Adult: Ibuprofen 300 mg and paracetamol 1,000 mg per 100 mL vial
Patient weighing <50 kg: 1.5 mL/kg via infusion over 15 minutes 6 hourly, as necessary, up to a Max single dose of 75 mL (Max daily dose: 300 mL); ≥50 kg: 100 mL via infusion over 15 minutes 6 hourly, as necessary (Max daily dose: 400 mL daily). Dosage and treatment recommendations may vary among individual products and between countries (refer to detailed local product guidelines). Elderly: Start at the low end of the dosing range.
Ibuprofen 200 mg and paracetamol 500 mg tab
1-2 tabs up to tid, with at least a 6-hour interval between doses. Max: 6 tabs daily. Max treatment duration: 3 days. Use the lowest effective dose for the shortest possible treatment duration. Dosage and treatment recommendations may vary among individual products and between countries (refer to detailed local product guidelines). Elderly: Use the lowest effective dose for the shortest possible treatment duration. Child: Ibuprofen 150 mg and paracetamol 500 mg tab ≥12 years Same as adult dose. Dosage and treatment recommendations may vary among individual products and between countries (refer to detailed local product guidelines).
What are the brands available for Ibuprofen + Paracetamol in Indonesia?
Ibuprofen is often administered as a racemic mixture containing both of its enantiomers, (R)-ibuprofen and (S)-ibuprofen; only (S)-ibuprofen inhibits the COX enzymes. CYP2C9 isoenzyme is the primary enzyme metabolising (S)-ibuprofen. CYP2C9 gene polymorphisms affect the metabolism and clearance of ibuprofen, thus affecting drug exposure and potential safety. Genetic testing may be considered.
The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline as of March 2020:
Phenotype and Genotype
Implications
Recommendations
CYP2C9 intermediate metaboliser (activity score of 1)
Individuals carrying 1 normal functional allele plus 1 decreased functional allele, or 1 normal functional allele plus 1 non-functional allele, or 2 decreased functional alleles (e.g. *1/*3, *2/*2)
Moderately reduced metabolism; higher plasma concentrations of ibuprofen may increase the risk of toxicities.
Initiate treatment with the lowest recommended starting dose. Cautiously titrate the dose upward until the desired clinical effect is achieved or the maximum recommended dose is reached. Use the lowest effective dose for the shortest duration (in accordance with prescribing information and consistent with individual patient treatment goals). Monitor for adverse events (e.g. blood pressure, kidney function) during therapy.
CYP2C9 poor metaboliser (activity score of 0 or 0.5)
Individuals carrying 1 non-functional allele plus 1 decreased function allele, or 2 non-functional alleles (e.g. *2/*3, *3/*3)
Significantly reduced metabolism and prolonged half-life; higher plasma concentrations of ibuprofen may increase the risk and/or severity of toxicities.
Cautiously titrate dose upward until the desired clinical effect is achieved or until 25-50% of the Max recommended dose is reached. Use the lowest effective dose for the shortest duration (in accordance with prescribing information and consistent with individual patient treatment goals). Upward dose titration should not occur until after steady-state is reached (at least 5 days following 1st dose). Monitor for adverse events (e.g. blood pressure, kidney function) during therapy. Alternatively, may consider other therapy not metabolised by CYP2C9 (e.g. aspirin, ketorolac, naproxen, sulindac) or not significantly impacted by CYP2C9 genetic variants in vivo.
Hepatic Impairment
Intravenous:
Severe: Contraindicated.
Contraindications
Hypersensitivity to ibuprofen or paracetamol; history of hypersensitivity reactions to aspirin or other NSAIDs, gastrointestinal bleeding, ulceration or perforation related to NSAIDs; active or history of recurrent gastrointestinal haemorrhage or peptic ulcer (≥2 distinct episodes of proven ulceration or bleeding); cerebrovascular or other active bleeding, blood clotting disorders, conditions with an increased tendency to bleed; active alcoholism; severe heart failure (NYHA Class IV). Patients undergoing CABG surgery. Severe hepatic impairment. Children (IV). Pregnancy (3rd trimester).
Special Precautions
Patient with cerebrovascular disease, CV disease (e.g. uncontrolled hypertension, CHF [NYHA class II-III], ischaemic heart disease, peripheral arterial disease), risk factors of CV disease (e.g. hyperlipidaemia, diabetes mellitus, smoking), recent MI; oedema; active or history of bronchial asthma or allergic disease; ulcerative colitis, Chron's disease; coagulation disorders; dehydration, hypovolaemia; SLE, mixed connective tissue disorders; asthma; alcoholic liver disease. CYP2C9 poor and intermediate metabolisers. Patient undergoing surgery. Concomitant use with aspirin, anticoagulants, corticosteroids. May mask signs or symptoms of infection. Renal and mild to moderate hepatic impairment. Children (oral) and elderly. Pregnancy (1st and 2nd trimester) and lactation.
