Co-Codamol Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-codamol Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains: Paracetamol BP 500.00mg and Codeine Phosphate BP 8.00mg For full list of excipients, see section 6.1
3. PHARMACEUTICAL FORM
Tablet
White, flat bevelled edge tablets with a breakline on one side and CO-MOL logo on the other, 12.5 - 12.9mm diameter
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses
4.1 Therapeutic indications
Co-codamol Tablets are indicated as relief of mild to moderate pain and as an antipyretic.
Co-codamol 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
Posology
Adults: 1-2 tablets 4 times daily
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.
Children aged 12 years to 18 years: The recommended codeine dose for children 12 years and older should be one to two tablets every 6 hours when necessary up to a maximum dose of codeine 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).
At least four hours should elapse between doses and not more than four doses should be taken in 24 hours.
Method of administration Oral
4.3. Contraindications
• Hypersensivity to paracetamol or codeine and or to any other constituents.
• Acute respiratory depression and obstructive airways disease.
• Diarrhoea due to pseudomembranous colitis or poisoning
• Acute asthma
• Acute alcoholism
• Severe hepatic dysfunction
• Patients at risk of paralytic ileus
• Raised intracranial pressure
• Head injuries
• Comatosed patients
• Following biliary tract 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
Keep out of the sight and reach of children.
Paracetamol Warnings
Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazard of overdose is greater in those with noncirrhotic alcoholic liver disease.
Co-codamol Tablets should not be taken with any other paracetamol-containing products.
Patients should not exceed the recommended dose.
If symptoms persist, patients should be advised to consult their doctor.
Codeine Warnings
• Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, particularly the elderly, who may be sensitive to their central and gastro-intestinal effects, and those on concurrent CNS depressant drugs. Care should also be observed if prolonged therapy is contemplated. A reduced dose may be necessary in elderly patients who may metabolise or eliminate opioid analgesics more slowly than younger adults.
• Codeine should be given in reduced doses or with caution to patients with asthma and decreased respiratory reserve. Avoid use during an acute asthma attack. Codeine should be avoided, or the dose reduced in patients with hepatic or renal impairment.
• Codeine should be given in reduced doses or with caution in debiltated patients, adrenocortical insufficiency, prostatic hyperplasia, urethral stricture, hypotension, shock, inflammatory or obstructive bowel disorders, hypothyroidism or convulsive disorders. However, these conditions should not necessarily be a deterrent to use in palliative care.
• Codeine should also be used with caution in patients with myasthenia gravis, a history of cardiac arrhythmias and in patients with a history of drug abuse or emotional instability.
• Codeine should also be used with caution in patients with Gall bladder disease, or phaeochromocytoma.
• Prolonged use of codeine should be avoided as this may lead to dependency.
• Codeine may enhance the effects of alcohol (see section 4.3). Alcohol should be avoided whilst under treatment with codeine.
CYP2D6 metabolism: Codeine is partially metabolised by liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme, they will not obtain adequate analgesic effects. 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 low doses/ 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 summarised 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% |
The risk-benefit of continued use should be assessed regularly by the prescriber.
The leaflet will state in the “Pregnancy and breast-feeding” subsection of section 2 “Before taking your medicine”:
Do not take codeine if you are breast-feeding.
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
Post-operative use in children
There have been reports in the published literature that codeine given post-operatively 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.
4.5 Interaction with other medicinal products and other forms of interaction
The risk of hepatotoxicity with single toxic doses or prolonged administration of paracetamol may be increased in chronic alcoholics or in patients regularly taking other hepatotoxic medications or hepatic-enzyme inducing agents.
Paracetamol may increase the elimination half-life of chloramphenicol. Oral contraceptives may increase its rate of clearance.
Enzyme-inducing medicines, such as some antiepileptic drugs (phenytoin, phenobarbital, carbamazepine) may reduce the plasma level of paracetamol and potentially reduce the efficacy.
