Co-Codamol 30mg/500mg Capsules
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Zapain 30mg/500mg Capsules Co-codamol 30mg/500mg Capsules
2. Qualitative and Quantitative Composition
Each capsule contains Paracetamol 500 mg, and Codeine Phosphate 30mg.
3. Pharmaceutical Form
Capsule.
4 CLINICAL PARTICULARS
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
Adults: The usual dose is one or two capsules 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 60 mg are associated with an increase in unwanted effects.
Method of administration: Oral.
4.3. Contraindications
Hypersensitivity to either Paracetamol or codeine, or any of the excipients of Zapain capsules.
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 and patients suffering from diarrhoea of any cause.
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 risk-benefit of continued use should be assessed regularly by the prescriber.
The efficacy and safety of Zapain capsules in children below the age of 12 years has not been established, and use in such children is contraindicated.
Zapain capsules must be used with caution in patients with acute abdominal conditions like inflammatory or obstructive bowel disorders, the elderly, the debilitated, impaired hepatic or renal function, CNS depression, pre-existing respiratory depression or those with the potential to develop respiratory depression, hypothyroidism, Addison’s disease, prostatic hypertrophy, urethral stricture, myasthenia gravis, and biliary tract disorders (including recent biliary tract surgery).
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 hazards of paracetamol overdose are greater in those with non-cirrhotic alcoholic liver disease.
Severe liver damage may occur if the maximal daily dose of paracetamol is exceeded or if this product is taken while consuming large amounts of alcohol or with another paracetamol-containing product.
Although paracetamol might logically be presumed to be the best alternative analgesic in patients with aspirin sensitivity, cross reactions have been reported. Patients positively identified with aspirin induced asthma, or who have ever experienced an asthmatic reaction to aspirin or non-steroidal antiinflammatory drugs (NSAIDs) or are at high risk of aspirin induced asthma should avoid all products that contain aspirin or NSAIDs indefinitely. In these patients paracetamol should be recommended in low or moderate dose (< 1000 mg in a single dose) unless contraindicated.
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.
Administration of pethidine and possibly other opioid analgesics to patients taking a monoamine oxidase inhibitor (MAOI) has been associated with very severe and sometimes fatal reactions. If the use of codeine is considered essential then great care should be taken in patients taking MAOIs or within 14 days of stopping MAOIs (see section 4.5).
Patients should be advised that immediate medical advice should be sought in the event of an overdose, because of the risk of delayed serious liver damage.
Patients must be advised not to exceed the recommended doses.
Patients must be advised not to take other products containing opiate derivatives or other paracetamol-containing products.
Patients should be advised to consult their doctor if symptoms persist and to keep the product out of the reach of children.
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 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 your prescriber as taking codeine regularly for a long time can lead to addiction.
The label will state (boxed):
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
The leaflet will state “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.”
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 Zapain may be enhanced by co administration with any other drug which have a CNS depressant effect (eg. sedative hypnotics, phenothiazines, antipsychotics, other opioid analgesics, tranquilisers 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 agent.
MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has not been documented with codeine, it is possible that a similar interaction may occur and therefore the use of codeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.
Enzyme-inducing medicines, such as some antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) have been shown in pharmacokinetic studies to reduce the plasma AUC of paracetamol to approximately 60 %. Other substances with enzyme-inducing properties, e.g. rifampicin and St. John's wort (hypericum) are also suspected of causing lowered concentrations of paracetamol. In addition, the risk of liver damage during treatment with maximum recommended doses of paracetamol will be higher in patients being treated with enzyme inducing agents.
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 co administration with an antimuscarine drug may cause urinary retention.
The absorption of paracetamol is speeded by metoclopramide or domperidone, and absorption is reduced by colestyramine.
Codeine may delay the absorption of mexiletine and thus reduce the antiarrhythmic effect of the latter. 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.
Concurrent use with centrally acting muscle relaxants may increase the risk of respiratory depression.
4.6. Fertility, pregnancy and lactation
Zapain is not recommended during pregnancy since safety in pregnant women has not been established.
Use during pregnancy may lead to withdrawal syndromes in neonates, and use during labour may cause neonatal respiratory depression.
Paracetamol is excreted in breast milk but not in a clinically significant amount.
Codeine should not be used during breastfeeding (see section 4.3).
At normal therapeutic doses codeine and its active metabolites 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
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
Reported adverse reactions seem more prominent in ambulatory than nonambulatory patients and some of these effects may be alleviated if the patient lies down.
A tabulated list of adverse reactions is outlined below:
|
System Organ Class |
Adverse Effects (Frequency not know) |
|
Blood and lymphatic system disorders |
Thrombocytopenia, agranulocytosis |
|
Immune system disorders |
Anaphylactic reaction, hypersensitivity |
|
Psychiatric disorders |
Dysphoria, euphoria |
|
Nervous system disorders |
Dizziness, sedation, headache |
|
Ear and labyrinth disorders |
Deafness1 |
|
Respiratory thoracic and mediastinal disorders |
Bronchospasm, dyspnoea |
|
Gastro-intestinal disorders |
Nausea, vomiting, constipation, abdominal pain, pancreatitis2 |
|
Skin and subcutaneous tissue disorders |
Pruritus, rash, urticaria |
1Deafness has been reported in patients after long term use of high doses of codeine-paracetamol.
Drug-induced pancreatitis associated with paracetamol has been reported in literature to be a rare reaction only occurring in patients taking in excess of the recommended doses. Literature reports have also associated cases of pancreatitis with codeine.
In addition, miosis, visual disturbances, respiratory depression, difficult micturition and urinary retention can occur.
Allergic reactions (including skin rash), urticaria 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 cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.
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.
Anaphylaxis, angioedema and toxic epidermal necrolysis have also been associated with the use of paracetamol.
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.
Long-term usage of high doses of codeine + paracetamol can be rarely associated with ototoxicity leading to sensorineural hearing loss.
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, phenobarbital, 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). 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 over dosage 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 patients for at least four hours after ingestion.
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. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
Maize Starch
Sodium Lauryl Sulphate
Talc
Magnesium Stearate Croscarmellose Sodium Gelatin
Titanium dioxide E171 (capsule) Erythrosin E127 (capsule)
Red Iron Oxide E172 (capsule)
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 capsule container with low density polyethylene child resistant closure.
OR
Aluminium foil over PVC/PVDC film blisters.
In pack sizes of 56, 100 or 112 capsules
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 12762/0033
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
03/03/2009
10 DATE OF REVISION OF THE TEXT
10/09/2014