Document: spc-doc_PL 29831-0045 change

• spc-doc_PL 20416-0045
• spc-doc_PL 20416-0178
• spc-doc_PL 29831-0045
• spc-doc_PL 29831-0432
• spc-doc_PL 30306-0280

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Co-Codamol 8mg/500mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Paracetamol 500mg Codeine phosphate 8mg For excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablets

White tablets, broken breakline on one face. Debossed <AB> on other side.

4.1    Therapeutic indications

Codeine is indicated in patients older than 12 years of age for the treatment of acute moderate pain which is not considered to be relieved by other analgesics such as paracetamol or ibuprofen (alone).

For the symptomatic relief of pain including headache, migraine, toothache, period pains, rheumatic pains, including muscle pains and backache.

4.2    Posology and method of administration

Adults: One or two tablets to be swallowed with water. The dose should not be repeated more frequently than every four to six hours and not more than four times in any 24 hour period. Maximum dose is 8 tablets (4.0gm of paracetamol and 64mg of codeine in divided doses) per 24 hours.

Elderly: The dosage should be reduced.

Hepatic impairment: The dosage should be reduced. Use in liver disease is contraindicated (see 4.3 Contraindications).

Renal impairment: The dosage should be reduced in moderate to severe renal impairment (see also 4.8 Undesirable Effects). For concomitant illnesses/conditions where dose reduction may be appropriate, see 4.4 Special Warnings and Precautions for Use.

The duration of treatment should be limited to 3 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a physician.

Paediatric population:

Children aged 12 years to 18 years:

The recommended dose for children 12 years and older should be one or two tablets to be swallowed with water. The dose should not be repeated more frequently than every four to six hours and not more than four times in any 24 hour period. Maximum dose is 8 tablets (4.0gm of paracetamol and 64mg of codeine in divided doses) per 24 hours.

Children aged less than 12 years:

Codeine should not be used in children below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).

4.3    Contraindications

i.    Paracetamol: Hypersensitivity to paracetamol and/or other constituents.

ii.    Codeine: Acute respiratory depression, obstructive airways disease. Hypersensitivity to codeine or other opioid analgesics, or to any of the excipients. Liver disease. Severe hepatic dysfunction. Acute alcoholism. Use should be avoided in patients with raised intracranial pressure or head injury (in addition to the risk of respiratory depression and increased intracranial pressure, may affect pupillary and other responses vital for neurological assessment). Codeine should not be given to comatose patients.

Codeine is also contraindicated in conditions where inhibition of peristalsis is to be avoided, where there is a risk of paralytic ileus, where abdominal distension develops, or in acute diarrhoeal conditions such as acute ulcerative colitis or antibiotic associated colitis (e.g. pseudomembranous colitis) or diarrhoea caused by poisoning. Codeine is contraindicated:

•    In all paediatric patients (0-18 years of age) who undergo tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions (see section 4.4)

•    In women during breastfeeding (see section 4.6)

•    In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers Not to be used in children of 12 years and under.

4.4    Special warnings and precautions for use

i. Paracetamol: Care is advised in the administration of paracetamol to patients with renal or hepatic impairment. The hazards of overdose are greater in those with noncirrhotic alcoholic liver disease. Paracetamol should be given with care to patients with alcoholic dependence. Paracetamol is well tolerated by the majority of people with asthma. However, a small percentage of aspirin sensitive asthmatics are also sensitive to paracetamol. The likelihood of a reaction to paracetamol increases with a patient’s level of sensitivity to aspirin (see also 4.8 Undesirable Effects). Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with intravenous busulfan (see section 4.5 Interactions). Do not exceed the recommended dose. Patients should be advised not to take other paracetamol-containing products concurrently.

Label:

Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor.

Contains paracetamol.

Do not take anything else containing paracetamol while taking this medicine.

Talk to your doctor at once if you take too much of this medicine, even if you feel well.

