Paracetamol/ Ibuprofen

Registered South African indications:

• Relief of mild to moderate pain and the reduction of fever in adults, where an IV route of administration is considered clinically necessary

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 ingredients or any of the excipients in this combination product
• Pregnancy or when planning to become pregnant
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• Severe cardiovascular disease or heart failure
• History of gastrointestinal perforation, ulceration, or bleeding (PUBs) related to previous NSAIDs
• History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, fatal anaphylactic-like reactions to NSAIDs have been reported in such patients
• Treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery
• Active alcoholism, as chronic excessive alcohol ingestion may predispose patients to hepatotoxicity (due to the paracetamol component)
• Patients with spinal cord injuries

Contraindications registered in other jurisdictions

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Third trimester of pregnancy
• Severe renal impairment
• Severe hepatic impairment
• Severe heart failure (NYHA Class IV)
• Active alcoholism, as chronic excessive alcohol ingestion may predispose patients to hepatotoxicity (due to the paracetamol component)
• History of asthma, urticaria, or allergic-type reactions after taking acetylsalicylic acid or other NSAIDs
• History of gastrointestinal bleeding or perforation related to previous NSAID therapy
• Active, or a history of, recurrent peptic ulceration/haemorrhage (two or more distinct episodes of proven ulceration or bleeding)
• Cerebrovascular or other active bleeding
• Blood clotting disorders and conditions involving an increased tendency to bleed
• Severe dehydration (caused by vomiting, diarrhoea, or insufficient fluid intake)
• Patients under the age of 18 years

South African recommendations

Caution in the following patient groups

• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Glucose 6 phosphate dehydrogenase (G6PD) deficiency (as it may lead to haemolytic anaemia)
• Anorexia, bulimia, or cachexia (due to low hepatic glutathione reserves)
• Chronic malnutrition, dehydration, or hypovolaemia

Transition to oral analgesics

• It is recommended to switch to oral analgesic treatment as soon as the oral administration route is feasible

Maximum daily dose

• The total dose of paracetamol should not exceed 4g per day
• Consider all sources of paracetamol, including non-prescription oral or parenteral medicines, before administering IV paracetamol/ ibuprofen
• Exceeding the maximum daily dose of paracetamol may cause severe hepatic injury

Hepatic injury

• Patients with hepatic insufficiency, chronic alcoholism, chronic malnutrition, or dehydration may be at a higher risk of liver damage following administration of IV paracetamol/ ibuprofen

Hypertension and heart failure

• Caution is required in patients with a history of hypertension and/or heart failure, as fluid retention and oedema have been reported with ibuprofen use in IV paracetamol/ ibuprofen
• The fluid retention potential of IV paracetamol/ ibuprofen may precipitate heart failure in compromised patients
• NSAIDs, including ibuprofen in IV paracetamol/ ibuprofen, may:
  • Cause new-onset hypertension or worsen pre-existing hypertension
  • Increase the incidence of cardiovascular events

Cardiovascular risk considerations

• Patients with significant risk factors for cardiovascular events (e.g. hypertension, hyperlipidaemia, diabetes mellitus, smoking) should be treated with caution
• To minimise cardiovascular risk:
  • Use the lowest effective dose for the shortest duration possible
  • Monitor blood pressure closely at treatment initiation and throughout therapy
  • Patients taking ACE inhibitors, thiazides, or loop diuretics may have an impaired response to these medications when taken with NSAIDs

Cardiovascular and thrombotic risks

• All NSAIDs, including ibuprofen in IV paracetamol/ ibuprofen, have been linked to an increased risk of cardiovascular and thrombotic events when taken long-term
• Clinical trials of COX-2 selective and nonselective NSAIDs (up to three years) have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal
• Patients with known CV disease or CV risk factors may be at greater risk
• To minimise risk:
  • Use the lowest effective dose for the shortest duration possible
  • Monitor patients closely for signs of CV events, even if they have no previous symptoms
  • Inform patients about the signs of serious CV events and steps to take if they occur

Concurrent use of aspirin

• There is no consistent evidence that using aspirin alongside NSAIDs mitigates the increased risk of serious CV thrombotic events
• Aspirin + IV paracetamol/ ibuprofen increases the risk of serious gastrointestinal (GI) events, including bleeding and ulceration

