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COMBOGESIC® IV

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Prescribing Information

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COMBOGESIC® IV FAQs

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General Information

  • COMBOGESIC® IV was approved in October 2023 for use in adults where an intravenous route of administration is considered clinically necessary for¹:
  • the relief of mild to moderate pain
  • the management of moderate to severe pain as an adjunct to opioid analgesics
  • COMBOGESIC® IV contains acetaminophen and ibuprofen as active drug substances.¹
  • Acetaminophen is a non-opiate, non-salicylate analgesic. The precise mechanism of the analgesic properties of acetaminophen is not established but is thought to primarily involve central actions.¹
  • Ibuprofen is a nonsteroidal anti-inflammatory drug (NSAID). Its mechanism of action for analgesia, like that of other NSAIDs, is not completely understood, but involves inhibition of cyclooxygenase (COX-1 and COX-2). Ibuprofen is a potent inhibitor of prostaglandin synthesis in vitro. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because ibuprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.¹
  • A number of known or potential interactions between COMBOGESIC IV® and other drugs/drug classes exist. COMBOGESIC IV® may interact with drugs that interfere with hemostasis including warfarin, aspirin, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs), angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), beta-blockers, diuretics, digoxin, lithium, methotrexate, cyclosporine, other NSAIDs and salicylates, and pemetrexed.¹
  • Ordering is simple. COMBOGESIC® IV comes in a 10-vial carton and a minimum order quantity is one carton.

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Dosing and Administration

  • For adult patients weighing greater than or equal to 50 kg (actual body weight): The recommended dosage of COMBOGESIC® IV is one vial (100 mL; acetaminophen 1,000 mg/ibuprofen 300 mg) administered as a 15-minute infusion every 6 hours, as necessary.1
  • For adult patients weighing less than 50 kg (actual body weight): The recommended dosage is 15 mg/kg acetaminophen and 4.5 mg/kg ibuprofen, administered as a 15-minute infusion every 6 hours, as necessary. This equates to a maximum single dose of 750 mg acetaminophen and 225 mg ibuprofen (discard remaining medicine in vial), and a total daily dose of 3,000 mg (3 g) acetaminophen and 900 mg ibuprofen.1
  • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals1
  • Do not exceed the maximum total daily dose of COMBOGESIC® IV (4,000 mg acetaminophen and 1,200 mg ibuprofen) in 24 hours1
  • Administer as a 15-minute intravenous infusion1
  • Do not mix other medications with the COMBOGESIC® IV vial or infusion device1
  • As for all solutions for infusion presented in glass vials, monitor closely, particularly at the end of infusion, regardless of administration route, in order to avoid air embolism. This applies particularly for central route infusion1
  • To decrease the likelihood of bung fragmentation or the bung being forced into the vial, use a syringe or giving set with a diameter equal to or below 0.8 mm for solution sampling and ensure that the bung is pierced at the location specifically designed for needle introduction (where the thickness of the bung is the lowest)1
  • The entire 100 mL container of COMBOGESIC® IV is not intended for use in patients weighing less than 50 kg. For doses less than 1,000 mg acetaminophen and 300 mg ibuprofen, the appropriate dose must be withdrawn from the container and placed into a separate container prior to administration. Using aseptic technique, withdraw the appropriate dose (weight-based) from an intact sealed COMBOGESIC® IV container and place the measured dose in a separate empty, sterile container (e.g., glass bottle, plastic intravenous container, or syringe) for intravenous infusion to avoid the inadvertent delivery and administration of the total volume of the commercially available container. COMBOGESIC® IV is supplied in a single-dose container and the unused portion must be discarded1

Study Design

  • COMBOGESIC® IV was studied in a Phase 3, placebo-controlled, prospective, randomized, double-blind, factorial design trial comparing the analgesic efficacy and safety of COMBOGESIC® IV (n=75/276) with acetaminophen alone (n=75/276), ibuprofen alone (n=76/276) and placebo (n=50/276), after bunionectomy surgery.1
  • The primary efficacy endpoint was the time-adjusted Sum of Pain Intensity Differences over 48 hours (SPID48) and analyzed with each pre-rescue Visual Analogue Scale (VAS) carried forward up to 2 hours. An analysis of covariance was used for the primary efficacy analysis with treatment as the fixed effect and baseline pain intensity score as the covariate on the intent-to-treat population.1
  • The demographic and baseline characteristics of the 276 eligible patients were balanced between the treatment groups with the majority of patients being female (82%) and white (62%) with a mean (SD) age of 42.4 (12.2) years.1
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Important Safety Information

WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK, and GASTROINTESTINAL RISK

  • RISK OF MEDICATION ERRORS: Take care when prescribing, preparing, and administering COMBOGESIC® IV to avoid dosing errors which could result in accidental overdose and death.
  • HEPATOTOXICITY: COMBOGESIC® IV contains acetaminophen which has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most cases of liver injury are associated with doses exceeding 4,000 mg per day and often involve more than one acetaminophen-containing product.
  • CARDIOVASCULAR RISK: COMBOGESIC® IV contains ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID). NSAIDs cause an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
  • COMBOGESIC® IV is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
  • GASTROINTESTINAL RISK: NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk.

CONTRAINDICATIONS

COMBOGESIC® IV is contraindicated in:

  • Patients with known hypersensitivity to acetaminophen, ibuprofen, other NSAIDs or to any components of this product.
  • Patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.
  • Patients with severe hepatic impairment or severe active liver disease.

