Co-Codamol 8/500mg Tablets
Summary of Product Characteristics
1 Name of the medicinal product
Co-Codamol 8/500mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Paracetamol BP 500mg and Codeine Phosphate BP 8mg per tablet.
3. PHARMACEUTICAL FORM
Co-Codamol tablets are presented as white, flat bevelled edge tablets with a bar and A459 embossed on one face and company logo on the other.
4 Clinical particulars
4.1 Therapeutic indications
Co-Codamol Tablets are 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:
As this medicine contains codeine it should be used at the lowest effective dose for the shortest period of time. One to two tablets may be taken, up to 4 times a day at intervals of not less than 6 hours. Maximum 8 tablets 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.
Paediatric population:
Children aged 12 years to 18 years:
The recommended dose for children 12 years and older should be one to two tablets every 6 hours when necessary up to a maximum dose of 8 tablets 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 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).
Route of administration: Oral
4.3 Contraindications
Hypersensitivity to paracetamol, to codeine or to any of the other ingredients.
Conditions where morphine and opioids are contraindicated e.g:
Respiratory depression.
Acute asthma Acute alcoholism Head injuries
Raised intra-cranial pressure Following biliary tract surgery
Monoamine oxidase inhibitor therapy, concurrent or 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
Caution should be exercised when administering to the elderly with hepatic and renal impairment. Caution should also be exercised in administration of paracetamol to patients with severe hepatic or severe renal dysfunction.
The hazards of paracetamol overdose are greater in those with non-cirrhotic alcoholic liver disease.
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, those on concurrent CNS depressant drugs, those with prostatic hypertrophy and those with inflammatory or obstructive bowel disorders. Care should also be observed if prolonged therapy is contemplated.
The risk benefit of continued use should be assessed regularly by the prescriber.
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, 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 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% to 2% |
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.
The leaflet will state in the “Pregnancy and breast-feeding” subsection of Section 2 “Before taking your medicine”:
Do not take codeine while you are breastfeeding. Codeine and morphine passes into breast milk.
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 pain killer regularly for headaches too often or for too long can make them worse
The leaflet will also state:
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.
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 also state:
Contains paracetamol.
Do not take more medicine than the label tells you to. If you do not get better, talk to your doctor. (This must appear adjacent to either the directions for use or the recommended dosage).
Do not take anything else containing paracetamol while taking this medicine. Talk to a doctor at once if you take too much of this medicine, even if you feel well.
4.5. Interaction with other medicinal products and other forms of interaction
Paracetamol may increase the elimination half-life of chloramphenicol. Oral contraceptives may increase its rate of clearance. The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine.
The anti-coagulant 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.
The effects of CNS depressants (including alcohol) may be potentiated by codeine.
Codeine when administered concurrently with metoclopramide or domperidone opposes the effect of metoclopramide or domperidone on gastro-intestinal motility
4.6 Fertility, pregnancy and lactation
There is inadequate evidence of the safety of codeine in human pregnancy, but there is epidemiological evidence for the safety of paracetamol. Both substances have been widely used for many years without apparent ill consequence and animal studies have not shown any hazard. Nonetheless careful consideration should be given before prescribing the products for pregnant patients.
Opioid analgesics may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers.
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 metabolite 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
Codeine may occasionally cause drowsiness, dizziness or sedation 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:
- The medicine has been prescribed to treat a medical or dental problem and
- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
- It was not affecting your ability to drive safely.
4.8 Undesirable effects
Adverse effects with paracetamol are rare. Immune system disorders:
Hypersensitivity, including skin rash, may occur.
Not known - Anaphylactic shock, angioedema.
There have been reports of blood dyscrasias including thrombocytopenia and agranulocytosis, but these were not necessarily causally related to paracetamol.
Very rare occurrence of pancreatitis.
Codeine can produce typical opioid effects including constipation, nausea, vomiting, dizziness, light-headedness, confusion, drowsiness and urinary retention. The frequency and severity are determined by dosage, duration of treatment and individual sensitivity. Tolerance and dependence can occur, especially with prolonged high doses of codeine.
Regular prolonged use of codeine is known to lead to addiction and tolerance, and symptoms of restlessness and irritability may result when treatment is then stopped.
Prolonged use of a painkiller for headaches can make them worse.
Other side effects due to codeine are sedation.
Rare cases of sensorineural hearing loss have been reported with codeine and codeine containing products.
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 symptoms, emergency procedures, antidotes
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
b) Regularly consumes ethanol in excess of recommended amounts.
c) Is likely to be glutathione deplete eg. 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 24 hours from ingestion should be discussed with the NPIS or a liver unit.
The effects in 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 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.
5.1 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 prostaglandin or 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 vasodilation resulting in increased blood flow through the skin, sweating and heat loss. The central action probably involves 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 30-60minutes and the half-life in 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 and sulphuric acid. When high doses are ingested, paracetamol undergoes N-hydroxylation to form N-acetyl-benzo-quinoneimine, a highly reactive intermediate. This metabolite reacts with sulphdryl 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 pre-clinical data of relevance to the prescriber which are not already covered in other sections of the SPC.
6.1 List of excipients
Maize starch Povidone
Magnesium stearate Pregelatinised starch
6.2. Incompatibilities
None.
6.3. Shelf Life
5 years in plastic containers. 2 years in blister packs.
6.4 Special precautions for storage
Protect from heat, light and moisture.
6.5. Nature and contents of container
Opaque plastic containers composed of polypropylene tubes and polyethylene tamper evident closures (packs of 10, 12, 20, 24, 30, 50, 100, 250, 500, 1000 and bulk).
Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a tamper evident or child resistant tamper evident closure composed of high density polyethylene (packs of 10, 12, 20, 24, 30, 50, 100, 250, 500, 1000 and bulk).
Blister packs of 20pm hard aluminium foil laminated to 15 pm rigid PVC film, and 250pm white opaque PVC in printed boxboard cartons (packs of 10, 12, 20, 24, 30, 50, 100, 250, 500 and 1000).
Not all pack sizes may be marketed.
6.6. Instructions for Use/Handling
No special instructions for use/handling.
7. MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
Units 3 and 4, Quidhampton Business units
Polhampton Lane
Overton
Hampshire
RG25 3ED
United Kingdom
8. MARKETING AUTHORISATION NUMBER
PL 20416/0045
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
04/03/2009
21/06/2016