Codeine and Ibuprofen interacts in the following cases:
Dependence of codeine hypoalgesia on morphine formation via CYP2D6 makes this effect liable to interaction with drugs that are inhibitors of CYP2D6. Examples of potent inhibitors of CYP2D6 are quinidine, some selective serotonin reuptake inhibitors, some neuroleptics and ritornavir.
In patients with mild to moderate renal impairment, the dose should be kept as low as possible and renal function monitored.
In patients with mild to moderate renal impairment, the dose should be kept as low as possible.
Ibuprofen/codeine should be used with caution in patients with raised intracranial pressure or head injury.
Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or the embryo/foetal development. Data from epidemiological studies suggest an increased risk of miscarriage and of cardiac malformation and gastroschisis after use of a prostaglandin synthesis inhibitor in early pregnancy. The absolute risk for cardiovascular malformation was increased from less than 1%, up to approximately 1.5%. The risk is believed to increase with dose and duration of therapy.
In animals, administration of a prostaglandin synthesis inhibitor has been shown to result in increased pre- and postimplantation loss and embryo-foetal lethality. In addition, increased incidences of various malformations, including cardiovascular, have been reported in animals given a prostaglandin synthesis inhibitor during the organogenetic period.
From the 20th week of pregnancy onward, ibuprofen use may cause oligohydramnios resulting from foetal renal dysfunction. This may occur shortly after treatment initiation and is usually reversible upon discontinuation. In addition, there have been reports of ductus arteriosus construction following treatment in the second trimester, most of which resolved after treatment cessation. Therefore, during the first and second trimester of pregnancy, ibuprofen should not be given unless clearly necessary. If ibuprofen is used by a woman attempting to conceive, or during the first and second trimester of pregnancy, the dose should be kept as low and duration of treatment as short as possible. Anti-natal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure for several days from gestational week 20 onward. Treatment should be discontinued if oligohydramnios or ductus arteriosus constriction are found.
During the third trimester of pregnancy, all prostaglandin synthesis inhibitors may expose the foetus to:
the mother and the neonate, at the end of pregnancy, to:
Consequently, ibuprofen is contraindicated during the third trimester of pregnancy.
This product should not be used during breastfeeding. 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.
There is some evidence that drugs which inhibit cyclo-oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.
Patients may become dizzy and sedated with ibuprofen/codeine. Rare side effects may include convulsions, hallucinations, blurred or double vision and orthostatic hypotension. If affected, patients should not drive or operate machinery.
The list of the following adverse effects relates to those experienced with Ibuprofen and Codeine at OTC doses (maximum 1200 mg ibuprofen per day), in short-term use. In the treatment of mild to moderate pain and fever. In the treatment of other indications or under long-term treatment, additional adverse effects may occur.
Adverse events which have been associated with Ibuprofen and Codeine are given below tabulated by System Organ Class (SOC) and frequency. Frequencies are defined as: very common (≥1/10), common (≥1/100 and <1/10), uncommon (≥1/1000 and <1/100), rare (≥1/10,000 and <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse events are presented in order of decreasing seriousness.