WARNINGS & PRECAUTIONS

  • Hepatotoxicity. COMBOGESIC® IV contains acetaminophen and ibuprofen. Acetaminophen has been associated with cases of acute liver failure; the risk is higher in those with underlying liver disease and in those who ingest alcohol. Use in patients with hepatic impairment is not recommended. Elevations of ALT or AST have been reported in NSAID-treated patients.
  • Cardiovascular Thrombotic Events. To minimize the risks of CV events, use the lowest effective dose for the shortest duration possible.
  • Gastrointestinal Bleeding, Ulceration, and Perforation. NSAIDs may cause serious and sometimes fatal GI adverse events at any time and without warning. Avoid use in patients at higher risk. In concomitant use with low-dose aspirin, monitor patients more closely for evidence of GI bleeding.
  • Hypertension. NSAIDs can lead to onset of new hypertension or worsening of pre-existing hypertension, which may contribute to the increased incidence of CV events.
  • Heart Failure and Edema. Avoid use in patients with severe heart failure unless benefits outweigh risk.
  • Renal Toxicity and Hyperkalemia. Use in patients with renal impairment is not recommended. Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Increases in serum potassium concentration, including hyperkalemia, have been reported.
  • Hypersensitivity and Anaphylactic Reactions. Hypersensitivity and anaphylaxis associated with ibuprofen and acetaminophen have been reported, including life-threatening anaphylaxis associated with acetaminophen.
  • Exacerbation of Asthma Related to Aspirin Sensitivity. Patients with asthma may have intolerance to aspirin and other NSAIDs.
  • Serious Skin Reactions. Acetaminophen or NSAIDs may cause serious skin reactions such as exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal and may occur without warning. Discontinue the use of COMBOGESIC® IV at the first appearance of skin rash or any other sign of hypersensitivity.
  • Drug Rash with Eosinophilia and Systemic Symptoms (DRESS). DRESS that may be life-threatening or fatal has been reported in patients taking NSAIDs.
  • Fetal Toxicity: Premature Closure of Fetal Ductus Arteriosus. Avoid use of COMBOGESIC® IV in pregnant women at about 30 weeks gestation and later. COMBOGESIC® IV increases the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age.
  • Hematologic Toxicity. Anemia has occurred in NSAID-treated patients and NSAID-treatment may increase the risk of bleeding events.
  • Ophthalmological Effects. Blurred or diminished vision, scotomata, and/or changes in color vision have been reported with oral ibuprofen.
  • Aseptic Meningitis. Aseptic meningitis with fever and coma has been observed in patients on oral ibuprofen.
  • Masking of Inflammation and Fever. Activity of COMBOGESIC® IV in reducing inflammation, and possibly fever, may diminish signs of infections.
  • Laboratory Monitoring. Monitor patients on NSAID treatment with a CBC and a chemistry profile as clinically indicated.

ADVERSE REACTIONS

The most common adverse reactions (≥ 3%) were infusion site pain, nausea, constipation, dizziness, infusion site extravasation, vomiting, headache, and somnolence.

DRUG INTERACTIONS

  • Drugs That Interfere with Hemostasis. Ibuprofen and anticoagulants have a synergistic effect on bleeding. Concomitant use increases the risk of serious bleeding. Concomitant use of drugs that interfere with serotonin reuptake and an NSAID may increase the risk of bleeding.
  • ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers. NSAIDs may diminish the antihypertensive effect of ACE inhibitors, ARBs, or Beta-Blockers. In the elderly, volume depleted, or those that have renal impairment, concomitant use with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure.
  • Diuretics. NSAIDs can reduce the natriuretic effect of loop diuretics and thiazides in some patients.
  • Digoxin. Concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.
  • Lithium. NSAIDs produced an elevation of plasma lithium levels and a reduction in renal lithium clearance.
  • Methotrexate. Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity.
  • Cyclosporine. Concomitant use of NSAIDS and cyclosporine may increase cyclosporine’s nephrotoxicity.
  • NSAIDs and Salicylates. Concomitant use with other NSAIDs or salicylates increases the risk of GI toxicity.
  • Pemetrexed. Concomitant use of NSAIDS and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity.

INDICATIONS AND USAGE

COMBOGESIC® IV is indicated in adults (over age 18) where an intravenous route of administration is considered clinically necessary for:

  • The relief of mild to moderate pain.
  • The management of moderate to severe pain as an adjunct to opioid analgesics.

LIMITATIONS OF USE

COMBOGESIC® IV is indicated for short-term use of five days or less.

For more information, please see the full Prescribing Information , available at www.hikma.com .

To report an adverse event or product complaint, please contact us at [email protected] or call 1-877-845-0689 or 1-800-962-8364 . Adverse events may also be reported to the FDA directly at 1-800-FDA-1088 or www.fda.gov/medwatch .
References:
  1. COMBOGESIC® IV (acetaminophen 1000 mg and ibuprofen 300 mg) [package insert]. Hikma Pharmaceuticals USA Inc.

Important Safety Information

WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK, and GASTROINTESTINAL RISK

  • RISK OF MEDICATION ERRORS: Take care when prescribing, preparing, and administering COMBOGESIC® IV to avoid dosing errors which could result in accidental overdose and death.
  • HEPATOTOXICITY: COMBOGESIC® IV contains acetaminophen which has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most cases of liver injury are associated with doses exceeding 4,000 mg per day and often involve more than one acetaminophen-containing product.
  • CARDIOVASCULAR RISK: COMBOGESIC® IV contains ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID). NSAIDs cause an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use.
  • COMBOGESIC® IV is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.
  • GASTROINTESTINAL RISK: NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk.
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