Drug Facts
Composition & Profile
Identifiers & Packaging
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.; PRINCIPAL DISPLAY PANEL NDC 0143- 9150 -01 Rx only KEEP OUT OF REACH OF CHILDREN COMBOGESIC IV (acetaminophen and ibuprofen) injection 1,000 mg/300 mg per 100 mL (10 mg/3 mg per mL) For Intravenous Infusion Only 100 mL Single-Dose Vial. Discard unused portion. NDC 0143- 9150 -10 Rx only KEEP OUT OF REACH OF CHILDREN COMBOGESIC IV (acetaminophen and ibuprofen) injection 1,000 mg/300 mg per 100 mL (10 mg/3 mg per mL) For Intravenous Infusion Only Single-Dose Vial. Discard unused portion. 10 x 100 mL Vials COMBOGESIC IV Vial Label COMBOGESIC IV Carton
- 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.
- PRINCIPAL DISPLAY PANEL NDC 0143- 9150 -01 Rx only KEEP OUT OF REACH OF CHILDREN COMBOGESIC IV (acetaminophen and ibuprofen) injection 1,000 mg/300 mg per 100 mL (10 mg/3 mg per mL) For Intravenous Infusion Only 100 mL Single-Dose Vial. Discard unused portion. NDC 0143- 9150 -10 Rx only KEEP OUT OF REACH OF CHILDREN COMBOGESIC IV (acetaminophen and ibuprofen) injection 1,000 mg/300 mg per 100 mL (10 mg/3 mg per mL) For Intravenous Infusion Only Single-Dose Vial. Discard unused portion. 10 x 100 mL Vials COMBOGESIC IV Vial Label COMBOGESIC IV Carton
Overview
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
Indications & 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 & 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 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). • 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 discarded.
Warnings & Precautions
• Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure. ( 5.5 ) • Heart Failure and Edema: Avoid use of COMBOGESIC IV in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure. ( 5.6 ) • Renal Toxicity: Long-term administration of NSAIDs, including the ibuprofen component of COMBOGESIC IV, has resulted in renal papillary necrosis and other renal injury. ( 5.7 ) • Anaphylactic Reactions: Discontinue use immediately if symptoms occur. ( 5.8 ) • Exacerbation of Asthma Related to Aspirin Sensitivity: COMBOGESIC IV is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity). ( 5.9 ) • Serious Skin Reactions: Discontinue COMBOGESIC IV at first appearance of skin rash or other signs of hypersensitivity. ( 5.10 ) • Drug Rash with Eosinophilia and Systemic Symptoms (DRESS): Discontinue and evaluate clinically. ( 5.11 ) • Fetal Toxicity: Limit use of NSAID-containing products, including COMBOGESIC IV, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAID-containing products, including COMBOGESIC IV, in women at about 30 weeks gestation and later in pregnancy due to the risks of oligohydramnios/fetal renal dysfunction and premature closure of the fetal ductus arteriosus. ( 5.12 ) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.13 ). 5.1 Risk of Medication Errors Take care when prescribing, preparing, and administering COMBOGESIC IV in order to avoid dosing errors which could result in accidental overdose and death. In particular, be careful to ensure that: • the dose in milligrams (mg) and milliliters (mL) is not confused; • the dosing is based on weight for patients under 50 kg; • infusion pumps are properly programmed; and • the total daily dose of acetaminophen from all sources does not exceed maximum daily limits [see Dosage and Administration (2) ] . 5.2 Hepatotoxicity Acetaminophen 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 the use of acetaminophen at doses that exceed 4,000 mg per day, and often involve more than one acetaminophen-containing product. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Ibuprofen COMBOGESIC IV contains ibuprofen, a NSAID. Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported. Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs, including ibuprofen. Clinical Recommendations COMBOGESIC IV is contraindicated in patients with severe hepatic impairment or severe active liver disease. COMBOGESIC IV has not been studied in patients with impaired hepatic function. Use in these patients is not recommended [see Use in Specific Populations (8.6) ] . If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue COMBOGESIC IV immediately, and perform a clinical evaluation of the patient. 5.3 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, including myocardial infarction (MI) and stroke, which can be fatal. Based on available data, it is unclear that the risk for CV thrombotic events is similar for all NSAIDs. The relative increase in serious CV thrombotic events over baseline conferred by NSAID use appears to be similar in those with and without known CV disease or risk factors for CV disease. However, patients with known CV disease or risk factors had a higher absolute incidence of excess serious CV thrombotic events, due to their increased baseline rate. Some observational studies found that this increased risk of serious CV thrombotic events began as early as the first weeks of treatment. The increase in CV thrombotic risk has been observed most consistently at higher doses. To minimize the potential risk for an adverse CV event in NSAID-treated patients, the lowest effective dose for the shortest duration possible should be used. Physicians and patients should remain alert for the development of such events, throughout the entire treatment course, even in the absence of previous CV symptoms. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID, such as ibuprofen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.4) ]. Status Post Coronary Artery Bypass Graft (CABG) Surgery Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke. NSAIDs are contraindicated in the setting of CABG [see Contraindications (4) ]. Post-MI Patients Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up. Avoid the use of COMBOGESIC IV in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If COMBOGESIC IV is used in patients with a recent MI, monitor patients for signs of cardiac ischemia. 