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

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).

Posology

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. Codeine Phosphate tablets should not be used longer than necessary.

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

Treatment goals and discontinuation

Before initiating treatment with Codeine Phosphate tablets, a treatment strategy including treatment duration and treatment goals, and a plan for end of the treatment, should be agreed together with the patient, in accordance with pain management guidelines. During treatment, there should be frequent contact between the physician and the patient to evaluate the need for continued treatment, consider discontinuation and to adjust dosages if needed. When a patient no longer requires therapy with codeine, it may be advisable to taper the dose gradually to prevent symptoms of withdrawal. In absence of adequate pain control, the possibility of hyperalgesia, tolerance and progression of underlying disease should be considered (see section 4.4).

4.3. Contraindications

Patients with:

- Hypersensitivity to the active substance 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;

- 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

Tolerance and opioid use disorder (abuse and dependence)

Tolerance, physical and psychological dependence, and opioid use disorder (OUD) may develop upon repeated administration of opioids such as Codeine Phosphate tablets. Repeated use of Codeine Phosphate tablets can lead to OUD. A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of Codeine Phosphate tablets may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).

Before initiating treatment with Codeine Phosphate tablets and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see section 4.2). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should contact their physician.

Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

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 take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

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.

As with other opioids, in case of insufficient pain control in response to an increased dose of codeine, the possibility of opioid-induced hyperalgesia should be considered. A dose reduction or treatment review may be indicated.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Codeine Phosphate Tablets 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 Phosphate Tablets 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).

Hepatobiliary disorders

Codeine may cause dysfunction and spasm of the sphincter of Oddi, thus increasing the risk of biliary tract symptoms and pancreatitis. Therefore, codeine has to be administered with caution in patients with pancreatitis and diseases of the biliary tract.

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 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 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% 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 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:

- 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)

- Drug abuse or dependence (including alcoholism)

- Pregnancy and breast feeding (see section 4.6)

- Convulsions – they may be induced or exacerbated

- 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

- 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

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

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

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

This medicinal product contains less than 1 mmol sodium (23 mg) per maximum daily dose, that is to say essentially 'sodium- free'.

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

- 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)

- G abapentinoids (gabapentin and pregabalin) - the concomitant use with gabapentinoids (gabapentin and pregabalin) may result in respiratory depression, hypotension, profound sedation, coma or death (see section 4.4)

- 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

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

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).

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

Psychiatric disorders: frequency unknown: drug dependence (see section 4.4).

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, pancreatitis.

Muscoskeletal, connective tissue and bone density: muscle rigidity.

Hepatobiliary disorders: sphincter of Oddi dysfunction.

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

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

General disorders and administration site conditions: uncommon: drug withdrawal syndrome.

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.

Drug dependence: repeated use of Codeine Phosphate tablets can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see section 4.4).

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

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.