Paracetamol/ Ibuprofen/ Codeine

Registered South African indications: 

• Relief of mild to moderate pain of inflammatory origin with or without fever

Paracetamol/ibuprofen/codeine contains paracetamol which may be fatal in overdose. In the event of overdosage or suspected overdose and notwithstanding the fact that the person may be asymptomatic, the nearest doctor, hospital or Poison Centre must be contacted immediately

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Respiratory depression, especially in the presence of cyanosis and excessive bronchial secretion, after operations on the biliary tract, acute alcoholism, head injuries and conditions in which intracranial pressure is raised
• Coadministration with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such treatment
• Coadministration with coumarin anticoagulants
• Diarrhoea associated with pseudomembranous colitis
• Impaired hepatic function
• Impaired renal function
• Heart failure or cardiovascular disease
• Active or a history of recurrent ulcer/haemorrhage/perforations
• History of gastrointestinal perforation, ulceration or bleeding (PUBs) related to previous NSAIDs, including paracetamol/ibuprofen/codeine
• Sensitivity to aspirin or another nonsteroidal anti-inflammatory medicines (NSAIDs)
• During an attack of bronchial asthma, uncontrolled asthma, bronchospasm or in heart failure secondary to chronic lung disease
• Nasal polyps associated with aspirin-induced bronchospasm
• Bleeding disorders
• Newborn babies (up to 4 weeks old) as the suspension contains sodium benzoate and may increase jaundice (sus)
• Breastfeeding as safety has not been established
• Women around 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/ foetal renal dysfunction and premature closure of the foetal ductus arteriosus
• Children younger than 12 years old (cap)

Additional contraindications related to capsules and 400/10/500 (mg) film-coated tablets

• Paediatric patients (0 to 18 years of age) who have undergone a tonsillectomy and/or adenoidectomy for obstructive sleep apnoea syndrome due to an increased risk of developing serious and life-threatening adverse reactions
• CYP2D6 ultra-rapid metabolisers
• Chronic constipation

South African recommendations

Caution in the following patient groups

• First and second trimester of pregnancy
• Elderly

Duration of use and excess dosage

• Continuous administration for 5 days is not advised, as safety has not been established
• Dosages in excess of those recommended may cause severe liver damage
• Dependence may develop with prolonged use of high doses

High anion gap metabolic acidosis (HAGMA)

• Caution is advised with coadministration with flucloxacillin due to increased risk of high anion gap metabolic acidosis (HAGMA), particularly in patients with severe renal impairment, sepsis, malnutrition and other sources of glutathione deficiency (e.g. chronic alcoholism), as well as those using maximum daily doses of treatment. Close monitoring, including measurement of urinary 5 oxoproline, is recommended

Ibuprofen specific considerations

Respiratory disorders and hypersensitivity reactions

• Caution is required when administered to patients suffering from, or with a previous history of chronic rhinitis or allergic diseases since NSAIDs, have been reported to precipitate bronchospasm, urticaria or angioedema in such patients
• Acute asthma attack or respiratory impairment or disease may decrease respiratory drive and increase airway resistance in these patients. Asthma may be exacerbated

Renal effects

• The administration of an NSAID, such as ibuprofen, may cause a dose dependent reduction in prostaglandin formation and precipitate renal failure. Risk is increased by habitual concomitant intake of various similar pain medicines
• Patients at greatest risk, are those taking diuretics and the elderly. For these patients, use the lowest effective dose, for the shortest possible duration and monitor renal function
• There is a risk of renal impairment in dehydrated children and adolescents. Severe hypokalaemia and renal tubular acidosis have been reported due to prolonged use of ibuprofen at higher than recommended doses. This risk is increased with the use of codeine/ibuprofen as patients may become dependent on the codeine component
• Presenting signs and symptoms include reduced level of consciousness and generalised weakness. Ibuprofen induced renal tubular acidosis should be considered in patients with unexplained hypokalaemia and metabolic acidosis

Hepatic effects

• Hepatic impairment may increase the risk of hepatotoxicity

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. Abuse or intentional misuse may result in overdose and/or death
• Serious clinical outcomes, including fatalities, have been reported in association with abuse and dependence with codeine/ibuprofen combinations, particularly when taken for prolonged periods at higher than recommended doses. These have included reports of gastrointestinal perforations, gastrointestinal haemorrhages, severe anaemia, renal failure, renal tubular acidosis and severe hypokalaemia associated with the ibuprofen component
• Patients should be informed about the risks and signs of OUD as well as serious clinical outcomes. If these signs occur, patients should be advised to contact their doctor. Withdrawal symptoms, such as restlessness and irritability may occur once the medicine is stopped

