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

1 NAME OF THE MEDICINAL PRODUCT

Co-codamol 8mg/500mg Effervescent Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Co-codamol 8mg/500mg Effervescent Tablets contain:

Paracetamol 500mg

Codeine Phosphate Hemihydrate 8mg

Excipients with known effect:

Each tablet contains 418.5 mg sodium and 100 mg of sorbitol

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Effervescent Tablets

White to off white round, flat, bevelled edge tablets, plain on both sides.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

1. 1) Co-codamol 8mg/500mg Effervescent Tablets is indicated in children 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).
2. 2) As an antipyretic.

4.2 Posology and method of administration

Treatment goals and discontinuation

Before initiating treatment with Co-codamol 8mg/500mg Effervescent Tablets, 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).

Posology

Duration of treatment

Co-codamol 8mg/500mg Effervescent Tablets 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. Co-codamol 8mg/500mg Effervescent Tablets should not be used longer than necessary.

Adults: 1-2 tablets which may be repeated every 6 hours. Do not take more than 8 tablets in any 24 hour period.

Paediatric population:

Children aged 16-18 years: 1-2 tablets every 6 hours when necessary up to a maximum of 8 tablets in 24 hours.

Children aged 12 years to 15 years: The recommended Co-codamol 8mg/500mg Effervescent Tablets dose for children 12-15 years should be 1 tablet which may be repeated every 6 hours when necessary up to a maximum dose of 4 tablets in any 24 hour period.

Children aged less than 12 years: Co-codamol 8mg/500mg Effervescent Tablets 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).

Elderly: Dosage should be reduced in the elderly where there is impairment of hepatic function.

Method of administration

For oral administration.

Directions

The tablets must be dissolved in half a glass of water. The tablets dissolve more quickly in warm water, or if stirred.

4.3 Contraindications

• Diarrhoea caused by poisoning until the toxic material has been eliminated, or diarrhoea associated with pseudomembraneous colitis
• Respiratory depression
• Obstructive airways disease
• In children below the age of 12 years for the symptomatic treatment of cough and cold due to an increased risk of developing serious and life-threatening adverse reactions
• 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 that they are CYP2D6 ultra-rapid metabolisers.
• Hypersensitivity to Paracetamol, codeine phosphate hemihydrate or any excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Co-codamol 8mg/500mg Effervescent Tablets should be used with caution in patients with:

• hepatic function impairment (avoid if severe) and those with noncirrhotic
• alcoholic liver disease. The hazards of overdose are greater in those with alcoholic liver disease.
• prolonged use of Co-codamol 8mg/500mg Effervescent Tablets may cause hepatic necrosis.
• renal function impairment
• risk of toxic megacolon
• opioids should not be administered during an asthma attack
• convulsions may be induced or exacerbated
• drug abuse, dependence (including alcoholism), enhanced instability, suicidal ideation or attempts predisposed to drug abuse
• head injuries or conditions where intracranial pressure is raised
• gall bladder disease or gall stones opioids may cause biliary contraction
• gastrointestinal surgery use with caution after recent GI surgery as opioids may alter GI motility
• recent urinary tract surgery
• adrenocortical insufficiency
• hypotension and shock
• pheochromocytoma opioids may stimulate catecholamine release by inducing the release of endogenous histamine
• mild-to-moderate hepatocellular insufficiency
• severe renal insufficiency.

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

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).

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 see 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.

The risk-benefit of continued use should be assessed regularly by the prescriber.

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 inflammatory or obstructive bowel disorders, Addison's disease or myasthenia gravis. Care should also be observed if prolonged therapy is contemplated.

Where analgesics are used long-term (>3 months) with administration every two days or more frequently, headache may develop or worsen. Headache induced by overuse of analgesics (MOH medication-overuse headache) should not be treated by dose increase. In such cases, the use of analgesics should be discontinued in consultation with the doctor.

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.

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.

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 or very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarised below:

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

Concomitant use of Co-codamol 8mg/500mg Effervescent Tablets 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 Co-codamol 8mg/500mg Effervescent Tablets 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).

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.

Paediatric population

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 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 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
• Contains paracetamol.
• 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.

