Codeine Phosphate Tablets Bp 15mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Codeine Phosphate Tablets BP 15mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 15mg of codeine phosphate
Excipients with known effect:
Each tablet contains 28.85mg of lactose.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablet.
White circular normal biconvex tablets, embossed with R114.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Codeine is indicated in adults as an analgesic, an anti-tussive, and for the symptomatic treatment of chronic diarrhoea.
Codeine is indicated in patients older than 12 years 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
As an analgesic:
Adults : 30-60mg every four hours, when necessary to a maximum 240mg daily.
Elderly: Dosage should be reduced in the elderly where there is impairment of hepatic or renal function.
As an anti-tussive:
Adults: 15-30mg three or four times daily.
Elderly: Dosage should be reduced in the elderly where there is impairment of hepatic or renal function.
For the symptomatic treatment of chronic diarrhoea.:
Adults: 15-60mg every four to six hours.
Elderly: Dosage should be reduced in the elderly where there is impairment of hepatic or renal function.
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 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.
Paediatric population Children over 12 years
30-60mg every four hours, when necessary to a maximum 240mg daily.
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 and/or cold (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 and/or cold (see section 4.3)
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).
Method of administration For oral use
4.3 Contraindications
Patients with:
• Known hypersensitivity to codeine phosphate, other opioid analgesics or any other of the excipients in the tablets;
• 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;
• Diarrhoea associated with either pseudomembranous colitis or poisoning;
• Risk of paralytic ileus.
This product is also contraindicated:
• 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 and/or cold 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 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 therapeutic 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 % |
|
Afri can/Ethi opi an |
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 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.
Codeine phosphate should be used with caution in the following conditions:
• Codeine Phosphate Tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
• Convulsions - they may be induced or exacerbated
• Drug abuse or dependence (including alcoholism) Prolonged use of high doses has produced drug dependence of the Morphine type. Codeine should be used with caution in patients with a history of drug dependence.
• There is a possible risk of CNS excitation or depression with concomitant use of opioids with MAOIs and use is not recommended (see section 4.5).
• Myasthenia gravis
• Phaeochromocytoma - opiods may stimulate catecholamine release by inducing the release of endogenous histamine
• Adrenocortical insufficiency e.g. Addison’s Disease
• Hypothyroidism
• Hypotension and shock, history of cardiac arrhythmias.
• Reduced respiratory function or history of asthma
• 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.
• Gastro-intestinal surgery - use with caution after recent GI surgery as opioids may alter GI motility.
• Gall bladder disease or gall stones - opioids may cause biliary contraction. Avoid in biliary disorders.
• Hepatic impairment - avoid if severe. Codeine may precipitate coma
• Renal impairment
• 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
• Prostatic hypertrophy
• Pregnancy (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.
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 tablets.
• 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.
Excipients
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
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 (e.g. 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 (e.g. 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 e.g. buprenorphine, naltrexone, naloxone - may precipitate withdrawal symptoms
• Quinidine - reduced analgesic effect
• Antihypertenstive 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
Forms codeine-phenobarbital complex with phenobarbital sodium and crystals of codeine periodide with potassium iodide.
Codeine also interferes with some laboratory tests e.g. plasma amylase, lipase, bilirubin.
4.6 Pregnancy and lactation
Pregnancy
Not recommended during pregnancy due to neonatal withdrawal symptoms and impaired effect of foetus. 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 neonates.
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 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 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.
4.7 Effects on ability to drive and use machines
Pregnancy
Not recommended during pregnancy due to neonatal withdrawal symptoms and impaired effect of foetus. 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 neonates.
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 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 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.
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 nightmare, 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.
Muscoskeletal, 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 4 hours after ingestion, or 8 hours if a sustained release preparation has been taken.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Opium alkaloids and derivatives, codeine ATC code: R05DA04
The action of codeine is largely that of Morphine from which it is derived i.e. it is a CNS suppressant.
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.
5.2 Pharmacokinetic properties
Codeine is metabolised in the liver and is excreted in the urine, largely in inactive forms. A small fraction (approximately 10%) of administered Codeine is demethylated to form Morphine; traces of free morphine can be found in the urine after therapeutic doses of codeine.
5.3 Preclinical safety data
Animal work suggested that the analgesic activity of Codeine was not affected by Acetylation.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose
Starch
Magnesium Stearate Sodium Starch Glycolate
6.2 Incompatibilities
None stated.
6.3 Shelf life
3 years: Polypropylene tamper-evident containers. 2 years: Blister strips.
Special precautions for storage
6.4
3 years: Polypropylene tamper-evident containers. 2 years: Blister strips.
6.5 Nature and contents of container
Polypropylene tamper-evident containers: 1000, 500, 100, 90, 80, 70, 60, 50, 40, 30, 20 and 10 tablets
Blister strips: 100, 90, 80, 70, 60, 50, 40, 30, 28, 20 and 10 tablets.
Not all pack types or sizes may be marketed
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Sun Pharmaceutical Industries Europe B.V.
Polarisavenue 87 2132JH Hoofddorp The Netherlands
8 MARKETING AUTHORISATION NUMBER(S)
PL 31750/0110
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION 13/2/90
10 DATE OF REVISION OF THE TEXT
02/09/2016