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COMBOGESIC IV is a brand name for Acetaminophen (also known as Paracetamol), supplied as a solution. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: COMBOGESIC IV (Acetaminophen/Ibuprofen Solution for Infusion) is indicated for the short term management of: • mild to moderate pain • moderate to severe pain as an adjunct to opioid analgesics and where an intravenous route of administration is considered clinically necessary and/or when other routes of…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations For intravenous administration and short-term use for up to two days. Undesirable effects may be minimised by using the lowest effective dose for the shortest duration necessary to control symptoms. The safety and efficacy of COMBOGESIC IV has been evaluated in treatment of post-operative pain for up to 2 days (8 doses) with additional safety data in a small number of patients treated for up to 5 days (20 doses).
Patients who require longer treatment may be dosed to a maximum of 5 days if justified by ongoing benefit-risk assessments. Lower total daily doses may be used. 1 Pharmacodynamics). Prolonged or frequent use is discouraged. It is recommended that a suitable analgesic oral treatment be used as soon as this route of administration is possible.
). In order to avoid the risk of overdose, check that other medicines administered do not contain either ibuprofen, acetaminophen or its prodrug. Adjust dose as required. Take care when prescribing and administering COMBOGESIC IV to avoid dosing errors due to confusion between milligram (mg) and millilitre (mL), which could result in accidental overdose and death.
Ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Ensure the dose is measured and administered accurately. 2 Recommended Dose and Dosage Adjustment Adults (weighing > 50 kg) Administer one vial (100 ml) COMBOGESIC IV as 15-minute infusion every 6 hours, as necessary.
2 g) ibuprofen. 5 mg/kg ibuprofen), as a 15-minute infusion every 6 hours, as necessary. Product Monograph Version 2 COMBOGESIC® IV (acetaminophen and ibuprofen sodium dihydrate) Page 7 of 41 This equates to a maximum single dose of 75 ml (discard remaining medicine in vial), and a total daily dose of 3000 mg (3 g) acetaminophen and 900 mg ibuprofen.
Pediatrics (< 18 years of age):
Safety and effectiveness of COMBOGESIC IV in pediatric and adolescent patients have not been established; therefore, Health Canada has not authorized an indication for pediatric use (see Indications).
Geriatrics (≥ 65 years of age):
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 (see Warnings and Precautions – Special Populations).
1 Adverse Reaction Overview Adverse effects of COMBOGESIC IV (acetaminophen and ibuprofen) are similar to those of the individual ingredients and represent an extension of their pharmacological effects. The major hazards of ibuprofen, like other NSAIDs, are gastrointestinal disturbances including bleeding and thromboembolic events.
For acetaminophen, the major hazard is hepatotoxicity following overdose. The most common adverse reactions (greater than or equal to 3%) are infusion site pain, nausea, vomiting, constipation, headache, dizziness, somnolence, infusion site extravasation.
2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.
Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use. Two phase 3 clinical trials have been conducted with COMBOGESIC IV to assess efficacy and safety in postoperative musculoskeletal pain and soft tissue pain models.
In the active controlled study, AFT- MXIV-07, 276 participants were treated every 6 hours with COMBOGESIC IV, acetaminophen IV, ibuprofen IV or placebo for a treatment period of 48 hours (8 doses). In an open label study, AFT-MXIV- 11, 169 participants were treated for 48 hours and 50 participants were treated five days (20 doses) with COMBOGESIC IV.
The study population for AFT-MXIV-07 was comprised of adults aged 18 to 65 years, mean age: 42 years. AFT-MXIV-11 included adults aged 19 – 87 years, mean age: 53 years. Safety data for the first 48 hours of both studies was pooled. 3% of the patients (N = 182/307) administered COMBOGESIC IV experienced one or more treatment-emergent adverse event (TEAE) during the first 48 hours of treatment, accounting for a total of 436 TEAEs (see Table 2).
Please see the SERIOUS WARNINGS AND PRECAUTIONS BOX at the beginning of Part I Health Professional Information General • Frail or debilitated patients may tolerate side effects less well and therefore special care should be taken in treating this population.
To minimize the potential risk for an adverse event, the lowest effective dose should be used for the shortest possible duration. As with other NSAIDs, caution should be used in the treatment of elderly patients who are more likely to be suffering from impaired renal, hepatic, or cardiac function.
For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. • COMBOGESIC IV is NOT recommended for use with other NSAIDs, with the exception of low-dose ASA for cardiovascular prophylaxis, because of the absence of any evidence demonstrating synergistic benefits and the potential for additive adverse reactions.
(See Drug Interactions – Drug/Drug Interactions – Acetylsalicylic acid (ASA)]. Carcinogenesis and Mutagenesis See 16 NON-CLINICAL TOXICOLOGY. Cardiovascular COMBOGESIC IV contains a non-steroidal anti-inflammatory drug (NSAID). Use of some NSAIDs is associated with an increased incidence of cardiovascular adverse events (such as myocardial infarction, stroke, or thrombotic events) which can be fatal.
The risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk. Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Intravenous Acetaminophen 10 mg/mL and Ibuprofen (as ibuprofen sodium ) 3 mg/mL, Solution Cysteine hydrochloride monohydrate, Disodium phosphate dihydrate, Mannitol, Hydrochloric acid (for pH adjustment), Sodium hydroxide (for pH adjustment), and Water for injection Product Monograph Version 2 COMBOGESIC® IV (acetaminophen and ibuprofen sodium dihydrate) Page 10 of 41 Caution should be exercised in prescribing COMBOGESIC IV to patients with risk factors for cardiovascular disease, cerebrovascular disease, or renal disease, such as any of the following (NOT an exhaustive list): • Hypertension • Dyslipidemia / Hyperlipidemia • Diabetes Mellitus • Congestive Heart Failure (NYHA I) • Coronary Artery Disease (Atherosclerosis) • Peripheral Arterial Disease • Smoking • Creatinine Clearance < 60 mL/min or 1 mL/sec Use of COMBOGESIC IV can lead to new hypertension or can worsen pre-existing hypertension, either of which may increase the risk of cardiovascular events as described above.
COMBOGESIC IV is contraindicated in: • COMBOGESIC IV is contraindicated in patients who are hypersensitive to acetaminophen, ibuprofen or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. e. complete or partial syndrome of ASA-intolerance - rhinosinusitis, urticaria/ angioedema, nasal polyps, asthma) (see Warnings and Precautions – Hypersensitivity Reactions – Anaphylactoid Reactions).
• The peri-operative setting of coronary artery bypass graft surgery (CABG) (see WARNINGS AND PRECAUTIONS – Peri-operative). • Patients with severe uncontrolled heart failure. • Patients with cerebrovascular bleeding or other bleeding disorders.
• Patients with severe liver impairment or active liver disease. • Patients with active gastric/duodenal/peptic ulcer, active GI bleeding. • Patients with inflammatory bowel disease. 5 mL/sec) or deteriorating renal disease (individuals with lesser degrees of renal impairment are at risk of deterioration of their renal function when prescribed NSAIDs and must be monitored) (see Warnings and Precautions – Renal).
• Patients with systemic lupus erythematosus, as an anaphylaxis-like reaction with fever may Product Monograph Version 2 COMBOGESIC® IV (acetaminophen and ibuprofen sodium dihydrate) Page 5 of 41 occur, particularly when ibuprofen has been administered previously.
• Patients with known hyperkalemia (see Warnings and Precautions – Renal – Fluid and Electrolyte Balance). • Patients with blood formation disturbances. • Patients with active alcoholism as chronic excessive alcohol ingestion may predispose patients to hepatotoxicity.
• The third trimester of pregnancy, because of risk of premature closure of the ductus arteriosus and prolonged parturition (see WARNINGS AND PRECAUTIONS – Special Populations). • Women who are breastfeeding, because of the potential for serious adverse reactions in nursing infants.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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The use of a lower dose for a shorter duration should be considered.
Hepatic Impairment:
COMBOGESIC IV should not be used in patients with severe hepatic impairment (see 2 CONTRAINDICATIONS). In patients with impaired hepatic function or additional risk factors for hepatoxicity, longer dosing intervals and/or reduced total daily dose may be warranted.
Renal Impairment:
COMBOGESIC IV should not be used in patients with severe renal impairment (creatinine clearance ≤ 30 mL/min) (see 2 CONTRAINDICATIONS). Caution should be taken in patients with renal insufficiency, dehydrated patients, patients on salt restricted diets, those with congestive heart failure, cirrhosis, liver dysfunction, taking angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, cyclosporin, diuretics, and those who are elderly (see WARNINGS AND PRECAUTIONS – Renal).
In these patients, longer dosing intervals and/or reduced total daily dose may be warranted. 3 Reconstitution COMBOGESIC IV is a single-use solution for infusion, which does not require re-constitution. Any unused portion of the solution must be discarded.
4 Administration • COMBOGESIC IV is administered as a 15-minute infusion every 6 hours, as necessary. • DO NOT USE if particulate matter, cloudiness or change in color of the solution is observed. • In the absence of compatibility studies, COMBOGESIC IV should not be mixed with diluents or with other medicines.
• The solution should be used in one patient on one occasion only. It contains no antimicrobial preservative. Any unused solution should be discarded. • If less than a full vial is required for a single dose, the correct amount should be infused and the remaining solution discarded.
5 Missed Dose If a dose is missed, it should be administered as soon as remembered. If it is almost time for the next dose, the missed dose should not be administered and the next scheduled dose should be given. Do not try to make up for the missed dose by taking a double dose next time.