Adverse Reactions
Significant: New-onset or exacerbation of hypertension, Na and fluid retention, oedema, hyperkalaemia, blurred or diminished vision, scotomata, changes in colour vision, impairment of female fertility, renal papillary necrosis (long-term use); bronchospasm, Kounis syndrome. Rarely, severe blood dyscrasias, aseptic meningitis. Ear and labyrinth disorders: Tinnitus. Gastrointestinal disorders: Abdominal pain, vomiting, diarrhoea, dyspepsia, nausea, abdominal discomfort. General disorders and administration site conditions: Local infusion-site pain. Investigations: Increased blood creatinine and urea, ALT increased, γ-glutamyltransferase increased. Metabolism and nutrition disorders: Decreased appetite. Nervous system disorders: Headache, dizziness, nervousness. Psychiatric disorders: Depression, confusion. Renal and urinary disorders: Urinary retention. Respiratory, thoracic and mediastinal disorders: Dyspnoea. Skin and subcutaneous tissue disorders: Urticaria, pruritus, rash, hyperhidrosis. Potentially Fatal: CV thrombotic events (e.g. MI, stroke); gastrointestinal ulceration, inflammation, perforation or haemorrhage; drug reaction with eosinophilia and systemic symptoms. Rarely, severe anaphylactic reactions, severe hepatic reactions (e.g. fulminant hepatitis, liver necrosis, hepatic failure), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis.
Patient Counseling Information
This drug may cause drowsiness, dizziness and blurred vision, if affected, do not drive or operate machinery.
Monitoring Parameters
Monitor blood pressure (during treatment initiation and periodically); CBC (periodically, with long-term use); electrolytes; LFTs; renal function (particularly in patients at risk for renal impairment); treatment response. Assess for signs and symptoms of gastrointestinal ulceration and bleeding, hypersensitivity and serious skin reactions.
Overdosage
Symptoms: Ibuprofen: Drowsiness, dizziness, tinnitus, headache, nausea, vomiting, abdominal pain, gastrointestinal bleeding, hypertension, lethargy, metabolic acidosis, prolonged prothrombin time or INR, acute renal failure, liver damage, respiratory depression, convulsions, excitation, disorientation, loss of consciousness, coma. Paracetamol: Nausea, vomiting, anorexia, pallor, abdominal pain, abnormalities in glucose metabolism, metabolic acidosis, cardiac arrhythmias, pancreatitis; acute renal failure with acute tubular necrosis manifested by loin pain, haematuria, proteinuria; liver damage (may be evident 12-48 hours after ingestion); hepatic failure, encephalopathy, coma, death. Management: Symptomatic and supportive treatment. Maintain a clear airway and consider performing gastric lavage or giving activated charcoal within 1 hour of ingestion. May give alkaline solutions and induce diuresis. Administer IV diazepam or lorazepam for frequent or prolonged convulsions. Acetylcysteine must be instituted as early as possible (for up to 24 hours, most effective when administered within 8 hours); if necessary, IV acetylcysteine may be administered, according to the established dosing schedule. Oral methionine may be given as an alternative if vomiting is not a problem.
Drug Interactions
Ibuprofen: May increase the risk of ulceration or bleeding with other NSAIDs, oral corticosteroid, anticoagulants (e.g. warfarin), anti-platelet (e.g. aspirin), SSRIs, SNRIs. Increased risk of haematological toxicity with zidovudine. May diminish the antihypertensive effect of ACE inhibitors, ARBs, β-blockers (e.g. propranolol), diuretics (e.g. furosemide). May increase the serum concentration of digoxin and pemetrexed. Decreased excretion of lithium and methotrexate. Increased risk of nephrotoxicity with ciclosporin and tacrolimus. May increase the risk of convulsions with quinolone antibiotics.
Paracetamol: Prolonged regular use of paracetamol may enhance the anticoagulant effect of warfarin and other coumarins, thus increasing the risk of bleeding. Increased absorption with metoclopramide and domperidone. Reduced rate of absorption with colestyramine. Increased plasma concentration of chloramphenicol. Increased risk of high anion gap metabolic acidosis with flucloxacillin.
Food Interaction
May increase the risk of gastrointestinal bleeding and hepatotoxicity with alcohol.
Lab Interference
Ibuprofen: May lead to a false-positive aldosterone/renin ratio (ARR). May interact with urinary detection of phencyclidine.
Paracetamol: May result in false-positive urinary 5-hydroxyindoleacetic acid.
Action
Description: Mechanism of Action: Ibuprofen, an NSAID, is a propionic acid derivative that has antipyretic, analgesic, and anti-inflammatory properties. It reversibly inhibits cyclooxygenase-1 and -2 (COX-1 and -2) thereby reducing prostaglandin precursors production.
Paracetamol is a para-aminophenol derivative that exhibits analgesic and antipyretic properties and weak anti-inflammatory activity. The mechanism of its analgesic effect has not been fully elucidated but is associated with the stimulation of descending serotonin pathway activity in the CNS, as well as interactions with other nociceptive systems. It produces antipyresis by inhibiting the hypothalamic heat-regulating center. Synonym(s): Paracetamol: Acetaminophen. Onset: Ibuprofen: Oral: Within 30-60 minutes (analgesia).
