Boots Paracetamol and Codeine Extra Capsules

This medicine is indicated in patients older than 12 years of age.

For the fast relief of pain. For the short term treatment of acute moderate pain which is not considered to be relieved by other analgesics (e.g. paracetamol, ibuprofen or aspirin alone such as: headache, migraine, period pain, dental pain, neuralgia and rheumatic pain (including muscular pain and backache).

Adults

Two capsules to be taken up to four times a day, doses being repeated not more than every four hours, up to a maximum of eight capsules in 24 hours.

Children aged 16 to 18 years

One or two capsules every 6 hours when necessary up to a maximum of eight capsules in 24 hours. The minimum dosing interval is 6 hours.

Children aged 12 to 15 years

One capsule every 6 hours when necessary up to a maximum of 4 capsules in 24 hours. The minimum dosing interval is 6 hours.

Children under 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).

Elderly

In the elderly, the rate and extent of paracetamol absorption is normal, but plasma half-life is longer, and paracetamol clearance is lower than in young adults. Elderly patients, especially those who are frail or immobile, may require a reduced dose or frequency of dosing.

Renal impairment:

Patients who have been diagnosed with kidney impairment must seek medical advice before taking this medication. It is recommended, when giving paracetamol to patients with renal failure, to reduce the dose and to increase the minimum interval between each administration to at least 6 hours. The restrictions related to the use of paracetamol products in patients with renal impairment are primarily a consequence of the paracetamol content of the drug (see section 4.4).

Hepatic impairment:

Patients who have been diagnosed with hepatic impairment or Gilbert's Syndrome must seek medical advice before taking this medication. The restrictions related to the use of paracetamol products in patients with hepatic impairment are primarily a consequence of the paracetamol content of the drug (see section 4.4).

A reduced maximum daily dose should be considered in patients who are underweight (for adults, those under 50kg) (see section 4.4 and 4.9)

Method of administration

For oral administration only.

Do not exceed the recommended daily dosage or the specified number of doses because of the risk of liver damage (see section 4.4 and 4.9).

Minimum dosing interval: 4 hours for adults and 6 hours for children aged 12 to 18 years.

Treatment goals and discontinuation

Before initiating treatment with Boots Paracetamol and Codeine Extra Capsules, treatment duration and treatment goals, should be agreed together with the patient, in accordance with pain management guidelines.

Duration of treatment

Do not take for more than 3 days continuously without medical review. The duration of treatment should be as short as possible, and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a healthcare professional.

Hypersensitivity to paracetamol, caffeine, codeine, opioid analgesics or any of the ingredients.

Severe liver disease.

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 who are pregnant or breastfeeding (see section 4.6).

In patients with respiratory depression, chronic constipation or raised intracranial pressure.

In patients for whom it is known they are CYP2D6 ultra-rapid metabolisers.

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

Paracetamol should be administered only with particular caution under the following circumstances:

• Hepatocellular insufficiency

• Chronic alcoholism

• Renal failure (GFR ≤ 50 ml/min)

• Gilbert's Syndrome (familial non-haemolytic jaundice)

• Concomitant treatment with medicinal products affecting hepatic function

• Glucose-6-phosphatase dehydrogenase deficiency

• Haemolytic anaemia

• Glutathione deficiency

• Dehydration

• Chronic malnutrition

• The elderly, adults and adolescents weighing less than 50 kg

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 the underlying cause of HAGMA in patients with multiple risk factors.

Glutathione deficiency can also increase the risk of hepatotoxicity with paracetamol use, even at therapeutic doses. Caution is advised for patients at risk of glutathione depletion (see section 4.9).

Hepatotoxicity at therapeutic dose

Cases of paracetamol induced hepatotoxicity, including fatal cases, have been reported in patients taking paracetamol at doses within the therapeutic range. These cases were reported in patients with one or more risk factors for hepatotoxicity including low body weight (adults <50 kg), renal and hepatic impairment, chronic alcoholism, concomitant intake of hepatotoxic drugs and in acute and chronic malnutrition (low reserves of hepatic glutathione). Paracetamol should be administered with caution to patients with these risk factors. Caution is also advised in patients on concomitant treatment with drugs that induce hepatic enzymes and in conditions which may predispose to glutathione deficiency (see section 4.9).

Dosage adjustment of paracetamol should be considered where there are risk factors for glutathione deficiency or hepatotoxicity and for those of low weight (for adults weighing less than 50kg).

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.

Prolonged use of any type of painkiller for headaches can make them worse. If this situation is experienced or suspected, medical advice should be obtained, and treatment should be discontinued. The diagnosis of medication overuse headache should be suspected in patients who have frequent or daily headaches despite (or because of) the regular use of headache medications.

