This information is intended for use by health professionals

1. Name of the medicinal product

CODEINE PHOSPHATE TABLETS BP 30mg

2. Qualitative and quantitative composition

Each tablet contains 30mg Codeine Phosphate PhEur.

Each tablet contains 16.00mg lactose BP.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

White uncoated tablets.

White, circular, biconvex uncoated tablets impressed “C” on one face and the identifying letters “CR” on the reverse.

4. Clinical particulars
4.1 Therapeutic indications

1) Indicated as an analgesic for the relief of mild to moderate pain.

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).

2) For the symptomatic relief of unproductive cough and diarrhoea.

4.2 Posology and method of administration

Long term use – the risk benefit should be assessed regularly by the prescriber.

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 should not exceed 240mg.

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

Posology

Analgesia

Adults: 30-60mg every four hours to a maximum dosage of 240mg daily.

The analgesic effect is not materially enhanced by increasing the dose to a greater level than that recommended above.

Elderly: Dosage should be reduced in the elderly where there is impairment of hepatic or renal function.

Paediatric population:

Children aged 12 years to 18 years:

The recommended codeine dose for children 12 years and older should be 30 to 60 mg 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 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).

Diarrhoea

Adults and children over 12 years: 15-60mg three to four times daily.

Elderly: Dosage should be reduced in the elderly where there is impairment of hepatic or renal function.

Children under 12 years: Not recommended.

Cough

Adults and children over 12 years: 15-30mg three to four times daily.

Elderly: Dosage should be reduced in the elderly where there is impairment of hepatic or renal function.

Paediatric population:

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 for the symptomatic treatment of cough (see section 4.4).

Children aged less than 12 years:

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

Method of Administration

For oral use.

4.3 Contraindications

• Hypersensitivity to codeine, other opioids or to any of the excipients listed in section 6.1.

• Acute respiratory depression

• Obstructive airways disease- e.g. emphysema

• Asthma- Opioids should not be administered during an asthma attack

• Hepatic failure

• Head injuries or conditions where intracranial pressure is raised

• Acute alcoholism

• Risk of paralytic ileus

• 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 children below the age of 12 years for the symptomatic treatment of cough 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

4.4 Special warnings and precautions for use

Codeine phosphate should be used with caution in the following conditions:

• Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine

• There is a possible risk of CNS excitation or depression with concomitant use of opioids with Monoamine Oxidase Inhibitors (MAOIs) and use is not recommended (see section 4.5)

• Hepatic impairment - avoid if severe. Codeine may precipitate coma

• Renal impairment

• Hypothyroidism

• Inflammatory bowel disease - codeine reduces peristalsis, increases tone and segmentation in the bowel and can raise colonic pressure, therefore should be used with caution in diverticulitis, acute colitis, diarrhoea associated with pseudomembranous colitis or after bowel surgery

• Convulsions - may be induced or exacerbated

• Drug abuse or dependence (including alcoholism)

• Gall bladder disease or gall stones - opioids may cause biliary contraction. Avoid in biliary disorders

• Gastro-intestinal surgery - use with caution after recent GI surgery as opioids may alter GI motility

• Urinary tract surgery – following recent surgery patients will be more prone to urinary retention caused directly by spasm of the urethral sphincter, and via constipation caused by codeine

• Phaeochromocytoma - opioids may stimulate catecholamine release by inducing the release of endogenous histamine

• Prostatic hypertrophy

• Adrenocortical insufficiency, eg Addison's Disease

• Hypotension and shock

• Myasthenia gravis

• Reduced respiratory function or history of asthma

• Pregnancy and breast feeding (see section 4.6)

• Elderly patients may metabolise and eliminate opioid analgesics more slowly than younger patients (see section 4.2).

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

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 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.

The leaflet will state in 'What you need to know before you take Codeine Phosphate Tablets':

Other important warnings

• 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 tablets.

• Taking a painkiller regularly 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

Concomitant combinations not recommended (see section 4.4):

• MAOIs (e.g. linezolid, moclobemide, selegiline) due to the possible risk of excitation or depression – avoid concomitant use and for 2 weeks after discontinuation of MAOI

Combinations to be used with caution:

Respiratory related

• Alcohol - enhanced sedative and hypotensive effect, increased risk of respiratory depression

• Sedative antihistamines - enhanced sedative and hypotensive effect and increased risk of respiratory depression

• Hypnotics and anxiolytics - enhanced sedative effect, increased risk of respiratory depression

Gastrointestinal related

• Anticholinergics (eg atropine) - risk of severe constipation which may lead to paralytic ileus, and /or urinary retention

• Metoclopramide and domperidone – antagonise effect on GI activity

• Antidiarrhoeal drugs (eg loperamide, kaolin) – increased risk of severe constipation.

CNS related

• Anaesthetics - enhanced sedative and hypotensive effect

• Tricyclic antidepressants - enhanced sedative effect

• Antipsychotics - enhanced sedative and hypotensive effect

• Opioid antagonists eg buprenorphine, naltrexone, naloxone – may precipitate withdrawal symptoms

• Quinidine - reduced analgesic effect

• Antihypertensive drugs - enhanced hypotensive effect.

