SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Codeine phosphate 15mg Tablets BP

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Codeine phosphate 15mg For excipients, see 6.1

3    PHARMACEUTICAL FORM

Tablet

White circular tablets marked C15 on one face and CP on the other.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Mild to moderate pain Dry or painful cough Diarrhoea

4.2    Posology and method of administration

Oral route

For Mild to Moderate Pain Adults:

30-60mg every four hours when necessary, to a maximum of 240mg daily. Children:

Not recommended.

Elderly:

Dosage should be reduced in elderly patients.

For dry or _painful cough Adults:

15-30mg 3-4 times daily.

Paediatric Population:

Children aged less than 12 years:

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

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).

Diarrhoea

Adults:

30mg three to four times daily (range 15-60mg)

Children:

Not recommended.

Elderly:

Dosage should be reduced in elderly patients.

4.3 Contraindications

Acute respiratory depression, hypersensitivity to codeine or other opioid analgesics or to any of the excipients obstructive airways disease, liver disease, severe hepatic dysfunction, acute alcoholism.

Use should be avoided in patients with raised intracranial pressure or head injury (in addition to the risk of respiratory depression and increased intracranial pressure, may affect pupillary and other responses vital for neurological assessment).

Codeine should not be given to comatose patients.

Codeine is also contraindicated in conditions where inhibition of peristalsis is to be avoided, where there is a risk of paralytic ileus, where abdominal distension develops, or in acute diarrhoeal conditions such as acute ulcerative colitis or antibiotic associated colitis (e.g. pseudomembranous colitis) or diarrhoea caused by poisoning.

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.

Codeine is contraindicated in women during breastfeeding (see section 4.6).

Also contraindicated in patients for whom it is known they are CYP2D6 ultrarapid metabolisers.

4.4 Special warnings and precautions for use

Not recommended for use in patients with acute asthma. Use with caution or in reduced doses in asthma and decreased respiratory reserve; avoid use during an acute asthma attack (see 4.3 Contraindications). It should only be used with caution in those with renal or hepatic impairment, and in those with a history of drug abuse or in reduced dose in elderly patients or debilitated patients, or in patients with hypotension, hypothyroidism, prostatic hypertrophy, adrenocortical insufficiency, inflammatory or obstructive bowel disorders, urethral stricture, shock, convulsive disorders, myasthenia gravis. It should be avoided or the dose reduced in patients with renal or hepatic impairment (see 4.3 Contraindications, liver disease). Use with caution in those with a history of drug abuse. Discontinuation should be carried out gradually in patients who may have developed physical dependence, to avoid precipitating withdrawal symptoms.

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 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%

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.

Opioid analgesics should be avoided in patients with biliary tract disorders or used in conjunction with an antispasmodic.

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).

Alcohol should be avoided whilst under treatment with codeine.

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 leaflet will state in the section 2 ‘Before taking your medicine’:

‘Pregnancy and breast-feeding’

If you are pregnant or planning to become pregnant then consult your doctor or pharmacist before taking these medicines.

Do not take codeine while you are breast feeding. Codeine and morphine passes in to breast milk.

‘Warnings and precautions’

Codeine is transformed to morphine in the liver by an enzyme. Morphine is the substance that produces pain relief. Some people have a variation of this enzyme and this can affect people in different ways. In some people, morphine is not produced or produced in very small quantities, and it will not provide enough pain relief. Other people are more likely to get serious side effects because a very high amount of morphine is produced. If you notice any of the following side effects, you must stop taking this medicine and seek immediate medical advice: slow or shallow breathing, confusion, sleepiness, small pupils, feeling or being sick, constipation, lack of appetite.

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 to lead to addiction.

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 interaction

Alcohol: the hypotensive, sedative and respiratory depressive effects of alcohol may be enhanced.

Anaesthetics: concomitant administration of codeine and anaesthetics may cause increased CNS depression and/or respiratory depression and/or hypotension.

Anti-arrhythmics: codeine delays the absorption of mexiletine. The analgesic activity of codeine is likely to be significantly impaired by quinidine which impairs codeine metabolism.

Antidepressants: The depressant effects of opioid analgesics may be enhanced by tricyclic antidepressants.

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.

Antihistamines: concomitant administration of codeine and antihistamines with sedative properties may cause increased CNS depression and/or respiratory depression and/or hypotension.

Antipsychotics: enhanced sedative and hypotensive effect.

Anxiolytics and hypnotics: enhanced sedative effect.

Domperidone and metoclopramide: codeine antagonises the effect of cisapride, metoclopramide and domperidone on gastrointestinal activity.

Sodium oxybate: concomitant administration of codeine and sodium oxybate may cause increased CNS depression and/or respiratory depression and/or hypotension.

Ulcer-healing drugs: Cimetidine may inhibit the metabolism of codeine resulting in increased plasma concentrations.

Interference with laboratory tests: Opioids may interfere with gastric emptying studies as they delay gastric emptying and with hepatobiliary imaging using technetium Tc 99m disofenin as opioid treatment may cause constriction of the sphincter of Oddi and increase biliary tract pressure.

4.6 Fertility, pregnancy and lactation

Pregnancy:

As with all medications caution should be exercised during pregnancy, especially in the first trimester. A possible association with respiratory and cardiac malformations has been reported following first trimester exposure to codeine.

