Co-Codamol Tablets Bp
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Co-codamol Tablets BP
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains paracetamol 500mg and codeine phosphate 8mg For excipients see 6.1
3 PHARMACEUTICAL FORM
Tablets.
White, flat bevelled edge tablets with LPC separated by a break line on one side and “CO-MOL” embossing on the other side.
The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4 CLINICAL PARTICULARS
4.1. Therapeutic indications
Co-codamol Tablets are indicated for the relief of mild to moderate pain and as an antipyretic.
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).
Oral Use.
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.
Adults:
1 - 2 tablets 4 times daily. The maximum dose in any 24-hour period is 8 tablets in divided doses.
Elderly:
Caution should be exercised in both elderly and in debilitated patients who may be more susceptible to the respiratory depressant effects of codeine. In such cases a reduced dose may be required.
Paediatric population:
Children aged 12 years to 18 years:
1 - 2 tablets 4 times daily. The maximum dose in any 24-hour period is 8 tablets in divided doses.
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 4 hours should elapse between doses and not more than four doses should be taken in 24 hours.
4.3. Contra-indications
Co-codamol Tablets should not be used by patients suffering from the following:
• Hypersensitivity to paracetamol
• Hypersensitivity to codeine
• Hypersensitivity to any of the other constituents of the product or to other opioid analgesics
• Respiratory depression
• Obstructive airway disease
• Acute asthma
• Heart failure secondary to chronic lung disease
• Raised intracranial pressure
• Head injuries
• Acute alcoholism
• Acute abdomen and where there is a risk of paralytic ileus
• Codeine should not be used in infants
• Codeine should not be used in patients receiving monoamine oxidase inhibitor therapy, either concurrently or within 14 days of stopping such therapy.
• In all paediatric patients (under 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 reach and sight of children.
Paracetamol Warnings
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
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 non-cirrhotic alcoholic liver disease
The risk-benefit of continued use should be assessed regularly by the prescriber.
Patient Information Leaflet:
• Do not take for longer than directed by your prescriber.
• Taking codeine/dihydrocodeine 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.
Pack Label:
• Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction.
Codeine Warnings
Codeine should only be used with extreme caution in patients with decreased respiratory reserve and should be given with caution or in reduced doses to patients with hypotension, hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, shock or inflammatory or obstructive
bowel disorders.
Codeine should also be used with caution in patients with myasthenia gravis, a history of cardiac arrythmias or convulsions and in patients with a history of drug abuse or emotional instability.
Caution should be exercised in the administration of codeine to patients with renal or hepatic impairment; a reduction in dose may be necessary or the drug may need to be avoided.
Prolonged use of codeine should be avoided as this may lead to dependency. Codeine may enhance the effects of alcohol Avoid in children under one year of age
A reduced dose may be necessary in elderly patients who may metabolise or eliminate opioid analgesics more slowly than younger adults
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 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 Europe |
1 % to 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 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.
Chronic use of barbiturates or primidone decreases the therapeutic effects of paracetamol due to increased metabolism resulting from induction of hepatic microsomal enzyme activity.
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.
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). 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.
The effects of opioid analgesics are counteracted by the specific opioid antagonist naloxone. Naloxone is used therapeutically to reverse the central depression which may result from opioid treatment or overdosage (see 4.9).
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. Fertility, Pregnancy and Lactation
Paracetamol crosses the placental barrier. Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dosage, but patients should follow the advice of their doctor regarding its use.
Paracetamol is excreted in breast milk but not in a clinically significant amount. Available published data do not contraindicate breast-feeding.
Codeine crosses the placenta. There is inadequate evidence of safety of codeine in human pregnancy and there is a possible association with respiratory and cardiac malformations.
Codeine is excreted in small amounts in breast milk.
The risks and benefits should be considered prior to the administration of codeine during either pregnancy or lactation. There is evidence of depression of
neonatal respiration and withdrawal effects in neonates and therefore use should be avoided in pregnancy if at all possible. Use of opioid analgesia during labour may cause respiratory depression in the neonate, particularly premature neonates, and therefore should not be given during delivery of premature infants.
