- codeine phosphate hemihydrate
This information is intended for use by health professionals
Codeine Phosphate Hemihydrate
Excipients with known effect
Sodium Starch Glycolate (Type A)
45 mg (11 mg Sodium)
Recommended dosage:Adults over 18 years: One or two tablets every four to six hours.Do not take more than 6 tablets in 24 hours.Leave at least four hours between doses.Children aged 12 years to 18 years: The recommended dose for children 12 years and older is one or two tablets every 6 hours when necessary up to a maximum of 6 tablets in 24 hours.Children under 12 years: This medicine 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).
Elderly:No special dosage modifications are required for elderly patients, unless renal or hepatic function is impaired, in which case dosage should be assessed individually.Do not take for more than 3 days continuously without medical review.The patient should consult a doctor if symptoms persist or worsen, or if the product is required for more than 3 days.
Respiratory:Bronchospasm may be precipitated in patients suffering from or with a previous history of bronchial asthma or allergic disease.
Other NSAIDs:The use of this medicine with concomitant NSAIDs including cyclooxygenase-2 selective inhibitors should be avoided (see section 4.5).
SLE and mixed connective tissue disease:Systemic lupus erythematosus and mixed connective tissue disease -increased risk of aseptic meningitis (see section 4.8 Undesirable effects).
Renal:Renal impairment as renal function may further deteriorate (See section 4.3 and Section 4.8)
Hepatic:Hepatic dysfunction (See section 4.3 and Section 4.8)
Cardiovascular and cerebrovascular effects:Caution (discussion with doctor or pharmacist) is required prior to starting treatment in patients with a history of hypertension and/or heart failure as fluid retention, hypertension and oedema have been reported in association with NSAID therapy. Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke). Overall, epidemiological studies do not suggest that low dose ibuprofen (e.g. ≤ 1200 mg/day) is associated with an increased risk of arterial thrombotic events.Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease should only be treated with ibuprofen after careful consideration and high doses (2400 mg/day) should be avoided. Careful consideration should be made before initiating long-term treatment of patients with risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking), particularly if high doses of ibuprofen (2400 mg/day) are required.
Impaired female fertility:There is limited evidence that drugs which inhibit cyclo-oxygenase/ prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible upon withdrawal of treatment.
Gastrointestinal:NSAIDs should be given with care to patients with a history of gastrointestinal disease (ulcerative colitis, Crohn's disease) as these conditions may be exacerbated (See section 4.8 Undesirable effects).GI bleeding, ulceration or perforation, which can be fatal, has been reported with all NSAIDs at anytime during treatment, with or without warning symptoms or a previous history of serious GI events.The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with a history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3), and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g. misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and section 4.5).Patients with a history of GI toxicity, particularly when elderly, should report any unusual abdominal symptoms (especially GI bleeding) particularly in the initial stages of treatment.Caution should be advised in patients receiving concomitant medications which could increase the risk of gastrotoxicity or bleeding, such as corticosteroids, selective serotonin-reuptake inhibitors, anti-platelet agents such as aspirin or anticoagulants such as warfarin. In patients receiving anticoagulant therapy, prothrombin time should be monitored daily for the first few days of combined treatment (see section 4.5 Interactions). When GI bleeding or ulceration occurs in patients receiving ibuprofen, the treatment should be withdrawn.
Dermatological:Serious skin reactions, some of them fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported very rarely in association with the use of NSAIDs (see section 4.8). Patients appear to be at highest risk for these reactions early in the course of therapy: the onset of the reaction occurring in the majority of cases within the first month of treatment. This medicine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity.Exceptionally, varicella can be at the origin of serious cutaneous and soft tissue infectious complications. To date, the contributing role of NSAIDs in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of this medicine in case of varicella.Codeine should be used with caution in those with hypotension and/or hypothyroidism. The tablets should be used with caution in patients with raised intracranial pressure or head injury. The effects of CNS depressants (including alcohol) may be potentiated by codeine.Codeine is a narcotic analgesic. No more than the stated dose of this medicine should be taken. Prolonged regular use, except under medical supervision, may lead to physical and psychological dependence (addiction) and result in withdrawal symptoms, such as restlessness and irritability once the drug is stopped. It is important to consult a doctor if a patient experiences the need to use this product all the time.
