Co-codamol 8mg/500mg tablets – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Co-codamol 8mg/500mg tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 8mg Codeine Phosphate and 500mg Paracetamol

Excipients with known effect:

Lactose monohydrate (18 mg/tablet)

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet

Co-codamol 8mg/500mg tablets are white to almost white, capsule-shaped, biconvex, bevelled edged tablets, with ‘CC3’ on one side and ‘score line’ on the other side.

The score line is not intended for breaking the tablet

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the short-term treatment of acute moderate pain such as headaches, migraine, neuralgia, toothache, dysmenorrhoea and rheumatic 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

Posology

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with Codeine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

Adults

The usual dose is one or two tablets every 4 to 6 hours when needed, up to a maximum of 8 tablets in any 24 hour period.

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.

Elderly: A reduced dosage may be necessary.

Paediatric population:

Children aged 16 to 18 years

One to two tablets every 6 hours when necessary up to a maximum of 8 tablets in 24 hours.

Children aged 12 to 15 years

One tablet every 6 hours when necessary to a maximum of 4 tablets in 24 hours.

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 section 4.3 and 4.4).

Dosage needs to be adjusted according to the severity of pain and the response of the patient.

Method of administration

For oral administration

Treatment goals and discontinuation

Before initiating treatment with Co-codamol, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with codeine, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

Duration of treatment

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.

4.3 Contraindications

• Hypersensitivity to paracetamol or codeine which is rare.
• Hypersensitivity to the active substances, soya or peanut or to any of the other excipients listed in section 6.1.
• Children under 12 years of age.
• Patients who have taken MAOIs within 14 days.
• Severe renal or hepatic impairment.
• Conditions where morphine and opioids are contraindicated e.g.:
• Acute asthma
• obstructive airway disease
• Respiratory depression
• Acute alcoholism
• Head injuries
• Raised intra-cranial pressure
• Following biliary tract surgery
• In women during breast-feeding (see section 4.6)
• 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 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 Co-codamol tablets in children below the age of 12 years has not been established, and use in such children is contraindicated. Co-codamol tablets must be used with caution in patients with increases intracranial pressure, debilitated, impaired hepatic or renal function and urethral stricture. (See also “Contraindications”. Note particularly that Co-codamol is contraindicated in patients with severe renal or hepatic impairment.)

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring, is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors

Care should be observed in administering the product to any patient whose condition may be exacerbated by opioids, including the elderly, who may be sensitive to their central and gastro-intestinal effects, those on concurrent CNS depressant drugs, those with prostatic hypertrophy, hypothyroidism and those with with acute abdominal conditions like inflammatory or obstructive bowel disorders, Addison's disease or myasthenia gravis. Care should also be observed if prolonged therapy is contemplated.

Tolerance and opioid use disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as Co-codamol. Repeated use of Co-codamol can lead to OUD. A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Co-codamol may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with Co-codamol and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should contact their physician.

Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with Codeine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Paracetamol and Codeine Phosphate and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Paracetamol and Codeine Phosphate concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

CYP2D6 metabolism

Codeine is partially metabolised by the 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 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:

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

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.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

Risks from concomitant use of opioids and alcohol

Concomitant use of opioids, including codeine, with alcohol may result in sedation, respiratory depression, coma and death. Concomitant use with alcohol is not recommended (see section 4.5).

Co-codamol should be used upon medical advice in patients with:

• Mild-to-moderate hepatocellular insufficiency
• Severe renal insufficiency

Monitoring after prolonged use should include blood count, liver function and renal function

Care is advised in the administration of paracetamol to patients with severe renal or severe hepatic impairment. The hazards of overdose are greater in those with alcoholic liver disease.

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 Co-codamol, and to consult their doctor if symptoms persist.

The cough suppressant effect of codeine may be undesirable in patients with some respiratory conditions.

Caution is advised in patients with underlying sensitivity to aspirin and/or to nonsteroidal anti-inflammatory drugs (NSAIDs).

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

As with other opioids, in case of insufficient pain control in response to an increased dose of codeine, the possibility of opioid-induced hyperalgesia should be considered. A dose reduction or treatment review may be indicated.

