PARACETAMOL CODEINE AND CAFFEINE 500 MG / 8 MG / 30 MG SOLUBLE TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Paracetamol/Co­deine/Caffeine 500 mg/8 mg/30 mg soluble tablets.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each soluble tablet contains paracetamol 500 mg, codeine phosphate hemihydrate 8 mg and caffeine 30 mg.

Excipients with known effects

Each effervescent tablet contains 4.5 mg of aspartame

Each effervescent tablet contains 403.24 mg of sodium.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Soluble tablets.

White to off-white coloured circular flat bevelled tablets plain on both sides.

4.1 Therapeutic indications

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.

Paracetamol/Co­deine/Caffeine soluble tablets are recommended for the relief of migraine, headache, backache, rheumatic pain, period pain, dental pain, strains and sprains and sciatica.

4.2 Posology and method of administration

Posology

Adults (including the elderly)

One to two tablets dissolved in water every 4 to 6 hours when necessary up to a maximum of 8 tablets daily.

Paediatric , population

Children aged 16 years – 18 years:

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

Children aged 12 years – 15 years:

One tablet dissolved in water every 6 hours when necessary up to a maximum of 4 tablets daily.

Children aged less than 12 years

Codeine should not be used in children below the age of 12 years because of the risk of opioid toxicity due to the variable and unpredictable metabolism of codeine to morphine (see sections 4.3 and 4.4).

Method of administration

For oral administration only.

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, codeine, caffeine or to any of the excipients listed in section 6.1, or opioid analgesics.

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 breast-feeding (see section 4.6).

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

4.4 Special warnings and precautions for use

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.

Do not exceed the stated dose.

Patients should be advised to consult their doctor if their headaches become persistent.

Patients should be advised not to take other paracetamol or codeine-containing products concurrently.

If symptoms persist, consult your doctor.

Keep this medicine out of the sight and reach of children.

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

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

Paracetamol/Co­deine/Caffeine soluble tablet contains 403.24 mg of sodium and should be avoided by patients on a low sodium diet.

Paracetamol/Co­deine/Caffeine soluble tablet also contains aspartame (a source of phenylalanine) and so should not be taken by people with phenylketonuria.

CYP2D6 metabolism

Codeine is metabolised by the liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme an adequate analgesic effect will not be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an extensive or ultra-rapid metaboliser there is an increased risk of developing side effects of opioid toxicity even at commonly prescribed doses. These patients convert codeine into morphine rapidly resulting in higher than expected serum morphine levels.

General symptoms of opioid toxicity include confusion, somnolence, shallow breathing, small pupils, nausea, vomiting, constipation and lack of appetite. In severe cases this may include symptoms of circulatory and respiratory depression, which may be life-threatening and very rarely fatal.

Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:

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 label will state:

Front of pack

Can cause addiction.

For three days use only.

Back of pack

Paracetamol/Co­deine/Caffeine soluble tablet are for the short term treatment of acute moderate pain when other painkillers have not worked. Wait at least four hours after taking any other painkiller before you take this medicine.

For the treatment of migraine, headache, dental pain, period pain, backache, rheumatic pain, strains and sprains and sciatica.

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:

Headlines section (to be prominently displayed)

This medicine is for the short term treatment of acute moderate pain when other painkillers have not worked.

You should only take this medicine 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.

Paracetamol/Co­deine/Caffeine soluble tablets can be used in patients over 12 years age for the short term relief of moderate pain that is not relieved by other painkillers such as paracetamol or ibuprofen alone.

They can be used for migraine, headache, dental pain, period pain, strains and sprains, backache, rheumatic pain and sciatica.

Section 2: Before taking

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 a painkiller for headaches for more than three days it can make them worse.

This medicine should not be taken for more than 3 days. If the pain does not improve after 3 days, talk to your doctor for advice.

Possible withdrawal effects

This medicine contains codeine and can cause addiction if you take it continuously for more than three 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.

Some people may have side-effects when taking this medicine. If you have any unwanted side-effects you should seek advice from your doctor, pharmacist or other healthcare professional. Also you can help to make sure that medicines remain as safe as possible by reporting any unwanted side-effects via the internet at www.yellowcard.qov.uk; alternatively you can call Freephone 0808 100 3352 (available between 10am-2pm Monday – Friday) or fill in a paper form available from your local pharmacy.

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 your doctor:

You need to take the medicine for longer periods of time

You need to take more than the recommended dose

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

4.5 Interaction with other medicinal products and other forms of interaction

The speed of absorption of paracetamol may be increased by metoclopramide or domperidone and absorption reduced by colestyramine. The anticoagulant effect of warfarin and other coumarins may be enhanced by prolonged regular daily use of paracetamol with increased risk of bleeding; occasional doses have no significant effect.

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

Opioid analgesics should be given with care to patients receiving monoamine oxidase inhibitors. The effect of CNS depressants (including alcohol) may be potentiated by codeine; these interactions are unlikely to be significant at the dosage involved.

