SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Aspirin and Codeine Tablets BP

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Active ingredient    mg

Codeine Phosphate EP    8.00

Aspirin    400.00

3    PHARMACEUTICAL FORM

Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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, neuralgia, toothache, period pain and rheumatic pains.

4.2    Posology and method of administration

For oral administration.

Adults over 18 years: 1 to 2 tablets.

This dose may be taken, up to 4 times a day at intervals of not less than 4 hours.

Children aged 16 years to 18 years: The recommended dose for children 16 years and older is 1 to 2 tablets every 6 hours when necessary up to a maximum of 8 tablets in 24 hours.

Do not give to children aged under 16 years, unless specifically indicated (e.g. for Kawasaki’s disease).

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).

Elderly: The normal adult dose is still appropriate in the elderly.

Do not take for more than 3 days continuously without medical review.

4.3 Contraindications

Hypersensitivity to any of the ingredients. Active peptic ulceration or a history of ulceration, haemophilia or other clotting disorders. Gout, asthma, urticaria, angiodema, rhinitis or other evidence of hypersensitivity to aspirin.

Aspirin should be avoided in patients with severe renal or hepatic impairment. Obstructive airways disease, respiratory depression, acute alcoholism, where there is as risk of paralytic ileus, head injuries and conditions in which intracranial pressure is raised.

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 they are CYP2D6 ultra-rapid metabolisers.

4.4 Special warnings and precautions for use

If symptoms persist consult your doctor.

There is a possible association between aspirin and Reye's syndrome when given to children. Reye’s syndrome is a very rare disease, which affects the brain and liver, and can be fatal. For this reason aspirin should not be given to children aged under 16 years unless specifically indicated (e.g. for Kawasaki’s disease).

Codeine should be taken with caution or in reduced doses by patients with hypotension, decreased respiratory reserve, convulsive disorders, hypothyroidism, adrenocortical insufficiency, impaired kidney or liver function, prostatic hypertrophy, shock, inflammatory or obstructive bowel disorders and myasthenia gravis.

Aspirin and other NSAIDs may cause salt and water retention and renal failure especially in patients with pre-existing renal impairment. Aspirin should be used with caution by patients with asthma, allergic disease, dehydration, glucose-6-phosphate dehydrogenase deficiency and the elderly.

Keep all medicines out of the reach of children.

The Label will state:

Front of pack

•    Can cause addiction

•    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 should see your doctor or pharmacist

•    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:

‘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. If you need to use this medicine for more than 3 days you must speak to your doctor or pharmacist.

•    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

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. 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

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:

Population Afri can/Ethi opi an African American Asian Caucasian Greek Hungarian Northern 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.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol and corticosteroids may enhance the effects of aspirin on the gastrointestinal tract. Aspirin may enhance the effects of coumarin anticoagulants and oral hypoglycaemics of sulphonylurea type. The toxicity of methotrexate may be enhanced by concomitant use of aspirin. Aspirin diminishes the uricosuric action of probenecid and sulphinpyrazone.

Codeine may delay the absorption of mexiletine and thus reduce the antiarrhythmic effect of the latter. The depressant effects of codeine are enhanced by depressants of central nervous system such as hypnotics, sedatives, tricyclic antidepressants and phenothiazines. Codeine may antagonise the gastrointestinal effects of metoclopramide and domperidone.

4.6 Fertility, pregnancy and lactation

The safety of aspirin and codeine tablets during pregnancy has not been established and use in this period should be avoided. The use of aspirin during pregnancy, particularly during the third trimester, should be avoided since the drug may affect maternal and new born haemostatic mechanisms, leading to an increased risk of haemorrhage. Aspirin may also delay the onset and increase the duration of labour. With high doses, there may be premature closure of the ductus arteriosus, leading possibly to persistent pulmonary hypertension. In addition, codeine during pregnancy has been associated with respiratory and heart malformations.

As aspirin is secreted into breast milk in low concentrations, use of aspirin and codeine tablets should be avoided during lactation because of the risk of Reye's syndrome and the fact that high doses of aspirin could potentially impair platelet function.

Codeine should not be used during breastfeeding (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 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.

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Dyspepsia, nausea, vomiting, constipation, increased bleeding time, drowsiness, confusion, dry mouth, sweating, facial flushing, vertigo, bradycardia, tachycardia, palpitations, orthostatic hypotension, hypothermia, restlessness, changes of mood, miosis, respiratory depression, difficulty in micturition and possibly ureteric or biliary spasm, headache, hallucinations, dysphoria, decreased libido or potency, pruritis. Less commonly irritation of the gastrointestinal mucosa may lead to erosion, ulceration, gastrointestinal bleeding. Hepatotoxicity which occurs rarely.

Aspirin may precipitate bronchospasm and induce asthma attacks or other hypersensitivity reactions including urticaria, rhinitis and angioneurotic oedema in susceptible individuals.

Aspirin may also cause salt and water retention as well as deterioration in renal function (see also section 4.4).

Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is then stopped.

Prolonged use of a painkiller for headaches can make them worse.

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

Salicylate poisoning is usually associated with plasma concentrations >350mg/L (2.5mmol/L). Most adult deaths occur in patients whose concentrations exceed 700mg/L (5.1mmol/L). Single doses less than 100mg/kg are unlikely to cause serious poisoning.

Common features of salicylate poisoning include vomiting, dehydration, tinnitus, vertigo, deafness, sweating, warm extremities with bounding pulses, increased respiratory rate and hyperventilation. Some degree of acid-base disturbance is present in most cases.

A mixed respiratory alkalosis and metabolic acidosis with normal or high arterial pH (normal or reduced hydrogen ion concentration) is usual in adults and children over the age of 4 years. In children aged 4 years or less, a dominant metabolic acidosis with low arterial pH (raised hydrogen ion concentration) is common. Acidosis may increase salicylate transfer across the blood brain barrier.

Uncommon features of salicylate poisoning include haematemesis, hyperpyrexia, hypoglycaemia, hypokalaemia, thrombocytopaenia, increased INR/PTR, intravascular coagulation, renal failure and non-cardiac pulmonary oedema.

Central nervous system features including confusion, disorientation, coma and convulsions are less common in adults than in children.

Give activated charcoal if an adult presents within one hour of ingestion of more than 250mg/kg. The plasma salicylate concentration should be measured, although the severity of poisoning cannot be determined from this alone and the clinical and biochemical features must be taken into account. Elimination is increased by urinary alkalinisation, which is achieved by the administration of 1.26% sodium bicarbonate. The urine pH should be monitored. Correct metabolic acidosis with intravenous 8.4% sodium bicarbonate (first check serum potassium). Forced diuresis should not be used since it does not enhance salicylate excretion and may cause pulmonary oedema.

Haemodialysis is the treatment of choice for severe poisoning and should be considered in patients with plasma salicylate concentrations >700mg/L (5.1mmol/L), or lower concentrations associated with severe clinical or metabolic features. Patients under 10 years or over 70 have increased risk of salicylate toxicity and may require dialysis at an earlier stage.

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

Central nervous system depression, including respiratory depression, may develop but is unlikely to be severe unless other sedative agents have been coingested, including alcohol, or the overdose is very large. The pupils may be pin-point in size; nausea and vomiting are common. Hypotension and tachycardia are possible but unlikely.

Management 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 350mg or a child more than 5mg/kg.

Give naloxone if coma or respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life so large and repeated doses may be required in a seriously poisoned patient. Observe for at least 4 hours after ingestion, or eight hours if a sustained release preparation has been taken.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Aspirin has analgesic, antipyretic and anti-inflammatory actions which are considered to be due to inhibition of the synthesis of prostaglandins.

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

5.2 Pharmacokinetic properties

Absorption of non-ionised aspirin occurs in the stomach and intestine. Some aspirin is hydrolysed to salicylate in the gut wall. After absorption aspirin is rapidly converted to salicylate but during the first 20 minutes following oral administration, aspirin is the predominant form of the drug in the plasma. Aspirin is bound to plasma proteins and is widely distributed. Plasma aspirin concentrations decline rapidly (half-life 15-20 minutes) as plasma salicylate concentrations increase.

Salicylate is mainly eliminated by hepatic metabolism the metabolites including salicylic acid, salicyl phenolic glucuronide, salicylic acyl glucuronide, gentisic acid and gentisuric acid. As a result of zero order kinetics,    plasma    steady state salicylate concentrations increase

disproportionately with dose. Salicylate is also excreted unchanged in the urine to an extent which depends on the dosage and urinary pH. Renal excretion involves glomerular filtration, active renal tubular secretion and passive tubular reabsorption.

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.

5.3 Preclinical safety data

Not applicable

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Specially Dried Maize Starch Sodium Metabisulphite

6.2    Incompatibilities

None known

6.3    Shelf life

36 months: For glass bottle 24 months: For HDPE bottle

6.4    Special precautions for storage

HDPE bottle: Do not store above 25°C. Store in the original package.

Glass bottle: None

6.5    Nature and contents of container

Amber glass bottle with a child-resistant polythene/polypropylene cap, fitted with a lectraseal tamper-evident liner which is: surlyn/aluminium foil/polythene/bleached kraft paper/dot adhered to melinex coated carton board or a child-resistant polyethylene/polypropylene cap fitted with a waxed aluminium faced pulpboard liner.

Pack sizes: 24, 25, 30, 32 or

A white HDPE bottle with a polypropylene cap fitted with an induction heat seal membrane.

Pack sizes: 24, 25, 30, 32

6.6 Special precautions for disposal

None

7 MARKETING AUTHORISATION HOLDER

The Boots Company PLC 1 Thane Road West Nottingham NG2 3AA

8    MARKETING AUTHORISATION NUMBER(S)

PL 00014/0155R

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/04/1981

10    DATE OF REVISION OF THE TEXT

03/07/2014