Hepatobiliary disorders

Codeine may cause dysfunction and spasm of the sphincter of Oddi, thus increasing the risk of biliary tract symptoms and pancreatitis. Therefore, codeine/paracetamol has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.

Paediatric population

Not recommended for children under 12 years of age.

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 recommended dose should not be exceeded. This medicine should not be taken with any other paracetamol-containing products.

If symptoms persist, the patient should be advised to consult their doctor. The patient should be advised to seek immediate medical advice in the event of an overdose, even if they feel well, because of the risk of delayed, serious liver damage.

Use with caution in patients with convulsive disorders.

Label Warnings:

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, because of the risk of delayed, serious liver damage.

The label will state

Front of Pack

• Can cause addiction
• Contains opioid
• For three days use only

Back of Pack

This product is recommended

• For the short-term treatment of acute moderate pain such as headaches, migraine, neuralgia, toothache, dysmenorrhoea and rheumatic 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)
• If you need to take this medicine continuously for more than three days you should see your doctor or pharmacist
• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. If you take this medicine for headaches for more than three days it can make them worse

The leaflet will state:

Important things you should know about Co-codamol

• This medicine can only be used for the short-term treatment of acute moderate pain such as headaches, migraine, neuralgia, toothache, dysmenorrhoea and rheumatic 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).
• You should only take this product for a maximum of three days at a time. If you need to take it for longer than three days you should see your doctor or pharmacist for advice
• This medicine contains codeine which can cause addiction if you take it continuously for more than three days. This can give you withdrawal symptoms from the medicine when you stop taking it
• If you take this medicine for headaches for more than three days it can make them worse

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 Co-codamol 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 Co-codamol 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-diarrhoeal agent increases the risk of severe constipation, and coadministration with an antimuscarine drug may cause urinary retention.

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 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 enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses of paracetamol do not have a significant effect on these anticoagulants.

Caution should be taken when paracetamol is used concomitantly with flucloxacillin as concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risks factors (see section 4.4)

Patients receiving other narcotic analgesics, antitussive, antihypertensives, antihistamines, antipsychotics, antianxiety agents or other CNS depressants (including alcohol) concomitantly with this codeine containing drug may exhibit additive CNS depression.

Sedative medicines such as benzodiazepines or related drugs: The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4). Concomitant use of Co-codamol with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death (see section 4.4).

Alcohol and opioids

The concomitant use of alcohol and opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Concomitant use with alcohol is not recommended (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Epidemiological studies in human pregnancy have shown no ill effects due to paracetamol used in the recommended dose.

A large amount of data on pregnant women indicate neither malformative, nor feto/neonatal toxicity.

Paracetamol can be used during pregnancy if clinically needed however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Codeine can cause respiratory depression and withdrawal syndrome in newborns.

Results of one case control study suggest that there might be an increased risk of malformations of the respiratory tract in the offspring of women who consumed codeine during the first four months of pregnancy. This increase was statistically not significant. Evidence of other malformations is also reported in epidemiological studies on narcotic analgesics, including codeine.

Codeine has been used for many years without apparent ill consequence and animal studies have not shown any hazard. Patients should follow the advice of their doctor regarding the use of this product.

Breast-feeding

Paracetamol is excreted in breast milk but not in a clinically significant amount. Administration to nursing women is not recommended as codeine may be secreted in breast milk and may cause respiratory depression in the infant.

Codeine should not be used during breastfeeding (see section 4.3). Co-codamol Tablets 8/500mg are contraindicated during breast-feeding. 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.

Fertility

There are no data on the effects of Paracetamol and Codeine Phosphate tablets on human fertility. Fertility was unaffected following paracetamol and codeine treatment in animal studies (see section 5.3).

4.7 Effects on ability to drive and use machines

Patients should be advised not to drive or operate machinery if Co-codamol affected by 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:
• 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

Codeine phosphate 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 dosage of codeine phosphate.

• 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.

The information below lists reported adverse reactions, ranked using the following frequency classification:

Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Adverse effects of paracetamol are rare:

Undesirable effects

^a Codeine can cause respiratory depression particularly in overdosage and in patients

with compromised respiratory function.