4.6 Fertility, pregnancy and lactation

Pregnancy

Use during pregnancy should be avoided, unless advised by a physician. This includes maternal use during labour because of the potential for respiratory depression in the neonate.

The safety of paracetamol-caffeine-codeine during pregnancy has not been established relative to the possible adverse effects of foetal development and should be avoided during pregnancy due to the possible increased risk of lower birth weight and spontaneous abortion associated with caffeine consumption.

Breast-feeding

Codeine should not be used during breast-feeding (see section 4.3).

At normal therapeutic doses codeine and its active metabolite may be present in breast milk at very low doses and is unlikely to adversely affect the breast fed infant. However, if the patient is an ultra-rapid metaboliser of CYP2D6, higher levels of the active metabolites, 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 breast-fed infants, caffeine may have a stimulating effect on the infant.

Due to the caffeine content of this product it should not be used if you are pregnant or breast-feeding.

4.7 Effects on ability to drive and use machines

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 medicinal products 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:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely

4.8 Undesirable effects

Adverse events from historical clinical trial data are both infrequent and from small patient exposure. Accordingly, events reported from extensive postmarketing experience at therapeutic/la­belled dose and considered attributable are tabulated below by system.

The frequency of these adverse events is not known (cannot be estimated from available data).

Paracetamol

Hepatobiliary disorders

Hepatic dysfunction

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

Very rare cases of serious skin reactions have been reported.

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. The frequency of these reactions is not known.

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, website www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Overuse of this medicine, 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.

Codeine

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

Symptoms

An overdose of codeine is characterised, in the first phase, by nausea and vomiting. An acute depression of the respiratory centre can cause cyanosis, slower breathing, drowsiness, ataxia and, more rarely, pulmonary oedema. Respiratory pauses, miosis, convulsion, collapse and urine retention. Signs of histamine release have been observed as well.

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.

Paracetamol

Liver damage is possible in adults who have taken 10 g or more of paracetamol. Ingestion of 5 g 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 medicinal products 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 overdose in the first 24 hours are pallor, nausea, vomiting, anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may occur. In severe poisoning, hepatic failure may progress to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acute renal failure with acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria, may develop even in the absence of severe liver damage. Cardiac arrhythmias and pancreatitis have been reported.

Management

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

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

Caffeine

Symptoms

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

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 Paracetamol/Co­deine/Caffeine soluble tablets requires assessment of plasma paracetamol levels for antidote treatment, with signs and symptoms of codeine and caffeine toxicity being managed symptomatically.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other analgesics and antipyretics – anilides,

ATC Code: N02B E51

Paracetamol is a well established analgesic, caffeine has a stimulating effect on the central nervous system and possesses a weak diuretic action. Codeine phosphate has moderate analgesic and weak cough-suppressant effects.

Codeine is a centrally acting weak analgesic. Codeine exerts its effect through p opioid receptors, although codeine has low affinity for these receptors, and its analgesic effect is due to its conversion to morphine. Codeine, particularly in combination with other analgesics such as paracetamol, has been shown to be effective in acute nociceptive pain.

5.2 Pharmacokinetic properties

Paracetamol is rapidly and almost completely absorbed from the gastrointestinal tract. Concentration of the drug in plasma reaches a peak in 30 – 60 minutes and the plasma half-life is 1 – 4 hours. Paracetamol is relatively uniformly distributed throughout most body fluids and exhibits variable protein binding. Excretion is almost exclusively renal, in the form of conjugated metabolites.

Codeine phosphate is well absorbed after administration and distributes widely throughout the body. 86% of an oral dose is excreted in the urine within 24 hours, 40 – 70% of this being free or conjugated codeine, 5 – 15% free or conjugated morphine, 10 – 20% free or conjugated norcodeine, and trace amounts may be free or conjugated normorphine.

Caffeine is rapidly but irregularly absorbed after oral administration, absorption is pH – related. After an oral dose of 100mg, peak plasma concentrations of 1.5 – 2 pg/ml are attained within 1 – 2 hours. Plasma half-life = 4 – 10 hours. Caffeine rapidly distributes throughout the body water, and is approximately 15% bound to plasma proteins. In 48 hours, 45% of a dose is excreted in the urine as l-methylxanthine and l-methyluric acid.

5.3 Preclinical safety data

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

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Citric acid (anhydrous),

Povidone (K30),

Sodium hydrogen carbonate,

Saccharin sodium,

Sodium carbonate anhydrous,

Simeticone,

Polysorbate 80,

Aspartame (E951).

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 30°C. Store in the original package.

6.5 Nature and contents of container

Strip formed from 4 ply laminate (paper/LDPE/a­luminium/LDPE).

Pack sizes of 16, 24 or 32 tablets.

6.6. Special precautions for disposal

No special requirements for disposal.

7 MARKETING AUTHORISATION HOLDER

Cipla (EU) Limited,

Dixcart house, Addlestone Road,

Bourne Business Park, Addlestone,

Surrey, KT15 2LE, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 36390/0050