This information is intended for use by health professionals

1. Name of the medicinal product

Thornton & Ross Codeine Phosphate 25mg/5ml Oral Solution

2. Qualitative and quantitative composition

Codeine Phosphate 25mg per 5ml

Each 5ml of syrup contains 4.25g of sucrose

Each 5ml of syrup contains 2.1 vol% of ethanol (alcohol)

For a full list of excipients, see section 6.1

3. Pharmaceutical form

Oral Solution

A clear almost colourless syrupy liquid.

4. Clinical particulars
4.1 Therapeutic indications

1. For the relief of the symptoms of diarrhoea in adults and children over 12 years.

2. 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).

Label states “For use as directed by the practitioner”.

4.2 Posology and method of administration

Oral

1. For the relief of the symptoms of diarrhoea:

2. For the relief of acute moderate pain:

Adults: One or two 5ml spoonfuls (25-50mg codeine)

Codeine should be used at the lowest effective dose for the shortest period of time. This dose may be taken, up to 4 times a day at intervals of not less than 6 hours. Maximum daily dose of codeine should not exceed 240 mg.

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.

Elderly: Should be used with caution, doses as for adults may be given at the doctor's discretion. A reduced dose can be recommended by a doctor.

Paediatric population:

Children aged 12 years to 18 years:

The recommended codeine dose for children 12 years and older should be one or two 5ml spoonfuls (25-50mg codeine) every 6 hours when necessary up to a maximum dose of codeine of 240 mg daily. The dose is based on the body weight (0.5-1mg/kg).

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).

Label states “For use as directed by the practitioner”.

4.3 Contraindications

Suspected opiate abuse, known hypersensitivity to codeine or to any of the other ingredients.

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.

Contraindicated during an acute asthmatic attack, in cases of respiratory depression and liver failure.

In patients with raised intracranial pressure or head injury.

Contraindicated in patients at risk of paralytic ileus and in those with acute ulcerative colitis or antibiotic associated colitis.

Acute alcoholism

4.4 Special warnings and precautions for 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 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 European

1%-2%

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

Concomitant use of codeine and sedative medicines such as benzodiazepines or related drugs 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).

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.

Use with caution in patients with renal and hepatic impairment (but avoid if severe) , patients suffering from asthma or other respiratory disorders, or patients with a history of asthma, hypotension, shock, myasthenia gravis, cardiac arrhythmias, acute abdomen, gallstones, prostatic hypertrophy, urethral stenosis, obstructive or inflammatory bowel disorders, diseases of the biliary tract, and convulsive disorders.

Administration of pethidine and possibly other opioid analgesics to patients taking a monoamine oxidase inhibitor (MAOI) has been associated with very severe and sometimes fatal reactions. If the use of codeine is considered essential then great care should be taken in patients taking MAOIs or within 14 days of stopping MAOIs. (See section 4.5).

Prolonged use could aggravate irritable bowel syndrome.

Use with caution in the elderly as codeine may induce faecal impaction, producing incontinence, spurious diarrhoea, abdominal pain, and rarely, colonic obstruction.

A reduced dose is recommended in elderly or debilitated patients, in hepatic and renal impairment (but avoid if severe), in hypothyroidism, and in adrenocortical insufficiency. Repeated use of opioid analgesics is associated with the development of psychological and physical dependence; although this is rarely a problem with therapeutic use, caution is advised if prescribing for patients with a history of drug dependence or in acute alcoholism.

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. It contains 4.25g sucrose per 5ml. To be taken into account in people with diabetes. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before using this medicine.

The medicinal product contains 2.1 vol% ethanol (alcohol), i.e. up to 166mg per dose, equivalent to 4.2ml beer, 1.75ml per dose.

Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

The medicinal product also contains sodium hydroxybenzoates which may cause allergic reactions (possibly delayed).

If symptoms persist consult your doctor

Use is seldom necessary for the treatment of diarrhoea in children, where fluid and electrolyte replacement in gastro-enteritis and the specific treatment of other diseases causing diarrhoea, is usually more appropriate.

It is potentially harmful if used to treat infective diarrhoeas as it may delay the passage of liquid faeces, encourage proliferation of pathogens and cause the severity of the diarrhoea to be underestimated.

Convulsive disorders

The risk-benefit of continued use should be assessed regularly by the prescriber.

The leaflet will state in a prominent position in the 'before taking' section:

• Do not take for longer than directed by your prescriber.

• Taking codeine regularly for a long time can lead to addiction, which might cause you to feel restless and irritable when you stop the syrup.

• Taking a painkiller for headaches too often or for too long can make them worse

The label will state (To be displayed prominently on outer pack – not boxed):

Do not take for longer than directed by your prescriber as taking codeine regularly for a long time can lead to addiction.