Cardiovascular and cerebrovascular effects

• Caution is required in patients with a history of hypertension and/or heart failure as fluid retention and oedema have been reported in association with paracetamol/ibuprofen/codeine
• In view of paracetamol/ibuprofen/codeine's inherent potential to cause fluid retention, heart failure may be precipitated in some compromised patients
• The use of ibuprofen, particularly at a high dose (2400mg/day) and in long term treatment, may be associated with an increased risk of arterial thrombotic events such as myocardial infarction or stroke
• Caution is required in patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) and should only be treated with paracetamol/ibuprofen/codeine after careful consideration

Alcoholism, impaired liver function, drug abuse, drug dependence or if the patient is predisposed to drug abuse

• Avoid alcohol as there is an increased risk of liver toxicity, especially in alcoholics using high doses of paracetamol/ibuprofen/codeine for a prolonged period of time

Gastrointestinal (GI) bleeding, ulceration and perforation

• GI bleeding, ulceration, or perforation can be fatal and may occur at any time during treatment without warning symptoms or a prior history of serious GI events
• The risk of these events is increased with higher doses of paracetamol/ibuprofen/codeine, in the elderly, and in patients with a history of ulcers (especially those involving haemorrhage or perforation)
• Patients with a history of GI disease, particularly the elderly, must immediately report any unusual abdominal symptoms (especially bleeding), especially at the start of treatment
• Caution is required when using concomitant medicines that increase the risk of ulcers or bleeding, such as oral corticosteroids, SSRIs (antidepressants), or antiplatelet agents like aspirin
• If GI bleeding or ulceration occurs, treatment with paracetamol/ibuprofen/codeine must be stopped immediately
• Caution is necessary for patients with a history of GI diseases (e.g., ulcerative colitis, Crohn's disease, hiatus hernia, GERD) as these conditions may be exacerbated
• Avoid use with other NSAIDs (including COX-2 inhibitors) due to the cumulative risk of ulceration and bleeding
• Excessive alcohol consumption combined with this medication increases the risk of adverse gastrointestinal effects and potential hemorrhage

Dehydration

• Caution should be used when initiating treatment with in patients with considerable dehydration. There is a risk of renal impairment especially in dehydrated children, adolescents and the elderly

Masking of symptoms of underlying infections

• The antipyretic, analgesic and anti-inflammatory action of paracetamol/ibuprofen/codeine may mask symptoms of the occurrence of worsening of infection, which may lead to delayed initiation of appropriate treatment and thereby worsening the outcome of the infection
• This has been observed in bacterial community acquired pneumonia and bacterial complications to varicella. When paracetamol/ibuprofen/codeine is administered for fever or pain relief in relation to infection, monitoring of infection is advised. In nonhospital settings, the patient should consult a doctor if symptoms persist or worsen

Allergic conditions

• Possibility of cross sensitivity

Anaemia

• Anaemia may be exacerbated

Bleeding disorders

• Paracetamol/ibuprofen/codeine, like other NSAIDs, can interfere with platelet aggregation and prolong bleeding time in normal patients. Increased risk of bleeding

Elderly patients

• The elderly have an increased frequency of adverse reactions to NSAIDs including ibuprofen, especially gastrointestinal perforation, ulceration or bleeding (PUBs), which may be fatal

Surgery

• Possible enhanced bleeding, if surgery is required

Drug reaction with eosinophilia and systemic symptoms

• Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported in patients taking NSAIDs. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling among other clinical manifestations
• Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved
• Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue treatment and evaluate the patient immediately

Varicella

• In exceptional cases, varicella can be at the origin of serious cutaneous and soft tissues infectious complications. The contributing role of NSAIDs, such as ibuprofen, in the worsening of these infections cannot be ruled out. Thus, it is advisable to avoid use of paracetamol/ibuprofen/codeine in case of varicella

Systemic lupus erythematosus and mixed connective tissue disease

• In patients with systemic lupus erythematosus (SLE) and mixed connective tissue disorders there may be an increased risk of aseptic meningitis

Aseptic meningitis

• Aseptic meningitis has been observed on occasions in patients on ibuprofen. Although it is probably more likely to occur in patients with SLE and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease

