Co-Codamol 8/500mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-Codamol 8/500mg Capsules.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Paracetamol 500 mg, Codeine Phosphate 8 mg.
For the full list of excipients, see section 6.1
3 PHARMACEUTICAL FORM
Hard gelatine capsules
Pink translucent capsule, marked CO COD 8
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
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 relief of mild to moderate pain caused by headaches, sore throats, period pains, migraine, toothache, neuralgia, muscular and rheumatic pains.
4.2 Posology and method of administration
Adults:
1 or 2 capsules to be taken every 4 hours as required, swallowed whole with a glass of water, to a maximum of 4 doses in 24 hours.
Paediatric population:
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).
Children aged 12 years to 15 years:
One capsule to be taken every 4 - 6 hours as required, swallowed whole with a glass of water, to a maximum of 4 doses in 24 hours.
Children aged 16 to 18 years: Dosage as for adults.
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.
4.3 Contraindications
• Known hypersensitivity to paracetamol, codeine phosphate, other opioids or other constituents in the capsules
• Diarrhoea caused by poisoning until the toxic material has been eliminated, or diarrhoea associated with pseudomembranous colitis
• Respiratory depression
• Obstructive airways disease
• 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 should be used with caution in patients with:
• hepatic function impairment (avoid if severe) and those with non-cirrhotic alcoholic liver disease. The hazards of overdose are greater in those with alcoholic liver disease
• prolonged use of Co-codamol may cause hepatic necrosis
• renal function impairment
• hypothyroidism (risk of depression and prolonged CNS depression is increased)
• inflammatory bowel disease - risk of toxic megacolon
• opioids should not be administered during an asthma attack
• convulsions - may be induced or exacerbated
• drug abuse, dependence (including alcoholism), enhanced instability, suicidal ideation or attempts - predisposition to d rug abuse
• head injuries or conditions where intracranial pressure is raised
• gall bladder disease or gall stones - opioids may cause biliary contraction
• gastro-intestinal surgery - use with caution after recent GI surgery as opioids may alter GI motility
• prostatic hypertrophy or recent urinary tract surgery
• adrenocortical insufficiency, e.g. Addison’s disease
• hypotension and shock
• myasthenia gravis
• phaeochromocytoma - opioids may stimulate catecholamine release by inducing the release of endogenous histamine.
Do not take more than 2 capsules at any one time, or more than 8 capsules in 24 hours. Warning: Do not exceed the stated dose.
Label warnings
Do not take with any other Paracetamol-containing products.
Immediate medical advice should be sought in the event of an overdose, even if you feel well, because of the risk of delayed, serious liver damage.
or if leaflet present:
Immediate medical advice should be sought in the event of an overdose, even if you feel well.
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 lead to addiction
Keep out of the sight and reach of children.
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 summarised 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 postoperatively 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.
4.5 Interaction with other medicinal products and other forms of interaction
Paracetamol can interact with the following:
• Drugs which alter gastric emptying time (e.g. cimetidine, ethyl alcohol, oral steroid contraceptives). These drugs reduce or delay peak paracetamol blood levels
• Metoclopramide or domperidone increases the speed of absorption of paracetamol
• Colestyramine reduces paracetamol absorption
• Drugs which interfere with the metabolism of paracetamol by competition hepatic enzyme inducers, alcohol, barbiturate, tricyclic antidepressant. A poor diet (low protein) may also have a similar effect on the risk of serious paracetamol toxicity to hepatic enzyme inducers. Patients who have taken barbiturates, tricyclic antidepressants and alcohol may show diminished ability to metabolise large doses of paracetamol, the plasma half-life of which may be prolonged.
• 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
• Alcohol can increase the heptotoxicity of paracetamol overdosage and may have contributed to the acute pancreatitis reported in one patient who had taken an overdosage of paracetamol
Codeine phosphate can interact with the following:
• CNS depressants - enhanced sedative and/or hypotensive effect with alcohol, anaesthetics, hypnotics, anxiolytics, antipsychotics, hydroxyzine, tricyclic antidepressants
• Antibacterials e.g. ciprofloxacin - avoid premedication with opioids as this can cause reduced plasma ciprofloxacin concentration
• MAOIs - use only with extreme caution
• Cyclizine
• Mexiletine - delayed absorption
• Metoclopramide and domperidone - antagonise GI effects
• Cisapride - possible antagonism of GI effects
• Dopaminergics (e.g. selegiline) - possible risk of hyperpyrexia and CNS toxicity
• Ulcer healing drugs - cimetidine inhibits the metabolism of opioid analgesics
• Anticholinergics ( e.g. atropine) - risk of sever constipation which may lead to paralytic ileus and/or urinary retention
• Antidiarrhoeal drugs (e.g. loperamide, kaolin) - increased risk of severe constipation
• Antihypertensive drugs (e.g. guanethidine, diuretics) - enhanced hypotensive effect
• Opioid antagonists (e.g. buprenorphine, naltrexone, naloxone)
• Neuromuscular blocking agents - additive respiratory depressant effects.
4.6 Fertility, pregnancy and lactation
Epidemiological studies in human pregnancy have shown no ill effects due to Paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.