| System Organ Class | Frequency | Adverse Events |
|---|---|---|
| Blood and Lymphatic System Disorders | Very rare | Haematopoietic disorders1 |
| Immune system disorders | Uncommon | Hypersensitivity reactions with urticaria and pruritus2 |
| Very rare | Severe hypersensitivity reactions. Symptoms could be: facial, tongue and throat swelling, dyspnoea, tachycardia, and hypotension (anaphylaxis, angioedema or severe shock)2 | |
| Metabolism and Nutrition Disorders | Not known | Decreased appetite |
| Psychiatric Disorders | Not known | Depression, hallucination, confusional state, dependence, mood altered, restlessness, nightmares. |
| Nervous System Disorders | Uncommon | Headache |
| Very rare | Aseptic meningitis3 | |
| Not known | Dizziness, drowsiness, convulsion, intracranial pressure increased, dyskinesia | |
| Eye Disorders | Very rare | Vision blurred |
| Not known | Diplopia | |
| Ear and Labyrinth disorders | Not known | Vertigo |
| Cardiac Disorders | Very rare | Cardiac failure and oedema4. |
| Not known | Bradycardia, palpitations | |
| Vascular Disorders | Very rare | Hypertension4 |
| Not known | Orthostatic hypotension | |
| Respiratory, Thoracic and Mediastinal Disorders | Not known | Respiratory tract reactivity comprising asthma, bronchospasm or dyspnoea2 Respiratory depression, cough suppression |
| Gastro-intestinal Disorders | Uncommon | Abdominal pain, nausea and dyspepsia. Exacerbation of colitis and Crohn's disease, gastritis5. |
| Rare | Diarrhoea, flatulence, constipation and vomiting. | |
| Very rare | Peptic ulcer, gastrointestinal perforation or gastrointestinal haemorrhage, melaena, and haematemesis6. Mouth ulceration. | |
| Not known | Dry mouth | |
| Hepatobiliary Disorders | Very rare | Liver disorder7 |
| Not known | Biliary colic | |
| Skin and Subcutaneous Tissue Disorders | Uncommon | Skin rash2 |
| Very rare | Severe forms of skin reactions such as erythema multiforme can occur. Bullous reactions including Stevens-Johnson syndrome and toxic epidermal necrosis2. | |
| Not known | Flushing. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Acute generalised exanthematous pustulosis (AGEP) Photosensitivity reactions | |
| Musculoskeletal and Connective Tissue Disorders | Not known | Muscle rigidity |
| Renal and Urinary Disorders | Very rare | Acute renal failure8 |
| Not known | Ureteric colic, dysuria9. Renal tubular acidosis10 | |
| General and Administration Site Conditions | Not known | Hypothermia, hyperhidrosis, irritability, fatigue, malaise. |
| Investigations | Very rare | Haemogloblin decreased, urea renal clearance decreased. |
| Infections and infestations | Very rare | Exacerbation of infections related inflammation (e.g. development of necrotizing fasciitis), in exceptional cases, severe skin infections and soft-tissue complication may occur during a varicella infection. |
1 Examples include anaemia, leucopenia, thrombocytopenia, pancytopenia and agranulocytosis. First signs are fever, sore throat, superficial mouth ulcers, flu-like symptoms, severe exhaustion, nose and skin bleeding, and bruising.
2 Hypersensitivity reactions: These may consist of (a) non-specific allergic reactions and anaphylaxis, (b) respiratory tract reactivity, including asthma, aggravated asthma, bronchospasm, and dyspnoea, or (c) various skin reactions, including pruritius, urticaria, purpura, angioedema and, more rarely, exfoliative and bullous dermatoses, including toxic epidermal necrolysis, Stevens-Johnson Syndrome and erythema multiforme.
3 The pathogenic mechanism of drug-induced aseptic meningitis is not fully understood. However, the available data on NSAID-related aseptic meningitis points to a hypersensitivity reaction (due to a temporal relationship with drug intake, and disappearance of symptoms after drug discontinuation). Single cases of symptoms of aseptic meningitis (such as stiff neck, headache, nausea, vomiting, fever or disorientation) have been observed during treatment with ibuprofen in patients with existing auto-immune disorders (such as systemic lupus erythematosus and mixed connective tissue disease).
4 Clinical studies suggest that use of Ibuprofen, particularly at a high doses (2400 mg/day) may be associated with a small increased risk of arterial thrombotic events (for example myocardial infarction or stroke).
5 The adverse events observed most often are gastrointestinal in nature.
6 Sometimes fatal.
7 Especially in long-term treatment.
8 Especially in long-term use, associated with increased serum urea concentrations and oedema. Also includes papillary necrosis.
9 Increased frequency, decrease in amount.
10 Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting typically following prolonged use of the ibuprofen component at higher than recommended doses due to dependence on the codeine component.
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