Co-Codamol 15mg/500mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Copaz 15mg/500mg Tablets Codipar 15mg/500mg Tablets Co-codamol 15mg/500mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each coated tablet contains 15mg codeine phosphate and 500mg paracetamol.
3 PHARMACEUTICAL FORM
Coated tablet
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the relief of moderate pain.
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
Adults: The usual dose is one or two tablets every four hours as required. The total daily dose should not exceed 4g paracetamol (8 tablets in a day).
Codeine should be used at the lowest effective dose for the shortest period of time. This dose may be taken, up to 4 times a day at intervals of not less than 6 hours. Maximum daily dose 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.
Elderly: A reduced dosage may be necessary.
Paediatric population:
Children aged 12 years to 18 years:
“The recommended codeine dose for children 12 years and older should be 30 to 60 mg every 4-6 hours when necessary up to a maximum dose of 240 mg daily. The dose is based on the body weight (0.5-1mg/kg).”
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 needs to be adjusted according to the severity of pain and the response of the patient.
Method of administration: Oral.
4.3 Contraindications
Hypersensitivity to either Paracetamol or codeine, or any of the excipients of Copaz tablets.
Children under 12 years of age.
Patients who have taken MAOIs within 14 days.
Severe renal or hepatic impairment.
Copaz is contraindicated in patients for whom opiate medications are contraindicated.
This will include some patients with acute asthma, obstructive airway disease, respiratory depression, acute alcoholism, head injuries, raised intracranial pressure and following biliary surgery.
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
The efficacy and safety of Copaz tablets in children below the age of 12 years has not been established, and use in such children is contraindicated.
Copaz tablets must be used with caution in patients with increased intracranial pressure, acute abdominal conditions, the elderly, the debilitated, impaired hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy and urethral stricture.
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 metabolizer 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 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 ultrarapid 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 increased hazard of paracetamol overdosage in patients with alcoholic liver disease.
Patients should be advised not to exceed the recommended dose and not to take other products containing paracetamol or opiate derivatives.
Patients should be advised to consult their doctor if symptoms persist.
Tolerance to Codeine can develop with continued use. The incidence of unwanted effects is dose related.
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/dihydrocodeine (DHC) regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop taking 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 you prescriber as taking codeine/DHC regularly for a long time can lead to addiction.
4.5 Interaction with other medicinal products and other forms of interaction
The hypotensive effects of antihypertensive agents, including diuretics, may be potentiated by codeine.
Quinine or quinidine may inhibit the analgesic actions of codeine.
The CNS depressant action of Zapaain may be enhanced by coadministration with any other drug which has a CNS depressant effect (eg. anxiolytics, hypnotics, antidepressants, antipsychotics and alcohol). Concomitant use of any drug with a CNS depressant action should be avoided. If combined therapy is necessary, the dose of one or both agents should be reduced.
Concomitant administration of Copaz and MAOIs or tricyclic antidepressants may increase the effect of either the antidepressant or codeine.
Concomitant administration of codeine and anticholinergics may cause paralytic ileus. Concomitant administration of codeine with an anti-diarrhoel agent increases the risk of severe constipation, and coadministration with an antimuscarine drug may cause urinary retention.
The absorption of paracetamol is speeded by metaclopramide or domperidone, and absorption is reduced by cholestyramine.
Codeine may delay the absorption of mexilitine, and cimetidine may inhibit codeine metabolism.
Opioids may interfere with the results of plasma amylase, lipase, bilirubin,
ALP, LDH, AST, and ALT tests
The effects of codeine on the gut may interfere with diagnostic tests of gastrointestinal functions.
The anticoagulant effect of warfarin and other coumarins may be increased by long term regular daily use of paracetamol, with increased risk of bleeding.
Occasional doses of paracetamol do not have a significant effect on these anticoagulants.
4.6. Fertility, pregnancy and lactation
Copaz is not recommended during pregnancy.
