Co-Codamol 8mg/500mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-Codamol 8mg/500mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 500 mg of Paracetamol and 8 mg of Codeine phosphate 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 short term 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
Posology
Adults over 18 years:
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 (4.0gm of paracetamol
and 64mg of codeine in divided doses) per 24 hours.
Children aged 16 years to 18 years:
The recommended dose for children 16 years and older is 1 to 2 tablets every 6 hours when necessary up to a maximum of 8 tablets in 24 hours.
Children aged 12 years to 15 years:
The recommended dose for children 12 years to 15 years is 1 tablet every 6 hours when necessary up to a maximum of 4 tablets in 24 hours.
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).
Elderly: Dosage should be reduced in the elderly where there is impairment of hepatic function
Method of administration
For oral administration
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
• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1
• 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
• Diarrhoea caused by poisoning until the toxic material has been eliminated, or diarrhoea associated with pseudomembraneous colitis
• Respiratory depression
• Obstructive airways disease
4.4 Special warnings and precautions for use
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 noncirrhotic alcoholic liver disease.
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 - 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
• hypotension and shock
• myasthenia gravis
• phaeochromocytoma - opioids may stimulate catecholamine release by inducing the release of endogenous histamine
Where analgesics are used long-term (>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.
CYP2D6 metabolism
Codeine is metabolised by 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, shallow breathing, small pupils, nausea, vomiting, constipation, lack of appetite and somnolence. 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 summarizedbelow
|
Population |
Prevalance % |
|
Afri can/Ethi opi an |
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.
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.
Label:
1. Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor
2. Do not take anything else containing Paracetamol
3. Talk to a doctor at once if you take too much of this medicine, even if you feel well
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 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:
• Analgesics: Diflunisal increases blood concentrations of paracetamol.
• Antibacterials: Isoniazid may increase the risk of hepatotoxicity with therapeutic doses of paracetamol.
• Uricosurics: Probenecid can reduce the loss of paracetamol from the body.
• Drugs which alter gastric emptying time (eg 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 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 can interact with the following:
• Alcohol: the effects of alcohol may be enhanced.
• CNS depressants - enhanced sedative and/or hypotensive effect with alcohol, anaesthetics, hypnotics, anxiolytics,antipsychotics, hydroxyzine, tricyclic antidepressants
• Antibacterials, eg ciprofloxacin, - avoid premedication with opioids as 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 (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.
• Anticholinergics (eg atropine) - risk of severe constipation which may lead to paralytic illness, and /or urinary retention
• Antidiarrhoeal drugs (eg loperamide, kaolin) - increased risk of severe constipation
• Antihypertensive drugs (eg guanethidine, diuretics) - enhanced hypotensive effect
• Opioid antagonists (eg buprenorphine, naltrexone, naloxone)
• Neuromuscular blocking agents - additive respiratory depressant effects. 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.
4.6 Fertility, pregnancy and lactation Pregnancy:
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.
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 fetus, leading to withdrawal symptoms in the neonate. During labour opioids enter the fetal 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.
Lactation:
Codeine should not be used during breast-feeding (see section 4.3). At normal therapeutic doses codeine 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 can 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
The following undesirable effects have been observed and reported during treatment with Co-Codamol with the following frequencies.
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).
At the recommended dosage, paracetamol may cause the following side effects:
Most reports of adverse reactions to paracetamol relate to overdosage with the drug.
• Immune system disorders - rare but may include skin rash, drug fever, mucosal lesions.
• Nervous system disorders - drowsiness, impaired mental functions
• Gastrointestinal disorders - 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.
• Cardiac disorders - toxic myocarditis.
• Blood and lymphatic system disorders - There have been reports of blood dyscrasias including methaemoglobinaemia, neutropenia, pancytopenia, leukopenia, thrombocytopenic purpura, haemolytic anaemia andagranulocytosis, but these were not necessarily causality related to paracetamol.
• Renal and urinary disorders - Nephrotoxicity following therapeutic doses of paracetamol is uncommon, but papillary necrosis has been reported after prolonged administration.
Adverse effects of opioid treatment which have been reported include:
• Immune system disordersincluding rash, urticaria, difficulty breathing, increased sweating, redness or flushed face.
•Nervous system disorders - 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.
• Gastrointestinal disorders - constipation, GI irritation, biliary spasm, nausea, vomiting, loss of appetite, dry mouth, paralytic ileius or toxic megacolon.
• Cardiac disorders - bradycardia, palpitations, hypotension.
• Eye disorders -blurred or double vision.
• Renal and urinary disorders - ureteral spasm, antidiuretic effect.
• General disorders - trembling, unusual tiredness or weakness, malaise, miosis, hypothermia.
• Withdrawal effects - 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 tolerance. Symptoms of restlessness and irritability may result when treatment is then stopped.
• Prolonged use of a painkiller for headaches can make them worse.
• Skin and subcutaneous tissue disorders -very rare cases of serious skin reactions have been reported.
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
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 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.
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.
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.
PHARMACOLOGICAL PROPERTIES
5
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Paracetamol, combinations excl. Psycholeptics ATC Code: N02B E51
Paracetamol has analgesic and antipyretic properties but is has no useful antiinflammatory properties.
Codeine phosphate is a weak analgesic and is used in the treatment of cough and diarrhoea.
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 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 also binds weakly to k opioid receptors which mediates spinal analgesia, sedation and miosis.
5.2 Pharmacokinetic properties
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.
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.
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
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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Potato starch
Maize starch Talc
Povidone Stearic acid Magnesium stearate
Methyl parahydroxybenzoate (E218)
Propyl parahydroxybenzoate (E216)
Ethyl parahydroxybenzoate (E214)
6.2 Incompatibilities
None
6.3 Shelf life
Al/PVC Blisters: 4 years Containers: 3 years
6.4 Special precautions for storage
Do not store above 25oC
Blisters: Store in the original package Bottles: Keep the bottle tightly closed.
6.5 Nature and contents of container
Blister packs:
48, 50, 96 and 100 as POM packs.
Blister strips consist of a 35gsm paper/9p soft tempered aluminium foil lid and 250p PVC film base in cartons.
Or
Blister strips consist of a 250p hard aluminium foil laminated to 15 p rigid PVC film and 250p PVC film base in cartons.
Polypropylene/polyethylene containers: 50 and 100 as POM packs.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Bristol Laboratories Ltd,
Unit 3, Canalside,
Northbridge Road Berkhamsted HP4 1EG UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 17907/0478
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10/06/2015
10 DATE OF REVISION OF THE TEXT
27/09/2016