Co-Codamol 30mg/500mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-codamol 30mg/500mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Codeine Phosphate 30mg Paracetamol 500mg
For excipients, see 6.1.
3 PHARMACEUTICAL FORM
Tablet
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).
4.2 Posology and method of administration
For oral use.
Adults
One or two tablets every four to six hours with a maximum dose of eight tablets in any 24 hour period.
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.
Elderly
The dosage should be reduced.
Hepatic impairment
The dosage should be reduced.
Paediatric population:
Children aged 12 years to 18 years:
The recommended dose for children 12 years and older should be one or two tablets every four to six hours with a maximum dose of eight tablets in any 24 hour period.
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).
Dosage should be adjusted accordingly to the severity of the pain and the response of the patient. However, it should be kept in mind that tolerance to codeine can develop with continued use and that the incidence of untoward effects is dose related. Doses of codeine higher than 60 mg fail to give commensurate relief of pain but merely prolong analgesia and are associated with an appreciable increased incidence of undesirable side effects.
4.3 Contraindications
Known hypersensitivity to paracetamol or codeine, or other opioid analgesics, or to
any of the excipients.
Acute respiratory depression.
Obstructive airways disease.
Acute alcoholism.
Severe hepatic dysfunction
Head injury or raised intracranial pressure (in addition to the risk of respiratory depression and increased intracranial pressure, may affect papillary and other responses vital for neurological assessment).
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.
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
4.4 Special warnings and precautions for use
Co-codamol 30mg/500mg Tablets may cause drowsiness. Co-codamol 30mg/500mg Tablets should be given in reduced doses or with caution to elderly patients or debilitated patients or patients with hypothyroidism, asthma, decreased respiratory reserve, adrenocortical insufficiency, prostatic hypertrophy, hypotension, shock, inflammatory or obstructive bowel disorders, urethral stricture, convulsive disorders, myasthenia gravis. It should be avoided or the dose reduced in patients with hepatic or renal impairment. Use 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.
Avoid use during an acute asthma attack. 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.
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).
Co-codamol 30mg/500mg Tablets enhance the effects of alcohol. Their concurrent use should be avoided.
The hazard of overdose is greater in those with non-cirrhotic alcoholic liver disease.
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. They should be advised not to take other paracetamol-containing products concurrently and to keep the product out of the reach of children.
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 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 regularly for a long time can to lead to addiction.
4.5 Interaction with other medicinal products and other forms of interactions
In high doses or with regular treatment, paracetamol may potentiate the effects of warfarin. The absorption of paracetamol is reduced by cholestyramine and accelerated by domperidone and metoclopramide.
Cytotoxic drugs: Paracetamol possibly inhibits metabolism of intravenous busulfan (manufacturer of intravenous busulfan advises caution within 72 hours of paracetamol).
Anaesthetics: concomitant administration of codeine and anaesthetics may cause increased CNS depression and/or respiratory depression and/or hypotension.
Antihistamines: concomitant administration of codeine and antihistamines with sedative properties may cause increased CNS depression and/or respiratory depression and/or hypotension.
Codeine antagonises the effect of metoclopramide and cisapride on gastrointestinal activity. It delays the absorption of flecainide and mexiletine and potentiates the effect of hypnotics and anxiolytics. 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.
Alcohol: the hypotensive, sedative and respiratory depressive effects of alcohol may be enhanced.
Concurrent use of codeine with antidiarrhoeal and antiperistaltic 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.
Concomitant use of antimuscarinics may lead to paralytic ileus or urinary retention.
Ulcer-healing drugs: Cimetidine may inhibit the metabolism of dihydrocodeine 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 Fertility, pregnancy and lactation
Pregnancy
As with all medication, 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 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.
There is epidemiological evidence of safety in human pregnancy when paracetamol is used in normal stated dosages.
Breastfeeding
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.
4.7 Effects on ability to drive and to use machines
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 of 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
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: convulsions (especially in infants and children), dizziness, drowsiness, headache. Raised intracranial pressure may occur in some patients.
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, stomach cramps, pancreatitis.
Hepatobiliary disorders: Biliary spasm (may be associated with altered liver enzyme values).
Skin and subcutaneous tissue disorders: allergic reactions such as urticaria, pruritis, skin rashes, 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 micturation, urinary retention, ureteric spasm, dysuria. 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 30mg/500mg Tablets is relatively free of side-effects but skin rashes, urticaria or angioedema and other allergic reactions may occur. Very rare cases of serious skin reactions have been reported. Renal damage may occur rarely with long term use. Haematological side-effects including thrombocytopenia, neutropenia, pancytopenia and leucopenia have occurred in isolated cases.
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
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 may develop even in the absence of severe liver damage. Cardiac arrythmias and pancreatitis have been reported. Liver damage is possible in adults who have taken 10 g or more of paracetamol. It is considered that excess quantities of a toxic metabolite ( usually adequately detoxified by glutathione when normal doses of paracetamol are ingested),become irreversibly bound to liver tissue.
Treatment
Immediate treatment is essential in the management of paracetamol overdose.
Despite of lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention and any patient who has ingested around 7.5 g or more of paracetamol in the proceeding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.
An overdose with codeine is characterised by respiratory depression, extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. In severe overdose with codeine, apnoea, circulatory collapse, cardiac arrest and death may occur.
Primary attention should be given to the re-establishment of adequate
respiratory function through the provision of a patent airway and the institution of controlled ventilation. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. Opioid antagonists, such as naloxone may be administered.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Analgesics, ATC Code: N02B E51 Paracetamol has analgesic and antipyretic properties.
Codeine phosphate is an opioid 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
Both paracetamol and codeine phosphate are readily absorbed from the gastrointestinal tract giving peak plasma levels within one hour of administration.
Paracetamol 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 to four hours. At usual therapeutic concentrations plasma-protein binding is negligible.
Codeine 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 six hours and up to 80% 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 approximately three to four hours.
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber which are additional to those included in other sections.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Pregelatinised Maize Starch Magnesium Stearate
Nature and contents of container
6.5
6.4
Povidone
Incompatibilities
None
36 months
Do not store above 25°C.
Store in the original container.
28, 30, 56, 60, 84, 90 and 100 tablets in polypropylene/plyethylene containers or blister strips consisting of a 35gsm paper/9p soft tempered aluminium foil lid and 250p PVC film base in cartons.
Not applicable.
7 MARKETING AUTHORISATION HOLDER
Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF U.K.
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0047
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
2 09/07/1998 / 25/02/2009
10 DATE OF REVISION OF THE TEXT
15/04/2016