Use during pregnancy may lead to withdrawal syndromes in neonates, and use during labour may cause neonatal respiratory depression.
Codeine crosses the placenta and is found in breast milk.
The use of codeine is contraindicated 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 breastfed 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
Patients should be advised not to drive or operate machinery if Copaz causes dizziness or sedation. Codeine may cause visual disturbances.
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 commonest side effects of codeine are nausea, vomiting, light headaches, dizziness, sedation, shortness of breath and constipation. Some of these side effects appear more common in ambulatory: rather than non-ambulatory patients. Lying down may alleviate these effects they occur. In addition, miosis, visual disturbances, headache, bradycardia, respiratory depression, difficult micturition and urinary retention, and allergic reactions (including skin rash) can occur.
Codeine can cause respiratory depression particularly in overdosage and in patients with compromised respiratory function.
Euphoria, dysphoria, abdominal pain, and pruritus can occur as reactions to Copaz.
Liver damage in association with therapeutic use of paracetamol has been documented; most cases have occurred in conjunction with chronic alcohol abuse.
There have been some reports of blood dyscrasias - thrombocytopenia and agranulocytosis, with the use of paracetamol-containing products, but the causal relationship has not been established.
Regular prolonged use of codeine/DHC is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is then stopped.
Prolonged use of a pain killer 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 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.
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) but results should not delay initiation of treatment beyond 8 hours after ingestion, as 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.
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 coingested, including alcohol, or the overdose is very large. 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. 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
Paracetamol (N02B E51) has analgesic and antipyretic actions. It is a weak inhibitor of prostaglandin biosynthesis. Single or repeated therapeutic loses of paracetamol do not affect the cardiovascular or respiratory systems. Gastric irritation, erosion, or bleeding is not produced by paracetamol. There is minimal effect on platelets, no effect on bleeding time or excretion of uric acid.
Codeine (N02A A59) 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 affects the CNS and the gut, including analgesia, drowsiness, mood changes, respiratory depression, reduced gastrointestinal motility, nausea or vomiting, changes in the endocrine and autonomic nervous system. Codeine’s effect on pain relief is selective, and it does not effect other sensations such as touch, vibration, vision, or hearing.
5.2 Pharmacokinetic properties
Paracetamol is readily absorbed from the gastrointestinal tract with peak plasma concentrations occurring about 30 minutes to 2 hours after ingestion. Paracetamol is metabolised in the liver and excreted in the urine mainly as the glucuronide and sulphate conjugates, with about 10% as glutathione conjugates. Less than 5% is excreted as unchanged paracetamol. The elimination half life varies from about 1-4 hours. Plasma protein binding is negligible at usual therapeutic concentrations, although this is dose dependent. A minor hydrolated 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 and its salts are absorbed from the gastro-intestinal tract and peak plasma concentrations are produced in about 1 hour. It is metabolised in the liver to morphine and norcodeines. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The plasma half life is between 3 and 4 hours.
5.3. Preclinical Safety Data
None stated.
6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
Maize Starch sifted
Methylcellulose
Talc
Calcium Stearate Povidone Purified Water Hypromellose Macrogol 3350
6.2. Incompatibilities
None relevant
6.3. Shelf-Life
36 months
6.4. Special Precautions for Storage
Do not store above 25°C
6.5 Nature and contents of container
Polyethylene capsule container with low density polyethylene child resistant closure. Or
Aluminium foil over PVC/PVDC or ACLAR film blisters.
In pack sizes of 28, 30, 56, 100 or 112 tablets.
6.6. Instruction for Use, Handling and Disposal
None
7 MARKETING AUTHORISATION HOLDER
Mercury Pharmaceuticals Ltd
Capital House
85 King William Street
London
EC4N 7BL
UK
8. MARKETING AUTHORISATION NUMBER
PL 12762/0056
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
11/03/2009
10 DATE OF REVISION OF THE TEXT
10/09/2014