SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Codeine Phosphate BP 60mg Injection Codeine Phosphate BP Injection 60mg in 1ml

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Codeine Phosphate BP 6.0% w/v.

3. PHARMACEUTICAL FORM

Solution for injection.

4    CLINICAL PARTICULARS

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.

4.2.    Posology and method of administration

By intramuscular injection

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.

Adults, elderly and debilitated patients:

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

Paediatric population:

Children aged 12 years to 18 years:

The recommend codeine dose for children 12 years and older should be 30 to 60mg every 6 hours when necessary up to a maximum dose of 240mg daily. The dose is based on the body weight (0.5-1mg/kg).

Children less than 12 years:

Codeine should not be used in children below the age of 12 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).

4.3. Contraindications

Avoid in cases of:

•    Known hypersensitivity to any of the ingredients of the product.

•    Raised intracranial pressure or head injury.

•    Acute respiratory depression.

•    Asthma attack.

•    Acute alcoholism.

•    Risk of paralytic ileus.

•    Phaeochromocytoma.

•    Concurrent administration of MAOI drugs, including moclobemide, or for 2 weeks after stopping.

•    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-threating 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

Repeated administration may induce tolerance to the drug and morphine type dependence.

Caution in use is advised in cases of:

•    Hypotension.

•    Hypothyroidism.

•    Depressed respiratory reserve.

•    Prostatic hypertrophy.

•    Impaired hepatic or renal function. (reduce dose)

•    Convulsive disorders.

•    Pregnancy and breastfeeding.

•    Elderly or debilitated individuals. (reduce dose)

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 they will not obtain adequate analgesic effects. 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-threating and very rarely fatal. Estimates of prevalence of ultra-rapid metabolisers in different populations are summarized below:

Population	Prevalance %
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%

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 leaflet will state in the “Pregnancy and breastfeeding” subsection of section 2:

You should not be given Codeine Phosphate Injection if you are pregnant, or trying to become pregnant.

Do not use codeine while you are breast-feeding. Codeine and morphine passes into breast milk.

4.5 Interaction with other medicinal products and other forms of interaction

•    Alcohol - may induce serious respiratory depression and hypotension.

•    Analgesics

o Other opioid analgesics - additive CNS depression, respiratory depression and/or hypotension.

•    Antiarrhythmics

o Mexiletine - codeine may delay mexiletine absorption.

o Quinidine - the efficacy of codeine is significantly reduced when used with quinidine.

•    Antidepressants

o    MAOIs including moclobemide (concurrent or within 2 weeks of

discontinuation) are contra-indicated - risk of CNS excitation or depression.

o    Tricyclics - additive CNS depression, respiratory depression and/or

hypotension.

•    Antipsychotics - enhanced hypotensive and sedative effects when codeine is given with antipsychotics.

•    Antivirals

o Ritonavir - concomitant administration with ritonavir may increase the plasma concentration of codeine.

•    Ciprofloxacin - may increase codeine levels by inhibiting its metabolism.

•    CNS depressants, Anxiolytics and Hypnotics

o Sedative effects may be enhanced by simultaneous use with codeine. o Sodium Oxybate - concomitant use with codeine, may enhance the effects of sodium oxybate.

•    Gastro-intestinal drugs

o Metoclopramide and domperidone - gastrointestinal activity antagonised by codeine.

•    Ulcer-healing drugs

o Cimetidine - metabolism of codeine is inhibited by use with cimetidine (increased plasma concentration).

4.6. Fertility, pregnancy and lactation

Pregnancy:

Codeine Phosphate BP Injection 60mg in 1ml should not be used during pregnancy unless clearly necessary, in particular during the later stages.

Lactation:

Codeine should not be used during breastfeeding (see section 4.3).

At normal therapeutic doses codeine and its active metabolites 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.

Effects on ability to drive and use machines

May cause drowsiness, dizziness and confusion. If affected, patients should not drive or operate machinery.

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

Psychiatric disorders

•    Hallucinations

•    Mood changes

•    Dependence

•    Dysphoria

Nervous system disorders

•    Dizziness

•    Drowsiness

•    Headache

•    Vertigo

Eye disorders

•    Miosis

Cardiac disorders

•    Bradycardia

•    Palpitations

•    Tachycardia

Gastrointestinal disorders

•    Nausea

•    Vomiting

•    Constipation

•    Dry mouth

Skin and subcutaneous tissue disorders

•    Rashes

•    Urticaria

•    Pruritis

•    Facial flushing

•    Sweating

Renal and urinary disorders

•    Difficulty with micturition

General disorders and administration site conditions

•    Hypothermia

Vascular disorders

•    Postural hypotension

Reproductive system and breast disorders

•    Decreased libido or potency

Hepato-biliary disorders

•    Ureteric or biliary spasm

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

The effects in overdosage 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 also been taken, 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. Give naloxone if coma or respiratory depression is present. Naloxone is a competive 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 overdosage was diagnosed or suspected.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

It has less depressant effect on the respiratory system and causes less nausea and vomiting than morphine.

5.2 Pharmacokinetic properties

The plasma half-life of codeine, after intramuscular injection is between 3 and 4 hours.

About 80% of codeine is excreted in the urine after 24 hours. 15 - 20% is as free Codeine, about 10% is free or conjugated morphine.

5.3. Pre-clinical safety data

No relevant pre-clinical data is available which would be of value to the prescriber.

6. PHARMACEUTICAL PARTICULARS

6.1. List of excipients

Sodium Metabisulphite BP and Water for Injection BP.

6.2. Incompatibilities

None stated.

10 DATE OF REVISION OF THE TEXT

10/07/2014