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 8mg/500mg Effervescent Tablets. Repeated use of Co-codamol 8mg/500mg Effervescent Tablets 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 8mg/500mg Effervescent Tablets 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 8mg/500mg Effervescent Tablets 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.

The clinical need for analgesic treatment should be reviewed regularly.

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 phosphate and paracetamol.

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.

Hyperalgesia

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.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. A dose reduction or treatment review may be indicated to resolve symptoms of hyperalgesia.

Excipients

Sodium: This medicinal product contains 418.5 mg sodium per tablet, equivalent to 20.92 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. The maximum daily dose of this product is equivalent to 167.4% of the WHO recommended maximum daily intake for sodium. Co-codamol 8mg/500mg Effervescent Tablets is considered high in sodium. This should be particularly taken into account for those on a low salt diet. Sorbitol: This medicine contains 100 mg sorbitol in each tablet. Sorbitol is a source of fructose. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Paracetamol can interact with the following:

• Drugs which alter gastric emptying time (e.g. cimetidine, ethyl alcohol, oral steroid contraceptives). These drugs reduce or delay peak paracetamol blood levels.
• Metoclopramide or domperidone increases the speed of absorption of paracetamol.
• Colestyramine reduces paracetamol absorption.
• Drugs which interfere with the metabolism of paracetamol by competition with metabolic pathways or substrates e.g. anticonvulsants (phenytoin), hepatic enzyme inducers, alcohol, barbiturates, tricyclic antidepressants. A poor diet (low protein) may also have a similar effect on the risk of serious paracetamol toxicity to hepatic enzyme inducers. Patients who have taken barbiturates, tricyclic antidepressants and alcohol may show diminished ability to metabolise large doses of paracetamol, the plasma half-life of which may be prolonged.
• The anticoagulant 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.
• Alcohol can increase the hepatotoxicity of paracetamol overdosage and may have contributed to the acute pancreatitis reported in one patient who had taken an overdosage of paracetamol.

Codeine Phosphate can interact with the following:

• CNS depressants enhanced sedative and/or hypotensive effect with alcohol, antitussives, antihistamines, anaesthetics, hypnotics, anxiolytics, antipsychotics, hydroxyzine, tricyclic antidepressants
• Antibacterials, e.g. ciprofloxacin, avoid premedication with opioids as reduced plasma ciprofloxacin concentration
• Cyclizine
• Mexiletine delayed absorption
• Metoclopramide and domperidone antagonise GI effects
• Cisapride possible antagonism of GI effects
• Dopaminergics (e.g. selegiline) possible risk of hyperpyrexia and CNS toxicity. This risk is greater with pethidine but with other opioids the risk is uncertain
• Ulcer healing drugs cimetidine inhibits the metabolism of opioid analgesics.
• Anticholinergics (e.g. atropine) risk of severe constipation which may lead to paralytic illness, and /or urinary retention
• Antidiarrhoeal drugs (e.g. loperamide, kaolin) increased risk of severe constipation

• Antihypertensive drugs (e.g. guanethidine, diuretics) enhanced

  hypotensive effect

• Opioid antagonists (e.g. buprenorphine, naltrexone, naloxone)
• Neuromuscular blocking agents additive respiratory depressant effects.
• 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).

Concomitant administration of MAOI (e.g. tranylcypromine) can potentiate the central nervous effects and other side effects of unpredictable severity, Co-codamol should not be used within two weeks after the discontinuation of MAOI treatment.

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 8mg/500mg Effervescent Tablets with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Codeine

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. 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.

Paracetamol

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 foeto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Patients should follow the advice of their doctor regarding the use of this product.

Breastfeeding

Paracetamol is excreted in breast milk but not in a clinically significant amount.

Co-codamol is contraindicated in women during breast-feeding as codeine may be secreted in breast milk and may cause respiratory depression in the infant (see section 4.3).

4.7 Effects on ability to drive and use machines

Opioid analgesics can impair mental function and can cause blurred vision and dizziness. Patients should make sure they are not affected before driving or operating machinery.

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

• 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 painkillers for headaches can make them worse.

