Codeine Phosphate Tablets Bp 60mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Codeine Phosphate Tablets BP 60 mg.
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Codeine phosphate BP 60 mg per tablet.
3. PHARMACEUTICAL FORM
Tablet.
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
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 aged 12 years to 18 years:
The recommended codeine dose for children 12 years and older should be 30-60mg 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).
ROUTE OF ADMINISTRATION: Oral
4.3 Contraindications
Hypersensitivity to opioid analgesics or to any of the excipients.
Acute respiratory depression and obstructive airways disease.
Diarrhoea due to pseudomembranous colitis or poisoning.
Severe hepatic dysfunction.
Where there is a risk of paralytic ileus.
Raised intracranial pressure or head injury.
Comatose patients Acute alcoholism
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.
4.4 Special warnings and precautions for use
Codeine phosphate should be given in reduced doses or with caution to patients with asthma and decreased respiratory reserve. Avoid use during an acute asthma attack.
Codeine phosphate should be avoided, or the dose reduced, in patients with hepatic or renal impairment.
Codeine phosphate should be given in reduced doses or with caution to:
Debilitated patients, adrenocortical insufficiency, prostatic hypoplasia, urethral stricture, hypotension, shock, inflammatory or obstructive bowel disorders, hypothyroidism or convulsive disorders.
However, these conditions should not necessarily be a deterrent to use in palliative care.
Use with caution in those with a history of drug abuse.
Alcohol should be avoided whilst under treatment with codeine.
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, shallow breathing, small pupils, nausea, vomiting, constipation, lack of appetite and somnolence. 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:
Prevalence % 29%
3.4% to 6.5% 1.2% to 2% 3.6% to 6.5% 6.0%
1.9%
1% to 2%
Population African/Ethiopian African American Asian Caucasian Greek Hungarian Northern European
Avoid abrupt withdrawal after long-term treatment.
Administration of pethidine and possibly other opioid analgesics to patients taking a monoamine oxidase inhibitor (MAOI) has been associated with very severe and sometimes fatal reactions. If the use of codeine is considered essential then great care should be taken in patients taking MAOIs or within 14 days of stopping MAOIs (see section 4.5).
The risk-benefit of continued use should be assessed regularly by the prescriber. 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.
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.
The leaflet will state in the “Pregnancy and breast-feeding” subsection of Section 2 “Before taking your medicine”:
Do not take codeine while you are breastfeeding. Codeine and morphine passes into breast milk.
Patients with rare hereditary problems of galactose intolerance, the LAPP lactase deficiency or glucose-galactose malabsorption should not take this medicine as it contains lactose.
4.5 Interaction with other medicinal products and other forms of interactions
Concurrent administration of codeine with antidiarrhoeal and antiperistaltics such as difenoxin, atropine, kaolin, pectin, belladonna alkaloids, opium preparations and loperamide, may increase the risk of severe constipation and central nervous system depression.
Concurrent administration of codeine with antihypertensive agents especially ganglionic blockers such as guanethidine, diuretics, hypotension producing medication may potentiate the hypotensive effect and increase risk of orthostatic hypotension.
Concurrent administration of codeine with other medications with antimuscarinic action may lead to an increased risk of severe constipation and may lead to paralytic ileus and/or urinary retention.
Concurrent administration with metoclopramide or domperidone may antagonise the effects of metoclopramide or domperidone on gastrointestinal motility.
The depressant effects of opioid analgesics are enhanced by other CNS depressants such as:
Alcohol - enhanced hypotensive, sedative effect and respiratory depression. Anaesthetics - may increase anaesthetic and sedative effect.
Sedating antihistamines - may enhance the CNS depressive effects when taken with opioids.
Anxiolytics or hypnotics - may enhance CNS depressive effects when taken with opioids.
Tricyclic antidepressants - may enhance CNS depressive effects when taken with opioids.
Antipsychotics - enhanced hypotensive, sedative effect.
MAOIs taken with pethidine have been associated with severe CNS excitation or depression (including hypertension or hypotension). Although this has not been documented with codeine, it is possible that a similar interaction may occur and therefore the use of codeine should be avoided while the patient is taking MAOIs and for 2 weeks after MAOI discontinuation.
Administration with moclobemide may cause CNS excitation or depression (hypertension or hypotension).
Cimetidine may inhibit the metabolism of codeine, resulting in increased plasma concentrations.
4.6 Fertility, pregnancy and lactation
Codeine traverses the placental barrier, regular use during pregnancy may depress neonatal respiration and cause physical dependence in the foetus, leading to withdrawal symptoms. Gastric stasis and risk of inhalation pneumonia may occur in the mother during labour. Teratogenic effects have not been demonstrated in humans, however studies in mice have shown delayed ossification and increased resorption has been reported in rats. Therefore risk benefit must be considered when administering during pregnancy.
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 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
May cause drowsiness if affected do 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:
- 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
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.
Immune system disorders
Allergic reactions such as hives, itching, skin rashes, swelling of face, dyspnoea and difficulty in breathing.
