SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Codeine Phosphate 60mg in 1ml Solution for Injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Codeine Phosphate 60 mg in 1 mL.

For a full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Solution for injection.

The product is a clear, pale straw colour solution, visibly free from particles.

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 such as paracetamol or ibuprofen (alone).

4.2.    Posology and method of administration

For intramuscular use only.

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 of codeine should not exceed 240mg.

Hepatic impairment

Codeine Phosphate Solution for Injection is contraindicated in patients with hepatic impairment (see Section 4.3).

Renal impairment

The dosage for patients with renal impairment should be adjusted according to the table below.

20 - 50	Dose as for normal renal function
10 - 20	75% of normal dose
< 10	50% of normal dose

Children aged 12 years to 18 years:

The recommended codeine dose for children 12 years and older should be 500 micrograms/kg to 1mg/kg every 6 hours when necessary up to a maximum dose of codeine of 240mg 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).

4.3 Contraindications

Hypersensitivity to the active substance.

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.

Codeine Phosphate Solution for Injection is contraindicated in patients with hepatic impairment.

As codeine reduces peristalsis, increases tone in the bowel and can raise colonic pressure; it should not be used in diverticulitis, after bowel surgery or in those with acute colitis.

4.4. Special warnings and precautions for use

Use with care in patients with pre-existing respiratory depression, as opioids can further depress respiratory function.

Use with care in head injury as opioids can depress respiratory function, which can then complicate the situation (carbon dioxide retention causes dilatation of intracranial vessels and thus cerebral oedema).

Use with care in patient with hypovolaemia as this may be exacerbated with codeine.

Repeated administration of codeine phosphate may induce tolerance to the drug and morphine-type dependence.

Codeine potentiates the central depressive effects of central nervous system depressants including alcohol.

Patients should therefore avoid alcohol whilst taking codeine.

Codeine may cause drowsiness. If affected, patients should not drive or operate machinery.

Do not use if the solution is darker than pale straw.

Do not use if visible particles are present.

Once opened the product should be used immediately and any unused drug discarded.

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%

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.

4.5 Interaction with other medicinal products and other forms of interaction

Caution is advised when prescribing Codeine Phosphate Solution for Injection to patients taking drugs which also cause central nervous system depression; or induce liver enzymes (examples include nefopam, carbamazepine, rifampicin, quindine, secobarbital) as this may reduce the efficacy of the drug.

Patients should avoid alcohol whilst taking codeine (see Section 4.4.).

4.6 Fertility, pregnancy and lactation

There are no adequate data for the use of codeine in pregnant women.

Animal studies are insufficient with respect to effects on pregnancy and embryofetal development (see Section 5.3). The potential risk for humans is unknown. Codeine Phosphate Solution for Injection should not be used in pregnancy, in particular during the later stages, unless the clinical benefit outweighs the potential risks.

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 ultrarapid 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.

4.7 Effects on ability to drive and use machines

Codeine Phosphate Solution for Injection has a minor or moderate influence on the ability to drive and use machines. Codeine may cause drowsiness. If affected, patients should not operate machinery (see Section 4.4.).

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 adverse events are from published literature and frequencies are not known. Psychiatric disorders

Hallucination, mood altered, restlessness, confusion, dependence

Nervous system disorders

Somnolence, headache, seizures, dysphoria, euphoria, hyperalgesia, dizziness

Eye disorders Miosis

Ear and Labyrinth disorders Vertigo

Cardiac disorders

Bradycardia, palpitations, tachycardia Vascular disorders

Flushing, orthostatic hypotension, oedema, amenorrhoea Gastrointestinal disorders

Constipation, dry mouth, nausea, vomiting, abdominal pain, pancreatitis

Hepatobiliary disorders Biliary colic

Skin and subcutaneous tissue disorders Hyperhidrosis, rash, urticaria, pruritus

Renal and urinary disorders

Dysuria, ureteral spasm, urinary retention

General disorders and administration site conditions Hypothermia

Musculoskeletal and connective tissue disorders Muscle rigidity, muscle fasciculation

Respiratory disorders Respiratory depression

Sexual disorders Sexual dysfunction

Eating disorders Anorexia

4.9 Overdose

In acute overdosage, respiratory depression and hypotension may be observed. Circulatory failure and deepening coma may also be observed. The respiratory failure may cause convulsions. Respiratory failure must be guarded against. If respiration is dangerously depressed Naloxone should be used.

PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Opium alkaloids and derivatives, ATC code: R05D A04

Codeine is a centrally acting weak analgesic. Codeine exerts its effects through 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

Absorption: After intramuscular injection, peak plasma concentrations occur in about 30 minutes and the half-life is approximately 3 hours. The maximum plasma concentrations after normal therapeutic doses are in the range of 100-300 micrograms/L.

Distribution: The volume of distribution is approximately 3.6L/kg. Codeine enters the tissues rapidly and is concentrated in the kidney, lung, liver and spleen. The bulk of the total drug is in the skeletal muscle. The brain does not accumulate high levels of codeine. Within the brain, 80% or more is associated with opioid receptors which are especially concentrated in the caudate nucleus, amygdala and peri-aqueductal grey matter of the hypothalamus, mid brain and medial thalamus.

Biotransformation: The majority of codeine undergoes hepatic metabolism by glucuronidation to codeine-6-glucuronide, N-demethylation to norcodeine and o-demethylation to morphine.

Elimination: After an intramuscular dose, approximately 15-20% of the dose is excreted unchanged in acid urine in 24 hours.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Water for Injections

6.2 Incompatibilities

Not applicable.

6.3    Shelf life

3 years.

For single use only, discard any unused solution immediately after first use.

6.4    Special precautions for storage

Store below 25°C.

Keep ampoules in the original outer carton.

6.5    Nature and contents of container

Clear colourless type 1 glass ampoules containing 1mL of solution in packs of 10 ampoules in a cardboard carton.

6.6    Special precautions for disposal

Not applicable.

7    MARKETING AUTHORISATION HOLDER

Torbay and South Devon NHS Foundation Trust Torbay Pharmaceuticals,

Wilkins Drive,

Paignton,

Devon, TQ4 7FG UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 13079/0010

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 13/09/2011

10 DATE OF REVISION OF THE TEXT

25/08/2016