CYP2D6 metabolismCodeine 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, 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 summarised below:
3.4% to 6.5%
1.2% to 2%
3.6% to 6.5%
1% to 2%
Post operative use in childrenThere 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 functionCodeine 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 label will state:Front of pack • Can cause addiction• For three days use only
Back of packRead the enclosed leaflet before taking this product.• List of indications as agreed in 4.1 of the SPC• If you need to take this medicine continuously for more than 3 days you should see your doctor or pharmacist• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. If you take this medicine for headaches for more than 3 days it can make them worseDo not take if you:• have (or have had two or more episodes of) a stomach ulcer, perforation or bleeding • are allergic to ibuprofen or any other ingredient of the product, aspirin or other related painkillers • are taking other NSAID painkillers, or aspirin with a daily dose above 75mg Speak to a pharmacist or your doctor before taking if you: • have or have had asthma, diabetes, high cholesterol, high blood pressure, a stroke, liver, heart, kidney or bowel problems • are a smoker • are pregnant If symptoms persist or worsen, consult your doctor.
The leaflet (or combined label/leaflet) will state:
'Headlines' section (to be prominently displayed)• This medicine can be used for ..(indications)• You should only take this product for a maximum of 3 days at a time. If you need to take it for a longer than 3 days you should see your doctor or pharmacist for advice• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it• If you take this medicine for headaches for more than 3 days it can make them worse
'What this medicine is for' section• Succinct description of the indications from 4.1 of the SPC
'Before you take this medicine' section• This medicine contains codeine which can cause addiction if you take it continuously for more than 3 days. This can give you withdrawal symptoms from the medicine when you stop taking it• If you take a painkiller for headaches for more than 3 days it can make them worse
'How to take this medicine' section• Do not take for more than 3 days. If you need to use this medicine for more than 3 days you must speak to your doctor or pharmacist• This medicine contains codeine and can cause addiction if you take it continuously for more than 3 days. When you stop taking it you may get withdrawal symptoms. You should talk to your doctor or pharmacist if you think you are suffering from withdrawal symptoms
'Possible side effects' section
Reporting of side effectsIf you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. UK SPC only: You can also report side effects directly via the Yellow Card Scheme Website: www.mhra.go.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.ROI SPC only: You can also report side effects directly via HPRA Pharmacovigilance, Earlsfort Terrace, IRL Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: [email protected] By reporting side effects you can help provide more information on the safety of this medicine.'How do I know if I am addicted?' sectionIf you take the medicine according to the instructions on the pack it is unlikely that you will become addicted to the medicine. However, if the following apply to you it is important that you talk to your doctor:• You need to take the medicine for longer periods of time• You need to take more than the recommended amount• When you stop taking the medicine you feel very unwell but you feel better if you start taking the medicine again
Ibuprofen should not be used in combination with:Acetylsalicylic acid (aspirin): Unless low-dose aspirin (not above 75mg daily) has been advised by a doctor, Concomitant administration of ibuprofen and acetylsalicylic acid is not generally recommended because of the potential of increased adverse effects.Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Although there are uncertainties regarding extrapolation of data to the clinical situation, the possibility that regular, long-term use of ibuprofen may reduce the cardioprotective effect of low-dose acetylsalicylic acid cannot be excluded. No clinically relevant effect is considered to be likely for occasional ibuprofen use (see section 5.1).
Other NSAIDS including cyclooxygenase-2 selective inhibitors:Avoid concomitant use of two or more NSAIDs as this may increase the risk of adverse effects (see section 4.4).
Codeine:Interacts with monoamine oxidase inhibitors. Therefore caution should be exercised in patients taking monoamine oxidase inhibitors.
Ibuprofen should be used with caution in combination with:
Anticoagulants:NSAIDS may enhance the effects of anti-coagulants, such as warfarin (See section 4.4). Antihypertensives and diuretics:NSAIDs may diminish the effect of these drugs. Diuretics can increase the risk of nephrotoxicity of NSAIDs.
Corticosteroids:Increased risk of gastrointestinal ulceration or bleeding (See section 4.4 Special warnings).
Anti-platelet agents and selective serotonin reuptake inhibitors (SSRIs):Increased risk of gastrointestinal bleeding (see section 4.4)
Cardiac glycosides:NSAIDs may exacerbate cardiac failure, reduce GFR and increase plasma glycoside levels.