Codeine phosphate specific considerations

Dependency and addiction

• Exceeding the prescribed dose or using the medication continuously for prolonged periods can lead to physical and psychological dependency. High doses taken over time can produce an addiction similar to morphine

Mental health and substance abuse

• There is a significantly higher risk of addiction for patients who have a personal or family history of substance abuse or mental health disorders

To be used with caution in patients with the following

• Acute abdominal conditions as diagnosis or clinical course may be obscured
• Respiratory impairment or disease as treatment may decrease respiratory drive and increase airway resistance in these patients
• Cardiac dysrhythmias, as these may be induced or exacerbated
• Convulsions or history thereof, as these may be induced or exacerbated
• Gallbladder disease or gallstones as these may cause biliary tract spasm
• Recent gastrointestinal tract surgery
• Hypothyroidism, due to an increased risk of respiratory depression and prolonged central nervous system depression
• Adrenocortical insufficiency
• Prostatic hypertrophy, obstruction, urethral stricture or recent urinary tract surgery, as urinary retention may be precipitated by paracetamol/ibuprofen/codeine
• Shock
• Inflammatory or obstructive bowel disorders or ulcerative disease of the upper or lower gastrointestinal tract, as the risk of toxic megacolon may be increased
• Dehydration, especially in children and adolescents, due to the risk of renal impairment
• Myasthenia gravis

Excipient considerations

• Suspension
  • The suspension contains sorbitol and may have a laxative effect. Patients with the rare hereditary condition of sorbitol intolerance should not take paracetamol/ibuprofen/codeine suspension
  • The additive effect of concomitantly administered medicines containing sorbitol and dietary intake of sorbitol should be taken into account. The content of sorbitol in medicines for oral use may affect the bioavailability of other medicines for oral use administered concomitantly
  • Paracetamol/ibuprofen/codeine suspension contains less than 1 mmol sodium per 10ml, that is to say essentially ‘sodium-free’
  • The suspension contains 10mg sodium benzoate in each 10 mL which is equivalent 0.1% m/v. Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old)
  • Paracetamol/ibuprofen/codeine suspension contains sodium metabisulphite which may rarely cause severe hypersensitivity reactions and bronchospasm

Effects on ability to drive and use machines (solid oral dosage forms)

• Paracetamol/ibuprofen/codeine has a minor influence on the ability to drive or operate machinery. Since adverse reactions such as dizziness, drowsiness and visual impairment have been reported in patients receiving paracetamol/ibuprofen/codeine, patients should not drive, use machinery or perform any tasks that require concentration, until they are certain that it does not adversely affect their ability to do so

Forms avail. in SA and covered in this monograph: cap, fct, sus, tab

South African registered indications and dosages

Relief of mild to moderate pain of inflammatory origin with or without fever

Paracetamol/ Ibuprofen/ Codeine phosphate
250/200/10 (mg)
250/200/10 (mg/10ml)

• Oral (cap): 1-2 cap, 6hrly; Max: 8 cap/24hrs; Treatment duration: Up to 5 days
• Oral (sus): 10-20ml (2-4 medicine measures), 4hrly; Max: Do not exceed 60ml (12 medicine measures)/24hrs; Treatment duration: Up to 5 days

350/200/10 (mg)

• Oral (fct, tab): 1-2 tab, 6hrly; Max: 6 tab/24hrs; Treatment duration: Up to 5 days

500/400/10 (mg)

• Oral (fct): 1 tab, 3 times dly; Max: 3 tab/24hrs; Treatment duration: Up to 5 days

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Do not exceed the recommended dose. The duration of treatment should be limited to 5 days and if no effective pain relief is achieved the patients/carers should be advised to seek the views of a medical practitioner

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Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms

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Suspension should be shaken before use

Paed. forms avail. in SA and covered in this monograph: cap, fct, sus, tab

South African registered indications and dosages

Relief of mild to moderate pain of inflammatory origin with or without fever

Paracetamol/ Ibuprofen/ Codeine Phosphate
250/200/10 (mg/10ml)

Oral (sus)

• Younger than 3 years: Not established for use (no recommendation on a posology can be made)
• Between 3-5 years: 2.5-5ml (½-1 medicine measure), 3-4 times dly; Max: Do not exceed 1ml/kg of body weight/24hrs (max. of 20ml); Treatment duration: Up to 5 days
• Between 6-12 years: 5-10ml (1-2 medicine measures), 3-4 times dly; Max: Do not exceed 1ml/kg of body weight/24hrs (max. of 40ml); Treatment duration: Up to 5 days
• Older than 12 years: See adult dosage