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.
4.7 Effects on ability to drive and use machines
Codeine may occasionally cause drowsiness and patients are advised not to drive or operate machinery if so affected.
4.8 Undesirable effects
Adverse effects of paracetamol are rare, but hypersensitivity including skin rash may occur.
There have been a few reports of blood dyscrasias including thrombocytopenia and agranulocytosis but these were not necessarily causally related to paracetamol.
The most common adverse effects of codeine are constipation and drowsiness. Less frequent effects include nausea, vomiting, sweating, facial flushing, dry mouth, blurred or double vision, dizziness, tiredness, headache, anorexia, vertigo, slow or rapid heartbeat, breathing difficulties, difficulty in micturition, convulsions, hallucinations, nightmares, uncontrolled muscle movement or rigidity, mental depression, stomach cramps, allergic reactions (such as skin rashes, urticaria or pruritus), orthostatic hypotension, general malaise, tolerance and the euphoric effects of codeine which may lead to its abuse and dependence.
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.
Patient Information Leaflet:
• Do not take for longer than directed by your prescriber.
• Taking codeine/dihydrocodeine 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.
Pack Label:
• Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction.
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:
Immediate medical advice should be sought in the event of an overdose, even if the patient feels well, because of the risk of delayed, serious liver damage.
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, coma and death. Acute renal failure with acute tubular necrosis may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.
Liver damage is possible in adults who have taken 10g or more of paracetamol.
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 and any patient who has ingested around 7.5 g or more of paracetamol in the preceding 4 hours should undergo gastric lavage. Administration of oral methionine or intravenous N-acetylcysteine, which may have a beneficial effect up to at least 48 hours after the overdose, may be required. General supportive measures must be available.
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 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 dose may be required in a seriously poisoned patient. Observe for at least 4 hours after ingestion, or 8 hours if a sustained release preparation has been taken.
5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic Properties
Paracetamol is an analgesic with antipyretic properties. The mechanism of its 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. Its peripheral action may also be due to inhibition of the synthesis or actions of other substances which sensitise pain receptors to mechanical or chemical stimulation.
Paracetamol probably produces antipyrexia 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 involves inhibition of prostaglandin synthesis in the hypothalamus.
Codeine is an opioid analgesic which binds with stereospecific receptors at many sites within the CNS to alter processes affecting both the perception of pain and the emotional response to pain.
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.
The precise site and mechanism of action of codeine are not fully determined, but there seems to be an alteration in the release of various neurotransmitters from afferent nerves sensitive to painful stimuli which may be partially responsible for its analgesic effects.
At least two types of opioid receptors (Mu and Kappa) mediate analgesia. Codeine exerts its agonistic activity primarily at Mu receptors which are widely distributed throughout the CNS especially in the limbic system, thalamus, striatum, hypothalamus and mid brain as well as laminae I, II, IV and V of the dorsal horn in the spinal cord.
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 its 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 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 gastrointestinal 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 those already covered in other sections of the SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Maize starch, povidone, purified water, magnesium stearate, pregelatinised starch.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Container : 60 months.
Blister : 18 months
6.4 Special precautions for storage
Containers: Do not store above 25°C. Store in the original container. Blister packs: Do not store above 25 °C. Store in the original package.
6.5 Nature and contents of container
Polypropylene tablet containers closed with low density polyethylene tamper-evident lids and containing either 50,100, 250, 500 or 1000 tablets.
Al/PVC Blisters of 8 and 10 tablets Pack sizes: 100, 32 and 30 tablets
6.6 Special precautions for disposal
Not applicable
7 MARKETING AUTHORISATION HOLDER
Activase Pharmaceuticals Limited, 11 Boumpoulinas,
PC. 1060 Nicosia.
Cyprus
8 MARKETING AUTHORISATION NUMBER(S)
PL 28444/0147
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 22/04/2002
10 DATE OF REVISION OF THE TEXT
23/12/2015