Gastrointestinal bleeding, ulceration, and perforation (PUBs)

• IV paracetamol/ ibuprofen should be stopped immediately if gastrointestinal bleeding or ulceration occurs
• Caution is advised in patients with a history of GI diseases (e.g. ulcerative colitis, Crohn’s disease, hiatus hernia, gastroesophageal reflux disease, angiodysplasia), as these conditions may worsen
• Elderly patients are at a higher risk of NSAID-related gastrointestinal perforation, ulceration, and bleeding (PUBs), which may be fatal
• The risk increases with higher doses, history of ulcers, and in elderly patients
• Studies show that patients with prior peptic ulcer disease or GI bleeding have a 10-fold higher risk of developing GI bleeding when using NSAIDs
• Additional risk factors include:
  • Corticosteroid or anticoagulant therapy
  • Long-term NSAID use
  • Smoking, alcohol consumption, and poor health status
  • Older age

Severe skin reactions

• Fatal skin reactions such as exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported
• Discontinue IV paracetamol/ ibuprofen immediately at the first appearance of skin rash, mucosal lesions, or any hypersensitivity reaction

Pre-existing asthma

• Aspirin-sensitive asthma patients may develop fatal bronchospasm when taking aspirin or NSAIDs
• IV paracetamol/ ibuprofen is contraindicated in aspirin-sensitive asthma patients and should be used with caution in all asthma patients due to potential cross-reactivity with aspirin

Ophthalmological effects

• Blurred or diminished vision, scotomata, and colour vision changes have been reported with oral ibuprofen
• Discontinue IV paracetamol/ ibuprofen and refer for ophthalmologic evaluation if any visual disturbances occur

Hepatic effects

• Borderline elevations of liver tests may occur in some patients taking NSAIDs, including ibuprofen may progress, may remain unchanged, or may be transient with continuing therapy
• Significant ALT or AST elevations (≥3 times the upper limit of normal) have been reported in a small number of patients
• Severe hepatic reactions such as jaundice, fulminant hepatitis, liver necrosis, and hepatic failure (some fatal) have been reported
• If symptoms of liver dysfunction (e.g., eosinophilia, rash, jaundice) develop, discontinue IV paracetamol/ ibuprofen immediately

Renal effects

• Long-term NSAID use has been linked to renal papillary necrosis and other renal injury
• Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of
  renal perfusion
• Patients at greatest risk of renal decompensation include those with:
  • Pre-existing renal impairment
  • Heart failure or liver dysfunction
  • Use of diuretics, ACE inhibitors, or angiotensin receptor blockers
  • Elderly patients
• NSAIDs may reduce renal prostaglandin production, leading to reduced renal blood flow and potential renal failure
• If IV paracetamol/ ibuprofen must be used in advanced renal disease, renal function should be closely monitored

Aseptic meningitis

• Aseptic meningitis with fever and coma has been observed in patients taking ibuprofen
• It is more likely to occur in patients with systemic lupus erythematosus and connective tissue diseases but has also been reported in patients without underlying conditions
• If signs of meningitis develop, consider the possibility of an ibuprofen-related reaction

Haematological effects

• Anaemia may occur due to fluid retention, occult or gross gastrointestinal blood loss, or effects on erythropoiesis
• Long-term NSAID users should have haemoglobin and haematocrit levels monitored if they show signs of anaemia or blood loss
• NSAIDs inhibit platelet aggregation and may prolong bleeding time, though this effect is less severe than aspirin
• Careful monitoring is required for patients with coagulation disorders or those on anticoagulant therapy

Masking of inflammation and fever

• Ibuprofen's anti-inflammatory effects may mask fever and inflammation, potentially delaying the diagnosis of infections or complications in patients

Anaphylactoid reactions

• Severe allergic reactions (anaphylactoid reactions) may occur in patients without prior ibuprofen exposure
• IV paracetamol/ ibuprofen is contraindicated in patients with the aspirin triad (asthma, rhinitis, nasal polyps, and severe NSAID-induced bronchospasm)

Patients receiving spinal or epidural analgesia

• Potential bleeding around the spinal cord can have serious consequences
• Caution is advised when treating patients undergoing spinal or epidural analgesia