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Suspension should be shaken before use

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350/200/10 (mg)
250/200/10 (mg)
500/400/10 (mg)

Oral (cap, fct, tab)

• Younger than 12 years: Not established for use
• Older than 12 years: See adult dosage

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Do not exceed the recommended dose. Healthcare provider should be consulted if no relief is obtained with the recommended dosage. Use the lowest effective dose for the shortest possible duration of treatment

Pregnancy

South African recommendations

• First and second trimester: Caution
• Third trimester: Contraindicated

Paracetamol

• A large amount of data on pregnant women indicates neither malformative, nor foeto/neonatal toxicity. Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy, however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency (400/10/500 (mg) fct)
• Paracetamol as part of a combination medicine, as contained in MYBULEN CAPSULES, should not be taken. Frequent use of paracetamol in late pregnancy may be associated with an increased risk of persistent wheezing in the infant which may persist into childhood (cap)

Ibuprofen

• First trimester: Inhibition of prostaglandin synthesis may adversely affect the pregnancy and/or embryo/foetal development. Data from epidemiological studies raise concern about an increased risk of miscarriage and of cardiac malformation and gastroschisis after the use of a prostaglandin synthesis inhibitor in early pregnancy. 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 post- implantation losses 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
• Second and third trimester: During the third trimester of pregnancy, prostaglandin synthesis inhibitors, such as ibuprofen, may expose the foetus to
  • Cardiopulmonary toxicity (with premature closure of the ductus arteriosus and pulmonary hypertension)
  • Renal dysfunction, which may progress to renal failure with oligohydramnios
  • At the end of pregnancy, the mother and the neonate may be exposed to
    - Possible prolongation of bleeding time
    - Inhibition of uterine contractions, which may result in delayed or prolonged labour
• Because of these risks, the use of paracetamol/ibuprofen/codeine, dose and duration, between 20 and 30 weeks of gestation should be limited and avoided at around 30 weeks of gestation and later in pregnancy

Codeine phosphate

• Codeine phosphate is a narcotic analgesic. Use of narcotic analgesics during pregnancy is associated with foetal adverse effects, which include physical dependence and withdrawal, retardation of growth, and neonatal respiratory depression with high doses

Breastfeeding

South African recommendations

• Contraindicated
• NSAIDs, such as ibuprofen, can appear in the breast milk in very low concentrations. Paracetamol/ibuprofen/codeine is not recommended for use/should not be used by breastfeeding women

Fertility

South African recommendations

• The use of paracetamol/ibuprofen/codeine may impair female fertility and is not recommended in women attempting to conceive
• Ibuprofen: There is some evidence that medicines which inhibit cyclo- oxygenase/prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment

South African recommendations

• Contraindicated

South African recommendations

• Contraindicated

South African recommendations

• Caution; dose adjustment recommended
  The dosage should be reduced in elderly and debilitated patients

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Paracetamol

Blood and the Lymphatic System Disorders

Less frequent 

• Blood dyscrasias including*
• Thrombocytopenia*
• Leucopenia
• Pancytopenia
• Neutropenia
• Agranulocytosis*
• Anaemia

Immune System Disorders

Frequency unknown

• Anaphylactic shock
• Angioedema
• Allergic reactions (hypersensitivity) including skin rash*

Metabolism and Nutrition Disorders

Frequency unknown

• Pyroglutamic aciduria (5-oxoprolinuria)
• High-anion gap metabolic acidosis

Hepato-biliary Disorders

Frequency unknown 

• Hepatitis which may lead to acute hepatic failure
• Pancreatitis

Skin and Subcutaneous Tissue Disorders

Less frequent

• Skin rashes and other allergic reactions may occur. The rash is usually erythematous or urticaria but sometimes more serious and accompanied by fever and mucosal lesions
• Dermatitis

Frequency unknown 

• Drug-induced hypersensitivity syndrome (DIHS)
• Fixed drug eruptions (FDE)

Renal and Urinary Disorders

Less frequent

• Renal colic
• Renal failure
• Sterile pyuria

Ibuprofen

Infections and Infestations

Less frequent

• Rhinitis
• Aseptic meningitis
  - Especially in patients with existing autoimmune disorders, such as systemic lupus erythematosus and mixed connective tissue disease) with symptoms of stiff neck, headache, nausea, vomiting, fever or disorientation