Pharmacokinetic interactions

• Ciprofloxacin - avoid premedication with opioids as they reduce plasma ciprofloxacin concentration

• Ritonavir may increase plasma levels of opioid analgesics such as codeine

• Mexiletine - delayed absorption of mexiletine

• Cimetidine inhibits the metabolism of opioid analgesics causing increased plasma concentration of codeine.

4.6 Fertility, pregnancy and lactation

Pregnancy

Risk benefit must be considered because opioid analgesics cross the placenta. Studies in animals have shown opioids to cause delayed ossification in mice and increased resorption in rats.

Regular use during pregnancy may cause physical dependence in the foetus, leading to withdrawal symptoms in the neonate. During labour opioids enter the foetal circulation and may cause respiratory depression in the neonate. Respiratory malformation in neonates may be associated with exposure to codeine during pregnancy. Gastric stasis and a risk of inhalation pneumonia could occur in the mother during labour. Administration should be avoided during the late stages of labour and during the delivery of a premature infant.

Breast-feeding

Codeine is contraindicated in women during breast-feeding (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.

Opioid toxicity

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 may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. Effects such as confusion, drowsiness, dizziness, hallucinations, blurred or double vision or convulsions may occur. The effects of alcohol are enhanced with this combination. Do not drive or operate machinery if affected.

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:

- The medicine has been prescribed to treat a medical or dental problem and

- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

- It was not affecting your ability to drive safely.

4.8 Undesirable effects

Immune system disorders: (may be caused by histamine release) – including rash, urticaria, pruritus, difficulty breathing, increased sweating, redness or flushed face.

Nervous system disorders: confusion, drowsiness, malaise, tiredness, vertigo, dizziness, changes in mood, hallucinations, CNS excitation (restlessness/excitement), convulsions, mental depression, headache, or nightmares, raised intracranial pressure, tolerance or dependence, dysphoria, hypothermia.

Eye disorders: - miosis, blurred or double vision.

Cardiac disorders: bradycardia, palpitations, hypotension, orthostatic hypotension, tachycardia.

Respiratory, thoracic and mediastinal disorders: respiratory depression with larger doses.

Gastrointestinal disorders: constipation (too constipating for long-term use), biliary spasm, nausea, vomiting, dry mouth.

Musculoskeletal, connective tissue and bone density: muscle rigidity.

Renal and urinary disorders: ureteral spasm, antidiuretic effect, urinary retention.

Reproductive system and breast disorders: decrease in libido and potency.

Withdrawal effects: abrupt withdrawal precipitates a withdrawal syndrome. Symptoms may include tremor, insomnia, restlessness, irritability, anxiety, depression, anorexia, nausea, vomiting, diarrhoea, sweating, lacrimation, rhinorrhoea, sneezing, yawning, piloerection, mydriasis, weakness, pyrexia, muscle cramps, dehydration, and increase in heart rate, respiratory rate and blood pressure. NOTE - tolerance diminishes rapidly after withdrawal so a previously tolerated dose may prove fatal.

• 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.

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

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; website: 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 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 350mg or a child more than 5mg/kg.

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

Pharmacotherapeutic group: ATC code R05D A04.

Codeine is an analgesic with uses similar to those of morphine but it is much less potent as an analgesic and has only mild sedative effects. It is also used in the treatment of cough and diarrhoea.

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

Absorption and Distribution

Codeine and its salts are readily absorbed from the gastrointestinal tract and ingestion of codeine phosphate produces peak plasma concentrations in about one hour. Plasma half life is between 3 to 4 hours and oral/intramuscular analgesic ration is APPROXIMATELY EQUAL TO (8773) 1:1.5

Biotransformation

It is a metabolised by O- and N-demethylation in the liver to morphine and norcodeine.

Elimination

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

5.3 Preclinical safety data

Not applicable.

6. Pharmaceutical particulars
6.1 List of excipients

Also contains lactose, magnesium stearate, pregelatinised maize starch, maize starch, stearic acid.

6.2 Incompatibilities

None known.

6.3 Shelf life

PVC Blister packs

Four years from the date of manufacture.

All other containers

Three years from the date of manufacture.

6.4 Special precautions for storage

Store below 25°C in a dry place.

Protect from light.

6.5 Nature and contents of container

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with polyfoam wad or polyethylene ullage filler and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass bottles with screw caps and polyfoam wad or cotton wool. An alternative closure for polyethylene containers is a polypropylene, twist on, push down and twist off child-resistant, tamper-evident lid.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28s, 30s, 50s, 56s, 60s, 84s, 90s, 100s, 112s, 120s, 168s, 180s, 250s, 500s, 1000s.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material.

Maximum size of bulk packs: 50,000.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Not applicable.

7. Marketing authorisation holder

Actavis UK Limited

(Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon

EX32 8NS

8. Marketing authorisation number(s)

PL 0142/6459 R

9. Date of first authorisation/renewal of the authorisation

(Product Licence of Right issued: Pre 1974) 2.11.81 / 15.10.02

10. Date of revision of the text

11th October 2016