofen or aspirin alone. • You should only take this product for a maximum of three days at a time. If you need to

take it for longer than three days you should see your doctor or pharmacist for advice. • This medicine contains codeine which can cause addiction if you take it continuously for

more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it.

• If you take this medicine for headaches for more than three days it can make them worse. Section 1: What the medicine is for • Co-codamol 8/500 is for the short term treatment of acute moderate pain which is not

relieved by paracetamol, ibuprofen or aspirin alone. It is used to relieve muscular and rheumatic pains, headache, migraine, neuralgia (severe burning or stabbing pain following the line of a nerve), toothache and period pains.

Section 2: Before taking • This medicine contains codeine which can cause addiction if you take it continuously for

more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it.

• If you take a painkiller for headaches for more than three days it can make them worse. Section 3: Dosage • Do not take for more than 3 days. If you need to use this medicine for more than three

days you must speak to your doctor or pharmacist. • This medicine contains codeine and can cause addiction if you take it continuously for

more than three days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms.

Section 4: Side effects • Some people may have side-effects when taking this medicine. If you have any unwanted

side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.gov.uk; alternatively you can call Freephone 0808 100 3352 (available between 10am-2pm Monday – Friday) or fill in a paper form available from your local pharmacy.


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How do I know if I am addicted? If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor: - You need to take the medicine for longer periods of time. - You need to take more than the recommended dose. - When you stop taking the medicine you feel very unwell but you feel better if you

start taking the medicine again.

Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the caucasian population may be ultra-rapid metabolisers. The leaflet will state in the “Pregnancy and breast-feeding” subsection of section 2 “Before taking your medicine”: Usually it is safe to take Co-codamol 8/500 while breast feeding as the level of codeine in breast milk are too low to cause your baby any problems. However, some women who are at increased risk of developing side effects at any dose may have higher levels of codeine in their breast milk. If any of the following side effects develop in you or your baby stop taking this medicine and seek immediate medical advice; feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than normal, and shallow or slow breathing.

4.5 Interaction with other medicinal products and other forms of interaction

Avoid taking co-codamol effervescent tablets with CNS depressants or other paracetamol containing products. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. Opioid analgesics such as codeine antagonise the effects of domperidone or metoclopramide on gastrointestinal activity. Co-administration with colestyramine may reduce absorption. Patients on anticoagulants may take occasional doses of co-codamol effervescent but the anticoagulant effect of warfarin and coumarins may be enhanced by regular administration of paracetamol.

4.6 Pregnancy and lactation

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. Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers. There is a risk of gastric stasis and of inhalation pneumonia in mothers during labour. Lactation At normal therapeutic doses codeine and its active metabolites may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolites may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant.


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If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

4.7 Effects on ability to drive and use machines

Patients should be warned not to drive or operate machinery if they become dizzy or sedated while taking co-codamol effervescent tablets.

4.8 Undesirable effects

Co-codamol effervescent tablets are generally well tolerated but hypersensitivity reactions including skin rashes may occur. Rare cases of anaphylaxis, angioedema, urticaria, pruritus and fixed drug eruption have been reported with medications containing paracetamol and/or codeine. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to Co-codamol. Codeine may sometimes cause typical opioid effects such as vomiting, constipation, nausea, light-headedness, dizziness, confusion, drowsiness and urinary retention. The frequency and severity of these effects are determined by dosage, duration of treatment and individual sensitivity. There have been rare reports of acute pancreatitis in patients taking codeine or codeine/paracetamol combinations. • Regular prolonged use of codeine is known to lead to addiction and tolerance. Symptoms

of restlessness and irritability may result when treatment is then stopped. • Prolonged use of a painkiller for headaches can make them worse.

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, phenobarbital, phenytoin, primidone,

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

starvation, cachexia.

Symptoms Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia, and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported. 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.


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Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured 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. Codeine Nausea and vomiting are prominent symptoms of codeine toxicity, with circulatory and respiratory depression in severe overdose. The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs. Symptoms Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely. Management This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg. Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Paracetamol has antipyretic and analgesic actions with little anti-inflammatory effect. Codeine is an analgesic related to morphine but with only mild sedative effects.