The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine.
The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect. The effect appears to increase as the dose of paracetamol is increased, but can occur with doses as low as 1.5 -2 g paracetamol per day for at least 5 - 7 days. Occasional doses have no significant effect.
Prolonged concurrent use of paracetamol with a salicylate is not recommended because recent evidence suggests that chronic high dose administration of the combined analgesic (1.35g daily or cumulative ingestion of 1kg annually for 3 years or longer) increases the risk of analgesic nephropathy, renal papillary necrosis, end-stage renal disease and cancer of the kidney or the urinary bladder.
Codeine may have an additive depressant effect in patients receiving central nervous system depressants (including other opioid analgesics, anxiolytic agents, hypnotics, antipsychotics, tricyclic antidepressants, anaesthetic agents and alcohol). When concomitant use of Co-Codamol Tablets with such therapy is proposed, the dose of one or both agents should be reduced.
CNS excitation or depression (with hypertension or hypotension) may occur when opioid analgesics are administered to patients receiving monoamine oxidase inhibitors (MAOIs) like Isocarboxazid, selegiline, moclobemide, linezolid etc.
Co-Codamol Tablets should not be used in patients on MAOI therapy or within 14 days of stopping such therapy (see 4.3).
The gastrointestinal effects of codeine, which slows gastric emptying, counteract the effects of drugs, which stimulate gastric motility such as cisapride, metoclopramide and domperidone. The gastrointestinal effects of codeine may also delay absorption of mexiletine.
Cimetidine inhibits the metabolism of some opioid analgesics. Quinidine has also been reported to inhibit the metabolism of codeine; this may impair the efficacy of codeine since its analgesic effects have been attributed partly to its metabolite morphine.
HIV-protease inhibitors such as ritonavir may increase the plasma levels of some opioid analgesics.
Opioid analgesics may enhance the postural hypotension associated with thiazide diuretics or other antihypertensive agents.
Opiod antagonists eg. Buprenorphine, naltrexone, naloxone - may precipitate withdrawal symptoms.
Concurrent use of anticholinergics and codeine may result in an increased risk of severe constipation, which may lead to paralytic ileus and/or urinary retention.
4.6. Pregnancy and lactation
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 metabolites, 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
Codeine may occasionally cause drowsiness and the patients are advised not to drive or operate machinery if so affected.
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
Paracetamol:
Adverse effects of paracetamol are rare.
Haematological: There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.
Immune system: Hypersensitivity including skin rash may occur. A small percentage of aspirin-sensitive asthmatics are also sensitive to paracetamol. In such cases, the
deterioration in respiratory function induced by paracetamol is milder and shorter than with aspirin (see also 4.4 Special Warnings and Precautions for Use)
Renal and urinary disorders: Nephropathy has been associated with chronic high dose use.
Not known: Anaphylactic shock, angioedema.
Very rare occurrence of pancreatitis.
Codeine:
Codeine can produce typical opioid effects:
The frequency and severity are determined by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high dosage of codeine.
Immune system disorders
Allergic reactions such as hives, itching, skin rashes, swelling of face, dyspnoea and difficulty in breathing.
Metabolism and nutrition disorders Anorexia.
Psychiatric disorders
Euphoria, dysphoria, mood changes, hallucinations, confusion.
Unusual excitement in children, restlessness.
Nightmares, mental depression.
Nervous system disorders Dizziness (light-headedness), headache.
Convulsions, uncontrolled muscular movements, tremors.
Eye disorders
Miosis, visual disturbances.
Ear and labyrinth disorders Vertigo.
Cardiac disorders
Bradycardia, tachycardia, palpitations.
Irregularities of cardiac rhythm.
Vascular disorders
Larger doses produce hypotension.
Postural hypotension, flushing.
Respiratory, thoracic and mediastinal disorders Larger doses produce respiratory depression.