Leaflet:

Talk to a doctor at once if you take too much of this medicine even if you feel well. This is because too much paracetamol can cause delayed, serious liver damage.

ii. Codeine: Use in reduced doses or with caution in asthma, and decreased respiratory reserve. Avoid use during an acute asthma attack (see 4.3 Contraindications). It should only be used with caution or in reduced dose in elderly or debilitated patients, hypotension, hypothyroidism, inflammatory or obstructive bowel disorders, urethral stricture, adrenocortical insufficiency, prostatic hypertrophy, shock, convulsive disorders, myasthenia gravis. It should be avoided or the dose reduced in patients with renal or hepatic impairment (see 4.2 posology).

Opioid analgesics should be avoided in patients with biliary tract disorders or used in conjunction with an antispasmodic.

Administration of pethidine and possibly other opioid analgesics to patients taking a monoamine oxidase inhibitor (MAOI) has been associated with very severe and sometimes fatal reactions. If the use of codeine is considered essential then great care should be taken in patients taking MAOIs or within 14 days of stopping MAOIs (see section 4.5).

Alcohol should be avoided whilst under treatment with codeine.

It should be used with caution in those with a history of drug abuse. Discontinuation should be carried out gradually in patients who may have developed physical dependence, to avoid precipitating withdrawal symptoms.

CYP2D6 metabolism

Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.

Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:

Population	Prevalence %
African/Ethiopian	29%
African American	3.4% to 6.5%
Asian	1.2% to 2%
Caucasian	3.6% to 6.5%
Greek	6.0%
Hungarian	1.9%
Northern European	1%-2%

Post-operative use in children

There have been reports in the published literature that codeine given post-operatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function

Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

Co-codamol 8mg/500mg Tablets contain parahydroxybenzoates (E218, E214 and E216), which may cause allergic reactions (possibly delayed).

The label will state (to be displayed prominently on outer pack - not boxed in bold):

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 pain killers have not worked. For the symptomatic relief of pain including headache, migraine, toothache, period pains, rheumatic pains, including muscle pains and backache.

•    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 when other pain killers have not worked.

•    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

Codeine can be used in children over 12 years of age for the short-term relief of moderate pain that is not relieved by other painkillers such as paracetamol or ibuprofen alone. For the symptomatic relief of pain including headache, migraine, toothache, period pains, rheumatic pains, including muscle pains and backache.

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.

• Refer to section 4 (possible side effects) for the signs and symptoms of an allergic reaction.

Section 3: Dosage

This medicine should not be taken for more than 3 days. If the pain does not improve after 3 days, talk to your doctor for advice.

This medicine contains codeine which 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

• Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

How do I know if I am addicted?

If you take this 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.

4.5    Interaction with other medicinal products and other forms of interactions

i. Paracetamol:

Alcohol: Paracetamol should be given with care to patients with alcohol dependence (see Section 4.4).

Analgesics: Diflunisal increases blood concentrations of paracetamol.

Anion-exchange resins: Absorption reduced by colestyramine; administration should be separated by at least 1 hour.

Antibacterials: Isoniazid may increase the risk of hepatotoxicity with therapeutic doses of paracetamol.

Anticoagulants: 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.

Antiepileptics: Carbamazepine, phenobarbital, phenytoin and primidone can reduce the effects of paracetamol and increase the risk of hepatotoxicity.

Cytotoxic drugs: Paracetamol possibly inhibits metabolism of intravenous busulfan (manufacturer of intravenous busulfan advises caution within 72 hours of paracetamol).

Motility stimulants: The speed of absorption of paracetamol may be increased by metoclopramide or domperidone.

Oral Contraceptives: Paracetamol is cleared from the body more quickly in women taking oral contraceptives and the analgesic effects may be reduced. Uricosurics: Probenecid can reduce the loss of paracetamol from the body.

ii. Codeine:

Alcohol: the hypotensive, sedative and respiratory depressive effects of alcohol may be enhanced.

Anaesthetics: concomitant administration of codeine and anaesthetics may cause increased CNS depression and/or respiratory depression and/or hypotension.

Anti-arrhythmics: codeine delays the absorption of mexiletine. The analgesic activity of codeine is likely to be significantly impaired by quinidine which impairs codeine metabolism.