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

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).

Description of selected adverse reactions

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.

Drug dependence

Repeated use of Co-codamol 8mg/500mg Effervescent Tablets 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 authorization 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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Paracetamol

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain in the first 24 hours. 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, disseminated intravascular coagulation, 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 have been reported.

Liver damage is likely 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.

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.

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

Opioids

The effects in overdosage will be potentiated by simultaneous ingestion of alcohol and psychotropic drugs. 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.

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.

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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Anilides, Paracetamol combinations excl. psycholeptics ATC Code: N02B E51

Paracetamol has analgesic and antipyretic properties but it has no useful anti-inflammatory properties.

Paracetamol's effects are thought to be related to inhibition of prostaglandin synthesis. Codeine is much less potent than morphine and it is inadequate against severe pain even in the largest tolerable doses. It does not cause appreciable respiratory depression but does have antitussive and constipating effects. It differs from morphine in that for normal medical use serious dependence is not frequently associated with codeine and large doses produce excitement rather than depression. Codeine 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 also binds weakly to κ opioid receptors which mediates spinal analgesia, sedation and miosis.

5.2 Pharmacokinetic properties

Codeine

Absorption and Distribution

Codeine and its salts are readily absorbed from the GI tract and ingestion of codeine phosphate produces peak plasma concentrations in 30-60 minutes. Plasma half-life is 1-4 hours.

Biotransformation and Excretion

It is metabolised in the liver; and codeine and its metabolites are entirely excreted almost by the kidney, mainly as conjugates with glucuronic acid. The plasma half-life is reported to be 3-4 hours after administration by mouth. About 86% codeine is excreted in the urine in 24 hours; 40-70% if free or conjugated morphine, 5-15% is free or conjugated norcodeine.

Paracetamol

Absorption and Distribution

Paracetamol is readily absorbed from the GI tract with peak plasma concentrations occurring about 30 minutes-2 hours after ingestion.

Biotransformation and Excretion

It is metabolised in the liver and excreted in the urine, mainly as the glucuronide and sulfate conjugates. The elimination half-life varies from about 1-4 hours. Plasma-protein binding is negligible at usual therapeutic concentrations but increases with increasing concentrations.

A minor hydroxylated 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.

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. 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

Sodium hydrogen carbonate

Sodium carbonate

Sorbitol

Saccharin sodium

Citric acid

Polyethylene glycol 6000

Povidone K25

Simethicone

6.2 Incompatibilities

None stated.

6.3 Shelf life

Tube pack: Two years.

Strip pack: Two years.

6.4 Special precautions for storage

Do not store above 25°C.

Store your medicine in the original packaging in order to protect from moisture.

6.5 Nature and contents of container

Strip packs:

The Effervescent Tablets are available in Paper/PE/Aluminium/Surlyn Strip in following pack sizes.

Pack size: 10, 12, 16, 24, 30, 50, 56, 60, 100 or 112 tablets per carton.

Pack size(s) for strip: 4 or 10 tablets in a strip.

Polypropylene tube pack:

The Effervescent Tablets are packed in white opaque plain polypropylene tube and white opaque tamper evident polyethylene cap with inbuilt desiccant.

Pack size: 10 (1 x 10) tablets per carton, 16 (2 x 8) tablets per carton, 20 (1 x

1. 20) tablets per carton, 24 (3 x 8) tablets per carton, 24 (1 x 24) tablets per carton, 30 (3 x 10) tablets per carton, 50 (5 x 10) tablets per carton, 56 (7 x 8) tablets per carton, 60 (3 x 20) tablets per carton, 100 (5 x 20) tablets per carton and 112 (14 x 8) tablets per carton.

Pack size(s) for tube pack: 8, 10, 20 or 24 tablets in a tube.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

ACCORD HEALTHCARE LIMITED

GROUND FLOOR, SAGE HOUSE

319 PINNER ROAD

HARROW

HA1 4HF

UNITED KINGDOM

8 MARKETING AUTHORISATION NUMBER(S)

PL 20075/0516

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

11/03/2009

10 DATE OF REVISION OF THE TEXT

20/04/2026