CODEINE PHOSPHATE 60 MG IN 1ML SOLUTION FOR INJECTION - summary of medicine characteristics

Summary of medicine characteristics - CODEINE PHOSPHATE 60 MG IN 1ML SOLUTION FOR INJECTION

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

4.1. Therapeutic indications

4.2 Posology and method of 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 phosphate in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4).

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.

Glomerular filtration rate

Dose

(mL/minute)
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

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 pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. 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 phosphate.

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 use 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.

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 dilation of intracranial vessels and thus cerebral oedema).

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

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 summarised 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% to 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 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 ultrarapid 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 Pregnancy and lactation

Pregnancy

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.

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

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.

Breast feeding

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

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 – Drug dependence (see section 4.4), hallucination, mood altered, restlessness, confusion,

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 – Drug withdrawal syndrome, hypothermia Muscoskeletal and connective tissue disorders – Muscle rigidity, muscle fasciculation Respiratory disorders – Respiratory depression

Sexual disorders – Sexual dysfunction

Eating disorders – Anorexia

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.

4.9 Overdose

5.1. Pharmacodynamic properties

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