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COMBOGESIC is a brand name for Acetaminophen (also known as Paracetamol), supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: COMBOGESIC® (Acetaminophen/Ibuprofen) is indicated in adults over 18 years for the: • short term management of mild to moderate acute pain • reduction of fever. 1.1 Pediatrics Pediatrics (< 18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing Considerations • For oral administration and short term use only. • Do not take for fever for more than 3 days or pain for more than 5 days unless directed by a physician. • Do not take COMBOGESIC® tablets with other acetaminophen or ibuprofen containing products.
• Take with food or milk if stomach upset occurs. • Do not take more than 12 tablets per day. 2 Recommended Dose and Dosage Adjustment For the short-term management of mild to moderate acute pain and the reduction of fever, the recommended adult dose of COMBOGESIC® is 1-2 tablets every 6 hours.
If pain or fever does not respond to 2 tablets, 3 tablets may be taken at subsequent doses, but only on the advice of a physician. Do not exceed 12 tablets over a 24-hour period.
Pediatrics (< 18 years of age):
Safety and effectiveness of COMBOGESIC® 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):
No adjustment in labelled dosage is necessary for older patients, who require acetaminophen therapy. Those who require therapy for longer than 3 days should consult their physician for condition monitoring; however, no reduction in recommended dosage is necessary.
However, 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).
3 Administration This product is recommended to be taken with a full glass of water. 4 Missed Dose If the patient forgets a dose, they should take it as soon as they remember. But if it is almost time for the next dose, they should not take the missed dose.
Instead, they must take the next scheduled dose. The patient should not try to make up for the missed dose by taking a double dose next time.
1 Adverse Reaction Overview Adverse effects of COMBOGESIC® (acetaminophen and ibuprofen) tablets are similar to those of the individual ingredients and represent an extension of their pharmacological effects. 5 mg Page 17 of 47 major hazards of ibuprofen, like other NSAIDs, are gastrointestinal disturbances including bleeding and thromboembolic events.
For acetaminophen, the major hazard is hepatotoxicity following overdose. 5 and FDC 500/150), acetaminophen alone, ibuprofen alone or placebo (see Clinical Trials). The most common adverse reactions (incidence of ≥ 2% for patients receiving COMBOGESIC®) were: nausea, vomiting, post-procedural hemorrhage, headache, dizziness, somnolence, and swelling of the face (Table 2).
2 Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials 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 is useful for identifying drug-related adverse events and for approximating rates. The clinical trials of COMBOGESIC® have been conducted using postoperative dental pain and arthroscopic pain models lasting between 24 and 48 hours.
The data described below reflect exposure to COMBOGESIC® in 261 patients. COMBOGESIC® was studied primarily in placebo-and active-controlled trials (n = 217 COMBOGESIC®-treated patients in placebo-controlled studies, and n = 44, COMBOGESIC®-treated patients in non- placebo-controlled studies).
The population was aged between 16 and 74 (mean = 31), 61% were female, and 84% were Caucasian. During the double-blind treatment periods of the clinical trials, COMBOGESIC® was administered orally every 6 hours for up to 48 hours. The most common adverse reactions (incidence of ≥ 2%) are shown by system organ class (SOC) in 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® 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 Ibuprofen is considered not to present a genotoxic or carcinogenic hazard to human subjects. Acetaminophen also is considered not to present a genotoxic hazard to human subjects at therapeutic doses, based on a CPMP review in 1996 (see Non-clinical Toxicology – Carcinogenesis).
5 mg Page 10 of 47 Cardiovascular COMBOGESIC® 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. Caution should be exercised in prescribing COMBOGESIC® 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® 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® is contraindicated in: • The peri-operative setting of coronary artery bypass graft surgery (CABG). Although COMBOGESIC® has NOT been studied in this patient population, a selective COX-2 inhibitor NSAID studied in such a setting has led to an increased incidence of cardiovascular/thromboembolic events, deep surgical infections and sternal wound complications.