Monitoring

• Serious gastrointestinal ulcerations and bleeding can occur without warning symptoms
• Healthcare professionals should monitor for signs or symptoms of gastrointestinal bleeding
• Patients on long-term NSAID therapy should have regular full blood count (FBC) and chemistry profiles checked periodically
• If liver or renal dysfunction symptoms occur (e.g., eosinophilia, rash) or abnormal liver tests persist, discontinue IV paracetamol/ ibuprofen

Corticosteroid therapy

• Patients on prolonged corticosteroid therapy should have their treatment tapered slowly to prevent disease exacerbation or adrenal insufficiency when ibuprofen-containing products are introduced

Excipient cautions

• IV paracetamol/ ibuprofen contains 35.06mg sodium per 100ml
• IV paracetamol/ ibuprofen contains mannitol, which may have a laxative effect

Ability to drive and use machines

• When driving vehicles or operating machinery it should be taken into account that drowsiness, dizziness, light-headedness, or blurred vision may occasionally occur when receiving IV paracetamol/ ibuprofen

Recommendations in other jurisdictions

Caution in the following patient groups

• First & second trimester of pregnancy
• Breastfeeding
• Mild to moderate renal impairment
• Mild to moderate hepatic impairment
• Elderly
• Patients with a history of allergic reactions to other substances may have an increased risk of hypersensitivity reactions
• Patients with hay fever, nasal polyps, or chronic obstructive respiratory disorders are at higher risk of allergic reactions, including asthma attacks, Quincke’s oedema, or urticaria

Minimising undesirable effects

• Use the lowest effective dose for the shortest duration necessary to control symptoms
• IV paracetamol/ ibuprofen is for short-term use and is not recommended beyond 2 days

Avoid concomitant use with other NSAIDs

• IV paracetamol/ ibuprofen should not be used with other NSAIDs, including cyclooxygenase-2 selective inhibitors

Paracetamol overdose risk

• Do not administer other medicines containing paracetamol while giving IV paracetamol/ ibuprofen
• To avoid overdose, check that no other medicines contain paracetamol or ibuprofen
• Adhere to the maximum recommended doses

Cardiovascular thrombotic events

• High doses of ibuprofen (2400mg/day) may be associated with an increased risk of arterial thrombotic events, such as myocardial infarction or stroke
• Low-dose ibuprofen (1200mg/day) has not shown an increased risk of arterial thrombotic events in epidemiological studies
• Patients with uncontrolled hypertension, congestive heart failure (NYHA II-III), established ischaemic heart disease, peripheral arterial disease, or cerebrovascular disease should only be treated after careful consideration, and high doses (2400mg/day) should be avoided
• Careful assessment is needed before initiating long-term treatment in patients with cardiovascular risk factors such as hypertension, hyperlipidaemia, diabetes mellitus, and smoking, particularly if high doses of ibuprofen (2400mg/day) are required

Hepatic impairment

• The use of paracetamol at higher than recommended doses can lead to hepatotoxicity, hepatic failure, and death
• Patients with impaired liver function or a history of liver disease should have hepatic function monitored at regular intervals, especially those on long-term ibuprofen or paracetamol therapy
• Severe hepatic reactions, including jaundice and fatal hepatitis, have been reported with ibuprofen and other NSAIDs
• Dose reduction is recommended in patients with worsening hepatic function, and treatment should be discontinued in patients who develop severe liver failure

Renal impairment

• Paracetamol can be used in patients with chronic renal disease without dosage adjustment, as there is minimal risk of toxicity
• Caution is required when initiating ibuprofen therapy in dehydrated patients, as ibuprofen metabolites are primarily excreted in the urine and may accumulate in renal impairment
• NSAIDs have been associated with nephrotoxicity, including interstitial nephritis, nephritic syndrome, and renal failure
• Patients with renal, cardiac, or hepatic impairment, those taking diuretics and ACE inhibitors, and elderly patients should be monitored for renal function deterioration. Treatment should be stopped in those patients who develop severe renal failure
• Renal tubular acidosis and hypokalaemia may occur with long-term use of ibuprofen at high doses (>4 weeks) including doses
  exceeding the recommended daily dose

