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Acetaminophen And Ibuprofen Injection

FDA Drug Information • Also known as: Combogesic Iv

Brand Names
Combogesic Iv
Drug Class
Nonsteroidal Anti-inflammatory Drug [EPC]
Route
INTRAVENOUS
Dosage Form
INJECTION
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

BOXED WARNING 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 ( 5.1 ). HEPATOTOXICITY: COMBOGESIC IV contains acetaminophen. Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with doses of acetaminophen that exceed 4,000 mg per day, and often involve more than one acetaminophen-containing product [see Warnings and Precautions (5.2) ] . CARDIOVASCULAR RISK: COMBOGESIC IV contains ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID). NSAIDs cause an increased risk of serious cardiovascular 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 [see Warnings and Precautions (5.3) ] . COMBOGESIC IV is contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4) and Warnings and Precautions (5.3) ] . GASTROINTESTINAL RISK: NSAIDs cause an increased risk of serious gastrointestinal 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 for serious gastrointestinal events [see Warnings and Precautions (5.4) ] . WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK, and GASTROINTESTINAL RISK See full prescribing information for complete boxed warning.

  • Take care when prescribing, preparing, and administering COMBOGESIC IV to avoid dosing errors which could result in accidental overdose and death. ( 5.1 )
  • COMBOGESIC IV contains acetaminophen, which has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with doses of acetaminophen that exceed 4000 mg per day, and often involve more than one acetaminophen-containing product. ( 5.2 )
  • Nonsteroidal anti-inflammatory drugs (NSAIDS), like the ibuprofen in COMBOGESIC IV, may cause an increased risk of serious cardiovascular 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. ( 5.3 ).
  • COMBOGESIC IV is contraindicated in the setting of coronary artery bypass graft (CABG) surgery. ( 4 , 5.3 )
  • NSAIDS, like the ibuprofen in COMBOGESIC IV, 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events. ( 5.4 )

    • Description

    11 DESCRIPTION COMBOGESIC IV (acetaminophen and ibuprofen) injection contains acetaminophen and ibuprofen, a nonsteroidal anti-inflammatory drug. Acetaminophen chemical name is N-acetyl-p-aminophenol. Acetaminophen is a white, odorless, crystalline powder, possessing a slightly bitter taste. Acetaminophen is soluble in boiling water and 1N sodium hydroxide and is freely soluble in alcohol. Acetaminophen has a molecular weight of 151.16. The molecular formula is C 8 H 9 NO 2 and the structural formula is: Ibuprofen sodium dihydrate chemical name is 2-(4-isobutyl phenyl) propionic acid sodium salt dihydrate. Ibuprofen sodium dihydrate is a white powder. It has a molecular weight of 264.29. It is freely soluble in water. The molecular formula is C 13 H 21 NaO 4 and the structural formula of ibuprofen sodium dihydrate is represented below: COMBOGESIC IV injection is a sterile, clear, colorless, non-pyrogenic, isotonic solution, intended for intravenous infusion with a pH stability range of 6.3-7.3. Each single-dose 100 mL vial contains 1,000 mg of acetaminophen and 300 mg of ibuprofen base (equivalent to 385 mg of ibuprofen sodium dihydrate), 25 mg of Cysteine hydrochloride monohydrate, 13 mg of Disodium phosphate dihydrate, 3,285 mg of Mannitol, Hydrochloric acid (for pH adjustment), Sodium hydroxide (for pH adjustment), Water for injection. Acetaminophen Structural Formula Ibuprofen Structural Formula

    What Is Acetaminophen And Ibuprofen Injection Used For?

    1 INDICATIONS AND USAGE COMBOGESIC IV is indicated in adults 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. COMBOGESIC IV is indicated in adults 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.

    • Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals. ( 2.1 ).
  • Do not exceed the maximum total daily dose of COMBOGESIC IV (4,000 mg acetaminophen and 1,200 mg ibuprofen) in 24 hours. ( 2.1 )
  • Do not exceed a total daily dose of 4,000 mg (4 g) of acetaminophen from all sources. ( 2.1 )
  • Do not administer with other acetaminophen-containing products. ( 2.1 )
  • For adult patients weighing greater than or equal to 50 kg (actual body weight): The recommended dosage is 1,000 mg of acetaminophen and 300 mg of ibuprofen administered as a 15-minute infusion, every 6 hours, as necessary ( 2.2 ).
  • 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. ( 2.2 ) 2.1 Important Dosage and Administration Instructions
  • Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5.4) ].
  • Do not exceed the maximum total daily dose of COMBOGESIC IV (4,000 mg acetaminophen and 1,200 mg ibuprofen) in 24 hours.
  • Do not exceed a total daily dose of 4,000 mg (4 g) acetaminophen from all sources.
  • Do not co-administer COMBOGESIC IV with other acetaminophen or ibuprofen containing products [see Warnings and Precautions (5.2) ].
  • Visually inspect for particulate matter and discoloration prior to administration. If visibly opaque particles, discoloration, or other foreign particulates are observed, do not use.
  • Use COMBOGESIC IV in one patient on one occasion only. It contains no antimicrobial preservative. Discard any unused solution.
  • Do not mix with diluents or with other medicines. 2.2 Recommended Dosage 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. 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. 2.3 Instructions for Intravenous Administration
  • Administer as a 15-minute intravenous infusion.
  • Do not mix other medications with the COMBOGESIC IV vial or infusion device.
  • 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 infusion.
  • To decrease the likelihood of bung fragmentation or the bung being forced into the vial, use a...

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following clinically significant adverse reactions to ibuprofen or acetaminophen are described elsewhere in other sections of the labelling.

  • Hepatotoxicity [see Warnings and Precautions (5.2) ]
  • Cardiovascular Thrombotic Events [see Warnings and Precautions (5.3) ]
  • Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.4) ]
  • Hypertension [see Warnings and Precautions (5.5) ]
  • Heart Failure and Edema [see Warnings and Precautions (5.6) ]
  • Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.7) ]
  • Hypersensitivity and Anaphylactic Reactions [see Warnings and Precautions (5.8) ]
  • Exacerbation of Asthma Related to Aspirin Sensitivity [see Warnings and Precautions (5.9) ]
  • Serious Skin Reactions [see Warnings and Precautions (5.10) ]
  • Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.11) ]
  • Hematologic Toxicity [see Warnings and Precautions (5.13) ] The most common adverse reactions (greater than or equal to 3%) are infusion site pain, nausea, constipation, dizziness, infusion site extravasation, vomiting, headache, somnolence. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical trials of COMBOGESIC IV have been conducted in patients with postoperative musculoskeletal pain and soft tissue pain models lasting between two to five days. Two Phase 3 clinical trials have been conducted with COMBOGESIC IV to assess efficacy and safety after multiple doses. In AFT-MXIV-07 participants were treated with COMBOGESIC IV, acetaminophen IV, ibuprofen IV or placebo for a treatment period of 48 hours. In AFT-MXIV-11 participants were treated for between 48 hours and five days 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. Overall, 59.3% 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 1). 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. Table 1: Common TEAEs (occurring in ≥ 3% of COMBOGESIC IV-treated participants) Adverse Reactions COMBOGESIC IV (N=307) % Acetaminophen (N=75) % Ibuprofen (N=76) % Placebo (N=50) % Gastrointestinal disorders Nausea 16.3 33.3 34.2 32.0 Vomiting 6.2 14.7 6.6 2.0 Constipation 7.2 5.3 5.3 8.0 Infusion Site Complications Infusion site pain 17.6 0.0 9.2 2.0 Infusion site extravasation 6.5 2.7 6.6 14.0 Nervous System Disorders Headache 5.5 6.7 6.6 20.0 Dizziness 7.2 9.3 9.2 18.0 Somnolence 3.9 8.0 7.9 6.0 Other skin and subcutaneous-related TEAEs (pruritis, hyperhidrosis) also affected around 2-3% of the study population, as did procedural nausea and polyuria. AFT-MXIV-11 found no notable difference in the safety profile of COMBOGESIC IV in participants treated for 5 days compared to those treated for 48 hours. Additionally, the safety profile was comparable between older participants (aged 65-75 years and >75 years) and younger participants (aged <65 years); the type and incidence of treatment-emergent adverse events was comparable, and the incidence of clinically significant shifts in laboratory tests (hematocrit 1.3% (n=3/228), hemoglobin 1.3% (n=3/228) and...