5.2 Pharmacokinetic properties

Paracetamol is rapidly and well absorbed from the intestinal tract after it has left the stomach. Plasma protein binding is low and paracetamol is metabolised in the liver and mainly excreted in the urine as glucuronide and sulphate conjugates. The elimination half-life is 1-3 hours. Codeine is absorbed from the gastro-intestinal tract and peak plasma-codeine concentrations are found in about one hour. It is metabolised by O- and N-demethylation in the liver to morphine, norcodeine, and other metabolites including normorphine and hydrocodone. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The elimination half-life has been reported to be between 3 and 4 hours.

5.3 Preclinical safety data

None stated

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydrogen carbonate, citric acid, sodium carbonate anhydrous, povidone, simeticone, sodium saccharin, aspartame, polysorbate 80.


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6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25ºC. Store in a dry place and protect from light.

6.5 Nature and contents of container

4 layer paper/PE/aluminium/PE blisters. Pack sizes: 7, 10, 14, 20, 28, 30 and 32 tablets.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

STD Chemicals Limited, Hillbrow House, Hillbrow Road, Esher, Surrey, KT10 9NW

8 MARKETING AUTHORISATION NUMBER(S)

PL 36390/0005

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06/10/2011

10 DATE OF REVISION OF THE TEXT

06/10/2011


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The UK Summary of Product Characteristics (SmPC) for Co-codamol 30/500mg Effervescent Tablets (PL 36390/0006) is as follows: 1 NAME OF THE MEDICINAL PRODUCT

Co-codamol 30/500mg Effervescent Tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 30mg codeine phosphate hemihydrate and 500mg paracetamol.

Also contains aspartame and sodium

For a full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Effervescent tablet.

White circular, flat bevelled edge tablet, plain on both sides.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the relief of severe pain.

4.2 Posology and method of administration

For oral administration only. The tablets should be dissolved in at least half a tumbler of water before taking.

Adults One to two tablets dissolved in water not more frequently than every 4 hours to a maximum of 8 tablets in any 24-hour period.

Children Not recommended for use in children under 12 years of age. Elderly

A reduced dose may be required. Dosage is adjusted according to a patients response and the severity of the pain, however tolerance to codeine may develop with prolonged use and care should be taken as adverse effects are dose related.

4.3 Contraindications

Sensitivity to codeine or paracetamol or any of the constituents of the tablets. Conditions where morphine and opioids are contraindicated e.g. acute asthma, respiratory depression, acute alcoholism, head injuries, raised intra-cranial pressure and following biliary tract surgery.

4.4 Special warnings and precautions for use

Other paracetamol containing medication should not be taken when taking Co-codamol Effervescent Tablets. These tablets contain 438mg sodium per tablet and should be avoided by patients on a low sodium diet. The tablets contain aspartame and so should not be taken by patients with phenylketonuria.


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Care should be taken when prescribing these tablets to patients with severe liver or renal impairment. The hazards of overdose are greater in those with alcoholic liver disease. Care should be taken when prescribing for elderly patients who can be more susceptible to the opioid effects such as CNS and gastro-intestinal effects. Other susceptible patients include those on concurrent CNS depressent drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders. Caution is advised when taking codeine with monoamine oxidase inhibitor (MAOI) therapy. Co-codamol Effervescent Tablets should not be taken concurrently or within 14 days of MAOI’s. The risk-benefit of continued use should be assessed regularly by the prescriber. The leaflet will state in a prominent position in the ‘before taking’ section:

• Do not take for longer than directed by your prescriber.

• Taking codeine/dihydrocodeine (DHC) regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the tablets.

• Taking a painkiller for headaches too often or for too long can make them worse. The label will state (To be displayed prominently on outer pack – not boxed):

• Do not take for longer than directed by your prescriber as taking codeine/DHC regularly for a long time can lead to addiction.

Codeine is partially metabolised by CYP2D6. If a patient has a deficiency or is completely lacking this enzyme they will not obtain adequate analgesic effects. Estimates indicate that up to 7% of the caucasian population may have this deficiency. However, if the patient is an ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at low doses. General symptoms of opioid toxicity include nausea, vomiting, constipation, lack of appetite and somnolence. In severe cases this may include symptoms of circulatory and respiratory depression. Estimates indicate that up to 1 to 2% of the caucasian population may be ultra-rapid metabolisers. The leaflet will state in the “Pregnancy and breast-feeding” subsection of section 2 “Before taking your medicine”: Usually it is safe to take Co-codamol 30/500 while breast feeding as the level of codeine in breast milk are too low to cause your baby any problems. However, some women who are at increased risk of developing side effects at any dose may have higher levels of codeine in their breast milk. If any of the following side effects develop in you or your baby stop taking this medicine and seek immediate medical advice; feeling sick, vomiting, constipation, decreased or lack of appetite, feeling tired or sleeping for longer than normal, and shallow or slow breathing.