Combination use of ACE inhibitors or angiotensin receptor antagonists, anti-inflammatory drugs, diuretics and thiazide diuretics

• The simultaneous use of an ACE inhibitor (or angiotensin receptor antagonist), an NSAID, and a thiazide diuretic increases the risk of renal impairment
• Serum creatinine should be closely monitored, particularly at the initiation of combination therapy
• Caution is required in elderly patients or those with pre-existing renal impairment when using these drug combinations

Elderly

• Caution should be taken with regard to the use of ibuprofen as it should not be taken by adults over the age of 65 without consideration of co-morbidities and co medications because of an increased risk of adverse effects, in particular heart failure, gastrointestinal ulceration and renal impairment

Haematological effects

• Blood dyscrasias have been rarely reported with ibuprofen use
• Regular haematological monitoring is recommended for patients on long-term ibuprofen therapy

Anaphylactoid reactions

• Close monitoring is recommended, particularly at the start of infusion, to detect any anaphylactic reactions to the active substances or excipients
• Severe acute hypersensitivity reactions (e.g. anaphylactic shock) are rare but require immediate discontinuation of IV paracetamol/ ibuprofen and symptomatic treatment by specialist personnel

Coagulation defects

• Ibuprofen inhibits platelet aggregation and prolongs bleeding time within normal limits
• Caution is required in patients with coagulation disorders or those on anticoagulant therapy
• Special medical vigilance is required for patients undergoing major surgery or immediately post-surgery

Gastrointestinal (GI) events

• GI bleeding, ulceration, or perforation (which can be fatal) may occur at any time with NSAIDs, even without warning symptoms or a history of GI disease
• Risk factors for GI complications include high NSAID doses, history of ulcers (especially if previously complicated by bleeding or perforation), and advanced age
• At-risk patients should start on the lowest effective dose and consider combination therapy with protective agents (e.g. proton pump inhibitors or misoprostol)
• Patients with a history of GI toxicity (especially elderly patients) should report any unusual abdominal symptoms, particularly GI bleeding
• Caution is advised in patients receiving oral corticosteroids, anticoagulants (e.g. warfarin), selective serotonin reuptake inhibitors (SSRIs), or antiplatelet agents (e.g. acetylsalicylic acid), as these may increase the risk of ulceration or bleeding
• IV paracetamol/ ibuprofen should be used with caution in patients with GI diseases, including ulcerative colitis and Crohn’s disease, and in patients with porphyria
• The elderly have an increased risk of serious GI complications, including bleeding and perforation, which may be fatal
• Treatment should be discontinued immediately if there is any evidence of GI bleeding or ulceration

Hypertension

• NSAIDs can cause new-onset hypertension or worsen pre-existing hypertension
• Patients taking antihypertensive medications may experience an impaired response when taking NSAIDs
• Blood pressure should be monitored closely at the initiation of NSAID treatment and at regular intervals thereafter

Heart failure

• NSAIDs may cause fluid retention and oedema, which can exacerbate heart failure
• Caution is advised in patients with pre-existing heart failure or those at risk of fluid retention

Severe skin reactions

• NSAIDs may very rarely cause serious skin reactions, including exfoliative dermatitis, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal
• Acute generalised exanthematous pustulosis (AGEP) has been reported with ibuprofen-containing products. Highest risk occurs within the first month of treatment
• Patients should be advised to discontinue treatment and consult a doctor immediately at the first sign of a skin rash or hypersensitivity
• IV paracetamol/ ibuprofen should be avoided in varicella (chickenpox) due to a possible increased risk of severe skin and soft tissue infections

Pre-existing asthma

• Ibuprofen-containing products should not be used in patients with acetylsalicylic acid-sensitive asthma
• Caution is advised in all patients with pre-existing asthma

Ophthalmological effects

• Visual disturbances have been observed with NSAIDs, including ibuprofen
• Patients who experience visual disturbances should undergo an ophthalmological examination

Aseptic meningitis

• Aseptic meningitis has been rarely reported with ibuprofen
• This risk is higher in patients with systemic lupus erythematosus (SLE) or other connective tissue disorders, though it may occur in others