Precaution should be observed in patients with asthma who are sensitive to acetylsalicylic acid since mild bronchospasms are reported in association with paracetamol (cross reaction).

Do not take more than the label tells you to.

If symptoms persist for more than 3 days or get worse, or if any other symptoms occur, treatment should be discontinued, and a physician consulted.

Do not give to children under 12.

Contains paracetamol.

Do not take anything else containing paracetamol or codeine while taking this medicine.

Immediate medical advice should be sought in the event of overdosage even if the patient feels well because the risk of irreversible liver damage (see section 4.9).

Keep all medicines out of the reach of children.

Patients with obstructive bowel disorders or acute abdominal conditions should consult a doctor before using this product.

Patients with a history of cholecystectomy should consult a doctor before using this product as it may cause acute pancreatitis in some patients.

Excessive intake of caffeine (e.g. coffee, tea and some canned drinks) should be avoided while taking this product (see section 4.9).

Patients taking, or who have taken, monoamine oxidase inhibitors (MAOIs) within the preceding two weeks (see section 4.5) should not take this product.

Codeine, as with other opioids should be used with caution in patients with hypotension, hypothyroidism or head injury.

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.

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.

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 summarised 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.

Codeine 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 Boots Paracetamol and Codeine Extra Capsules. Repeated use of Boots Paracetamol and Codeine Extra Capsules 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 Boots Paracetamol and Codeine Extra Capsules 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).

The patient should be made aware of the risks and signs of OUD as set out in the package leaflet. If these signs occur, patients should contact their physician.

For patients who experience signs and symptoms of OUD, and/or exhibit drug seeking behaviours, review of concomitant opioids and psycho-active drugs (like benzodiazepines) and consultation with an addiction specialist may be required.

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. A dose reduction or treatment review may be indicated. Hyperalgesia may be diagnosed if the patient misuses this medicine and uses long-term opioid therapy and 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.

Drug withdrawal syndrome

Addiction can cause drug withdrawal syndrome upon abrupt cessation of therapy or dose reduction.

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.

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

Concomitant use of this medicine and sedative medicines such as benzodiazepines or related drugs (such as pregabalin and gabapentin) 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 this medicine 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).

Information about some of the ingredients in this medicine

This medicine contains Ponceau 4R (E124) which may cause allergic reactions.

This medicine contains less than 1 mmol sodium (23 mg) per capsule, that is to say essentially 'sodium-free'.

The label will state:

Talk to a doctor at once if you take too much of this medicine, even if you feel well.

Front of pack

• Can cause addiction

• Contains opioid

• For three days use only

Back of pack

• List of indications as agreed in 4.1 of the SPC

• If you need to take this medicine continuously for more than 3 days you must speak to your doctor or pharmacist for advice

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. If you take this medicine for headaches for more than 3 days it can make them worse.

The leaflet (or combined label/leaflet) will 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.

'Headlines' section (to be prominently displayed)

• This medicine can only be used for.....(indications)

• You should only take this product for a maximum of 3 days at a time. If you need to take it for longer than 3 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 3 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 3 days it can make them worse.

“What this medicine is for” section

• Succinct description of the indications from 4.1 of the SPC

“Before you take this medicine” section

• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it.

• If you take a painkiller for headaches for more than 3 days it can make them worse.

“How to take this medicine” section

• Do not take for more than 3 days. Boots Paracetamol and Codeine Extra Capsules should be used for 3 days only to relieve symptoms. If no effective pain relief is achieved while taking the medicine, you should seek the advice of a healthcare professional

• This medicine contains codeine and can cause addiction if you take it continuously for more than 3 days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms.

“Possible side effects” section

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.go.uk/yellowcard, or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

“How do I know if I am addicted?” section

If you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to you doctor:

• You need to take the medicine for longer periods of time

• You need to take more than the recommended amount

• When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again

Paracetamol:

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by cholestyramine. Cholestyramine should not be administered within one hour of taking paracetamol.

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.

Paracetamol is metabolized in the liver and can therefore interact with other medicines that follow the same pathway or may inhibit or induce this route (e.g. barbiturates, such as phenobarbitone, tricyclic antidepressants, alcohol, carbamazepine, phenytoin, primidone, rifampicin, St John's Wort or other drugs that induce liver enzymes), causing hepatotoxicity, particularly in overdose (see section 4.9).

In case of concomitant treatment with probenecid, the dose of paracetamol should be reduced because probenecid reduces the clearance of paracetamol by 50% since it prevents the conjugation of paracetamol with glucuronic acid.

There is limited evidence suggesting that paracetamol may affect chloramphenicol pharmacokinetics, but its validity has been criticized and evidence of a clinically relevant interaction appears to be lacking. Although no routine monitoring is needed, it is important to bear in mind this potential interaction when these two medications are concomitantly administered, especially in malnourished patients.