The most common TEAEs were related to the infusion site (infusion site pain, infusion site extravasation), or affected the gastrointestinal (nausea, vomiting, constipation) or nervous (dizziness, headache, somnolence) systems. 0 Other skin and subcutaneous-related TEAEs (pruritis, hyperhidrosis) also affected around 2-3% of the study population, as did procedural nausea and polyuria.
3 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data Clinical Trial Findings The AFT-MXIV-07 study was not specifically designed to detect any abnormal laboratory values which might be associated with using acetaminophen and ibuprofen in a fixed combination.
AFT-MXIV-11 included an assessment of clinical laboratory values at baseline and at the end of treatment. Clinically significant changes from baseline in laboratory test results were classified as adverse events and included in all analyses of adverse events.
6% of subjects with available evaluations respectively. 2% of subjects with available evaluations, respectively. Elevations were transient, as levels reduced to normal, or to lower levels, in participants with repeated laboratory tests conducted at follow-up.
Increases in platelets occurred in 6 patients treated for ≥ 5 days compared to none in subjects treated for ≤ 48 hours; however, none of these elevations resulted in platelet values considered clinically significant. 4 Post-Market Adverse Reactions Because post-market adverse events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
The following adverse events have been reported with acetaminophen or ibuprofen:
Table 3 – Common adverse reactions reported in patients taking acetaminophen or ibuprofen (frequency of ≥ 1/100, < 1/10) Cardiovascular disorders Oedema, fluid retention; fluid retention generally responds promptly to discontinuation of the drug.
Ear and labyrinth disorders Tinnitus (for medicines containing ibuprofen). Product Monograph Version 2 COMBOGESIC® IV (acetaminophen and ibuprofen sodium dihydrate) Page 19 of 41 Gastrointestinal disorders Abdominal pain, diarrhea, dyspepsia, stomach discomfort, flatulence, constipation, slight gastrointestinal blood loss that may cause anemia in exceptional cases.
Investigations Alanine aminotransferase increased, gamma-glutamyl-transferase increased and liver function tests abnormal with acetaminophen. Blood creatinine increased and blood urea increased. Nervous system disorders Nervousness. Skin and subcutaneous tissue disorders Rash (including maculopapular type), pruritus.
Table 4– Adverse reactions reported in patients taking acetaminophen or ibuprofen at a frequency of < 1/100 Blood and lymphatic system disorders Uncommon: Decrease in hemoglobin and […]
Thus blood pressure should be monitored regularly. Consideration should be given to discontinuing COMBOGESIC®IV should hypertension either develop or worsen with its use. For patients with a high risk of developing an adverse CV event, other management strategies that do NOT include the use of medicines that contain NSAIDs should be considered first.
To minimize the potential risk for an adverse CV event, the lowest effective dose should be used for the shortest possible duration.
Endocrine and Metabolism Corticosteroids:
COMBOGESIC IV is NOT a substitute for corticosteroids. It does NOT treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
(See Drug Interactions – Drug-Drug Interactions – Glucocorticoids). Gastrointestinal Serious GI toxicity (sometimes fatal), such as peptic / duodenal ulceration, inflammation, perforation, obstruction and gastrointestinal bleeding, can occur at any time, with or without warning symptoms, in patients treated with NSAIDs, such as COMBOGESIC IV.
Minor upper GI problems, such as dyspepsia, commonly occur at any time. Health care providers should remain alert for ulceration and bleeding in patients treated with COMBOGESIC IV even in the absence of previous GI tract symptoms. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event, the lowest effective dose should be used for the shortest possible duration. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered. (See Warnings and Precautions – Special Populations – Geriatrics).
Patients should be informed about the signs and/or symptoms of serious GI toxicity and instructed to discontinue using COMBOGESIC IV and seek emergency medical attention if they experience any such symptoms. The utility of periodic laboratory monitoring has NOT been demonstrated, nor has it been adequately assessed.
Most patients who develop a serious upper GI adverse event on NSAID therapy have no symptoms. Upper GI ulcers, gross bleeding or perforation, caused by NSAIDs, appear to occur Product Monograph Version 2 COMBOGESIC® IV (acetaminophen and ibuprofen sodium dihydrate) Page 11 of 41 in approximately 1% of patients treated for 3-6 months, and in about 2-4% of patients treated for one year.
These trends continue, thus increasing the likelihood of developing a serious GI event at some time during the course of therapy. Even short-term therapy has its risks. Caution should be taken if prescribing COMBOGESIC IV to patients with a prior history of peptic / duodenal ulcer disease or gastrointestinal bleeding as these individuals have a greater than 10-fold higher risk for developing a GI bleed when taking a NSAID than patients with neither of these risk factors.
g. g. g. prednisone) • […]
• Children and adolescents less than 18 years of age.