Potential laboratory test interferences

• Paracetamol may interfere with urine tests for 5-hydroxyindoleacetic acid (5HIAA), causing false-positive results
• To avoid false results, paracetamol should be withheld several hours before and during urine sample collection

Masking of symptoms of underlying infections

• IV paracetamol/ ibuprofen can mask infection symptoms, delaying appropriate treatment and worsening infection outcomes
• This has been observed in bacterial community-acquired pneumonia and bacterial complications of varicella
• Patients using IV paracetamol/ ibuprofen for fever or pain relief should be monitored for infection signs
• In non-hospital settings, medical consultation is advised if symptoms persist or worsen

Prolonged use of analgesics

• Prolonged use of analgesics can cause medication-overuse headaches, which should not be treated by increasing the dose

Flucloxacillin interaction

• Caution is advised when administering paracetamol concomitantly with flucloxacillin due to the increased risk of high anion gap metabolic acidosis (HAGMA)
• Patients at particular risk include those with severe renal impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g. chronic alcoholism), or those using maximum daily paracetamol doses
• Close monitoring, including urinary 5-oxoproline measurement, is recommended

Fertility

• NSAIDs, including ibuprofen, may impair female fertility by affecting ovulation, but this effect is reversible upon discontinuation

Congenital disorders

• Ibuprofen should only be used with strict benefit/risk assessment in patients with congenital disorders of porphyrin metabolism (e.g. acute intermittent porphyria)

Alcohol use

• Concurrent alcohol use may enhance NSAID-related adverse effects, particularly gastrointestinal or central nervous system effects

Sodium content

• This medicinal product contains 35mg sodium per 100ml vial, equivalent to 1.75% of the WHO recommended maximum daily intake of 2 g sodium for an adult

Ability to drive and use machines

• NSAIDs may cause dizziness, drowsiness, fatigue, and visual disturbances
• Patients experiencing these effects should avoid driving or operating machinery

Forms avail. in SA and covered in this monograph: inf

South African registered indications and dosages

Relief of mild to moderate pain and the reduction of fever, where an IV route of administration is considered clinically necessary

Paracetamol/ Ibuprofen
1000/300 (mg/100ml)

• IV: One vial, as an infusion over 15min, every 6hrs as needed; Max: 4 vials (totalling 4000mg (4g) paracetamol and 1200mg ibuprofen)/24hrs

---

Do not exceed the recommended dose. Use the lowest effective dose for the shortest possible duration of treatment

---

It is recommended to use a suitable oral analgesic treatment as soon as this administration route is possible

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Use of NSAIDs, including ibuprofen in IV paracetamol/ ibuprofen, during the third trimester of pregnancy increases the risk of premature closure of the foetal ductus arteriosus in utero and possibly, in persistent pulmonary hypertension of the new-born
• The onset of labour may be delayed, and its duration increased. As there is insufficient information on the use of IV paracetamol/ ibuprofen during pregnancy, its use during pregnancy or in patients planning to become pregnant is contraindicated
• Labour and delivery The effects of IV paracetamol/ ibuprofen on labour and delivery in pregnant women are unknown but, based on the known pharmacology of ibuprofen, administration is not recommended as the onset of labour may be delayed and the duration increased with a greater bleeding tendency in both mother and child

Recommendations in other jurisdictions

• First & second trimester: Caution; not recommended
• Third trimester: Contraindicated
• There is no experience of use of this product in humans during pregnancy. Because of the ibuprofen-component IV paracetamol/ ibuprofen is contraindicated during the third trimester of pregnancy (see below)

Ibuprofen

• 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 post-implantation 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, IV paracetamol/ 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 constriction 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
• Antenatal monitoring for oligohydramnios and ductus arteriosus constriction should be considered after exposure to IV paracetamol/ ibuprofen for several days from gestational week 20 onward
• IV paracetamol/ ibuprofen 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:
  - cardiopulmonary toxicity (premature constriction/closure of the ductus arteriosus and pulmonary hypertension);
  - renal dysfunction (see above), which may progress to renal failure with oligo-hydroamniosis;
  the mother and the neonate, at the end of pregnancy, to:
  - possible prolongation of bleeding time, an anti-aggregating effect which may occur even at very low doses;
  - inhibition of uterine contractions resulting in delayed or prolonged labour
• Consequently, IV paracetamol/ ibuprofen is contraindicated during the third trimester of pregnancy