Antidepressants: The depressant effects of opioid analgesics may be enhanced by tricyclic antidepressants. MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has not been documented with codeine, it is possible that a similar interaction may occur and therefore the use of codeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.

Antihistamines: concomitant administration of codeine and antihistamines with sedative properties may cause increased CNS depression and/or respiratory depression and/or hypotension.

Antipsychotics: enhanced sedative and hypotensive effect.

Anxiolytics and hypnotics: enhanced sedative effect.

Domperidone and metoclopramide: codeine antagonises the effect of cisapride, metoclopramide and domperidone on gastrointestinal activity.

Antidiarrhoeal and antiperistaltic agents: Concurrent use of codeine with agents such as loperamide and kaolin may increase the risk of severe constipation.

Sodium oxybate: concomitant administration of codeine and sodium oxybate may cause increased CNS depression and/or respiratory depression and/or hypotension.

Ulcer-healing drugs: cimetidine inhibits the metabolism of opioid analgesics resulting in increased plasma concentrations.

Interference with laboratory tests: Opioids may interfere with gastric emptying studies as they delay gastric emptying and with hepatobiliary imaging using technetium Tc 99m disofenin as opioid treatment may cause constriction of the sphincter of Oddi and increase biliary tract pressure.

4.6 Pregnancy and lactation

i.    Paracetamol: Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol use 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.

ii.    Codeine: As with all medications caution should be exercised during pregnancy, especially in the first trimester. A possible association with respiratory and cardiac malformations has been reported following first trimester exposure to codeine.

Regular use of codeine during pregnancy may cause physical dependence in the foetus leading to withdrawal symptoms in the neonate. Administration of codeine during labour may depress respiration in the neonate. Opioid analgesics may cause gastric stasis during labour, increasing the risk of inhalation pneumonia in the mother. Codeine should not be used during breastfeeding (see section 4.3). At normal therapeutic doses, codeine and its active metabolite 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 metabolite, morphine, may be present in breast milk and on very rare occasions may result in symptoms of opioid toxicity in the infant, which may be fatal.

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

i.    Paracetamol: None.

ii.    Codeine: Codeine produces sedation and may also cause changes in vision, including blurred or double vision. If affected, patients should not drive or operate machinery. The effects of alcohol are enhanced by opioid analgesics.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely

4.8 Undesirable effects

i.    Paracetamol:

Adverse effects of paracetamol are rare.

Haematological: There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol. Leucopenia, neutropenia and pancytopenia have been reported in association with paracetamol.

Immune system: Hypersensitivity including skin rash, urticaria or angioedema may occur. A small percentage of aspirin-sensitive asthmatics are also sensitive to paracetamol. In such cases, the deterioration in respiratory function induced by paracetamol is milder and shorter than with aspirin (see also 4.4 Special Warnings and Precautions for Use)

Skin and subcutaneous tissue disorders: Very rare cases of serious skin reactions have been reported.

Renal and urinary disorders: Nephropathy has been associated with chronic high dose use.

ii.    Codeine:

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.

Tolerance and some of the most common side effects - drowsiness, nausea, and vomiting, and confusion - generally develops with long term use.

Immune system disorders: maculopapular rash has been seen as part of a hypersensitivity syndrome associated with oral codeine phosphate; fever, splenomegaly and lymphadenopathy also occurred.

Endocrine disorders: hyperglycaemia.

Metabolism and nutrition disorders: anorexia.

Psychiatric disorders: mental depression, hallucinations and nightmares, restlessness, confusion, mood changes, euphoria, dysphoria.

Nervous system disorders: dizziness, drowsiness, headache (prolonged use of a painkiller for headaches can make them worse), convulsions (especially in infants and children). Raised intracranial pressure may occur in some patients.

Eye disorders: blurred or double vision or other changes in vision. Miosis.

Ear and labyrinth disorders: vertigo

Cardiac disorders: tachycardia, bradycardia and palpitations.

Vascular disorders: Postural hypotension, facial flushing. Larger doses produce hypotension.