Paracetamol: Oral: <1 hour. IV: 5-10 minutes (analgesia); within 30 minutes (antipyretic). Duration: Ibuprofen: Oral: 6-8 hours (antipyretic).
Paracetamol: Oral, IV: 4-6 hours (analgesia). IV: ≥6 hours (antipyretic). Pharmacokinetics: Absorption: Ibuprofen: Rapidly absorbed from the gastrointestinal tract. Bioavailability: 80%. Time to peak plasma concentration: Approx 1-2 hours.
Paracetamol: Readily absorbed from the gastrointestinal tract. Time to peak plasma concentration: 10-60 minutes. Distribution: Ibuprofen: Enters breast milk. Plasma protein binding: >99%.
Paracetamol: Distributed into most body tissues. Crosses the placenta and enters breast milk. Plasma protein binding: 10-25%. Metabolism: Ibuprofen: Metabolised in the liver via oxidation.
Paracetamol: Metabolised mainly in the liver into sulfate and glucuronide conjugate, while a small amount is metabolised by CYP2E1 to a minor hydroxylated metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which is conjugated rapidly with glutathione and inactivated to non-toxic cysteine and mercapturic acid conjugates. Undergoes first-pass metabolism (oral). Excretion: Ibuprofen: Mainly via urine (45-80% mainly as metabolites; approx 1% as unchanged drug; 14% as conjugates); faeces. Elimination half-life: Approx 2 hours (oral).
Paracetamol: Via urine (<5% unchanged drug; 60-80% as glucuronide metabolites; 20-30% as sulfate metabolites; approx 8% as cysteine and mercapturic acid metabolites). Elimination half-life: 1-3 hours.
Chemical Structure
Ibuprofen Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 3672, Ibuprofen. https://pubchem.ncbi.nlm.nih.gov/compound/Ibuprofen. Accessed Sept. 25, 2024.
Paracetamol Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 1983, Acetaminophen. https://pubchem.ncbi.nlm.nih.gov/compound/Acetaminophen. Accessed Sept. 25, 2024.
Storage
Tab: Store below 30°C. Solution for infusion: Store below 25°C. Do not freeze or refrigerate. Protect from light. Storage recommendations may vary among countries and individual products (refer to specific product guidelines).
N02BE51 - paracetamol, combinations excl. psycholeptics ; Belongs to the class of anilide preparations. Used to relieve pain and fever.
References
Theken KN, Lee CR, Gong L et al. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clinical Pharmacology and Therapeutics. 2020 Aug;108(2):191-200. doi: 10.1002/cpt.1830. Accessed 30/07/2024AFT Pharmaceuticals Ltd. Maxigesic IV Solution for Infusion data sheet April 2023. Medsafe. http://www.medsafe.govt.nz. Accessed 30/07/2024.AFT Pharmaceuticals Ltd. Maxigesic Tablet data sheet May 2024. Medsafe. http://www.medsafe.govt.nz. Accessed 30/07/2024.Annotation of CPIC Guidelines for Celecoxib, Flurbiprofen, Ibuprofen, Lornoxicam, and CYP2C9. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org. Accessed 19/09/2024.Anon. Ibuprofen. AHFS Clinical Drug Information [online]. Bethesda, MD. American Society of Health-System Pharmacists, Inc. https://www.ahfscdi.com. Accessed 30/07/2024.Brayfield A, Cadart C (eds). Ibuprofen. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/07/2024.Brayfield A, Cadart C (eds). Paracetamol. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/07/2024.Combogesic IV (Hikma Pharmaceuticals USA Inc.). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed. Accessed 30/07/2024.Combogesic IV 10 mg/mL + 3 mg/mL Solution for Infusion (AFT Pharma UK Limited). MHRA. https://products.mhra.gov.uk. Accessed 30/07/2024.CPIC Guideline for NSAIDs Based on CYP2C9 Genotype. Clinical Pharmacogenetics Implementation Consortium (CPIC). https://cpicpgx.org. Accessed 30/07/2024.CYP2C9 - Ibuprofen. UpToDate Lexidrug, Pharmacogenomics Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 30/07/2024.Ibuprofen and Paracetamol [Acetaminophen]. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 30/07/2024.Ibuprofen. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 30/07/2024.Joint Formulary Committee. Ibuprofen. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/07/2024.Joint Formulary Committee. Paracetamol. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 30/07/2024.Nuromol Pain Relief 200 mg/500 mg Film Coated Tablets (Reckitt Benckiser Healthcare [UK] Ltd). MHRA. https://products.mhra.gov.uk. Accessed 30/07/2024.Paracetamol [Acetaminophen]. UpToDate Lexidrug, Lexi-Drugs Multinational Online. Waltham, MA. UpToDate, Inc. https://online.lexi.com. Accessed 30/07/2024.
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