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 risk factors (see section 4.4).

Caffeine:

Caffeine, a CNS stimulant, has an antagonistic effect towards the action of sedatives and tranquilizers. Caffeine may enhance the tachycardia effect of some decongestants.

Codeine:

Codeine may antagonize the effects of metoclopramide and domperidone on gastrointestinal motility.

Concomitant use of codeine with central nervous system depressants (e.g. alcohol, hypnotics, sedatives including benzodiazepines, tricyclic antidepressants, antipsychotics including phenothiazines, general anaesthetics and centrally acting muscle relaxants) may cause additive CNS depression and respiratory depression and hypotensive effects.

Opioid analgesics should be given with care to patients receiving monoamine oxidase inhibitors. The depressant effects of codeine are enhanced by depressants of the central nervous system including alcohol; these interactions are unlikely to be significant at the dosage involved.

MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has not been documented with codeine, it is possible that a similar interaction may occur and therefore the use of codeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.

Opiate analgesics may interact with monoamine oxidase inhibitors (MAOIs) and result in serotonin syndrome. It is recommended that the product should not be taken concurrently or within two weeks of stopping treatment with a MAOI.

Gabapentinoids and sedative medicines such as benzodiazepines or related drugs:

The concomitant use of Boots Paracetamol and Codeine Extra Capsules with gabapentinoids (gabapentin and pregabalin) or sedative medicines such as benzodiazepines or related drugs may result in respiratory depression, hypotension, profound sedation, coma and death (see section 4.4).

Pregnancy:

Boots Paracetamol and Codeine Extra Capsules should not be used during pregnancy (see section 4.3).

Codeine

In view of the possible association of codeine with respiratory depression and heart malformations. This includes maternal use during labour because of the potential for respiratory depression in the neonate.

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

The patient should be advised of the risk of neonatal opioid withdrawal syndrome, and it should be ensured that appropriate treatment will be available.

Caffeine

Due to the caffeine content of this product it should not be used during pregnancy.

Paracetamol

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

Lactation:

Boots Paracetamol and Codeine Extra Capsules should not be used during breastfeeding (see section 4.3) as codeine may be excreted in breast milk and may cause respiratory depression in the infant.

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.

Although significant caffeine toxicity has not been observed in breastfed infants, caffeine may have a stimulating effect on the infant.

Due to the caffeine content of this product it should not be used during breastfeeding.

Fertility:

There are no data available regarding the influence of this medicine on fertility.

Patients should be advised not to drive or operate machinery if affected by dizziness or sedation.

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 a '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

Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive post-marketing experience at therapeutic/labelled dose and considered attributable are tabulated below by system. The following convention has been utilized for the classification of undesirable effects:

very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, 363 <1/1000), very rare (<1/10,000), not known (cannot be estimated from the available data).

Paracetamol:

* There have been cases of bronchospasm with paracetamol, but these are more likely in asthmatics sensitive to aspirin or other NSAIDs.

** 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.

Caffeine

When the recommended paracetamol-caffeine-codeine dosing regimen is combined with dietary caffeine intake, the resulting higher dose of caffeine may increase the potential for caffeine-related adverse effects such as insomnia, restlessness, anxiety, irritability, headaches, gastrointestinal disturbances and palpitations.

Codeine

Adverse reactions identified during post-marketing use are listed below by MedDRA system organ class.

* Repeated use of Boots Paracetamol and Codeine Extra Capsules 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.

Overuse of this product, defined as consumption of quantities in excess of the recommended dose, or consumption for a prolonged period of time may lead to physical or psychological dependency. Symptoms of restlessness and irritability may result when treatment is stopped.

Paracetamol

Liver damage is possible in patients who have taken more than recommended doses of paracetamol.

Ingestion of paracetamol at therapeutic doses 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 depleted e.g. diet (malnutrition, fasting, dietary restrictions, eating disorders and starvation), catabolic states (sepsis), cachexia and chronic illness (cystic fibrosis, liver disease, HIV, and muscular dystrophy).

Symptoms

Symptoms of paracetamol overdosage in the first 24 hours include pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

Immediate treatment is essential in the management of paracetamol overdose. Despite a lack of significant early symptoms, patients should be referred to hospital urgently for immediate medical attention. Symptoms may be limited to nausea or vomiting and may not reflect the severity of overdose or the risk of organ damage. Management should be in accordance with established treatment guidelines, see BNF overdose section.

