Codeine Phosphate Tablets BP 30mg

Summary of Product Characteristics Updated 25-Mar-2020 | Ranbaxy (UK) Limited a Sun Pharmaceutical Company

1. Name of the medicinal product

Codeine Phosphate Tablets BP 30mg

2. Qualitative and quantitative composition

Each tablet contains 30mg of codeine phosphate

Excipients with known effect:

Each tablet contains 38.46mg of lactose.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablet

White to off white circular normal biconvex tablets, embossed with R115.

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

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.

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:

- 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

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

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.

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.

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:

- 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, 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

- 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

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

- 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 Fertility, pregnancy and lactation

Pregnancy

Not recommended during pregnancy due to neonatal withdrawal symptoms and impaired effect of foetus. 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.

Breast-feeding

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

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.

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.

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.

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.

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 µ 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 monohydrate

Starch, pregelatinised

Magnesium Stearate

Sodium Starch Glycolate

6.2 Incompatibilities

None stated.

6.3 Shelf life

3 years: HDPE tamper-evident containers.

2 years: Blister strips.

6.4 Special precautions for storage

Store below 25°C

6.5 Nature and contents of container

HDPE 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 and other handling

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 31750/0111

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 13/02/1990

Date of latest renewal: 18/02/2009

10. Date of revision of the text

23/03/2020

Company Contact Details
Ranbaxy (UK) Limited a Sun Pharmaceutical Company
Address

5th Floor, Hyde Park, Hayes, 3, 11 Millington Road, Hayes, UB3 4AZ, UK

Telephone

+44 (0) 208 848 8688

Medical Information Direct Line

+44 (0) 208 848 5052

Out of Hours contact
WWW

http://www.sunpharma.com

E-mail
Medical Information e-mail