Recommended as an anti-tussive for a non productive cough by oral administration.

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with codeine in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

The usual dosage for adults is 5 to 10 ml, 3 to 4 times daily. Dosage should be reduced in elderly or debilitated patients.

Paediatric population:

Children aged less than 12 years:

Codeine is contraindicated in children below the age of 12 years (see sections 4.3).

Children aged 12 years to 18 years:

Codeine is not recommended for use in children aged 12 years to 18 years with compromised respiratory function (see section 4.4).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Liver disease: drug may accumulate.

Ventilatory failure condition may be exacerbated.

In children below the age of 12 years due to an increased risk of developing serious and life threatening adverse reactions.

In women during breastfeeding (see section 4.6).

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

Geriatric patients should be supervised while on this medication, and consideration of reduced dosage should be based on response. Codeine should only be used with caution in patients with kidney or liver impairment. Care should be taken in patients with asthma, hypothyroidism, and in patients with a history of drug abuse. Tolerance and dependency may occur with prolonged use.

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 therapeutic 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:

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

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of relief as initially experienced. Patients may also supplement their treatment with additional medicines. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with codeine.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy 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.

Sunset Yellow may cause allergic reactions.

This product contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicine.

CNS depressants, anticholinergics, hydroxyzine and methadone – concurrent use of these medicines may result in potentiation of effects and hypotensive effects and CNS depressant effects may be increased; levallorphan is a morphine antagonist; the respiratory effects of neuromuscular blocking agents may be addictive to the central respiratory effects of the opioid analgesics; metoclopramide and codeine have opposing effects on gastro – intestinal activity; codeine causes delayed absorption of mexiletine; the effects of hypnotics and sedatives may be potentiated by codeine; hypertensive crisis may be caused by concurrent use of codeine and monoamine – oxidase inhibitors.

Pregnancy

Risk – benefit must be considered before using codeine during pregnancy. Codeine crosses the placenta and is excreted in small amounts in breast milk. Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate. Teratogenic effects in humans have not been documented but controlled studies have not been done. There is a risk of gastric stasis in the mother during labour which may lead to inhalation pneumonia.

If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.

Breastfeeding

Codeine is contraindicated in women 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.

If symptoms of opioid toxicity develop in either the mother or the infant, then all codeine containing medicines should be stopped and alternative non-opioid analgesics prescribed. In severe cases consideration should be given to prescribing naloxone to reverse these effects.

Administration to nursing women is not recommended as codeine may be secreted in breast milk and may cause respiratory depression in the infant.

Codeine may cause drowsiness. Patients receiving this medication should not drive or operate machinery unless it has been shown not to affect mental or physical ability.

This medicine can impair cognitive function and can affect a patient's ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

• The medicine is likely to affect your ability to drive

• Do not drive until you know how the medicine affects you

• It is an offence to drive while under the influence of this medicine

• However, you would not be committing an offence (called 'statutory defence') if:

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

Gastrointestinal side effects, constipation is not uncommon; loss of appetite; flushing of face might occasionally occur; respiratory depression may be experienced; sputum retention may occur particularly in patients with chronic bronchitis and bronchiectasis.

Psychiatric disorders:

Frequency unknown: Drug dependence (see section 4.4).

General disorders and administration site conditions:

Uncommon: drug withdrawal syndrome.

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.

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

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

Symptoms

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

Management

This should include general symptomatic and supportive measures including a clear airway and monitoring vital signs until stable. Consider administering activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or if more than 2.5 mg/kg (in adults and children) has been ingested.

Give naloxone if respiratory depression is present. Naloxone is a competitive antagonist and has a short half-life. So large and repeated doses of naloxone 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.

Morphine derivative. Antitussive – suppresses the cough reflex by a direct central action, probably in the medulla or pons.

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

Protein binding is very low.

Half life from 2.5 to 4 hours.

Duration of action approximately 4 hours.

Onset of action after oral administration is 30 to 45 minutes.

Excretion is primarily renal with 5 to 15% of the drug excreted unchanged.

Not applicable

Sodium Benzoate (E211)

Citric Acid Monohydrate

Saccharin Sodium (E954)

Sunset Yellow (E110)

Sorbitol Solution 70% (E420)

Purified Water (to volume)

Orange Flavour

Carboxymethylcellulose 7H3SFX

Propylene Glycol

None known

Do not store above 25° C. Protect from light.

Pharmaceutical Grade III Amber Glass Bottles with CRC caps:

100 ml, 125 ml and 200 ml

High Density Polyethylene Bottles:

2000 ml and 1000 ml

As for all medicines – no special warnings.