Paracetamol

• A large amount of data on pregnant women using paracetamol indicate 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

Breastfeeding

South African recommendations

• Contraindicated
• After oral administration, paracetamol is excreted into breast milk in small quantities
• No undesirable effects on nursing infants have been reported. No signs of toxicity were observed in rat pups of dams that received IV propacetamol postpartum at maternal exposures (based on AUC) greater than twice those anticipated at the maximum clinical dose
• It is not known whether ibuprofen and/or its metabolites are excreted in human milk
• Because many medicines are excreted in milk and because of the potential for serious adverse reactions in nursing infants from IV ibuprofen, IV paracetamol/ ibuprofen is contraindicated for use in nursing mothers

Recommendations in other jurisdictions

• Caution
• Paracetamol is excreted in breast milk but not in a clinically significant amount and available published data do not contraindicate breastfeeding as long as the recommended dosage is not exceeded
• Ibuprofen and its metabolites can pass in very small amounts into breast milk. With therapeutic doses during short term treatment the risk for influence on infant seems unlikely
• In light of the above evidences it is not necessary to interrupt breastfeeding for short-term treatment with the recommended dose of this product

Fertility

South African recommendations

• The effects of IV paracetamol/ ibuprofen on fertility are unknown. Intravenous paracetamol (administered as propacetamol) had no effect on fertility of rats at systemic exposure levels (based on AUC) greater than twice those anticipated at the maximum clinical dose
• In rats, fertility was not affected by dietary administration of ibuprofen 20mg/kg/day to males and females from prior to mating through organogenesis, or by oral administration to females at up to 180mg/kg/day throughout gestation
• In rabbits, oral administration of ibuprofen 60mg/kg/day throughout gestation was associated with reduced implantations and live litter size, along with maternotoxicity; the no-effect dose was 20mg/kg/day

Recommendations in other jurisdictions

• The use of IV paracetamol/ ibuprofen may impair female fertility and is not recommended in women attempting to conceive
• In women who have difficulties conceiving or who are undergoing investigation of infertility, withdrawal of the product should be considered

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
  Caution is also recommended in patients with pre-existing renal disease
• Severe: Contraindicated
  No information is available from controlled clinical studies regarding the use of IV paracetamol/ ibuprofen in patients with advanced renal disease
  If therapy must be initiated in patients with advanced renal disease, closely monitor the patient’s renal function

Recommendations in other jurisdictions

• Mild to moderate: Caution; dose adjustment recommended
  Caution should be taken with ibuprofen dosage in patients with renal impairment
  The dosage should be assessed individually. The initial dose should be reduced in patients with mild to moderate renal impairment. The dose should be kept as low as possible and be used for the shortest possible duration necessary to control the symptoms. Renal function should be monitored
• Severe: Contraindicated

South African recommendations

• Mild to moderate: Caution; no dose adjustment recommended
  The use of paracetamol at higher than recommended doses can lead to hepatotoxicity, hepatic failure and death
  A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ibuprofen
  If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), IV paracetamol/ ibuprofen should be discontinued
• Severe: Contraindicated

Recommendations in other jurisdictions

• Mild to moderate: Caution; dose adjustment recommended
  The use of paracetamol at higher than recommended doses can lead to hepatotoxicity and even hepatic failure and death. In patients with additional risk factors for hepatotoxicity, like hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of glutathione in the liver), or dehydration, a total daily dose of 3000mg (3g) paracetamol should not be exceeded
• Severe: Contraindicated
  A patient with symptoms and/or signs suggesting liver dysfunction, or with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with ibuprofen, and the combination product should be discontinued
  If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), IV paracetamol/ ibuprofen should be discontinued

South African recommendations

• Caution; dose adjustment recommended
  A clinical study of IV paracetamol/ ibuprofen did not include sufficient numbers of subjects 65 years of age and over to determine whether they respond differently to younger subjects
  Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other medicine therapy
  Elderly patients are at increased risk for serious GI adverse events