5.4 Gastrointestinal Bleeding, Ulceration, and Perforation NSAIDs, including ibuprofen, cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occurred in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. However, even short-term therapy is not without risk. Risk Factors for GI Bleeding, Ulceration and Perforation Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-fold increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking; use of alcohol; older age; and poor general health status. Most post-marketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for getting an ulcer or bleeding. Strategies to Minimize the GI Risks in NSAID-treated Patients • Use the lowest effective dosage for the shortest possible duration. • Avoid administration of more than one NSAID at a time. • Avoid use in patients at higher risk, unless benefits are expected to outweigh the increased risk of bleeding. For such patients, as well as those with active GI bleeding, consider alternate therapies other than NSAIDs. • Remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy. • If a serious GI adverse event is suspected, promptly initiate evaluation and treatment, and discontinue COMBOGESIC IV until a serious GI adverse event is ruled out. • In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, monitor patients more closely for evidence of GI bleeding [see Drug Interactions (7) ]. 5.5 Hypertension NSAIDs, including the ibuprofen in COMBOGESIC IV, can lead to onset of new hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme (ACE) inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy. 5.6 Heart Failure and Edema The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death. Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of ibuprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [ see Drug Interactions (7) ]. Avoid the use of COMBOGESIC IV in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If COMBOGESIC IV is used in patients with severe heart failure, monitor patients for signs of worsening heart failure. 5.7 Renal Toxicity and Hyperkalemia Renal Toxicity Use of COMBOGESIC IV is not recommended in patients with renal impairment. Long-term administration of NSAIDs, including the ibuprofen component of COMBOGESIC IV, has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state. No information is available from controlled clinical studies regarding the use of COMBOGESIC IV in patients with advanced renal disease. The renal effects of COMBOGESIC IV may hasten the progression of renal dysfunction in patients with pre-existing renal disease. Correct volume status in dehydrated or hypovolemic patients prior to initiating COMBOGESIC IV. Hyperkalemia Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs,even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state. 5.8 Hypersensitivity and Anaphylactic Reactions Acetaminophen There have been post-marketing reports of hypersensitivity and anaphylaxis associated with the use of acetaminophen. Clinical signs included swelling of the face, mouth, and throat, respiratory distress, urticaria, rash, pruritus, and vomiting. There were infrequent reports of life-threatening anaphylaxis requiring emergency medical attention. Discontinue COMBOGESIC IV immediately if symptoms associated with allergy or hypersensitivity occur. Do not use COMBOGESIC IV in patients with acetaminophen allergy. Ibuprofen NSAIDS, including the ibuprofen in COMBOGESIC IV, has been associated with anaphylactic reactions in patients with and without known hypersensitivity to ibuprofen and in patients with aspirin-sensitive asthma [see Contraindications (4) and Warnings and Precautions (5.9) ]. Discontinue COMBOGESIC IV immediately if symptoms associated with allergy or hypersensitivity occur. 5.9 Exacerbation of Asthma Related to Aspirin Sensitivity A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, COMBOGESIC IV is contraindicated in patients with this form of aspirin sensitivity [ see Contraindications (4) ]. When COMBOGESIC IV is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma. 5.10 Serious Skin Reactions COMBOGESIC IV contains acetaminophen and ibuprofen. Acetaminophen, or NSAIDs, including ibuprofen, 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. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and discontinued the use of the drug at the first appearance of skin rash or any other sign of hypersensitivity. COMBOGESIC IV is contraindicated in patients with previous serious skin reactions to acetaminophen or NSAIDs [see Contraindications (4) ]. 5.11 Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs such as the ibuprofen in COMBOGESIC IV. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling. Other clinical manifestations may include hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Sometimes symptoms of DRESS may resemble an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its presentation, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, discontinue COMBOGESIC IV and evaluate the patient immediately. 