Combogesic
ACETAMINOPHEN and IBUPROFEN · Tablet, Film Coated · Oral
Uses
1 INDICATIONS AND USAGE COMBOGESIC is indicated in adults for the short-term management of mild to moderate acute pain. COMBOGESIC is a combination of acetaminophen and ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), and is indicated in adults for the short term management of mild to moderate acute pain ( 1 ).
Dosage and administration
Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5) ]. Do not exceed the recommended dose of COMBOGESIC in 24 hours [see (2) below]. Do not co-administer COMBOGESIC with other acetaminophen- or NSAID-containing products [see Warnings and Precautions (5.1 , 5.2 , 5.3) ]. The recommended dose of COMBOGESIC is 3 tablets every 6 hours as needed for pain relief, up to a maximum of 12 tablets per day. Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals ( 2 ). Do not administer with other acetaminophen-containing products ( 2 ). Three tablets every 6 hours as needed for pain relief, up to a maximum of 12 tablets per day ( 2 ).
Dosage forms and strengths
Tablets: white, biconvex, capsule-shaped, film-coated tablets, debossed with the letters "CG" on one side and plain on the other side, each containing 325 mg acetaminophen and 97.5 mg ibuprofen. Film-coated tablet containing 325 mg acetaminophen and 97.5 mg ibuprofen ( 3 ).
Contraindications
4 CONTRAINDICATIONS COMBOGESIC is contraindicated in: patients with a known hypersensitivity (e.g., anaphylactic reactions, serious skin reactions) to acetaminophen, ibuprofen, other NSAIDs, or to any of the excipients in this product [see Warnings and Precautions (5.7 , 5.8 , 5.9) ]. patients with a history of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDS [see Warnings and Precautions (5.7 and 5.8) ] . the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.2) ] . COMBOGESIC is contraindicated in: patients with known hypersensitivity to acetaminophen, ibuprofen, other NSAIDs, or to any of the excipients in this product ( 4 ). 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 ( 4 ). the setting of coronary artery bypass graft (CABG) surgery ( 4 ).
Warnings and precautions
Hypertension : Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 ). Heart Failure and Edema : Avoid use of COMBOGESIC in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ). Renal Toxicity : Long-term administration of NSAIDs, including the ibuprofen component of COMBOGESIC, has resulted in renal papillary necrosis and other renal injury ( 5.6 ). Anaphylactic Reactions : Seek emergency help if an anaphylactic reaction occurs ( 5.7 ). Exacerbation of Asthma Related to Aspirin Sensitivity : COMBOGESIC is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ). Serious Skin Reactions : Discontinue COMBOGESIC at first appearance of skin rash or other signs of hypersensitivity ( 5.9 ). Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) : Discontinue and evaluate clinically ( 5.10 ). Fetal Toxicity : Limit use of NSAID-containing products, including COMBOGESIC, 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 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 ( 5.11 ). Hematologic Toxicity : Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 ). 5.1 Hepatotoxicity Acetaminophen COMBOGESIC 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 milligrams per day, and often involved more than one acetaminophen-containing product. The excessive intake of acetaminophen may be intentional to cause self-harm or unintentional as patients attempt to obtain more pain relief or unknowingly take other acetaminophen-containing products. The risk of acute liver failure is higher in individuals with underlying liver disease and in individuals who ingest alcohol while taking acetaminophen. Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well. Ibuprofen 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. Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue COMBOGESIC immediately, and perform a clinical evaluation of the patient. COMBOGESIC has not been studied in patients with impaired hepatic function. The use of COMBOGESIC in patients with hepatic impairment is not recommended. 5.2 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, use the lowest effective dose for the shortest duration possible. 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 signs and/or 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 (5.3) ] . 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.