Blood and the Lymphatic System Disorders

Frequent 

• Leucopenia
• Thrombocytopenia
• Neutropenia
• Pancytopenia
• Agranulocytosis
• Aplastic anaemia
• Haemolytic anaemia

Immune System Disorders

Less frequent

• Anaphylactic reaction
• Hypersensitivity reactions including fever and angioedema

Frequency unknown

• Respiratory tract reactivity
  - Asthma
  - Aggravated asthma
  - Bronchospasm or dyspnoea

Psychiatric Disorders

Frequent

• Nervousness
• Insomnia
• Depression

Less frequent

• Anxiety
• Confusional state
• Hallucination

Nervous System Disorders

Frequent

• Headache
• Dizziness
• Drowsiness

Frequency unknown

• Optic neuritis
• Paraesthesia
• Somnolence

Eye Disorders

Less frequent

• Visual impairment
• Toxic optic neuropathy

Ear and Labyrinth Disorders

Frequent

• Vertigo
• Tinnitus

Frequency unknown

• Impaired hearing

Cardiac Disorders

Frequent

• Oedema
• Cardiac failure

Less frequent

• Angina pectoris
• Cardiac dysrhythmias
• Oedema
• Hypertension

Vascular Disorders

Less frequent

• Hypertension

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Asthma
• Bronchospasm
• Dyspnoea

Frequency unknown

• Alveolitis
• Pulmonary eosinophilia

Gastrointestinal Disorders

Frequent

• Dyspepsia
• Gastritis
• Peptic ulcers
• Diarrhoea
• Nausea
• Vomiting
• Abdominal pain
• Flatulence
• Constipation
• Melaena
• Mouth ulcer
• Haematemesis
• Gastrointestinal haemorrhage (sometimes fatal)
• Gastrointestinal perforation
• Exacerbation of colitis and Crohn´s disease

Less frequent

• Pancreatitis

Hepato-biliary Disorders

Less frequent

• Abnormal liver function
• Hepatic failure
• Hepatitis
• Jaundice

Frequency unknown

• Hepatotoxicity

Skin and Subcutaneous Tissue Disorders

Frequent

• Rash

Less frequent

• Pruritus
• Urticaria
• Purpura
• Photosensitivity reaction

Frequency unknown

• Severe cutaneous adverse reactions
  - Erythema multiforme
  - Bullous reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS)
  - Acute generalised exanthematous pustulosis (AGEP)

Renal and Urinary Disorders

Less frequent

• Impaired renal function and toxic nephropathy in various forms, including
  - Interstitial nephritis
  - Nephrotic syndrome
  - Renal failure

Frequency unknown

• Haematuria
• Fluid retention

General Disorders and Administrative Site Conditions

Frequent

• Fatigue

Investigations

Less frequent

• Increased blood urea nitrogen
• Increased serum transaminases
• Increased alkaline phosphatase
• Decrease in haemoglobin and haematocrit values
• Inhibition of platelet aggregation
• Prolonged bleeding time
• Decrease of serum calcium
• Increase in serum uric acid

Codeine Phosphate

Psychiatric Disorders

Less frequent

• Confusion
• Restlessness
• Change of mood
• Euphoria

Nervous System Disorders

Frequent

• Drowsiness

Less frequent

• Vertigo
• Raised intracranial pressure

Frequency unknown

• Dizziness
• Light-headedness
• Confusion*

Eye Disorders

Less frequent

• Changes in miosis
• Blurred or double vision

Ear and Labyrinth Disorders

Frequency unknown

• Vertigo
• Ototoxicity leading to sensorineural hearing loss*

Cardiac Disorders

Less frequent

• Bradycardia
• Palpitations
• Orthostatic hypotension

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Respiratory depression
• Cough suppression

Gastrointestinal Disorders

Frequent

• Constipation

Less frequent

• Nausea
• Vomiting
• Dry mouth

Hepato-biliary Disorders

Less frequent

• Biliary spasm

Skin and Subcutaneous Tissue Disorders

Less frequent

• Urticaria
• Pruritus

Renal and Urinary Disorders

Less frequent

• Micturition difficulties
• Ureteric antidiuretic effect
• Urinary retention*

General Disorders and Administrative Site Conditions

Less frequent

• Sweating
• Facial flushing
• Hypothermia

Post-Marketing Experience

Skin and Subcutaneous Tissue Disorders (Paracetamol)