4.5 Interaction with other medicinal products and other forms of interaction

Antimuscarinics: codeine phosphate may increase the risk of antimuscarinic side effects such as dry mouth, urine retention and constipation (but this does not generally apply to antimuscarinics taken by inhalation).

Metabolism of codeine is accelerated by rifampicin leading to reduced effects.

As an opioid analgesic, codeine phosphate may potentiate the effects of tranquillisers such as barbiturates, general anaesthetics, anxiolytics and hypnotics, sedatives and alcohol.

Possible CNS excitation or depression (hypertension or hypotension) can occur when opioid analgesics are given with antidepressants such as moclobemide (a reversible MAO-A inhibitor). The sedative effects of codeine can possibly be increased when given with tricyclic antidepressants, with anxiolytics or hypnotics, or with sedating antihistamines. Antipsychotic medicines can enhance hypotensive and sedative effects when opioid analgesics are given with antipsychotics.

Monoamine oxidase inhibitors: 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, including MAO-B inhibitor selegiline. This may also apply to the antibacterial linezolid, which is a reversible, non-selective MOA inhibitor.

Anti-emetics: The reduction in intestinal motility caused by codeine may delay the absorption or antagonise the gastrointestinal effects of other drugs e.g. metoclopramide and domperidone.

Metabolism of opioid analgesics is inhibited by cimetidine leading to increased plasma concentration.

Anti-arrhythmics: May delay the gastro-intestinal absorption of mexiletine or quinidine (which may also reduce the efficacy of codeine).

Opioid analgesics enhance the effects of sodium oxybate, used to treat symptoms of narcolepsy, and concomitant use should be avoided.

Sedative medicines such as benzodiazepines or related drugs: The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

4.6 Fertility, pregnancy and lactation

The product should not be used during pregnancy unless considered necessary by the physician and should be avoided in the first trimester. Opioid administration in the third trimester may cause respiratory depression in the new born, withdrawal effects in neonates of dependent mothers, gastric stasis and risk of inhalation pneumonia in the mother during labour.

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 a CYP2D6 ultra-rapid metaboliser, 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

The use of codeine phosphate at higher doses or in more sensitive individuals may cause sedation, dizziness and nausea. 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 “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

The following undesirable effects have been reported following use of codeine phosphate or opioid analgesics and may arise following use of Codeine Phosphate Syrup. The frequency of adverse effects cannot be estimated from available data.

Psychiatric disorders: hallucinations, dysphoria, euphoria, mood changes, restlessness, confusion.

Nervous system disorders: dizziness, drowsiness, seizures, addiction, tolerance, dependence, headache, vertigo, malaise, sleep disturbances.

Eye disorders: miosis, visual disturbances.

Cardiac disorders: palpitations, bradychardia, tachycardia.

Vascular disorders: postural hypotension, hypothermia, facial flushing, oedema.

Respiratory, thoracic and mediastinal disorders: respiratory depression.

Gastrointestinal disorders: nausea, vomiting, constipation, abdominal pain, anorexia, pancreatitis, dry mouth.

Hepatobiliary disorders: biliary spasm.

Skin and subcutaneous tissue disorders: rashes, urticaria, pruritus, sweating.

Musculoskeletal and connective tissue disorders: muscle fasciculation or rigidity.

Renal and urinary disorders: difficulty with micturition, ureteric spasm or retention.

Reproductive system and breast disorders: decreased libido or potency.

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

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

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 professional 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.

4.9 Overdose

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

Symptoms

Central nervous system depression, including 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 of vital signs until stable. Consider activated charcoal if an adult presents within one hour of ingestion of more than 350 mg or if more than 2.5mg/kg (adults and children) has been ingested.

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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

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 such as paracetamol, has been

shown to be effective in acute nociceptive pain.

5.2 Pharmacokinetic properties

Codeine phosphate is absorbed from the gastro-intestinal tract, it is metabolised by O- and N-demethylation in the liver to morphine and norcodeine.

Codeine and its metabolites are excreted almost enlirely by the kidney, mainly as conjugates with glucuronic acid.

Ingestion of codeine phosphate produces peak plasma codeine concentration in about 1 hour. The plasma half-life has been reported to be between 2½ and 4 hours after ingestion.

5.3 Preclinical safety data

There are no preclinical 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

Purified Water

Sodium Methyl Hydroxybenzoate (E219)

Ethanol (96%)

Syrup

6.2 Incompatibilities

None

6.3 Shelf life

24 months unopened.

6.4 Special precautions for storage

None.

6.5 Nature and contents of container

500ml: Amber glass bottle with lined plastic cap.

6.6 Special precautions for disposal and other handling

None.

7. Marketing authorisation holder

Thornton & Ross Ltd

Linthwaite Laboratories

Huddersfleld

HD7 5QH

8. Marketing authorisation number(s)

PL 00240/6213R

9. Date of first authorisation/renewal of the authorisation

12 May 1982 / 09 December 1983

10. Date of revision of the text

09/10/2018