CODANT Tablet Ref.[108792] Active ingredients: Codeine

Codeine Phosphate should be used in caution in the following conditions:

• Impaired respiratory function (avoid in chronic obstructive pulmonary disease) and asthma (avoid during an acute attack)
• 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)
• Hepatic Impairment – avoid if severe
• Renal Impairment
• Hypothyroidism
• Convulsions – may be induced or exacerbated
• Drug abuse or dependence (including alcoholism)
• Gall bladder disease or gall stones – opioids may cause biliary obstructions Avoid in biliary disorders
• Gastro intestinal surgery – use with caution after recent GI surgery as codeine may alter GI mobility
• Urinary tract surgery – following recent surgery patient 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, e.g. Addison’s Disease.
• Hypotension and shock
• Myasthenia gravis
• Elderly patients may metabolize and eliminate opioid analgesics more slowly than younger patients, a reduced dose is recommended in elderly patients.
• The risk benefit of continued use of codeine should be assessed regularly by the Prescriber.

Regular or prolonged use may produce psychic and physical dependence.

Tolerance may develop with repeated administration of codeine.

Agents which inhibit intestinal motility have been reported to induce toxic megacolon in some patients with ulcerative colitis.

Codeine is metabolized by liver enzyme CYP2D6 into morphine, its active metabolite. If a patient has a deficiency or is completely lacking this enzyme anadequate analgesic effect willnot be obtained. Estimates indicate that up to 7% of the Caucasian population may have this deficiency. However, if the patient is an ultrarapid metabolizer 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 nausea, vomiting, confusion, shallow breathing, small pupils, 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 metabolizer in different populations are summarized below:

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs: Concomitant use of codeine and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe codeine concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Paediatric population

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 metabolizers in their ability to metabolize 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.

Codant contains Lactose Monohydrate

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

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
• Antihypertensive drugs – enhanced hypotensive effect
• Pharmacokinetic interactions
• Ciprofloxacin – avoid premedication with opioids as they reduce plasma 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

Sedative medicines such as benzodiazepines or related drugs:

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Pregnancy

There is inadequate evidence of the safety of codeine in human pregnancy and administration of the drug during pregnancy should be considered only if the potential benefit justifies the potential risk to the foetus.

Opioid analgesics cross the placenta and newborn infants should be observed closely for signs of respiratory depression if the mother has received codeine during labour. Use of codeine during pregnancy may lead to withdrawal symptoms in neonates. Should such signs/symptoms be noted in mother or baby, the mother should immediately stop taking all codeine-containing medicines and seek medical advice.

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 should not be used during breastfeeding (see section 4.3).

At normal therapeutic doses codeine 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 metabolites 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.

Fertility

No data available.

Codeine may cause sedation and dizziness and patients should be advised not to drive or to operate machinery if affected.

Undesirable effects are especially likely to occur at treatment onset or at dose increase.

The undesirable effects are listed below by organ class and the following frequency convention:

Not known – cannot be estimated from the available data.

^* 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. Symptoms of restlessness and irritability may result when treatment is then stopped.

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.
• 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 HPRA Pharmacovigilance, Website: www.hpra.ie.

Not applicable.