Metabolism and nutrition disorders Anorexia.
Psychiatric disorders
Mental depression, hallucinations, restlessness, confusion, mood changes, euphoria, dysphoria, unusual excitement in children, nightmares.
Nervous system disorders
Convulsions, uncontrolled muscular movements, tremors, dizziness, headache.
Eye disorders
Miosis, visual disturbances.
Ear and labyrinth disorders Vertigo.
Rare cases of sensorineural hearing loss have been reported with codeine and codeine containing products
Cardiac disorders
Irregularities of cardiac rhythm, bradycardia, tachycardia, palpitations.
Vascular disorders Postural hypotension, flushing.
Larger doses produce hypotension.
Respiratory, thoracic and mediastinal disorders Larger doses produce respiratory depression.
Gastrointestinal disorders
Pancreatitis, nausea and vomiting, constipation, dry mouth, biliary spasm, stomach cramps.
Skin and subcutaneous tissue disorders Sweating.
Musculoskeletal, connective tissue and bone disorders Muscle rigidity especially respiratory muscles.
Renal and urinary disorders
Difficulty with micturition, urinary retention, ureteric spasm, dysuria.
Reproductive system and breast disorders Sexual dysfunction.
General disorders and administration site conditions Drowsiness.
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
Symptoms resulting from overdose are cold clammy skin, confusion, convulsions, dizziness, drowsiness, asthenia, hypotension, bradycardia, nervousness, restlessness, pin-point pupils, slow or troubled breathing and unconsciousness. Treatment entails emptying the stomach via induction of emesis or gastric lavage. Maintenance of a patent airway and institution of assisted or controlled respiration if necessary. Administration of opioid antagonist naloxone 10 mcg/kg of body-weight or 400 mcg-2 mg as a single dose preferably intravenous may be required. It must be borne in mind that naloxone may also antagonise the analgesic action of opioid analgesics and may precipitate withdrawal symptoms in physically dependent patients. For reversal of post operative opioid depression, dosage of naloxone must be carefully titrated to avoid interfering with post operative pain or causing other adverse effects; hypertension and tachycardia, sometimes resulting in left ventricular failure and pulmonary oedema has resulted following naloxone administration in these circumstances especially cardiac patients.
Initial doses as low as 0.5 mcg/kg of body weight have been recommended. Supportive measures such as intravenous fluids arid vasopressor drugs may be required.
Patients should be monitored continuously while administering additional naloxone as needed.
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.
Codeine also has an antidiarrhoeal action, it acts locally and probably centrally to alter the intestinal motility.
It has anti-tussive action due to suppression of the cough reflex by a direct action probably in the medulla or pons.
Codeine is also a suppressant of the narcotic abstinence syndrome and acts as a substitute for other opioid drugs. When administered orally it prevents or attenuates the withdrawal symptoms during detoxification. The resulting withdrawal symptoms which may occur when the substituted opioid is discontinued are less severe.
Codeine is much less potent as an analgesic as compared with morphine and has only mild sedative effect.
5.2 Pharmacokinetic properties
Codeine is well absorbed from the gastro-intestinal tract following oral administration and a small quantity is bound to plasma proteins. Peak levels of plasma codeine concentration are attained in an hour following ingestion. Plasma half-life has been reported to be between 3-4 hours after oral ingestion. Codeine is metabolised in the liver by O- and N- demethylation in the liver to morphine and norcodeine.
Codeine and its metabolites are excreted entirely by the kidneys mainly as conjugates with glucuronic acid.
Codeine and its salts are used to allay unproductive cough.
5.3. Preclinical Safety Data
Not applicable.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Maize starch Lactose monohydrate Sodium laurilsulfate Talc
Magnesium stearate
6.2. Incompatibilities
None reported.
6.3. Shelf Life
3 years for opaque plastic containers and amber glass bottles. 2 years for blister packs.
6.4.
Special Precautions for Storage
Keep out of the reach of children. Protect from heat, light and moisture.
6.5. Nature and Contents of Container
For pack sizes of 28, 30, 42, 50, 56, 84,100, 112, 250; 500, 1000 and bulk tablets.
The product is packed in:
i. Opaque plastic containers (securitainers) fitted with plastic caps.
ii. Amber glass bottles.
iii. Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a tamper evident or child resistant tamper evident closure composed of high density polyethylene. There is a packing inclusion of standard polyether foam or polyethylene or polypropylene made filler.
For pack sizes of 28, 30, 42, 56, 84 and 112 tablets, the product is packed in blister packs of aluminium/opaque PVC. It is subsequently packed in printed boxboard cartons.
6.6. Instruction for Use/Handling
Not applicable.
7. MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
UNITS 3 AND 4, QUIDHAMPTON BUSINESS UNITS
POLHAMPTON LANE
OVERTON
HAMPSHIRE
RG25 3ED
8. MARKETING AUTHORISATION NUMBER
PL 20416/0057
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
08/01/2009
10 DATE OF REVISION OF THE TEXT
15/11/2013