5.12 Fetal Toxicity Premature Closure of Fetal Ductus Arteriosus Avoid use of NSAID-containing products, including COMBOGESIC IV, in pregnant women at about 30 weeks gestation and later. NSAID-containing products, including COMBOGESIC IV, increase the risk of premature closure of the fetal ductus arteriosus at approximately this gestational age. Oligohydramnios/Neonatal Renal Impairment Use of NSAID-containing products, including COMBOGESIC IV, at about 20 weeks gestation or later in pregnancy may cause fetal renal dysfunction leading to oligohydramnios and, in some cases, neonatal renal impairment. These adverse outcomes are seen, on average, after days to weeks of treatment, although oligohydramnios has been infrequently reported as soon as 48 hours after NSAID initiation. Oligohydramnios is often, but not always, reversible with treatment discontinuation. Complications of prolonged oligohydramnios may, for example, include limb contractures and delayed lung maturation. In some post-marketing cases of impaired neonatal renal function, invasive procedures such as exchange transfusion or dialysis were required. If, after careful consideration of alternative treatment options for pain management, NSAID treatment is necessary between about 20 weeks and 30 weeks gestation, limit COMBOGESIC IV use to the lowest effective dose and shortest duration possible. Consider ultrasound monitoring of amniotic fluid if COMBOGESIC IV treatment extends beyond 48 hours. Discontinue COMBOGESIC IV if oligohydramnios occurs and follow up according to clinical practice [see Use in Specific Populations (8.1) ] . 5.13 Hematologic Toxicity Anemia has occurred in NSAID-treated patients. This may be due to occult or gross GI blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient being treated with COMBOGESIC IV has any signs or symptoms of anemia, monitor hemoglobin or hematocrit. NSAIDs, including the ibuprofen in COMBOGESIC IV, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders or concomitant use of warfarin, other anticoagulants, antiplatelet agents (e.g., aspirin), serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [ see Drug Interactions (7) ]. 5.14 Ophthalmological Effects Blurred or diminished vision, scotomata, and/or changes in color vision have been reported with oral ibuprofen. If a patient develops such complaints while receiving COMBOGESIC IV, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing. 5.15 Aseptic Meningitis Aseptic meningitis with fever and coma has been observed in patients on oral ibuprofen. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have underlying chronic disease. If signs or symptoms of meningitis develop in a patient on COMBOGESIC IV, the possibility of its being related to ibuprofen should be considered. 5.16 Masking of Inflammation and Fever The pharmacological activity of COMBOGESIC IV in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections. 5.17 Laboratory Monitoring Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on NSAID treatment with a CBC and a chemistry profile as clinically indicated [see Warnings and Precautions (5.3 , 5.4 , 5.8 )] .
Boxed Warning
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 )
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 )
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 erythrocytes 0.9% (n=2/218), was low in participants over the age of 65.
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 patients. This effect has been attributed to the NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of COMBOGESIC IV with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.7) ] . Digoxin Clinical Impact: The concomitant use of ibuprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin. Intervention: During concomitant use of COMBOGESIC IV and digoxin, monitor serum digoxin levels. Lithium Clinical Impact: NSAIDs have produced elevations in plasma lithium levels and reductions in renal lithium clearance. The mean minimum lithium concentration increased 15%, and the renal clearance decreased by approximately 20%. This effect has been attributed to NSAID inhibition of renal prostaglandin synthesis. Intervention: During concomitant use of COMBOGESIC IV and lithium, monitor patients for signs of lithium toxicity. Methotrexate Clinical Impact: Concomitant use of NSAIDs and methotrexate may increase the risk for methotrexate toxicity (e.g., neutropenia, thrombocytopenia, renal dysfunction). Intervention: During concomitant use of COMBOGESIC IV and methotrexate, monitor patients for methotrexate toxicity. Cyclosporine Clinical Impact: Concomitant use of NSAIDS and cyclosporine may increase cyclosporine’s nephrotoxicity. Intervention: During concomitant use of COMBOGESIC IV and cyclosporine, monitor patients for signs of worsening renal function. NSAIDs and Salicylates Clinical Impact: Concomitant use of ibuprofen with other NSAIDs or salicylates (e.g., diflunisal, salsalate) increases the risk of GI toxicity, with little or no increase in efficacy [see Warnings and Precautions (5.4) ] . Intervention: The concomitant use of ibuprofen with other NSAIDs or salicylates is not recommended. Pemetrexed Clinical Impact: Concomitant use of NSAIDS and pemetrexed may increase the risk of pemetrexed-associated myelosuppression, renal, and GI toxicity (see the pemetrexed prescribing information). Intervention: During concomitant use of COMBOGESIC IV and pemetrexed, in patients with renal impairment whose creatinine clearance ranges from 45 to 79 mL/min, monitor for myelosuppression, renal and GI toxicity. NSAIDs with short elimination half-lives (e.g., diclofenac, indomethacin) should be avoided for a period of two days before, the day of, and two days following administration of pemetrexed. In the absence of data regarding potential interaction between pemetrexed and NSAIDs with longer half-lives (e.g., meloxicam, nabumetone), patients taking these NSAIDs should interrupt dosing for at least five days before, the day of, and two days following pemetrexed administration. A number of known or potential interactions between COMBOGESIC IV and other drugs/drug classes exist. Please refer to the Drug Interactions section ( 7 ) for further information.
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