    • Drug Interactions

    7 DRUG INTERACTIONS Table 2. Drug Interactions with COMBOGESIC IV Drugs That Interfere with Hemostasis Clinical Impact:

  • Ibuprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of ibuprofen and anticoagulants have an increased risk of serious bleeding compared to the use of either drug alone.
  • Serotonin release by platelets plays an important role in hemostasis. Case-control and cohort epidemiological studies showed that concomitant use of drugs that interfere with serotonin reuptake and an NSAID may potentiate the risk of bleeding more than an NSAID alone. Intervention: Monitor patients with concomitant use of COMBOGESIC IV with anticoagulants (e.g., warfarin), antiplatelet agents (e.g., aspirin), selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) for signs of bleeding [see Warnings and Precautions (5.13) ] . Aspirin Clinical Impact: Controlled clinical studies showed that the concomitant use of NSAIDs and analgesic doses of aspirin does not produce any greater therapeutic effect than the use of NSAIDs alone. In a clinical study, the concomitant use of an NSAID and aspirin was associated with a significantly increased incidence of GI adverse reactions as compared to use of the NSAID alone [see Warnings and Precautions (5.3) ] . Intervention: Concomitant use of COMBOGESIC IV and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.4 , 5.13 )] . COMBOGESIC IV is not a substitute for low dose aspirin for cardiovascular protection. ACE Inhibitors, Angiotensin Receptor Blockers, and Beta-Blockers Clinical Impact:
  • NSAIDs may diminish the antihypertensive effect of angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), or beta-blockers (including propranolol).
  • In patients who are elderly, volume-depleted (including those on diuretic therapy), or have renal impairment, co-administration of an NSAID with ACE inhibitors or ARBs may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Intervention:
  • During concomitant use of COMBOGESIC IV and ACE-inhibitors, ARBs, or betablockers, monitor blood pressure to ensure that the desired blood pressure is obtained.
  • During concomitant use of COMBOGESIC IV and ACE-inhibitors or ARBs in patients who are elderly, volume-depleted, or have impaired renal function, monitor for signs of worsening renal function [see Warnings and Precautions (5.7) ] .
  • When these drugs are administered concomitantly, patients should be adequately hydrated. Assess renal function at the beginning of the concomitant treatment and periodically thereafter. Diuretics Clinical Impact: Clinical studies, as well as post-marketing observations, showed that NSAIDs reduced the natriuretic effect of loop diuretics (e.g., furosemide) and thiazide diuretics in some...

    • Contraindications

    4 CONTRAINDICATIONS COMBOGESIC IV is contraindicated in:

  • patients with a known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to acetaminophen, ibuprofen, other NSAIDs or to any other components of this product [see Warnings and Precautions (5.8 , 5.10 , 5.11 )]
  • patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.8 , 5.9 )]
  • in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.3) ]
  • patients with severe hepatic impairment or severe active liver disease [see Warnings and Precautions (5.2) ] COMBOGESIC IV is contraindicated in:
  • patients who have previously demonstrated hypersensitivity to acetaminophen, ibuprofen, other NSAIDs or to any of the excipients in the IV formulation ( 4 )
  • patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, sometimes fatal, anaphylactic reactions to NSAIDs have been reported in such patients ( 4 , 5.9 , 5.11 )
  • the setting of coronary artery bypass graft (CABG) surgery ( 4 , 5.3 )
  • patients with severe hepatic impairment or severe active liver disease ( 4 )

