Combogesic

Warnings and Precautions ( 5.9 ) 11/2024

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 ).

2 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 ).

3 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 ).

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 ).

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 (5.1) ] • 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 AFT Pharmaceuticals US, Inc at 01-248-631-4810 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).

7 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 pati …

8 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 ca …

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.

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

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.

16 HOW SUPPLIED/STORAGE AND HANDLING 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 71335-3161-1: 30 Tablets in a BOTTLE NDC 71335-3161-2: 60 Tablets in a BOTTLE NDC 71335-3161-3: 90 Tablets in a BOTTLE NDC 71335-3161-4: 120 Tablets in a BOTTLE 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. Repackaged/Relabeled by: Bryant Ranch Prepack Burbank, CA 91504