Risk benefit must be considered because opioid analgesics cross the placenta. Studies in animals have shown opioids to cause delayed ossification in mice and increased resorption in rats. Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate. During labour opioids enter the foetal circulation and may cause respiratory depression in the neonate. Administration should be avoided during the late stages of labour and during the delivery of a premature infant.
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
Opioid analgesics can impair mental function and cause blurred vision and dizziness. Patients should make sure they are not affected before driving or operating machinery.
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
At the recommended dosage paracetamol may cause the following side effects:
• Allergic reactions - rare but may include skin rash, drug fever, mucosal lesions
• Effects on CNS - drowsiness, impaired mental functions
• Effects on GI system - chronic hepatic necrosis has been reported in patients who took daily therapeutic doses of paracetamol for about a year, and liver damage has been reported after daily ingestion of excessive amounts for shorter periods. Acute pancreatitis has been reported. A review of a group of patients with chronic active hepatitis failed to reveal differences in the abnormalities of liver function in those who were long-term uses of paracetamol, nor was the control of their disease improved after paracetamol withdrawal.
• Effect on CV S - toxic myocarditis
• Effects on blood - there have been reports of blood dyscrasias including methaemoglobinaemia, neutropenia, pancytopenia, leukopenia, thrombocytopenic purpura, haemolytic anaemia and agranulocytosis, but these were not necessarily causally related to paracetamol
• Effects on GU system - nephrotoxicity following therapeutic doses of paracetamol is uncommon but papillary necrosis has been reported after prolonged administration.
• Other effects - most reports of adverse reactions to paracetamol related to overdosage with the drug
Adverse effects of opioid treatment which have been reported include:
• Allergic reactions (may be caused by histamine release) - including rash, urticaria, difficulty breathing, increased sweating, redness or flushed face
• Effects on CNS - confusion , drowsiness, vertigo, dizziness, changes in mood, hallucinations, CNS excitation (restlessness/excitement), convulsions, mental depression, headache, trouble sleeping, or nightmares, raised intracranial pressure, tolerance or dependence
• Effects on GI system - constipation, GI irritation, biliary spasm, nausea, vomiting, loss of appetite, dry mouth, paralytic ileus or toxic megacolon
• Effects on CV S - bradycardia, palpitations, hypotension
• Effects on sensory system - blurred or double vision
• Effects on GU system - urethral spasm, antidiuretic effect
• Other effects - trembling, unusual tiredness or weakness, malaise, miosis, hypothermia
• 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.
Regular prolonged use of codeine is known to lead to addiction, and symptoms of restlessness and irritability may result when treatment is stopped.
Prolonged use of a painkiller for headaches can make them worse.
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. Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
Paracetamol
Liver damage is possible in adults who have taken 10g or more of paracetamol. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).
Risk factors
If the patient:
- is on long term treatment with carbamazepine, phenobarbital, phenytoin, rimidone, rifampicin, St John’s Wort or other drugs that induce liver enzymes. Or
- regularly consumes ethanol in excess of recommended amounts.
Or
- is likely to be glutathione depleted e.g. eating disorders, cystic fibrosis, HIV infection, starvation, cachexia.
Symptoms
Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and
metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.
Management
Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.
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.
Codeine
The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs.
Symptoms
Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been co-ingested, including alcohol, or the overdose is very large. The pupils may be pin-point in seize, nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.
Management
Management should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or a child more than 5 mg/kg.
Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life, so large and repeated doses may be required in a seriously poisoned patient. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
ATC code: N02B E51
Paracetamol has analgesic and antipyretic effects that do not differ significantly from Aspirin. It has only a weak anti-inflammatory effect.
The analgesic effect appears to be due to the different sensitivities to the drug of central and peripheral prostaglandin synthetase systems.
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. Codeine and its salts are absorbed from the gastrointestinal tract.
5.2 Pharmacokinetic properties
Codeine and its salts are readily absorbed from the GI tract and ingestion of codeine phosphate produces peak plasma concentrations in about one hour. It is metabolised by the liver; and codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The plasma half life is reported to be 3 - 4 hours after administration by mouth.
Paracetamol is readily absorbed from the GI tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. It is metabolised in the liver and excreted in the urine, mainly as the glucuronide and sulphate conjugates. The elimination half life varies from about 1-4 hours. Plasma protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.
A minor hydroxylated metabolite which is usually produced in very small amounts by mixed-function oxidases in the liver and which is usually detoxified by conjugation with liver gluthione may accumulate following paracetamol overdosage and cause liver damage.
5.3 Preclinical safety data
None stated
List of excipients
6.1
Light kaolin Magnesium stearate
Capsule Shell
Gelatin
Erythrosine
Printing Ink Shellac
Black iron oxide E172
6.2 Incompatibilities
None known
6.3 Shelf life
Securitainer - 36 months Blister pack - 24 months
6.4 Special precautions for storage
Store below 25°C
6.5 Nature and contents of container
Securitainer or tracerpack containing 250, 100 or 30 capsules.
Child resistant blister strips (PVC/PVdC/Glassine/aluminium foil) in packs of 32, 30 or 10 capsules
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
Not applicable.
MARKETING AUTHORISATION HOLDER
7
Custom Healthcare Limited
Conway Street
Hove
East Sussex BN3 3LW UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 33446/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
18 July 2005
10 DATE OF REVISION OF THE TEXT
25/11/2016