FDA label 45f02695-cdf9-3cb2-e054-00144ff88e88

Cardiovascular Risk NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk (See WARNINGS ). Ibuprofen tablets are contraindicated for treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS ). Gastrointestinal Risk NSAIDS cause an increased risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events (see WARNINGS ).

WARNINGS

Cardiovascular Effects 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, myocardial infarction, and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, the lowest effective dose should be used for the shortest duration possible. Physicians and patients should remain alert for the development of such events, 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 does increase the risk of serious GI events (see WARNINGS, Gastrointestinal Effects-Risk of Ulceration, Bleeding, and Perforation ). 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 (see CONTRAINDICATIONS ). Hypertension NSAIDs including ibuprofen tablets, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Patients taking thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. NSAIDs, including ibuprofen tablets, should be used with caution in patients with hypertension. Blood pressure (BP) should be monitored closely during the initiation of NSAID treatment and throughout the course of therapy. Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Ibuprofen tablets should be used with caution in patients with fluid retention or heart failure.

Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation NSAIDs, including ibuprofen tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the 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. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk. NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to patients treated with neither of these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high-risk patients, alternate therapies that do not involve NSAIDs should be considered.

Renal Effects Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

ADVERSE REACTIONS The most frequent type of adverse reaction occurring with ibuprofen tablets is gastrointestinal. In controlled clinical trials the percentage of patients reporting one or more gastrointestinal complaints ranged from 4% to 16%. In controlled studies when ibuprofen tablets were compared to aspirin and indomethacin in equally effective doses, the overall incidence of gastrointestinal complaints was about half that seen in either the aspirin- or indomethacin-treated patients. Adverse reactions observed during controlled clinical trials at an incidence greater than 1% are listed in the table. Those reactions listed in Column one encompass observations in approximately 3,000 patients. More than 500 of these patients were treated for periods of at least 54 weeks. Still other reactions occurring less frequently than 1 in 100 were reported in controlled clinical trials and from marketing experience. These reactions have been divided into two categories: Column two of the table lists reactions with therapy with ibuprofen tablets where the probability of a causal relationship exists: for the reactions in Column three, a causal relationship with ibuprofen tablets has not been established. Reported side effects were higher at doses of 3200 mg/day than at doses of 2400 mg or less per day in clinical trials of patients with rheumatoid arthritis. The increases in incidence were slight and still within the ranges reported in the table. Incidence Greater than 1% (but less than 3%) Probable Causal Relationship Unknown* Precise Incidence Unknown (but less than 1%) Probable Causal Relationship* Precise Incidence Unknown (but less than 1%) Causal Relationship GASTROINTESTINAL Nausea†, epigastric pain†, heartburn†, diarrhea, abdominal distress, nausea and vomiting, indigestion, constipation, abdominal cramps or Pain, fullness of GI tract (bloating and flatulence) Gastric or duodenal ulcer with bleeding and/or perforation, gastrointestinal hemorrhage, melena, gastritis, hepatitis, jaundice, abnormal liver function tests; pancreatitis CENTRAL NERVOUS SYSTEM Dizziness†, headache, nervousness Depression, insomnia, confusion, emotional lability, somnolence, aseptic meningitis with fever and coma (see PRECAUTIONS ) Paresthesias, hallucinations, dream abnormalities, pseudo-tumor cerebri DERMATOLOGIC Rash† (including maculopapular type), pruritus Vesiculobullous eruptions, urticaria, erythema multiforme, Stevens-Johnson syndrome, alopecia Toxic epidermal necrolysis, photoallergic skin reactions SPECIAL SENSES Tinnitus Hearing loss, amblyopia (blurred and/or diminished vision, scotomata and/or changes in color vision) (see PRECAUTIONS ) Conjunctivitis, diplopia, optic neuritis, cataracts HEMATOLOGIC Neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (sometimes Coombs positive), thrombocytopenia with or without purpura, eosinophilia, decreases in hemoglobin and hematocrit (see PRECAUTIONS ) Bleeding episodes (eg epistaxis, menorrhagia) METABOLIC/ENDOCRINE Decreased appetite Gynecomastia, hypoglycemic reaction, acidosis CARDIOVASCULAR Edema, fluid retention (generally responds promptly to drug discontinuation) (see PRECAUTIONS ) Congestive heart failure in patients with marginal cardiac function, elevated blood pressure, palpitations Arrhythmias (sinus tachycardia, sinus bradycardia) ALLERGIC Syndrome of abdominal pain, fever, chills, nausea and vomiting; anaphylaxis; bronchospasm (see CONTRAINDICATIONS ) Serum sickness, lupuserythematosus syndrome. Henoch-Schonlein vasculitis, angioedema RENAL Acute renal failure (see PRECAUTIONS ), decreased creatinine clearance, polyuria, azotemia, cystitis, Hematuria Renal papillary necrosis MISCELLANEOUS Dry eyes and mouth, gingival ulcer, rhinitis * Reactions are classified under “Probable Causal Relationship (PCR)” if there has been one positive rechallenge or if three or more cases occur which might be causally related. Reactions are classified under “Causal Relationship Unknown” if seven or more events have been reported but the criteria for PCR have not been met. † Reactions occurring in 3% to 9% of patients treated with ibuprofen tablets. (Those reactions occurring in less than 3% of the patients are unmarked).

