Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: M & A Pharmachem Ltd, Allenby Laboratories Wigan, Road, Westhoughton, Bolton BL5, 2AL
Known hypersensitivity to paracetamol, codeine or other opioid analgesics or to any of the excipients.
Moderate to severe renal failure.
Moderate to severe liver disease.
Acute respiratory depression and obstructive airways disease.
Bronchial asthma attack or heart failure secondary to chronic lung disease.
Raised intracranial pressure or head injuries (in addition to the risk of respiratory depression and increased intracranial pressure, may affect papillary and other responses vital for neurological assessment).
Acute alcoholism.
Comatose patients.
Where there is a risk of paralytic ileus.
In acute diarrhoeal conditions such as acute ulcerative colitis or antibiotic associated colitis (e.g. pseudomembranous colitis) or diarrhoea caused by poisoning until the toxic material has been eliminated from the gastrointestinal tract.
Not to be used in infants.
Following biliary tract surgery; monoamine oxidase inhibitor therapy, concurrent or within 14 days.
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.
Caution is advised in the administration of both paracetamol and codeine to patients with impaired kidney or liver function. The hazard of overdose with paracetamol is greater in those with alcoholic liver disease.
Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, including the elderly, who may be sensitive to their central and gastro-intestinal effects.
Co-codamol 30mg/500mg Tablets should be given with caution or in reduced doses to elderly patients or debilitated patients or to patients with hypotension, hypothyroidism, decreased respiratory reserve , adrenocortical insufficiency, prostatic hypertrophy, shock, inflammatory or obstructive bowel disorders, urethral stricture, acute abdominal conditions, recent gastrointestinal surgery, gallstones, myasthenia gravis, a history of cardiac arrhythmias or convulsions and in patients with a history of drug abuse or emotional instability.
Avoid use during an acute asthma attack.
Care should be observed in those on concurrent CNS depressant drugs.
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).
Caution should be exercised when using paracetamol prior to (less than 72 hours) or concurrently with intravenous busulfan (see section 4.5 Interactions).
Patients should be advised that immediate medical advice should be sought in the event of an overdose, because of the risk of delayed, serious liver damage
Care should also be observed if prolonged therapy is contemplated. Prolonged use of codeine may lead to dependence and should be avoided.
Abrupt withdrawal of opioids from persons physically dependent on them precipitates a withdrawal syndrome, the severity of which depends on the individual, the drug used, the size and frequency of the dose, and the duration of drug use. Discontinuation should be carried out gradually in patients who may have developed physical dependence, to avoid precipitating withdrawal symptoms.
Codeine may induce faecal impaction, producing incontinence, spurious diarrhoea, abdominal pain, and rarely, colonic obstruction. Elderly patients may metabolise or eliminate opioid analgesics more slowly than younger adults.
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% |
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.
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.
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 codeine while you are breast feeding. Codeine and morphine pass into breast milk.
Talk to your 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.
The label will state (to be displayed prominently on outer pack – not boxed):
Do not exceed the stated dose.
Patients should be advised not to take other paracetamol or codeine containing products concurrently.
If symptoms persist, consult your doctor. Keep out of the sight and reach of children.
The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine.
The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding ; occasional doses have no significant effect.
The risk of paracetamol toxicity may be increased in patients receiving other potentially hepatotoxic drugs or drugs that induce liver microsomal enzymes. The plasma-paracetamol concentrations considered an indication for antidote treatment should be halved in patients receiving enzyme-inducing drugs such as carbamazepine, phenobarbital, phenytoin, primidone or rifampicin.
Excretion of paracetamol may be reduced and plasma concentrations increased when given with probenecid.
Hepatotoxicity at therapeutic doses of paracetamol has been reported in patients receiving isoniazid.
The depressant effects of codeine are enhanced by depressants of the central nervous system such as alcohol, hypnotics, sedatives, tricyclic antidepressants and phenothiazines.
Anaesthetics: concomitant administration of codeine and anaesthetics may cause increased CNS depression and/or respiratory depression and/or hypotension.
Alcohol: the hypotensive, sedative and respiratory depressive effects of alcohol may be enhanced.
The hypotensive actions of diuretics and antihypertensive agents may be potentiated when used concurrently with opioid analgesics.
Concurrent use of hydroxyzine with codeine may result in increased analgesia as well as increased CNS depressant and hypotensive effects.
Concurrent use of codeine with antidiarrhoeal and antiperistaltic agents such as loperamide and kaolin may increase the risk of severe constipation.