Side effects
The following clinically significant adverse reactions to ibuprofen or acetaminophen are described elsewhere in other sections of the labelling. Hepatotoxicity [see Warnings and Precautions (5.1) ] Cardiovascular Thrombotic Events [see Warnings and Precautions (5.2) ] Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.3) ] Hypertension [see Warnings and Precautions (5.4) ] Heart Failure and Edema [see Warnings and Precautions (5.5) ] Renal Toxicity and Hyperkalemia [see Warnings and Precautions (5.6) ] Anaphylaxis and Other Hypersensitivity Reactions [see Warnings and Precautions (5.7) ] Serious Skin Reactions [see Warnings and Precautions (5.9) ] Hematologic Toxicity [see Warnings and Precautions (5.12) ] The most common adverse reactions (incidence of ≥ 2% for patients receiving COMBOGESIC) are: nausea, vomiting, headache, dizziness, somnolence, post-procedural hemorrhage, and swelling of the face (Table 1). The most common adverse reactions (greater than or equal to 2%) are nausea, vomiting, headache, dizziness, somnolence, post-procedural hemorrhage, and swelling of the face ( 6 ). 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 varying conditions, adverse reaction rates observed in the clinical trials of one drug cannot be directly compared to the rates reported from clinical trials of another drug and may not reflect the rates observed in practice. The clinical trials of COMBOGESIC have been conducted in patients with postoperative pain following dental and arthroscopic procedures, who received double-blind treatment every 6 hours for 24 or 48 hours. Most commonly (≥2%) reported adverse reactions by organ system during double-blind treatment are listed in the table below. Adverse reactions are closely related to the extent (the level and length) of exposure. The incidences of overall and individual adverse reactions reported during the double-blind treatment period did not suggest an increase of risks associated with short-term (up to one or two days) use of the combination drug, COMBOGESIC in comparison to each individual component, acetaminophen or ibuprofen, and to placebo. Table 1: Most commonly (≥2%) reported adverse reactions by organ system during double-blind treatment COMBOGESIC Acetaminophen Ibuprofen Placebo N=261 N=231 N=231 N=199 Total number of AEs 145 142 101 133 % of patients with ≥1 AE 30 38 29 37 Gastrointestinal disorders Nausea 15 19 12 23 Vomiting 7 10 3 10 Constipation 1 2 1 1 Dyspepsia 0.4 1 2 1 Injury, poisoning and procedural complications Post Procedural Hemorrhage 2 0.4 1 2 Nervous system disorders Headache 5 6 4 7 Dizziness 3 4 4 5 Somnolence 2 1 0 1 Skin and subcutaneous tissue disorders Swelling face 2 4 4 3 Pruritus 0.4 0.4 0.4 3 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of acetaminophen and ibuprofen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Appendages: Exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and fixed drug eruption (FDE).
Drug interactions
Table 2: Clinically Significant Drug Interactions with COMBOGESIC 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 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 (5.12) ]. 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 and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [ see Warnings and Precautions (5.3) ]. COMBOGESIC 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 and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of COMBOGESIC 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 (5.6) ] . 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 with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [ see Warnings and Precautions (5.4 and 5.6) ]. 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 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 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 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 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 (5.3) ] . 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 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 and other drugs/drug classes exist. Please refer to the Drug Interactions section ( 7 ) for further information.
Use in specific populations
Infertility: NSAID-containing products, including COMBOGESIC, are associated with reversible infertility. Consider withdrawal of COMBOGESIC tablets in women who have difficulties conceiving. ( 8.3 ) Renal or hepatic impairment: Not recommended ( 5.1 , 5.6 , 8.6 , 8.7 ). 8.1 Pregnancy Risk Summary Ibuprofen Use of NSAID-containing products, including COMBOGESIC, 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 use between about 20 and 30 weeks of gestation and avoid COMBOGESIC 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, 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, 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. In published animal reproduction studies, there were no clear developmental effects at doses up to 2.7-times the maximum human daily dose (MHDD) in the rabbit and 1.5-times in the MHDD rat when dosed throughout gestation. In contrast, an increase in membranous ventricular septal defects was reported in rats treated on Gestation Days 9 & 10 with 2.2-times the MHDD. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Acetaminophen Prolonged experience with acetaminophen in pregnant women over several decades, based on published observational epidemiological studies and case reports, did not identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data ) . 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 abnormal sperm in their offspring and reduced birth weight in the next generation. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAID-containing products, including COMBOGESIC, in women at about 30 weeks gestation and later in pregnancy, because NSAID-containing products, including COMBOGESIC, can cause premature closure of the fetal ductus arteriosus (see Data ) . Oligohydramnios/Neonatal Renal Impairment: If, after consideration of alternative treatments for pain management, an NSAID-containing product, including COMBOGESIC, is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If COMBOGESIC treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue COMBOGESIC and follow up according to clinical practice (see Data ). Labor or Delivery There are no studies on the effects of COMBOGESIC during labor or delivery. In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Ibuprofen: Premature Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis.