Frequency unknown 

• Drug-induced hypersensitivity syndrome (DIHS) and fixed drug eruptions (FDE)

Metabolism and Nutrition Disorders (Ibuprofen)

Frequency unknown 

• Hypokalaemia

Renal and Urinary Disorders (Ibuprofen)

Frequency unknown 

• Renal tubular acidosis

Gastrointestinal Disorders (Codeine Phosphate)

Frequency unknown

• Abdominal pain, including pancreatitis

Key

*Reported for combined paracetamol and codeine phosphate treatment

Combination products may have additional pharmacological effects not accounted for by the action of the individual ingredients

Paracetamol

• Isoniazid
• Antiepileptics
• Carbamazepine
• Phenobarbital
• Phenytoin
• Primidone
• Chloramphenicol
• Oral contraceptives
• Metoclopramide
• Domperidone
• Cholestyramine
• Warfarin and other coumarins
• Enzyme inducing and hepatotoxic medicines
• Probenecid
• Salicylates
• Rifampicin
• Flucloxacillin
• Zidovudine
• Co-trimoxazole
• Interferon alfa

Ibuprofen

• Antihypertensives (ACE inhibitors, angiotensin II antagonists)
• Beta-blockers
• Diuretics (including potassium-sparing diuretics)
• Cardiac glycosides
• Cholestyramine
• Digoxin
• Phenytoin
• Lithium
• Methotrexate
• Ciclosporin
• Mifepristone
• Probenecid
• Sulfinpyrazone
• NSAIDs (including COX-2 selective inhibitors)
• Aspirin
• Corticosteroids
• Anticoagulants (warfarin, heparin)
• Quinolone antibiotics
• Sulfonylureas
• Anti-platelet agents
• Selective serotonin reuptake inhibitors (SSRIs)
• Tacrolimus
• Zidovudine
• Ritonavir
• Alcohol
• Bisphosphonates
• Oxpentifylline
• Baclofen
• Captopril
• Aminoglycosides
• Ginkgo biloba
• CYP2C9 Inhibitors (voriconazole, fluconazole)
• Bone marrow depressants

Codeine Phosphate

• Monoamine Oxidase Inhibitors (MAOIs)
• Tricyclic antidepressants
• Alcohol
• CNS depressants
• Opioid analgesics
• Tranquilisers
• Sedative hypnotics 
• Benzodiazepines
• Anticholinergics
• Antidiarrhoeals
• Loperamide
• Antiperistaltic agents
• Kaolin 
• Antimuscarinics
• Atropine
• Hypotension-producing medications
• Cimetidine
• Antihistamines
• Antihypertensives
• Neuromuscular blocking agents
• Quinidine
• Mexiletine
• Metoclopramide
• Cisapride
• Domperidone
• Naloxone
• Naltrexone

None routine. Specific cases may require

• Measurement of urinary 5 oxoproline
• Renal function
• Serum potassium

Paracetamol
Paracetamol is the active metabolite of phenacetin. Paracetamol has analgesic and antipyretic effects. However, it has weak anti-inflammatory effects, and has been thought to have a generally poor ability to inhibit cyclooxygenase (COX) in the presence of high concentrations of peroxides, as are found at sites of inflammation. COX inhibition might be disproportionately pronounced in the brain, explaining its antipyretic efficacy.

Ibuprofen
Ibuprofen is a propionic acid derivative with analgesic, anti- inflammatory and anti-pyretic activity. The medicine’s therapeutic effects as an NSAID are thought to result from its inhibitory effect on the enzyme cyclo-oxygenase, which results in a marked reduction in prostaglandin synthesis.

Codeine Phosphate
Codeine phosphate is a centrally acting weak analgesic. Codeine exerts its effects 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.

COMBINATION PREPARATIONS

Ibuprofen/Paracetamol/Codeine phosphate

Capsule 200mg/250mg/10mg

• Gen-Payne (Adcock)
• Ibugesic Forte (Cipla Medpro)
• Ibupain Forte (Sandoz)
• Mybulen (Pharmacare)
• Myprodol (Adcock Ingram) originator

Tablet 200mg/350mg/10mg

• Mybucod (Pharmacare)
• Mybulen (Pharmacare)

Suspension (per 10ml) 200mg/250mg/10mg

• Mybulen (Pharmacare)
• Myprodol (Adcock Ingram)