Recommendations in other jurisdictions

• Caution; dose adjustment recommended
  Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy
  The elderly are at increased risk of the serious consequences of adverse reactions. If an NSAID is considered necessary, the lowest effective dose should be used for the shortest possible duration
  Treatment should be reviewed at regular intervals and discontinued if no benefit is seen or intolerance occurs. The patient should be monitored regularly for gastrointestinal bleeding during NSAID therapy

Infections and Infestations

Very rare

• Exacerbation of infection-related inflammations
  • Development of necrotising fasciitis

Blood and Lymphatic System Disorders

Uncommon

• Decreased haemoglobin 
• Decreased haematocrit
• Bleeding episodes
  • Epistaxis
  • Menorrhagia

Very rare

• Haematopoietic disorders
  • Agranulocytosis
  • Anaemia
  • Aplastic anaemia
  • Haemolytic anaemia
  • Leucopenia
  • Neutropenia
  • Pancytopenia
  • Thrombocytopenia with or without purpura

Immune System Disorders

Very rare

• Hypersensitivity reactions
  • Skin rash
  • Cross-sensitivity with sympathomimetics

Uncommon

• Serum sickness
• Lupus erythematosus syndrome
• Henoch-Schönlein vasculitis
• Angioedema

Metabolic and Nutrition Disorders

Very rare

• Metabolic acidosis (in paracetamol overdose)

Uncommon

• Gynaecomastia
• Hypoglycaemic reaction

Not known

• Hypokalaemia
  • Renal tubular acidosis and hypokalaemia have been reported in the post-marketing setting

Nervous System Disorders

Common

• Dizziness
• Headache
• Nervousness

Uncommon

• Depression
• Insomnia
• Confusion
• Emotional lability
• Somnolence
• Aseptic meningitis with fever and coma

Rare

• Paraesthesia
• Hallucinations
• Dream abnormalities

Very rare

• Paradoxical stimulation
• Optic neuritis
• Psychomotor impairment
• Extrapyramidal effects
• Tremor
• Convulsions

Eye Disorders

Uncommon

• Amblyopia
  • Blurred and/or diminished vision
  • Scotomata
  • Changes in colour vision

Ear and Labyrinth Disorders

Very rare

• Vertigo

Common

• Tinnitus

Cardiac Disorders

Common

• Oedema
• Fluid retention

Very rare

• Palpitations
• Tachycardia
• Arrhythmia and other cardiac dysrhythmias
• Hypertension and cardiac failure

Respiratory, Thoracic and Mediastinal Disorders

Uncommon

• Thickened respiratory tract secretions
• Stridor (in children undergoing tonsillectomy)
• Hypoxemia

Very rare

• Respiratory reactivity
  • Asthma
  • Exacerbation of asthma
  • Bronchospasm
  • Dyspnoea

Gastrointestinal Disorders

Common

• Abdominal pain
• Diarrhoea
• Dyspepsia
• Nausea
• Stomach discomfort
• Vomiting
• Flatulence
• Constipation
• Slight gastrointestinal blood loss potentially causing anaemia

Uncommon

• Peptic/gastrointestinal ulcer
• Perforation or gastrointestinal haemorrhage (with symptoms of melaena haematemesis sometimes fatal, particularly in the elderly)
• Ulcerative stomatitis
• Exacerbation of colitis
• Exacerbation of Crohn's disease
• Gastritis
• Pancreatitis
• Acid peptic disease

Very rare

• Oesophagitis
• Formation of intestinal diaphragm-like strictures

Hepatobiliary Disorders

Very rare

• Hepatic damage (especially during long-term treatment)
• Hepatic failure
• Abnormal liver function
• Hepatitis
• Jaundice
• Acute hepatic failure (in paracetamol overdose)
• Hepatic necrosis  (in paracetamol overdose)
• Liver injury  (in paracetamol overdose)

Skin and Subcutaneous Tissue Disorders

Common

• Rash (including maculopapular type)
• Pruritus

Very rare

• Alopecia
• Hyperhidrosis
• Purpura
• Photosensitivity
• Exfoliative dermatoses
• Bullous reactions including erythema multiforme, Stevens Johnson Syndrome, and Toxic Epidermal Necrolysis
• Severe skin infections
• Soft-tissue complications during varicella infection