Pregnancy
8.1 Pregnancy Risk Summary Ibuprofen Use of NSAID-containing products, including COMBOGESIC, 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 use between about 20 and 30 weeks of gestation and avoid COMBOGESIC 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, 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, 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. In published animal reproduction studies, there were no clear developmental effects at doses up to 2.7-times the maximum human daily dose (MHDD) in the rabbit and 1.5-times in the MHDD rat when dosed throughout gestation. In contrast, an increase in membranous ventricular septal defects was reported in rats treated on Gestation Days 9 & 10 with 2.2-times the MHDD. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as ibuprofen, resulted in increased pre- and post-implantation loss. Prostaglandins also have been shown to have an important role in fetal kidney development. In published animal studies, prostaglandin synthesis inhibitors have been reported to impair kidney development when administered at clinically relevant doses. Acetaminophen Prolonged experience with acetaminophen in pregnant women over several decades, based on published observational epidemiological studies and case reports, did not identify a drug associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes (see Data ) . 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 abnormal sperm in their offspring and reduced birth weight in the next generation. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Premature Closure of Fetal Ductus Arteriosus: Avoid use of NSAID-containing products, including COMBOGESIC, in women at about 30 weeks gestation and later in pregnancy, because NSAID-containing products, including COMBOGESIC, can cause premature closure of the fetal ductus arteriosus (see Data ) . Oligohydramnios/Neonatal Renal Impairment: If, after consideration of alternative treatments for pain management, an NSAID-containing product, including COMBOGESIC, is necessary at about 20 weeks gestation or later in pregnancy, limit the use to the lowest effective dose and shortest duration possible. If COMBOGESIC treatment extends beyond 48 hours, consider monitoring with ultrasound for oligohydramnios. If oligohydramnios occurs, discontinue COMBOGESIC and follow up according to clinical practice (see Data ). Labor or Delivery There are no studies on the effects of COMBOGESIC during labor or delivery. In animal studies, NSAIDs, including ibuprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth. Data Human Data Ibuprofen: Premature Closure of Fetal Ductus Arteriosus Published literature reports that the use of NSAIDs at about 30 weeks of gestation and later in pregnancy may cause premature closure of the fetal ductus arteriosus. Oligohydramnios/Neonatal Renal Impairment Published studies and postmarketing reports describe maternal NSAID use at about 20 weeks gestation or later in pregnancy associated with 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. In many cases, but not all, the decrease in amniotic fluid was transient and reversible with cessation of the drug. There have been a limited number of case reports of maternal NSAID use and neonatal renal dysfunction without oligohydramnios, some of which were irreversible. Some cases of neonatal renal dysfunction required treatment with invasive procedures, such as exchange transfusion or dialysis. Methodological limitations of these postmarketing studies and reports include lack of a control group; limited information regarding dose, duration, and timing of drug exposure; and concomitant use of other medications. These limitations preclude establishing a reliable estimate of the risk of adverse fetal and neonatal outcomes with maternal NSAID use.
Pediatric use
8.4 Pediatric Use The safety and effectiveness of COMBOGESIC in pediatric patients have not been established. COMBOGESIC is not approved for patients under 18 years of age.