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary Use of NSAID-containing products, including COMBOGESIC IV, can cause premature closure of the fetal ductus arteriosus and fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. Because of these risks, limit dose and duration of COMBOGESIC IV use between about 20 and 30 weeks of gestation and avoid COMBOGESIC IV use at about 30 weeks of gestation and later in pregnancy (see Clinical Considerations, Data) . Premature Closure of Fetal Ductus Arteriosus: Use of NSAID-containing products, including COMBOGESIC IV, at about 30 weeks gestation or later in pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment: Use of NSAID-containing products, including COMBOGESIC IV, at about 20 weeks gestation or later in pregnancy has been associated with cases of fetal renal dysfunction leading to oligohydramnios, and in some cases, neonatal renal impairment. Data from observational studies regarding other potential embryofetal risks of NSAID use in women in the first or second trimester of pregnancy are inconclusive. No adequate and well-controlled studies have been conducted using COMBOGESIC IV in pregnant women. Animal reproduction studies have also not been conducted with COMBOGESIC IV. The following describes animal reproduction studies for Acetaminophen and Ibuprofen: Acetaminophen: Reproductive and developmental studies in rats and mice from the published literature have identified adverse events at clinically relevant doses of acetaminophen. Fetotoxicity, increases in bone variations in the fetuses, and necrosis in the fetus liver and kidney have been noted in studies in rats. In mice treated with acetaminophen at doses within the clinical dosing range, cumulative adverse effects on reproduction were seen in a continuous breeding study. A reduction in number of litters of the parental mating pair was observed as well as retarded growth and...

    Overdosage

    10 OVERDOSAGE COMBOGESIC IV is a combination product. The clinical presentation of overdose may include the signs and symptoms of acetaminophen toxicity, ibuprofen toxicity, or both. Acetaminophen The initial symptoms seen within the first 24 hours following an acetaminophen overdose are: anorexia, nausea, vomiting, malaise, pallor and diaphoresis. In acute acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia also occur. Plasma acetaminophen levels > 300 mcg/mL at 4 hours after oral ingestion were associated with hepatic damage in 90% of patients; minimal hepatic damage is anticipated if plasma levels at 4 hours are < 150 mcg/mL or < 37.5 mcg/mL at 12 hours after ingestion [see Warnings and Precautions (5.2) ] . Early symptoms following a potentially hepatotoxic overdose may include: nausea, vomiting, diaphoresis, and general malaise. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. If an acetaminophen overdose is suspected, obtain a serum acetaminophen assay as soon as possible, but no sooner than 4 hours following oral ingestion. Obtain liver function studies initially and repeat at 24-hour intervals. Administer the antidote N-acetylcysteine (NAC) as early as possible. As a guide to treatment of acute ingestion, the acetaminophen level can be plotted against time since oral ingestion on a nomogram (Rumack- Matthew). The lower toxic line on the nomogram is equivalent to 150 mcg/mL at 4 hours and 37.5 mcg/mL at 12 hours. If serum level is above the lower line, administer the entire course of NAC treatment. Withhold NAC therapy if the acetaminophen level is below the lower line. Ibuprofen Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which have been generally reversible with supportive care....

    How Supplied

    16 HOW SUPPLIED COMBOGESIC IV (acetaminophen/ ibuprofen) injection 1,000 mg/300 mg per 100 mL (10 mg/3mg per mL): clear, colorless solution in single-dose vial. Discard unused portion. NDC # 0143-9150-10: pack of 10 vials. COMBOGESIC IV is a clear, colorless solution, free from visible particles. Store at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Do not refrigerate or freeze. Store in the original carton in order to protect from light. Protect from heat.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.