^bLiver damage in association with therapeutic use of paracetamol has been documented; most cases have occurred in conjunction with chronic alcohol abuse.

^CSome of these side effects appear more common in ambulatory: rather than non-ambulatory patients. Lying down may alleviate these effects they occur.

^d High anion gap metabolic acidosis

Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

^*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.

Prolonged use of a pain killer for headaches can make them worse.

Drug dependence

Repeated use of Co-codamol can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

Codeine Phosphate

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 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

Management 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 4 hours after ingestion, or 8 hours if a sustained release preparation has been taken. The opioid antagonist naloxone hydrochloride is an antidote to respiratory depression and must be administered intravenously.

Patients should be advised to first consult their healthcare professional before taking codeine if they are taking a benzodiazepine.

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:

• is on long term treatment with carbamazepine, phenobarbitone, phenytoin, primidone, rifampicin, St. John's Wort or
• other drugs that induce liver enzymes, or
• regularly consumes ethanol in excess of recommended amounts, or
• 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. Also increased levels of hepatic transaminases, lactate dehydrogenase and bilirubin may occur, and the INR may increase. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema, gastrointestinal bleeding 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 lack of significant early symptoms, patients should be referred to hospital urgently for immediate 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 concentrations should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable) but results should not delay initiation of treatment beyond 8 hours after ingestion,

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 indigestion.

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. Further measures will depend on the severity, nature and course of clinical symptoms of paracetamol intoxication and should follow standard intensive care protocols.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Opiods Codeine, combinations with non-opioid analgesics,ATC Code: N02AJ06

Paracetamol (N02B E51) has analgesic and antipyretic actions. It is a weak inhibitor of prostaglandin biosynthesis. Single or repeated therapeutic loses 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.

Paracetamol is an analgesic which acts peripherally, probably by blocking impulse generation at the bradykinin sensitive chemo-receptors which evoke pain. Although it is a prostaglandin synthetase inhibitor, the synthetase system in the CNS rather than the periphery appears to be more sensitive to it. This may explain paracetamol's lack of appreciable anti-inflammatory activity. Paracetamol also exhibits antipyretic activity

Codeine (N02A A59)is a centrally acting weak analgesic. Codeine exerts its effect through μ 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 effect 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.

Following oral administration of two tablets (i.e. a dose of paracetamol 1000mg and codeine phosphate 60mg) the mean maximum plasma concentrations of paracetamol and codeine were 15.96μg/ml and 212.4ng/ml respectively.

The mean times to maximum plasma concentrations were 0.88 hours for paracetamol and 1.05 hours for codeine.

The mean AUC for the 9 hours following administration was 49.05μg/ml per hour for paracetamol and 885.0ng/ml per hour for codeine. The bioavailabilities of paracetamol and codeine, when given as the combination, are similar to those when they are given separately. Codeine is mainly metabolized by glucuronidation to codeine-6-glucuronide. Minor routes of metabolism include O- demethylation leading to morphine, Ndemethylation to norcodeine and after both O- and N-demethylation formation of normorphine. Morphine and norcodeine are further transformed in glucuroconjugates. Unchanged codeine and its metabolites are mainly excreted by urinary route within 48h (84.4±15.9%).

The O-demethylation of codeine to morphine is catalyzed by the cytochrome P450 isozyme 2D6 (CYP2D6) which shows genetic polymorphism that may affect the efficacy and toxicity of codeine.

Genetic polymorphism in CYP2D6 leads to ultra-rapid, extensive and poor metaboliser phenotypes.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Pregelatinized maize starch

Stearic acid

Povidone K-30

Lactose monohydrate

Powdered cellulose

Talc

Magnesium stearate

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicine does not require any special storage conditions.

6.5 Nature and contents of container

Codeine/Paracetamol 8mg/500mg tablets are available in Blister pack of white PVC and Aluminium foil, packaged into a cardboard carton, containing 10, 20, 30 or 32 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Lyrus Life Sciences Limited

C/O Thakur-Chabert 7a Vine Street

Uxbridge

United Kingdom

UB8 1QE

8 MARKETING AUTHORISATION NUMBER(S)

PL 48974/0041

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

21/09/2022

10 DATE OF REVISION OF THE TEXT

24/08/2026