Geriatric use
8.5 Geriatric Use Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [ see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.4 , 5.5 , 5.6 )]. This drug is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Overdosage
10 OVERDOSAGE COMBOGESIC 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. Clinical and laboratory evidence of hepatic toxicity may not be apparent until 48 to 72 hours post-ingestion. In acute acetaminophen overdosage, dose-dependent, potentially fatal hepatic necrosis is the most serious adverse effect. Renal tubular necrosis, hypoglycemic coma, and coagulation defects also may 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. 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. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression, and coma have occurred, but were rare [ see Warnings and Precautions (5.1 , 5.2 , 5.3 , 5.4 , 5.6 , 5.14 ) ]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. It is advisable to contact a poison control center (1-800-222-1222) to determine the latest recommendations because strategies for the management of overdose are continually evolving. If gastric decontamination may benefit the patient, e.g., short time since ingestion or a large overdosage (5 to 10 times the recommended dosage), consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or an osmotic cathartic in symptomatic patients if clinically appropriate.
Description
11 DESCRIPTION COMBOGESIC tablets are a combination of acetaminophen, an analgesic and antipyretic, and ibuprofen, a non-steroidal anti-inflammatory drug (NSAID). The chemical name for acetaminophen is N -acetyl- p -aminophenol. The molecular formula is C 8 H 9 NO 2 and the structural formula is: The molecular weight of acetaminophen is 151.17. 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. The chemical name for ibuprofen is (±)-2-(p-isobutylphenyl) propionic acid. The molecular formula is C 13 H 18 O 2 and the structural formula is: The molecular weight of ibuprofen is 206.29. Ibuprofen is a white powder with a melting point of 74-77°C and is very slightly soluble in water (<1 mg/mL) and readily soluble in organic solvents such as ethanol and acetone. COMBOGESIC tablets contain 325 mg acetaminophen and 97.5 mg ibuprofen and are white in color. The inactive ingredients in the tablet are croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, medium chain triglycerides, microcrystalline cellulose, polydextrose, povidone-30, sodium lauryl sulfate, talc, titanium dioxide. Chemical Structure Chemical Structure
Mechanism of action
12.1 Mechanism of Action Analgesia COMBOGESIC contains acetaminophen and ibuprofen. 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. 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.
How supplied
16 HOW SUPPLIED/STORAGE AND HANDLING COMBOGESIC tablets with acetaminophen 325 mg and ibuprofen 97.5 mg are white, biconvex, capsule-shaped film coated tablets, debossed with the letters "CG" on one side and plain on the other side and are available as follows: NDC 0143-9432-27 1 bottle containing 250 tablets Store at 20°C to 25°C (68°F to 77°F) with excursions permitted within USP controlled room temperature of 15°C to 30°C (59°F to 86°F). Protect from moisture and light.
Storage
Store at 20°C to 25°C (68°F to 77°F) with excursions permitted within USP controlled room temperature of 15°C to 30°C (59°F to 86°F). Protect from moisture and light.
