These Highlights Do Not Include All The Information Needed To Use Combogesic Safely And Effectively. See Full Prescribing Information For Combogesic.

HEPATOTOXICITY

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 involve more than one acetaminophen-containing product [see Warnings and Precautions (5.1)].

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.

COMBOGESIC is a combination product. The clinical presentation of overdose may include the signs and symptoms of acetaminophen toxicity, ibuprofen toxicity, or both.

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 C₈H₉NO₂ 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 C₁₃H₁₈O₂ 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.

NSAIDs, including the ibuprofen in COMBOGESIC, 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.

The safety and effectiveness of COMBOGESIC in pediatric patients have not been established. COMBOGESIC is not approved for patients under 18 years of age.

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.

In a Phase 3 efficacy study in 110 patients (aged from 16 to 55 years, approximately two-thirds female, and more than 80% Caucasian) with post-procedural pain following surgical extraction of impacted wisdom teeth, three tablets of COMBOGESIC provided greater pain reduction than placebo or comparable doses of acetaminophen or ibuprofen alone. The treatment differences were measured by the primary end point.

The treatment differences in the time-adjusted Summed Pain Intensity Difference over the first 48 hours (SPID 0-48), are statistically significant as summarized in the table below.

The observed treatment differences over the first six hours are illustrated by the separation of pain curves as shown in Figure 1 below.

Figure 1: Pain Intensity Differences from baseline over the first dose interval of AFT-MX-6

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)].

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).

COMBOGESIC is indicated in adults for the short-term management of mild to moderate acute pain.

Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen therapy. 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 an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on COMBOGESIC, the possibility of its being related to ibuprofen should be considered.

COMBOGESIC has not been studied in patients with impaired renal function. The use of COMBOGESIC in patients with renal impairment is not recommended [see Warnings and Precautions (5.6)].

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 upon erythropoiesis. If a patient treated with COMBOGESIC has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including the ibuprofen in COMBOGESIC, 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) ].

• 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).

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.1, 5.3, 5.6) ].

COMBOGESIC contains acetaminophen and ibuprofen. Acetaminophen or NSAIDs, including ibuprofen, may cause serious skin adverse events such as exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of COMBOGESIC at the first appearance of skin rash or any other sign of hypersensitivity. COMBOGESIC is contraindicated in patients with previous serious skin reactions to acetaminophen or NSAIDs [see Contraindications (4) ].

COMBOGESIC has not been studied in patients with impaired hepatic function. The use of COMBOGESIC in patients with hepatic impairment is not recommended [see Warnings and Precautions (5.1)].

• 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.

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 in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If COMBOGESIC is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

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.

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).

Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported in patients receiving ibuprofen. If a patient develops such complaints while receiving COMBOGESIC, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing.

• 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).

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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:

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)].

The pharmacological activity of COMBOGESIC in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

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 is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4) ]. When COMBOGESIC is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

NSAIDs, including the ibuprofen in COMBOGESIC tablets, can 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 occur 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.

NDC 0143-9432-27

Rx only

combogesic^®

(acetaminophen and ibuprofen)

Tablets 325 mg/97.5 mg

250 Film-coated tablets

ATTENTION PHARMACIST: EACH PATIENT IS

REQUIRED TO RECEIVE THE MEDICATION GUIDE

PROVIDED SEPARATELY

hikma.

Studies to evaluate the potential effects of COMBOGESIC on carcinogenicity, mutagenicity, or impairment of fertility have not been conducted.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs, such as the ibuprofen in COMBOGESIC. 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 and evaluate the patient immediately.

WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK AND GASTROINTESTINAL RISK

See full prescribing information for complete boxed warning.

• COMBOGESIC 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 4,000 milligrams per day, and often involve more than one acetaminophen containing product (5.1).
• Nonsteroidal anti-inflammatory drugs (NSAIDS), like the ibuprofen in COMBOGESIC, 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 (5.2).
• COMBOGESIC tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (5.2).
• NSAIDS, like the ibuprofen in COMBOGESIC, 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.3).

HEPATOTOXICITY

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 involve more than one acetaminophen-containing product [see Warnings and Precautions (5.1)].

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.

COMBOGESIC is a combination product. The clinical presentation of overdose may include the signs and symptoms of acetaminophen toxicity, ibuprofen toxicity, or both.