Regular use of codeine during pregnancy may cause physical dependence in the foetus leading to withdrawal symptoms in the neonate. Administration of codeine during labour may depress respiration in the neonate. Opioid analgesics may cause gastric stasis during labour, increasing the risk of inhalation pneumonia in the mother.

Lactation:

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

Codeine produces sedation and may also cause changes in vision, including blurred or double vision therefore treatment may impair ability to drive and use machines. If affected, patients should not drive or operate machinery.

The effects of alcohol are enhanced by opioid analgesics.

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.

In therapeutic doses, codeine is much less liable than morphine to produce adverse effects.

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

Tolerance and some of the most common side effects - drowsiness, nausea, and vomiting, and confusion - generally develops with long term use.

Immune system disorders: maculopapular rash has been seen as part of a hypersensitivity syndrome associated with oral codeine phosphate; fever, splenomegaly and lymphadenopathy also occurred.

Endocrine disorders: hyperglycaemia.

Metabolism and nutrition disorders: anorexia.

Psychiatric disorders: mental depression, hallucinations and nightmares, restlessness, confusion, mood changes, euphoria and dysphoria.

Nervous system disorders: convulsions (especially in infants and children), dizziness, drowsiness, headache (prolonged use of a painkiller for headaches can make them worse). Raised intracranial pressure may occur in some patients.

Eye disorders: blurred or double vision or other changes in vision. Meiosis.

Ear and labyrinth disorders: vertigo.

Cardiac disorders: tachycardia, palpitations and bradycardia.

Vascular disorders: postural hypotension, facial flushing. Large doses produce hypotension.

Respiratory, thoracic and mediastinal disorders: Dyspnoea. Large doses produce respiratory depression.

Gastrointestinal disorders: nausea, vomiting, constipation, dry mouth, stomach cramps, pancreatitis.

Hepatobiliary disorders: Biliary spasm (may be associated with altered liver enzyme values).

Skin and subcutaneous tissue disorders: allergic reactions such as skin rashes, urticaria, pruritus, sweating and facial oedema.

Musculoskeletal and connective tissue disorders: Uncontrolled muscle movements. Muscle rigidity may occur after high doses.

Renal and urinary disorders: difficulty with micturation, urinary retention, ureteric spasm, dysuria. An antidiuretic effect may also occur with codeine.

Reproductive system and breast disorders: sexual dysfunction, erectile dysfunction, decreased potency. Decreased libido.

General disorders and administration site conditions: malaise, tiredness, hypothermia.

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

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. Dry mouth, sweating and facial flushing are other symptoms of overdose. High doses of codeine may produce sedation or excitement and, in children, convulsions may occur.

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 350 mg or a child more than 5 mg/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 sustained release preparation has been taken.

Naloxone may be given according to the following dose regimens:

Intravenous Injection:

0.8-2mg repeated at intervals of 2-3 minutes to a maximum of 10mg.

Child: 10pg/kg and, if no response, subsequent doses of 100pg/kg. Subcutaneous or Intramuscular Injection:

As for intravenous injection but only if the i.v. route is not feasible. The onset of action is slower with s.c. or i.m. injection.

Continuous intravenous infusion:

2mg diluted in 500ml of intravenous infusion solution at a rate adjusted according to the patient's response.

5    PHARMACOLOGICAL PROPERTIES

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.

5.2 Pharmacokinetic properties

Codeine is well absorbed from the gastrointestinal tract following oral administration. It is metabolised in the liver to morphine and norcodeine, which are both excreted in the urine partly as conjugates with glucuronic acid. Most of the excretion products appear in the urine within 6 hours and up to 86% of the dose is excreted in 24 hours. About 70% of the dose is excreted as free codeine, 10% as free and conjugated morphine and a further 10% as free or conjugated norcodeine. Only traces are found in the faeces. The plasma half life is between approximately 3 and 4 hours.

5.3 Preclinical safety data

There are no pre-clinical data of relevance to the prescriber, which are additional to those included in other sections.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate Acacia Maize starch Magnesium stearate Stearic Acid

6.2    Incompatibilities

None

6.3    Shelf life

36 months for polypropylene/polyethylene containers 24 months for blister packaging

6.4    Special precautions for storage

Do not store above 25 °C Store in the original container.

6.5    Nature and contents of container

100, 250 and 500 tablets in polypropylene/polyethylene containers with polypropylene/polyethylene tamper evident closures.

28, 30, 56, 60, 84 and 90 tablets in polypropylene/polyethylene containers with polypropylene/polyethylene tamper evident closures in cartons.

28, 30, 56, 60, 84 and 90 tablets in blister pack strips of 20 micron, hard tempered aluminium foil, coated with PVC compatible heat seal lacquer on the reverse side, and PVC film, in cartons.

6.6    Special precautions for disposal

Not applicable

7    MARKETING AUTHORISATION HOLDER

Aurobindo Pharma Limited Ares Block,

Odyssey Business Park, West End Road,

South Ruislip HA4 6QD, United Kingdom

8    MARKETING AUTHORISATION NUMBER

PL 20532/0088

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/03/2009

10    DATE OF REVISION OF THE TEXT

06/10/2015