Gastrointestinal disorders
Nausea and vomiting, constipation, dry mouth, biliary spasm.
Stomach cramps.
Skin and subcutaneous tissue disorders
Sweating.
Musculoskeletal, connective tissue and bone disorders Muscle rigidity especially respiratory muscles.
Renal and urinary disorders
Difficulty with micturition, urinary retention, ureteric spasm.
Dysuria.
Reproductive system and breast disorders Sexual dysfunction.
General disorders and administration site conditions Drowsiness.
Tolerance may develop.
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.
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 internet at www.mhra.gov.uk/yellowcard.
4.9 Overdose
PARACETAMOL:
. Ingestion of 5g or more of paracetamol may lead to liver damage if the patient has risk factors (see below).
Liver damage is likely in adults who have taken 10g or more of paracetamol. 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, barbiturates, 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 of Codeine 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. 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.
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. 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.
5.1. Pharmacodynamic properties
Paracetamol is an analgesic with antipyretic properties, the mechanism of analgesic action has not been fully determined. It acts by inhibiting prostaglandin synthesis in the central nervous system (CNS) and through a peripheral action by blocking pain-impulse generation. The peripheral action may also be due to inhibition of the synthesis of actions of other substances, which sensitise pain receptors to mechanical or chemical stimulation.
Paracetamol probably produces antipyresis by acting centrally on the hypothalamic heat-regulating centre to produce peripheral vasodilatation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involved inhibition of prostaglandin synthesis in the hypothalamus.
“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.”
5.2 Pharmacokinetic properties
Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract following oral administration. Peak plasma concentrations are attained within 30 - 60 minutes and the half-life in the plasma is about 2 hours following therapeutic doses. The duration of action is 3 - 4 hours.
Protein binding of paracetamol is variable; 20 - 50% may be bound at concentrations encountered during acute intoxication. It is relatively uniformly distributed throughout the body fluids. Approximately 90 - 95% of the drug is metabolised in the liver primarily by conjugation with glucuronic acid, sulphuric acid and cysteine. When high doses are ingested, paracetamol undergoes N-hydroxylation to form N-acetyl-benzo-quinoneimine, a highly reactive intermediate. This metabolite reacts with sulphydryl groups in proteins and glutathione. When hepatic glutathione is depleted (following overdosage) reaction with hepatic proteins is increased and hepatic necrosis results.
Paracetamol is excreted by the kidneys primarily as conjugates, about 3% of the dose is excreted unchanged.
Codeine phosphate is absorbed from the gastro-intestinal tract. Following oral administration peak plasma concentrations are attained in about an hour. It is metabolised in the liver by O-and N-demethylation to morphine and norcodeine. Codeine and its metabolites are excreted by the kidney mainly as conjugates with glucuronic acid.
5.3 Preclinical safety data
There are no data of relevance to the prescriber additional to that already covered in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients
Maize starch, povidone, potable water, magnesium stearate, pregelatinised starch
6.2 Incompatibilities
None.
6.3 Shelf life
Securitainers: 5 years Blister packs: 3 years
6.4 Special precautions for storage
Protect from heat, light and moisture.
6.5 Nature and contents of container
Aluminium/PVC child resistant (20 ^m hard aluminium foil laminated to 15 ^m rigid PVC film & 250 ^m white opaque PVC film) blister packs in cardboard cartons containing 32 (2x16)or 100 (10x10) tablets
Opaque plastic containers (securitainers) with plastic caps containing 50, 100, 250, 500 or 1000 tablets
Not all pack sizes may be marketed.
6.6. Special precautions for disposal and Other handling
Keep out of the sight and reach of children.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
Tillomed Laboratories Limited
3 Howard Road
Eaton Socon
St. Neots
Cambs PE19 8ET
8 MARKETING AUTHORISATION NUMBER(S)
PL 11311/0153
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
27/02/2009
10 DATE OF REVISION OF THE TEXT
11/03/2014