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). Important Dosage and Administration Information : Clearly explain to patients the single-dose and 24-hour dose limit and the time interval between doses. Explain that exceeding these recommendations can result in hepatic toxicity and/or gastrointestinal bleeding, ulceration, and perforation [See Dosage and Administration (2) , Warnings and Precautions (5.1 , 5.3) ]. Inform patients that the concomitant use of COMBOGESIC with other NSAIDs, acetaminophen-containing products, or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of hepatic and gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.1 , 5.3) , Drug Interactions (7) ]. Alert patients that these may be present in "over the counter" medications for treatment of colds, fever, or insomnia. Alert patients that NSAIDs and acetaminophen may be present in "over the counter" medications for treatment of colds, fever, or insomnia. Hepatotoxicity : Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness and "flu-like" symptoms). Instruct patients to stop therapy and seek immediate medical assistance if these occur [see Warnings and Precautions (5.1) ] . Alcohol : Advise patients not to take COMBOGESIC concomitantly with alcohol-containing beverages [see Warnings and Precautions (5.1) ] . Cardiovascular Thrombotic Effects : Inform patients that COMBOGESIC, like other NSAID-containing medications, may cause serious CV side effects such as MI or stroke, which may result in hospitalization and even death. Advise patients to be alert for chest pain, shortness of breath, weakness, and slurring of speech, and to seek medical assistance when observing any sign or symptom indicative of CV effects [see Warnings and Precautions (5.2) ] . Gastrointestinal Bleeding, Ulceration, and Perforation : Inform patients that COMBOGESIC, like other NSAID-containing medications, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Advise patients to be alert for the signs and symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis, and to seek medical assistance should these symptoms occur [see Warnings and Precautions (5.3) ] . Heart Failure and Edema : Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5) ] . Weight Gain and Edema : Advise patients to promptly report unexplained weight gain or edema to their physicians [see Warnings and Precautions (5.5) ] . Anaphylactic Reactions : Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Warnings and Precautions (5.7) ] . Serious Skin Reactions, including DRESS : Advise patients to stop taking COMBOGESIC immediately if they develop any type of rash or fever and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9 , 5.10) ]. Female Fertility : Advise females of reproductive potential who desire pregnancy that NSAID containing products, including COMBOGESIC tablets, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3) ]. Fetal Toxicity : Inform pregnant women to avoid use of COMBOGESIC and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus. If treatment with COMBOGESIC is needed for a pregnant woman between about 20 to 30 weeks gestation, advise her that she may need to be monitored for oligohydramnios, if treatment continues for longer than 48 hours [see Warnings and Precautions (5.11) and Use in Specific Populations (8.1) ]. Use of NSAIDS and Low-Dose Aspirin : Inform patients not to use low-dose aspirin concomitantly with COMBOGESIC until they talk to their healthcare provider [see Drug Interactions (7) ] .
Label text from the FDA structured product label by Hikma Pharmaceuticals USA Inc (revised Jan 14, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Acetaminophen in 5 products
- Ibuprofen in 5 products
Combogesic NDC products (5)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 72260-129 | Acetaminophen 325 mg/1; Ibuprofen 97.5 mg/1 Tablet, Film Coated | AFT Pharmaceuticals US, Inc. | NDA |
| 71335-3161 | Acetaminophen 325 mg/1; Ibuprofen 97.5 mg/1 Tablet, Film Coated | Bryant Ranch Prepack | NDA |
| 0143-9432 | Acetaminophen 325 mg/1; Ibuprofen 97.5 mg/1 Tablet, Film Coated | Hikma Pharmaceuticals USA Inc | NDA |
| 68788-4009 | Acetaminophen 325 mg/1; Ibuprofen 97.5 mg/1 Tablet, Film Coated | Preferred Pharmaceuticals Inc. | NDA |
| 68788-4181 | Acetaminophen 325 mg/1; Ibuprofen 97.5 mg/1 Tablet, Film Coated | Preferred Pharmaceuticals Inc. | NDA |
Frequently asked questions
What is Combogesic used for?
1 INDICATIONS AND USAGE COMBOGESIC is indicated in adults for the short-term management of mild to moderate acute pain. COMBOGESIC is a combination of acetaminophen and ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), and is indicated in adults for the short term management of mild to moderate acute pain ( 1 ).
What are the side effects of Combogesic?
The following clinically significant adverse reactions to ibuprofen or acetaminophen are described elsewhere in other sections of the labelling. Hepatotoxicity [see Warnings and Precautions (5.1) ] Cardiovascular Thrombotic Events [see Warnings and Precautions (5.2) ] Gastrointestinal Bleeding, Ulceration, and Perforation [see Warnings and Precautions (5.3) ] Hypertension [see Warnings and… See the full label for the complete list.
Who makes Combogesic?
Combogesic is listed by 4 labelers in the FDA NDC directory, including AFT Pharmaceuticals US, Inc., Bryant Ranch Prepack, Hikma Pharmaceuticals USA Inc, Preferred Pharmaceuticals Inc..