Treatment with activated charcoal should be considered if the overdose has been taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours or later after ingestion (earlier concentrations are unreliable) Treatment with N-acetylcysteine may be used up to 24 hours after ingestion of paracetamol, however, the maximum protective effect is obtained up to 8 hours post-ingestion. The effectiveness of the antidote declines sharply after this time. If required the patient should be given intravenous N-acetylcysteine, in line with the established dosage schedule. If vomiting is not a problem, oral methionine may be a suitable alternative for remote areas, outside hospital. Management of patients who present with serious hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or a liver unit.

Codeine

Symptoms

Central nervous system depression may develop as well as respiratory depression. The pupils may be pin-point in size and nausea and vomiting are common. Possible but unlikely effects are hypotension and tachycardia. The effects in overdosage of codeine are potentiated by simultaneous ingestion of alcohol and psychotropic drugs.

Management

If coma or respiratory depression is present give naloxone, preferably intravenously, at a dose of 0.4 to 2mg for adults and 0.01mg/kg body weight for children. Repeat the dose if there is no response within two minutes. Large doses (4mg) of naloxone may be required in a seriously poisoned patient. Intramuscular naloxone is an alternative in the event that IV access is not possible, or if the patient is threatening to self-discharge when it may help reduce the risk of respiratory arrest. Failure of a definite opioid overdose to respond to large doses of naloxone suggests that another CNS depressant drug or brain damage is present.

Observe the patient carefully for recurrence of CNS and respiratory depression. Repeated doses of naloxone may be required. If so, intravenous infusion of naloxone may be useful. An infusion of 60% of the initial dose per hour is a useful starting point. A 200 microgram/ml solution for infusion using an IV pump can be used and the dose adjusted to clinical response. Infusions are not a substitute for frequent review of the patient's clinical state.

A clear airway, adequate ventilation and oxygenation should be established without delay if consciousness is impaired.

Consider activated charcoal (50g for adults; 10-15g for children) if an adult presents within 1 hour of ingestion of more than 350mg, or a child more than 5mg/kg, provided the airway can be protected.

Observe patient for at least 4 hours after ingestion. Other supportive measures should be taken as indicated by the patient's progress.

Caffeine

Symptoms

Overdose of caffeine may result in epigastric pain, vomiting, diuresis, tachycardia or cardiac arrhythmia, CNS stimulation (insomnia, restlessness, excitement, agitation, nervousness, jitteriness, tremors and convulsions).

The symptoms of caffeine overdose may be masked by the depression of consciousness associated with possible codeine overdose when associated with this combination.

It must be noted that for clinically significant symptoms of caffeine overdose to occur with this product, the amount ingested would be associated with serious paracetamol-related liver toxicity.

Management

Patients should receive general supportive care (e.g. hydration and maintenance of vital signs). The administration of activated charcoal may be beneficial when performed within one hour of the overdose, but can be considered for up to four hours after the overdose. The CNS effects of overdose may be treated with intravenous sedatives.

Summary

Treatment of overdose with this medicine requires assessment of plasma paracetamol levels for antidote treatment, with signs and symptoms of codeine and caffeine toxicity being managed symptomatically.

Paracetamol is an analgesic with antipyretic activity.

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, has been shown to be effective in acute nociceptive pain.

Caffeine is a central nervous system stimulant and contributes to the feeling of well being. Caffeine has also been shown to act as an analgesic adjuvant when used in combination with peripherally acting analgesics such as paracetamol

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 to 4 hours. Plasma protein binding is negligible at usual therapeutic concentrations, although this is dose dependent.

Codeine phosphate is absorbed from the gastrointestinal tract and peak plasma concentrations occur after about one hour. Codeine is metabolised by O- and N-demethylation in the liver to morphine and norcodeine. Codeine and its metabolites are excreted almost entirely by the kidney, mainly as conjugates with glucuronic acid. The plasma half life has been reported to be between 3 and 4 hours.

Caffeine is absorbed readily after oral administration and is widely distributed throughout the body. Caffeine passes readily into the CNS and into saliva. In adults, caffeine is metabolised almost completely via oxidation, demethylation and acetylation and is excreted in the urine as various metabolites with only about 1% being excreted unchanged. Elimination half life is approximately 3 to 6 hours in adults.

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

Sodium lauryl sulphate

Magnesium stearate

Sodium starch glycolate (type A)

Capsule shell

Gelatin

Yellow iron oxide (E172)

Titanium dioxide (E171)

Quinoline yellow (E104)

Ponceau 4R (E124)

Printing ink

Black iron oxide (E172)

Shellac

Propylene glycol

Not applicable.

24 months.

Do not store above 30°C. Store in the original package.

A child-resistant push through pack of opaque 250 micron PVC/40gsm PVdC blisters, heat sealed to 35gsm Glassine paper/9 micron soft temper aluminium foil.

Pack sizes: 6, 8, 12, 16, 18, 24, 32

Not applicable.