Lithium:There is evidence for potential increases in plasma levels of lithium. Methotrexate:There is a potential for an increase in plasma methotrexate. Ciclosporin:Increased risk of nephrotoxicity. UK SPC only: Mifepristone:NSAIDs should not be used for 8-12 days after mifepristone administration as NSAIDs can reduce the effect of mifepristone. Tacrolimus:Possible increased risk of nephrotoxicity when NSAIDs are given with tacrolimus. Zidovudine:Increased risk of haematological toxicity when NSAIDs are given with zidovudine. There is evidence of an increased risk of haemarthroses and haematoma in HIV(+) haemophiliacs receiving concurrent treatment with zidovudine and ibuprofen. Quinolone antibiotics:Animal data indicate that NSAIDs can increase the risk of convulsions associated with quinolone antibiotics. Patients taking NSAIDs and quinolones may have an increased risk of developing convulsions.
Female fertility:See section 4.4 regarding female fertility
Pregnancy:Whilst no teratogenic effects have been demonstrated in animal experiments, the use of this medicine should, if possible, be avoided during the first 6 months of pregnancy.During the 3rd trimester, ibuprofen is contraindicated as there is a risk of premature closure of the foetal ductus arteriosus with possible persistent pulmonary hypertension. The onset of labour may be delayed and the duration increased with an increased bleeding tendency in both mother and child. (See section 4.3 Contraindications).
CodeineCodeine 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.
IbuprofenIn limited studies, ibuprofen appears in the breast milk in very low concentration and is unlikely to affect the breast-fed infant adversely.
UK SPC only (MHRA Driver Warnings):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 a '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
Ibuprofen:The following list of adverse effects relates to those experienced with ibuprofen at OTC doses, for short-term use. In the treatment of chronic conditions, under long-term treatment, additional adverse effects may occur.
Hypersensitivity reactions:Uncommon: Hypersensitivity reactions with urticaria and pruritus. Very rare: severe hypersensitivity reactions. Symptoms could be: facial, tongue and laryngeal swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock). Exacerbation of asthma and bronchospasm.
Gastrointestinal:The most commonly-observed adverse events are gastrointestinal in nature.Uncommon: abdominal pain, nausea and dyspepsia.Rare: diarrhoea, flatulence, constipation and vomitingVery rare: peptic ulcer, perforation or gastrointestinal haemorrhage, melaena, haematemesis, sometimes fatal, particularly in the elderly. Ulcerative stomatitis, gastritis.Exacerbation of colitis and Crohn's disease (see section 4.4).
Nervous System:Uncommon: Headache, blurred vision Very rare: Aseptic meningitis single cases have been reported very rarely.
Renal:Very rare: Acute renal failure, papillary necrosis, especially in long-term use, associated with increased serum urea and oedema.
Hepatic:Very rare: liver disorders. Haematological: Very rare: Haematopoietic disorders (anaemia, leucopenia, thrombocytopenia, pancytopenia, agranulocytosis). First signs are: fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, unexplained bleeding and bruising.
Skin and subcutaneous tissue disorders:Uncommon: Various skin rashesVery rare: Severe forms of skin reactions such as bullous reactions, including Stevens-Johnson Syndrome, erythema multiforme and toxic epidermal necrolysis can occur.
Not known: Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
Immune System:In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed (see section 4.4).Cardiovascular and Cerebrovascular: Oedema, hypertension, and cardiac failure, have been reported in association with NSAID treatment.Clinical studies suggest that use of ibuprofen, particularly at a high dose (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke) (see section 4.4 Special warnings and precautions for use)
CodeineSide effects to codeine include constipation, respiratory depression, cough suppression, nausea and drowsiness.Regular prolonged use of codeine is known to lead to addiction and symptoms of restlessness and irritability may result when treatment is then stopped.Prolonged use of a pain killer for headache can make them worse.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. UK SPC only: 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. ROI SPC only: Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: [email protected]
Tablet Core:Cellulose, MicrocrystallineHypromelloseSodium Starch Glycloate (Type A)Maize Starch, Pregelatinised
Film Coat:HypromelloseTitanium dioxide (E171)Talc
26th August 2019