Co-Codamol 8 Mg/500 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-Codamol 8 mg/500 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains:
Codeine Phosphate BP 8 mg Paracetamol BP 500 mg
For a full list of excipients see section 6.1
3 PHARMACEUTICAL FORM
White FBE tablets for oral administration
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, including muscular and rheumatic pains, headache, migraine, neuralgia, toothache, sore throat, period pains, aches and pains, discomfort associated with influenza, feverishness and feverish colds.
4.2 Posology and method of administration
The maximum daily dose of codeine should not exceed 240 mg.
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.
Adults
1 - 2 tablets taken with a drink of water, which may be repeated every four to six hours with a maximum of 8 tablets in 24 hours.
Elderly
No current evidence for the alteration of the adult dose except where there is impaired hepatic function when dosage reduction may be necessary.
Children
Children aged less than 12 years:
Codeine is contraindicated in children below the age of 12 years for the symptomatic treatment of cough and/or cold (see section “Contraindications“).
Children aged 12 years to 18 years:
Codeine is not recommended for use in children aged 12 years to 18 years with compromised respiratory function for the symptomatic treatment of cough and/or cold (see section “Special warnings and precautions for use” ).
Route of administration
For oral administration.
4.3 Contraindications
• 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
• In patients who are hypersensitive to paracetamol, codeine, other opioid analgesics or to any of the excipient of Co-Codamol Tablets.
• In respiratory depression obstructive airways disease, acute alcoholism, convulsive disorders, head injuries or conditions in which intracranial pressure is raised.
• In diarrhoea caused by poisoning until the toxic material has been eliminated, or diarrhoea associated with pseudomembraneous colitis.
• In children below the age of 12 years for the symptomatic treatment of cough and/or cold due to an increased risk of developing serious and life-threatening adverse reactions.
4.4 Special warnings and precautions for use
Co-Codamol should be given with caution in patients with allergic disorders and should not be given during an attack of asthma.
Opioid analgesics should be given with caution or in reduced doses to patients with hypothyroidism (risk of depression and prolonged CNS depression is increased), adrenocortical insufficiency, impaired kidney or liver function, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders- risk of toxic megacolon or myasthenia gravis.
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, 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% to 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 “Contraindications”). 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.
The leaflet will state in the “Pregnancy and breast-feeding” subsection of section 2 “Before taking your medicine”:
Do not take codeine while you are breastfeeding. Codeine and morphine passes into breast milk.
Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment (avoid if severe) and those with noncirrhotic alcoholic liver disease. The hazards of overdose are greater in those with non-cirrhotic alcoholic liver disease. Prolonged use of co-codamol may cause hepatic necrosis.
In cases of renal insufficiency the rate of excretion of codeine and paracetamol metabolites may be reduced, and dosage schedules may need to be revised accordingly.
Co-codamol should be used with caution in patients with;
• 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 - predisposed to drug 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, eg Addison's Disease
• Phaeochromocytoma - opioids may stimulate catecholamine release by inducing the release of endogenous histamine Where analgesics are used longterm (>3 months) with administration every two days or more frequently, headache may develop or worsen. Headache induced by overuse of analgesics (MOH medication-overuse headache) should not be treated by dose increase. In such cases, the use of analgesics should be discontinued in consultation with the doctor.
Dosage should be reduced in debilitated patients.
Opioid analgesics should be given with great care to infants, especially neonates.
Alcohol should be avoided whilst under treatment with Co-Codamol.
Patients should be advised not to take other paracetamol or codeine containing products concurrently.
The recommended dose should not be exceeded. Immediate medical advice should be sought in the event of an overdose even if the patient feels well because of the risk of delayed, serious liver damage.
Keep out of sight and reach of children.
Patients should be advised to seek medical advice if symptoms persist. 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
4.5 Interaction with other medicinal products and other forms of interaction
Paracetamol can interact with the following:
Paracetamol should be given with care to patients taking other drugs which affect the liver.
Drugs which alter gastric emptying time (eg cimetidine, ethyl alcohol, oral steroid contraceptives). These drugs reduce or delay peak paracetamol blood levels.
Cholestyramine reduces absorption of paracetamol.
Metoclopramide and domperidone accelerate absorption of paracetamol.
Drugs which interfere with the metabolism of paracetamol by competition with metabolic pathways or substrates eg anticonvulsants (phenytoin), hepatic enzyme inducers, alcohol, barbiturates, tricyclic antidepressants. 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 hepatotoxicity 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- The depressant effects of codeine are enhanced (enhanced sedative and/or hypotensive effect) by CNS depressants such as alcohol, anaesthetics, hypnotics, anxiolytics, antipsychotics, hydroxyzine, and sedatives, tricyclic antidepressants and phenothiazines.
Antibacterials, eg ciprofloxacin, - avoid premedication with opioids as reduced plasma ciprofloxacin concentration
MAOIs - CNS depression or excitation may occur if codeine is given to patients receiving MAOIs or within 2 weeks of stopping treatment with them. Use only with extreme caution.
Cyclizine
Mexiletine - The absorption of mexiletine may be delayed by codeine, thus reducing the anti-arrhythmic effect.
Codeine may antagonise the gastro-intestinal effects of metoclopramide, cisapride and domperidone.
Dopaminergics (eg selegiline) - possible risk of hyperpyrexia and CNS toxicity. This risk is greater with pethidine but with other opioids the risk is uncertain.
Ulcer healing drugs cimetidine inhibits the metabolism of opioid analgesics possibly resulting in increased plasma concentrations.