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 C₈H₉NO₂ 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 C₁₃H₁₈O₂ 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.

NSAIDs, including the ibuprofen in COMBOGESIC, 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.

The safety and effectiveness of COMBOGESIC in pediatric patients have not been established. COMBOGESIC is not approved for patients under 18 years of age.

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.

In a Phase 3 efficacy study in 110 patients (aged from 16 to 55 years, approximately two-thirds female, and more than 80% Caucasian) with post-procedural pain following surgical extraction of impacted wisdom teeth, three tablets of COMBOGESIC provided greater pain reduction than placebo or comparable doses of acetaminophen or ibuprofen alone. The treatment differences were measured by the primary end point.

The treatment differences in the time-adjusted Summed Pain Intensity Difference over the first 48 hours (SPID 0-48), are statistically significant as summarized in the table below.

The observed treatment differences over the first six hours are illustrated by the separation of pain curves as shown in Figure 1 below.

Figure 1: Pain Intensity Differences from baseline over the first dose interval of AFT-MX-6

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)].

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).

COMBOGESIC is indicated in adults for the short-term management of mild to moderate acute pain.

Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen therapy. 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 an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on COMBOGESIC, the possibility of its being related to ibuprofen should be considered.

COMBOGESIC has not been studied in patients with impaired renal function. The use of COMBOGESIC in patients with renal impairment is not recommended [see Warnings and Precautions (5.6)].

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 upon erythropoiesis. If a patient treated with COMBOGESIC has any signs or symptoms of anemia, monitor hemoglobin or hematocrit.

NSAIDs, including the ibuprofen in COMBOGESIC, 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) ].

• 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).

Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions (5.1, 5.3, 5.6) ].

COMBOGESIC contains acetaminophen and ibuprofen. Acetaminophen or NSAIDs, including ibuprofen, may cause serious skin adverse events such as exfoliative dermatitis, acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. NSAIDs can also cause fixed drug eruption (FDE). FDE may present as a more severe variant known as generalized bullous fixed drug eruption (GBFDE), which can be life-threatening. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions and to discontinue the use of COMBOGESIC at the first appearance of skin rash or any other sign of hypersensitivity. COMBOGESIC is contraindicated in patients with previous serious skin reactions to acetaminophen or NSAIDs [see Contraindications (4) ].

COMBOGESIC has not been studied in patients with impaired hepatic function. The use of COMBOGESIC in patients with hepatic impairment is not recommended [see Warnings and Precautions (5.1)].

• 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.

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 in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If COMBOGESIC is used in patients with severe heart failure, monitor patients for signs of worsening heart failure.

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.

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).

Blurred and/or diminished vision, scotomata, and/or changes in color vision have been reported in patients receiving ibuprofen. If a patient develops such complaints while receiving COMBOGESIC, the drug should be discontinued, and the patient should have an ophthalmologic examination which includes central visual fields and color vision testing.

• 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).

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.

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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:

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)].

The pharmacological activity of COMBOGESIC in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.

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 is contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4) ]. When COMBOGESIC is used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.

NSAIDs, including the ibuprofen in COMBOGESIC tablets, can 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 occur 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.

NDC 0143-9432-27

Rx only

combogesic^®

(acetaminophen and ibuprofen)

Tablets 325 mg/97.5 mg

250 Film-coated tablets

ATTENTION PHARMACIST: EACH PATIENT IS

REQUIRED TO RECEIVE THE MEDICATION GUIDE

PROVIDED SEPARATELY

hikma.

Studies to evaluate the potential effects of COMBOGESIC on carcinogenicity, mutagenicity, or impairment of fertility have not been conducted.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported in patients taking NSAIDs, such as the ibuprofen in COMBOGESIC. 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 and evaluate the patient immediately.

WARNING: HEPATOTOXICITY, CARDIOVASCULAR RISK AND GASTROINTESTINAL RISK

See full prescribing information for complete boxed warning.

• COMBOGESIC 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 4,000 milligrams per day, and often involve more than one acetaminophen containing product (5.1).
• Nonsteroidal anti-inflammatory drugs (NSAIDS), like the ibuprofen in COMBOGESIC, 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 (5.2).
• COMBOGESIC tablets are contraindicated in the setting of coronary artery bypass graft (CABG) surgery (5.2).
• NSAIDS, like the ibuprofen in COMBOGESIC, 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 and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.3).