4.5 Interaction with other medicinal products and other forms of interaction

Avoid taking Co-codamol Effervescent Tablets with CNS depressants (including other opioid analgesics and alcohol) or other paracetamol containing products. Paracetamol may increase the elimination half-life of chloramphenicol. Oral contraceptives may increase its rate of clearance. There is increased absorption when taken with metoclopramide or domperidone. Co-administration with colestyramine may reduce absorption.


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Patients on anticoagulants may take occasional doses of Co-codamol Effervescent Tablets but the anticoagulant effect of warfarin and coumarins may be enhanced by prolonged regular administration of paracetamol with increased risk of bleeding. Occasional doses have no significant effect.

4.6 Pregnancy and lactation

There is inadequate evidence of the safety of codeine in human pregnancy, but there is epidemiological evidence for the safety of paracetamol. Both substances have been used for many years without apparent ill consequences and animal studies have not shown any hazard. Nonetheless careful consideration should be given before prescribing the product for pregnant patients. Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers. At normal therapeutic doses codeine and its active metabolites may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolites may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant. If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

4.7 Effects on ability to drive and use machines

Patients should be warned not to drive or operate machinery if they become dizzy or sedated while taking Co-codamol Effervescent Tablets.

4.8 Undesirable effects

Co-codamol Effervescent Tablets are generally well tolerated but hypersensitivity reactions including skin rashes may occur. Rare cases of anaphylaxis, angioedema, urticaria, pruritus and fixed drug eruption have been reported with medications containing paracetamol and/or codeine. There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to co-codamol. Codeine may sometimes cause typical opioid effects such as vomiting, constipation, nausea, light-headedness, dizziness, confusion, drowsiness and urinary retention. The frequency and severity of these effects are determined by dosage, duration of treatment and individual sensitivity. There have been rare reports of acute pancreatitis in patients taking codeine or codeine/paracetamol combinations. • Regular prolonged use of codeine/DHC is known to lead to addiction and tolerance.

Symptoms of restlessness and irritability may result when treatment is then stopped.

• Prolonged use of a painkiller for headaches can make them worse.

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, phenobarbital, phenytoin, primidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes.


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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 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 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 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. Codeine

Nausea and vomiting are prominent symptoms of codeine toxicity, with circulatory and respiratory depression in severe overdose. The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs. Symptoms Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely. Management

This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg. Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.


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5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Paracetamol has antipyretic and analgesic actions with little anti-inflammatory effect. Codeine is an analgesic related to morphine but with only mild sedative effects.

5.2 Pharmacokinetic properties

Paracetamol is rapidly and well absorbed from the intestinal tract after it has left the stomach. Plasma protein binding is low and paracetamol is metabolised in the liver and mainly excreted in the urine as glucuronide and sulphate conjugates. The elimination half-life is 1-3 hours. Codeine is absorbed from the gastro-intestinal tract and peak plasma-codeine concentrations are found in about one hour. It is metabolised by O- and N-demethylation in the liver to morphine, norcodeine, and other metabolites including normorphine and hydrocodone. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The elimination half-life has been reported to be between 3 and 4 hours.

5.3 Preclinical safety data

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium hydrogen carbonate Citric acid anhydrous Sodium carbonate anhydrous Povidone Simeticone Sodium saccharin Aspartame

Polysorbate 80

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 25ºC. Store in the original package.

6.5 Nature and contents of container

Aluminium / Aluminium foil strips Pack sizes: 30, 32, 56, 60, 84, 90 and 100 tablets.

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

STD CHEMICALS LIMITED, HILLBROW HOUSE, HILLBROW ROAD, ESHER,


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SURREY, KT10 9NW

8 MARKETING AUTHORISATION NUMBER(S)

PL 36390/0006

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

06/10/2011

10 DATE OF REVISION OF THE TEXT

06/10/2011


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PATIENT INFORMATION LEAFLET

Co-codamol 8/500mg Effervescent Tablets - PL 36390/0005


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LABELLING



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Braille

Blister foils


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Braille

Blister foil (front and back)


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Alternative blister foil (front and back)