Respiratory, thoracic and mediastinal disorders: larger doses produce respiratory depression and dyspnoea.

Gastrointestinal disorders: dry mouth, constipation, nausea and vomiting, stomach cramps, pancreatitis.

Hepatobiliary disorders: Biliary spasm (may be associated with altered liver enzyme values).

Skin and subcutaneous tissue disorders: allergic reactions such as skin rashes, urticaria and pruritus, sweating and facial oedema.

Musculoskeletal and connective tissue disorders: Uncontrolled muscle movements. Muscle rigidity may occur after high doses.

Renal and urinary disorders: difficulty with micturition, urinary retention, dysuria, ureteric spasm. An antidiuuretic effect may also occur with codeine.

Reproductive system and breast disorders: sexual dysfunction, erectile dysfunction, decreased libido or potency.

General disorders and administration site conditions: malaise, tiredness, hypothermia. Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9    Overdose

i. 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 overdose in the first 24 hours are sweating, 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, hypotension, cerebral oedema, coma and death. Prothrombin time may increase with deteriorating liver function. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Treatment Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section. Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable). Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

ii. Codeine:

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 triad of coma, pinpoint pupils and respiratory depression is considered indicative of opioid overdosage with dilation of the pupils occurring as hypoxia develops. Nausea and vomiting are common Other opioid overdose symptoms include hypothermia, confusion, convulsions, severe dizziness, severe drowsiness, hypotension and tachycardia (possible but unlikely), nervousness or restlessness, excitement, hallucinations, bradycardia, circulatory failure, slow or troubled breathing, severe weakness, convulsions, especially in infants and children. Rhabdomyolysis, progressing to renal failure, has been reported in overdosage with opioids. The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.

Treatment

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 350mg or a child more than 5mg/kg. In acute overdosage with respiratory depression or coma, the specific opioid antagonist naloxone is indicated using one of the recommended dose regimens-repeated doses may be required in a seriously poisoned patient as naloxone is a competitive antagonist with a short half life. Patients should be observed closely for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.

5.1    Pharmacodynamic properties

ii.    Paracetamol: Paracetamol has analgesic and antipyretic actions.

iii.    Codeine: Codeine has similar uses to morphine but is much less potent as an analgesic.

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through p opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.

5.2    Pharmacokinetic properties

i. Paracetamol: Paracetamol is readily absorbed from the gastro-intestinal tract with peak plasma concentrations occurring 30 minutes to two hours after ingestion. 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 one hour to four hours. At usual therapeutic concentrations plasma protein binding is negligible.

ii. Codeine: Codeine is well absorbed from the gastrointestinal tract following oral administration. It is metabolised in the liver to morphine and norcodeine which are both excreted in the urine partly as conjugates with glucuronic acid. Most of the excretion products appear in the urine within 6 hours and up to 86% of the dose is excreted in 24 hours. About 70% of the dose is excreted as free codeine, 10% as free and conjugated morphine and a further 10% as free or conjugated norcodeine. Only traces are found in the faeces. The plasma half life is between approximately three and four hours.

5.3    Preclinical safety data

Paracetamol & codeine: There is no pre-clinical data of relevance to the prescriber which is additional to that already included in the other sections of the SmPC.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Potato starch

Maize starch Talc Povidone Stearic acid Magnesium stearate Nipasept *

* Nipasept consists of methyl-p-hydroxybenzoate (E218), ethyl-p-hydroxy benzoate (E214) and propyl-p-hydroxybenzoate (E216).

6.2    Incompatibilities

None.

6.3    Shelf life 3 Years.

6.4    Special precautions for storage

Do not store above 25°C.

Blisters: Store in the original package.

Bottles: Keep the bottle tightly closed.

6.5    Nature and contents of container

Blister packs: 8, 10, 12, 16, 20, 24, 28, 30, 32 as Pharmacy packs. Blister strips consist of a 35gsm paper/9p soft tempered aluminium foil lid and 250p PVC film base in cartons.

Polypropylene/polyethylene containers: 25 as Pharmacy packs