Document: spc-doc_PL 20417-0064 change

• spc-doc_PL 20417-0064
• spc-doc_PL 36390-0050

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Paracetamol, Codeine and Caffeine 500mg/8mg/30mg Soluble Tablets.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For a full list of excipients see section 6.1.

3    PHARMACEUTICAL FORM

Effervescent tablet.

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

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Codeine is indicated in patients older than 12 years of age for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin 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

Adults (including the elderly)

2 tablets dissolved in at least half a tumbler of water. These doses may be given up to 3 or 4 times a day if necessary. The dose should not be repeated more frequently than every 4 hours. Do not take for more than 3 days without consulting a doctor.

Paediatric population:

Children and adolescents aged 12 - 18 years:

2 tablets dissolved in at least half a tumbler of water. The dose may be given up to 3 or 4 times a day if necessary. The dose should not be repeated more frequently than every 4 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 sections 4.3 and 4.4).

Do not take for more than 3 days continuously and if no effective pain relief is achieved the patients/carers should be advised to seek medical review.

4.3 Contraindications

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

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).

Paracetamol, Codeine and Caffeine 500mg/8mg/30mg Soluble Tablets.

are not recommended in children and adolescents between 12 and 18 years who have

breathing problems

Use of codeine containing products is contraindicated in mothers who are breast feeding unless prescribed by a doctor. (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 out of the sight and 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

Each tablet contains 403.24 mg of sodium and may be harmful to people on a low sodium diet.

The tablets also contain 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:

Population	Prevalence %
African/Ethiopian	29%
African American	3.4% to 6.5%
Asian	1.2% to 2%
Caucasian	3.6% to 6.5%
Greek	6.0%
Hungarian	1.9%
Northern	1%-2%
European

Post-operative use in children

There have been reports in the published literature that codeine given postoperatively in children after tonsillectomy and/or adenoidectomy for obstructive sleep apnoea, led to rare, but life-threatening adverse events including death (see also section 4.3). All children received doses of codeine that were within the appropriate dose range; however there was evidence that these children were either ultra-rapid or extensive metabolisers in their ability to metabolise codeine to morphine.

Children with compromised respiratory function

Codeine is not recommended for use in children in whom respiratory function might be compromised including neuromuscular disorders, severe cardiac or respiratory conditions, upper respiratory or lung infections, multiple trauma or extensive surgical procedures. These factors may worsen symptoms of morphine toxicity.

The label will state:

Front of Pack

•    Can cause addiction.

•    For three days use only.

Back of Pack

•    For the short term treatment of acute moderate pain when other painkillers have not worked. Do not take less than four hours after taking other painkillers.

•    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 can only be used for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin 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.

Section 1: What the medicine is for

Paracetamol, Codeine and Caffeine Tablets can be used in patients over 12 years of age for the short term treatment of acute moderate pain which is not relieved by paracetamol, ibuprofen or aspirin alone.

They are used to relieve 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.

Section 3: Dosage

•    Do not take for more than 3 days. If you need to use this medicine for more than three days you must speak to your doctor or pharmacist for advise.

•    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.

Section 4: Side effects

•    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.vellowcard.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.

How do I know if I am addicted?

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.

Lactation

Codeine-containing products must not be used while breast feeding unless prescribed by a doctor. (see section 4.3).

In nursing mothers, who are ultra-rapid metabolisers of codeine, higher than expected serum and breast milk morphine levels can occur. Morphine toxicity in babies can cause excessive somnolence, hypotonia and difficulty breast feeding or breathing. In severe cases respiratory depression and death can occur. The lowest effective dose should be used, for the shortest possible time. Nursing mothers should be informed about carefully monitoring the infant during treatment for any sign and symptoms of morphine toxicity such as increased drowsiness or sedation, difficulty breast feeding, breathing difficulties, and decreased tone, and seeking immediate medical care if such symptoms or signs are noticed.

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 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.

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

Body System	Undesirable effect
Blood and lymphatic	Thrombocytopenia
system disorders	Agranulocytosis
Immune system disorders	Anaphylaxis
	Cutaneous hypersensitivity reactions including skin rashes, angiodema and Stevens Johnson syndrome/toxic epidermal necrolysis
Respiratory, thoracic and mediastinal disorders	Bronchospasm*
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.

Caffeine

Body System	Undesirable effect
Central nervous system	Nervousness
	Dizziness

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.

Body System	Undesirable effect
Psychiatric disorders	Drug dependency can occur after prolonged use of codeine at higher doses
Gastrointestinal disorder	Constipation, nausea, vomiting, dyspepsia, dry mouth, acute pancreatitis in patients with a history of cholecystectomy
Nervous system disorder	Dizziness, worsening of headache with prolonged use, drowsiness.
Skin and subcutaneous tissue disorder	Pruritus, sweating

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the yellow card scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

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.

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.

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

5.1 Pharmacodynamic properties

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 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

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

None stated.

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.