Not known

• Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
• Acute generalised exanthematous pustulosis (AGEP)

Renal and Urinary Disorders

Uncommon

• Urinary retention

Rare

• Kidney tissue damage (papillary necrosis), particularly in long-term therapy

Very rare

• Nephrotoxicity in various forms
• Interstitial nephritis
• Nephrotic syndrome
• Acute and chronic renal failure
• Acute tubular necrosis (usually occurs with liver failure but has been observed as an isolated finding in rare cases)
• Renal cell carcinoma (chronic paracetamol use increases risk of occurrence)

Not known

• Renal tubular acidosis

General Disorders and Administration Site Conditions

Uncommon

• Pyrexia

Very rare

• Fatigue
• Malaise

Injury, Poisoning and Procedural Complications

Uncommon

• Post-operative haemorrhage following tonsillectomy

Investigations

Common

• Increased alanine aminotransferase
• Increased gamma-glutamyltransferase
• Abnormal liver function tests
• Increased blood creatinine
• Increased blood urea

Uncommon

• Increased aspartate aminotransferase
• Increased blood alkaline phosphatase
• Increased blood creatine phosphokinase
• Decreased haemoglobin
• Increased platelet count

Rare

• Elevated uric acid concentrations in the blood

Paracetamol/ Ibuprofen

• Other medicinal products containing paracetamol, ibuprofen, acetylsalicylic acid, salicylates, or other anti-inflammatory drugs (NSAIDs)

Ibuprofen

• Anticoagulants
• Dicumarol group
• Warfarin
• Antiplatelet agents
• Ticlopidine
• Methotrexate
• Acetylsalicylic acid
• Lithium
• Cardiac glycosides
• Digoxin
• Mifepristone
• ACE inhibitors
• Angiotensin II antagonists
• Beta blockers
• Sulphonylureas
• Zidovudine
• Quinolone antibiotics
• Thiazides, thiazide related preparations
• Furosemide
• Bumetanide
• Loop diuretics
• Potassium sparing diuretics
• Aminoglycosides
• Selective serotonin re-uptake inhibitors (SSRIs)
• Cyclosporine
• Captopril
• Tacrolimus
• Corticosteroids
• CYP2C9 inhibitors
• Voriconazole
• Fluconazole
• Phenytoin
• Probenecid
• Sulfinpyrazone

Other interactions

• Ginkgo biloba

Paracetamol

• Probenecid
• Enzyme-inducing agents
• Antiepileptics
• Phenytoin
• Phenobarbital
• Carbamazepine
• Rifampicin
• Zidovudine
• Anticoagulant agents
• Warfarin
• Isoniazid monotherapy or with other medicines for tuberculosis
• Chloramphenicol
• Flucloxacillin

Other interactions

• Ethyl alcohol
• Hypericum perforatum
• Tests for uric acid using phosphotungstic acid
• Blood sugar tests using glucose-oxidase-peroxidase

• Blood pressure (during initiation and periodically thereafter)
• Hepatic function

Specific cases may require

• Complete blood count (periodically with long-term use and as clinically indicated)
• Electrolytes (as clinically indicated)
• Renal function (in patients at risk for renal impairment)

Additional observations

• Relief of pain

Paracetamol
Although the exact site and mechanism of analgesic action of paracetamol is not clearly defined, it appears that it induces analgesia by elevation of the pain threshold. The potential mechanism may involve inhibition of the nitric oxide pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate and substance P.

Ibuprofen
Ibuprofen is a propionic acid derivative with analgesic, anti-inflammatory and anti-pyretic activity. The drug's therapeutic effects as an NSAID result from its inhibitory effect on the enzyme cyclo-oxygenase, leading to reduction in prostaglandin synthesis. Experimental data suggest that ibuprofen may competitively inhibit the effect of low dose acetylsalicylic acid on platelet aggregation when they are dosed concomitantly. Some pharmacodynamic studies show that when single doses of ibuprofen 400mg were taken within 8 hours before or within 30 minutes after immediate release acetylsalicylic acid dosing (81mg), a decreased effect of acetylsalicylic acid on the formation of thromboxane or platelet aggregation occurred. Although there are uncertainties regarding extrapolation of these 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.