Anticholinergics (eg atropine) - risk of severe constipation which may lead to paralytic illness, and /or urinary retention
Antihypertensive drugs (eg guanethidine, diuretics) - enhanced hypotensive effect Opioid antagonists (eg buprenorphine, naltrexone, naloxone)
Neuromuscular blocking agents - additive respiratory depressant effects.
Quinidine can inhibit the analgesic effects of codeine.
Concurrent use of codeine with antidiarrhoeal and antiperistaltic agents, such as loperamide and kaolin, may increase the risk of severe constipation. Concurrent use of antimuscarinics may also lead to severe constipation.
4.6 Fertility, pregnancy and lactation
Pregnancy
There is inadequate evidence of safety of the drug in human pregnancy, but it has been in wide use for many years without apparent ill-consequence.
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.
It is advised that Co-Codamol be avoided in the latter stages of pregnancy due to the risk of respiratory depression in the neonate.
Paracetamol:
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.
Codeine:
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.
Breast-feeding
Paracetamol:
Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast-feeding.
Codeine:
Codeine is contraindicated in women during breastfeeding (see section “Contraindications”).
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.
4.7 Effects on ability to drive and use machines
Opioid analgesics can impair mental function and can cause blurred vision and dizziness . Patients should be advised not to drive or operate machinery if affected by dizziness or sedation. Patients should make sure they are not affected before driving or operating machinery.
4.8 Undesirable effects
At the recommended dosage, paracetamol may cause the following side effects
Side effects with paracetamol are rare, but skin rashes and other allergic reactions, drug fever, mucosal lesions, and acute pancreatitis after prolonged use have been reported.
Effects on CNS - drowsiness, impaired mental functions
Effects on GI system - Chronic hepatic necrosis has been reported in a patient 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 users of paracetamol, nor was the control of their disease improved after paracetamol withdrawal.
Effects on CVS - 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 causality 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 relate 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 ileius or toxic megacolon according to dosage and individual susceptibility.
Effects on CVS - bradycardia, palpitations, hypotension.
Effects on sensory system -blurred or double vision, miosis.
Effects on GU system - ureteral spasm (ureteric and biliary spasm), antidiuretic effect. difficulty with micturition
Other effects - trembling, unusual tiredness or weakness, malaise, hypothermia, vertigo, tachycardia, postural hypotension, dysphoria. Muscle rigidity has been reported following high doses.
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.
Larger doses produce respiratory depression and hypotension.
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.
4.9 Overdose
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. Cold clammy skin, confusion, convulsions, severe drowsiness, tiredness, slow heart beat and respiratory rate coma. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.
Management
This should include general symptomatic and supportive measures including a clear airway and monitoring of vital signs until stable. Treat respiratory depression or other life-threatening adverse effects first. Empty the stomach via gastric lavage or induction of emesis. 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.
The opioid antagonist naloxone (0.4-2mg subcutaneous) can be given and repeated at 2-3 minute intervals to a maximum of 10mg. Naloxone may also be given by intramuscular injection or intravenous infusion . 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. The patient should be monitored as the duration of opioid analgesic may exceed that of the antagonist. Observe for at least four hours after ingestion, or eight hours if a sustained release preparation has been taken.
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). 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.
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 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, coma 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 and any patient who had ingested around 7.5g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. 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). 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. 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. General supportive measures must be available.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Paracetamol has analgesic and antipyretic actions but it has no useful antiinflammatory properties.
Codeine phosphate is a weak analgesic and is used in the treatment of cough and diarrhoea.
Codeine phosphate is a narcotic analgesic for relief of mild to moderate pain with only mild sedative effects.
Paracetamol's effects are thought to be related to inhibition of prostaglandin synthesis.
Codeine is much less potent than morphine and it is inadequate against severe pain even in the largest tolerable doses. It does not cause appreciable respiratory depression but does have antitussive and constipating effects. It differs from morphine in that for normal medical use serious dependence is not frequently associated with codeine and large doses produce excitement rather than depression. Codeine produces its analgesic effects by binding to p opioid receptors. Codeine also binds weakly to k opioid receptors which mediates spinal analgesia, sedation and miosis.
5.2 Pharmacokinetic properties
Paracetamol is readily absorbed from the gastro-intestinal 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. Less than 5% is excreted as unchanged paracetamol. The elimination half-life varies from about 1 to 4 hours.
Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.
Codeine phosphate is absorbed from the gastro-intestinal tract and produces peak concentrations within 1 hour. It is metabolised in the liver; and codeine and its metabolites are entirely excreted almost by the kidney, mainly as conjugates with glucuronic acid. The plasma half-life is reported to be between 3 to 4 hours after administration by mouth..
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 glutathione may accumulate following paracetamol overdosage and cause liver damage.
5.3 Preclinical safety data
None available
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Maize Starch BP Pregelatinised Maize Starch BP Povidone BP
Hydroxybenzoate Esters BP Sodium Starch Glycolate BP Magnesium Stearate BP
6.2 Incompatibilities
No other major incompatibilities are known.
6.3 Shelf life
3 years in PP containers. 2 years in Blisters.
6.4 Special precautions for storage
Store in a cool dry place
6.5 Nature and contents of container
i) Polypropylene tubular container with an open end equipped to accept a polyethelene snap-on closure with a tamper-evident tear strip or ‘Tampertainers’ in pack sizes of 100 and 500 tablets.
ii) PVdC coated PVC/Aluminium blisters (60g/m2 PVdC on 250pm PVC/20pm Al) in pack sizes of 32 and 100 tablets.
6.6 Special precautions for disposal
No special instructions
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited Brampton Road Hampden Park Eastbourne East Sussex BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/1426
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 06/03/2009
10 DATE OF REVISION OF THE TEXT
11/09/2015