• The third trimester of pregnancy, because of risk of premature closure of the ductus arteriosus and prolonged parturition. • Patients with severe uncontrolled heart failure. • Patients with known hypersensitivity to acetaminophen, ibuprofen or to any of the components/excipients.
• Patients with systemic lupus erythematosus, as an anaphylaxis-like reaction with fever may occur, particularly when ibuprofen has been administered previously. e. complete or partial syndrome of ASA-intolerance - rhinosinusitis, urticaria/ angioedema, nasal polyps, asthma).
Fatal anaphylactoid reactions have occurred in such individuals. Individuals with the above medical problems are at risk of a severe reaction even if they have taken NSAIDs in the past without any adverse reaction. The potential for cross-reactivity between different NSAIDs must be kept in mind (see Warnings and Precautions – Hypersensitivity Reactions – Anaphylactoid Reactions).
• Patients with active gastric/duodenal/peptic ulcer, active GI bleeding. • Patients with cerebrovascular bleeding or other bleeding disorders. • Patients with inflammatory bowel disease. • Patients with severe liver impairment or active liver disease.
5 mg Page 5 of 47 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).
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
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Table 2 – Treatment-emergent adverse events reported in at least 2% of patients receiving COMBOGESIC® by organ system during double-blind treatment. 5 and FDC 500/150 pooled from the 4 clinical studies. The most commonly affected SOCs were Gastrointestinal Disorders and Nervous System Disorders.
In no case did the incidence of adverse reactions in patients treated with COMBOGESIC® exceed the incidence of adverse reactions in the placebo group. In fact, the incidence of reactions in the COMBOGESIC® group was consistently lower than the incidence seen in the placebo group.
Furthermore, the incidence of any common adverse reaction in the COMBOGESIC® group did not exceed the incidence recorded in either of the mono-component treatment groups, suggesting that the safety profile of COMBOGESIC® is comparable to similar doses of either acetaminophen or ibuprofen alone.
3 Less Common Clinical Trial Adverse Reactions Adverse reactions occurring fewer than 2% of COMBOGESIC®-treated patients in clinical trials are presented in Table 3. Table 3 – Treatment-emergent adverse events reported in fewer than 2% of patients receiving COMBOGESIC® by organ system during double-blind treatment.
4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and other The clinical studies of COMBOGESIC® were not specifically designed to detect any abnormal laboratory values which might be associated with using acetaminophen and ibuprofen in a fixed combination.
The pharmacokinetic studies of COMBOGESIC® demonstrated that there is no potential drug interaction when the two drugs are administered together. Normal hematology and biochemistry, including renal and liver functions, were monitored only in one study of the FDC 500/150.
Blood samples were collected prior to the first dose of study medication and at Day 8-10. Study participants were treated with the FDC 500/150 for a 24 hour double-blind treatment period, following which participants took either the FDC 500/150 or acetaminophen 500 mg for up to 4 days during an open label phase treatment.
Therefore, the hematology and biochemistry results obtained at Day 8-10 follow-up visit reflect the safety status of patients who have taken FDC 500/150 or acetaminophen tablets in multiple doses (up to 4 days) for the treatment of post-operative pain.
Overall, 229 of the 300 (76%) subjects requested the FDC 500/150 for the open label […]
Thus blood pressure should be monitored regularly. Consideration should be given to discontinuing COMBOGESIC® should hypertension either develop or worsen with its use. Use of COMBOGESIC® can induce fluid retention and edema, and may exacerbate congestive heart failure, through a renally-mediated mechanism.
(See Warnings and Precautions – Renal – Fluid and Electrolyte Balance). 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® 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® .
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®, 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. 5 mg Page 11 of 47 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® 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 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® 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 […]
• Patients with known hyperkalemia (see Warnings and Precautions – Renal – Fluid and Electrolyte Balance). • Children and adolescents less than 18 years of age (see Indications). • Patients with active alcoholism as chronic excessive alcohol ingestion may predispose patients to hepatotoxicity.
• Patients with blood formation disturbances. 5 mg Page 6 of 47