Co-Codamol 30mg/500mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zapain 30mg/500mg Tablets and/or Co-Codamol 30mg/500mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Paracetamol Ph. Eur 500mg, and Codeine Phosphate BP 30mg
3 PHARMACEUTICAL FORM
Tablet
4.1. Therapeutic indications
For the relief of severe 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
Method of administration: Oral
Adults: The usual dose is one or two tablets every four hours as required. The total daily dose should not exceed 4 g paracetamol (8 capsules 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.
Tolerance to Codeine can develop with continued use. The incidence of unwanted effects is dose related. Doses of Codeine above 60mg are associated with an increase in unwanted effects.
4.3 Contraindications
Hypersensitivity to either paracetamol or codeine, or any of the excipients of Zapain tablets.
Children under 12 years of age.
Zapain is contraindicated in patients with moderate to severe degrees of renal or hepatic impairment.
It is contraindicated in patients for whom opiate medications should not be used, such as patients with acute asthma, obstructive airway disease, respiratory depression, acute alcoholism, head injuries, raised intracranial pressure, after biliary surgery, patients suffering from diarrhoea of any cause, and patients who have taken MAOIs within 14 days.
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 Zapain tablets in children below the age of 12 years has not been established, and use in such children is contraindicated.
Zapain tablets must be used with caution in patients with increases intracranial pressure, acute abdominal conditions, the elderly, the debilitated, impaired hepatic or renal function, hypothyroidism, Addison’s disease, prostatic hypertrophy, and urethral stricture. (See also “Contraindications”. Note particularly that Zapain is contraindicated in patients with severe renal or hepatic impairment.)
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.”
Overdosage in patients with non-cirrhotic alcoholic liver disease can be hazardous. The hazard of paracetamol overdose is greater in those with alcoholic liver disease.
Codeine at high doses has the same disadvantages as morphine, including respiratory depression. Drug dependence of the morphine type can be produced by the Codeine, and the potential for drug abuse with codeine must be considered. Codeine may impair mental or physical abilities required in the performance of potentially hazardous tasks.
Patients must be advised not to exceed the recommended doses.
Patients must be advised not to take other products containing paracetamol or opiate derivatives when taking Zapain, and to consult their doctor if symptoms persist.
The cough suppressant effect of codeine may be undesirable in patients with some respiratory conditions.
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 Interactions 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 Zapain may be enhanced by coadministration with any other drug which has a CNS depressant effect (e.g. 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 Zapain 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
Zapain 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. CLINICAL PARTICULARS
4.7 Effects on ability to drive and use machines
Patients should be advised not to drive or operate machinery if Zapain 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 headedness, dizziness, sedation, shortness of breath and constipation. Some of these side effects appear more commonly in ambulatory rather than non-ambulatory patients. Lying down may alleviate these effects if they occur. In addition, miosis, visual disturbances, headache, bradycardia, respiratory depression, difficult micturition and urinary retention, and allergic reaction (including skin rash) can occur.
Codeine can cause respiratory depression particularly in overdosage and in patients with compromised respiratory function.
Euphoria, dysphoria, constipation, abdominal pain, and pruritus can occur as reactions to Zapain.
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 argranulocytosis, 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
Symptoms of overdosage with paracetamol in the first 24 hours are pallor, nausea, vomiting, anorexia, and abdominal pain. In 12 to 48 hours liver damage may become apparent, together with abnormalities of glucose metabolism, and metabolic acidosis.
Liver damage has occurred in adults taking 10g or more of paracetamol. Excess quantities of a toxic metabolite become irreversibly bound to liver tissue, and immediate treatment is essential. Patients ingesting 7.5g or more of paracetamol in 4 hours should be referred to hospital urgently.
Overdose with paracetamol can commonly cause acute hepatic necrosis with severe liver damage and may lead to fulminant hepatic failure, which is usually fatal. In severe overdose hepatic failure may progress to encephalopathy, coma and death. Even in the absence of severe liver damage, acute renal failure due to acute tubular necrosis may develop without hepatic failure.
There are no specific early signs of severe poisoning with paracetamol. Consciousness is not usually impaired, and maximum abnormality of liver function tests is delayed for at least three days. Liver damage is caused by conversion of paracetamol to a highly reactive metabolite. Necrosis does not occur unless hepatic glutathione is depleted.
Early treatment of paracetamol overdose with agents which facilitate glutathione synthesis, for example N-acetylcysteine and methionine, can prevent liver damage, renal failure, and death. Treatment must be started within 8 to 10 hours, and is not effective if delayed beyond 15 hours.
Cardiac arrhythmias and pancreatitis have been reported.
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 350mg or a child more than 5mg/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 doses 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 affect 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
6.1 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 Content of Container
Polyethylene container with low density polyethylene child resistant closure OR
Aluminium foil over PVC/PVDC film blisters In pack sizes of 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(S)
PL 12762/0034
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
22/11/1999 / 03/03/2009
10 DATE OF REVISION OF THE TEXT
15/08/2014