Co-Codamol 8mg/500mg Tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Co-Codamol 8mg/500mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:

Paracetamol 500mg; Codeine phosphate 8mg

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablets

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

4 CLINICAL PARTICULARS

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

Treatment goals and discontinuation

Before initiating treatment with co-codamol, treatment duration and treatment goals should be agreed together with the patient, in accordance with pain management guidelines.

Duration of treatment

The duration of treatment should be as short as possible, and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a healthcare professional.

For oral use.

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 (4.0g 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.

Paediatric population:

Children aged 16 to 18 years:

One to two tablets every six hours when necessary to a maximum of eight tablets per 24 hours.

Children aged 12 years to 15 years:

One tablet every six hours to be swallowed with water when necessary to a maximum of four tablets (2.0g of paracetamol and 32mg of codeine in divided doses) per 24 hours.

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.

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 or any of the excipients.

ii. Codeine:

• Acute respiratory depression
• Hypersensitivity to codeine or other opioid analgesics, or to any of the excipients.
• Liver disease
• 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).
• 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
• Concomitant use of monoamine oxidase inhibitors (MAOIs) or within two weeks of MAOI discontinuation as severe CNS excitation or depression (including hypertension or hypotension) may occur.

Codeine is also contraindicated in conditions where:

• inhibition of peristalsis is to be avoided,
• there is a risk of paralytic ileus,
• abdominal distension develops,
• acute diarrhoeal conditions such as acute ulcerative colitis or antibiotic associated colitis (e.g. pseudomembranous colitis).

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 non-cirrhotic 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.

Caution is advised if paracetamol is administered concomitantly with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

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 a 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).

Hepatobiliary disorders

Codeine may cause dysfunction and spasm of the sphincter of Oddi, thus increasing the risk of biliary tract symptoms and pancreatitis. Therefore, codeine has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.

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.

Risks from concomitant use of opioids and benzodiazepines

Concomitant use of opioids, including codeine, with benzodiazepines may result in sedation, respiratory depression, coma and death. Because of these risks, reserve concomitant prescribing of opioids and benzodiazepines for use in patients for whom alternative treatment options are inadequate. If a decision is made to prescribe codeine concomitantly with benzodiazepines, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of sedation and respiratory depression (see section 4.5).

Risks from concomitant use of opioids and alcohol

Concomitant use of opioids, including codeine, with alcohol may result in sedation, respiratory depression, coma and death. Concomitant use with alcohol is not recommended (see section 4.5)

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:

Tolerance and opioid use disorder (abuse and dependence) Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as co-codamol. Repeated use of co-codamol can lead to OUD. A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of co-codamol may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should contact their physician.

Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with codeine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

As with other opioids, in case of insufficient pain control in response to an increased dose of codeine, the possibility of opioid-induced hyperalgesia should be considered. A dose reduction or treatment review may be indicated.

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage

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
• Contains opioid
• 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

• 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.

• 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.

Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis, especially in patients with risks factors (see section 4.4)

Gabapentinoids: The concomitant use of co-codamol with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death (see section 4.4).

ii. Codeine:

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

Anaesthetics: sedative antihistamines, sodium oxybate: concomitant administration of codeine 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.

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.

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

Interference with laboratory tests: Opioid analgesics interfere with a number of laboratory tests including plasma amylase, lipase, bilirubin, alkaline phosphatase, lactate dehydrogenase, alanine aminotransferase and aspartate aminotransferase. Opioids may also 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.

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

• 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.

• 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 affects 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Use during pregnancy should be avoided, unless advised by a physician. This includes maternal use during labour because of the potential for respiratory depression in the neonate.

The safety of paracetamol-codeine during pregnancy has not been established relative to the possible adverse effects of fetal development.

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. A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency. Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breast-feeding.

ii. Codeine: There is inadequate evidence of the safety of codeine in human pregnancy. 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.

Breastfeeding

i. Paracetamol: Paracetamol is excreted in breast milk, but not in a clinically significant amount. Available published data do not contraindicate breast-feeding.

ii. 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:

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

4.8 Undesirable effects

List of adverse reactions

The adverse reactions reported below are classified according to frequency of occurrence as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data)

Effects of withdrawal -abrupt withdrawal precipitates a withdrawal syndrome. Symptoms may include tremor, insomnia, nausea, vomiting, sweating and increase in heart rate, respiratory rate and blood pressure. NOTE tolerance diminishes rapidly after withdrawal so a previously tolerated dose may prove fatal.

Other effects -Most reports of adverse reactions to paracetamol relate to overdosage with the drug.

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.

Drug dependence

Repeated use of co-codamol can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics, ATC Code: N02B E51

i. Paracetamol: Paracetamol has analgesic and antipyretic actions.

ii. 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 μ 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. Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

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/9µ soft tempered aluminium foil lid and 250µ PVC film base in cartons.

Polypropylene/polyethylene containers: 25 as Pharmacy packs

Not all pack sizes may be marketed

6.6 Special precautions for disposal

None.

7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Limited

Ash Road North

Wrexham

LL13 9UF

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 29831/0045

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

Date of latest renewal: 25 February 2009

10 DATE OF REVISION OF THE TEXT

02/06/2026