Concomitant use of antimuscarinics or medications with antimuscarinic action may result in an increased risk of severe constipation which may lead to paralytic ileus and/or urinary retention.
The respiratory depressant effects caused by neuromuscular blocking agents may be additive to the central respiratory depressant effects of opioid analgesics.
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.
Quinidine can inhibit the analgesic effect of codeine.
Codeine may delay the absorption of flecainide and mexiletine and thus reduce the antiarrhythmic effect of the latter.
Codeine may antagonise the gastrointestinal effects of metoclopramide, cisapride and domperidone.
Ulcer-healing drugs: Cimetidine inhibits the metabolism of opioid analgesics resulting in increased plasma concentrations.
Naloxone antagonises the analgesic, CNS and respiratory depressant effects of opioid analgesics. Naltrexone also blocks the therapeutic effect of opioids.
Antihistamines: concomitant administration of codeine and antihistamines with sedative properties may cause increased CNS depression and/or respiratory depression and/or hypotension.
Paracetamol may increase the elimination half-life of chloramphenicol. Oral contraceptives may increase its rate of clearance.
Codeine potentiates the effect of hypnotics and anxiolytics.
Cytotoxic drugs: Paracetamol possibly inhibits metabolism of intravenous busulfan (manufacturer of intravenous busulfan advises caution within 72 hours of paracetamol).
Antipsychotics: enhanced sedative and hypotensive effects
Sodium oxybate: concomitant administration of codeine and sodium oxybate may cause increased CNS depression and/or respiratory depression and/or hypotension.
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 Tc99m disofenin as opioid treatment may cause constriction of the Sphincter of Oddi and increases biliary tract pressure.
Codeine crosses the placenta. There is no adequate evidence of safety in human pregnancy and a possible association with respiratory and cardiac malformations has been reported. Regular use during pregnancy may cause physical dependence in the foetus leading to withdrawal symptoms in the neonate. Use during pregnancy should be avoided if possible.
Use of opioid analgesia during labour may cause respiratory depression in the neonate, especially the premature neonate. These agents should not be given during the delivery of a premature baby.
Opioid analgesics may cause gastric stasis during labour, increasing the risk of inhalation pneumonia in the mother.
There is epidemiological evidence of safety in human pregnancy when paracetamol is used in normal stated dosages.
Paracetamol is excreted in breast milk but not in clinically significant quantities.
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.
Codeine may cause drowsiness, changes in vision, including blurred or double vision. If affected patients should be advised not to 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 information below lists reported adverse reactions, ranked using the following frequency classification:
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).
The frequency and severity of side effects are determined by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high dosage of 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: hallucinations, nightmares, confusion, restlessness, mood changes, mental depression, dysphoria, euphoria (The euphoric activity of codeine may lead to its abuse and dependence).
Nervous system disorders: convulsions (especially in infants and children), dizziness, headache, drowsiness, light-headedness.
Eye disorders: miosis, blurred or double vision, other visual disturbances
Ear and labyrinth disorders: vertigo
Cardiac disorders: orthostatic hypotension, palpitations, tachycardia and bradycardia
Vascular disorders: Postural hypotension, facial flushing. Large doses produce hypotension.
Respiratory, thoracic and mediastinal disorders: dyspnoea, larger doses produce respiratory depression.
Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth and stomach cramps. There have been very rare occurrences of pancreatitis.
Hepatobiliary disorders: biliary spasm (may be associated with altered liver enzyme values)
Skin and subcutaneous tissue disorders: allergic reactions such as urticaria, pruritus, skin rash, sweating and facial oedema.
Musculoskeletal and connective tissue disorders: uncontrolled muscle movements, muscular rigidity may occur after high doses.
Renal and urinary disorders: urinary retention, uretic spasm, difficulties in micturition (dysuria, increased frequency, decrease in amount) An antidiuretic effect may also occur with codeine.
Reproductive system and breast disorders: sexual dysfunction, erectile dysfunction, decreased potency, decreased libido.
General disorders and administration site conditions: malaise, tiredness, hypothermia.
The paracetamol component of Co-codamol 30/500 mg Tablets is relatively free of side-effects but immune system disorders, hypersensitivity including skin rash, urticaria, anaphylactic shock or angioedema may occur. Very rare cases of serious skin reactions such as Toxic Epidermal Necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis, fixed drug eruption have been reported.
Haematological side-effects including thrombocytopenia, agranulocytosis, neutropenia, pancytopenia and leucopenia have occurred in isolated cases, but these were not necessarily causally related to paracetamol.
Renal damage may occur rarely with long term use.
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.
Not applicable.
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