<table ID="i94d56b10-ce92-45c9-8996-dcdc65703d06" border="2" width="100%"> <col width="32%"/> <col width="36%"/> <col width="32%"/> <tbody> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Incidence Greater than 1% (but less than 3%) Probable Causal Relationship Unknown* </content> </td> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Precise Incidence Unknown (but less than 1%) Probable Causal Relationship* </content> </td> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">Precise Incidence Unknown (but less than 1%) Causal Relationship </content> </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">GASTROINTESTINAL</content> Nausea&#x2020;, epigastric pain&#x2020;, heartburn&#x2020;, diarrhea, abdominal distress, nausea and vomiting, indigestion, constipation, abdominal cramps or Pain, fullness of GI tract (bloating and flatulence) </td> <td styleCode="Lrule Rrule" valign="top"> Gastric or duodenal ulcer with bleeding and/or perforation, gastrointestinal hemorrhage, melena, gastritis, hepatitis, jaundice, abnormal liver function tests; pancreatitis </td> <td valign="top"> </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">CENTRAL NERVOUS SYSTEM</content> Dizziness&#x2020;, headache, nervousness </td> <td styleCode="Lrule Rrule" valign="top"> Depression, insomnia, confusion, emotional lability, somnolence, aseptic meningitis with fever and coma (see <content styleCode="bold"> <linkHtml href="#s16">PRECAUTIONS</linkHtml> </content>) </td> <td styleCode="Lrule Rrule" valign="top"> Paresthesias, hallucinations, dream abnormalities, pseudo-tumor cerebri </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">DERMATOLOGIC</content> Rash&#x2020; (including maculopapular type), pruritus </td> <td styleCode="Lrule Rrule" valign="top"> Vesiculobullous eruptions, urticaria, erythema multiforme, Stevens-Johnson syndrome, alopecia </td> <td styleCode="Lrule Rrule" valign="top"> Toxic epidermal necrolysis, photoallergic skin reactions </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">SPECIAL SENSES</content> Tinnitus </td> <td styleCode="Lrule Rrule" valign="top"> Hearing loss, amblyopia (blurred and/or diminished vision, scotomata and/or changes in color vision) (see <content styleCode="bold"> <linkHtml href="#s16">PRECAUTIONS</linkHtml> </content>) </td> <td styleCode="Lrule Rrule" valign="top"> Conjunctivitis, diplopia, optic neuritis, cataracts </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">HEMATOLOGIC</content> </td> <td styleCode="Lrule Rrule" valign="top"> Neutropenia, agranulocytosis, aplastic anemia, hemolytic anemia (sometimes Coombs positive), thrombocytopenia with or without purpura, eosinophilia, decreases in hemoglobin and hematocrit (see <content styleCode="bold"> <linkHtml href="#s16">PRECAUTIONS</linkHtml> </content>) </td> <td styleCode="Lrule Rrule" valign="top"> Bleeding episodes (eg epistaxis, menorrhagia) </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">METABOLIC/ENDOCRINE</content> Decreased appetite </td> <td styleCode="Lrule Rrule" valign="top"> </td> <td styleCode="Lrule Rrule" valign="top"> Gynecomastia, hypoglycemic reaction, acidosis </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">CARDIOVASCULAR</content> Edema, fluid retention (generally responds promptly to drug discontinuation) (see <content styleCode="bold"> <linkHtml href="#s16">PRECAUTIONS</linkHtml> </content>) </td> <td styleCode="Lrule Rrule" valign="top"> Congestive heart failure in patients with marginal cardiac function, elevated blood pressure, palpitations </td> <td styleCode="Lrule Rrule" valign="top"> Arrhythmias (sinus tachycardia, sinus bradycardia) </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">ALLERGIC</content> </td> <td styleCode="Lrule Rrule" valign="top"> Syndrome of abdominal pain, fever, chills, nausea and vomiting; anaphylaxis; bronchospasm (see <content styleCode="bold"> <linkHtml href="#s5">CONTRAINDICATIONS</linkHtml> </content>) </td> <td styleCode="Lrule Rrule" valign="top"> Serum sickness, lupuserythematosus syndrome. Henoch-Schonlein vasculitis, angioedema </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">RENAL</content> </td> <td styleCode="Lrule Rrule" valign="top"> Acute renal failure (see <content styleCode="bold"> <linkHtml href="#s16">PRECAUTIONS</linkHtml> </content>), decreased creatinine clearance, polyuria, azotemia, cystitis, Hematuria </td> <td styleCode="Lrule Rrule" valign="top"> Renal papillary necrosis </td> </tr> <tr> <td styleCode="Lrule Rrule" valign="top"> <content styleCode="bold">MISCELLANEOUS</content> </td> <td styleCode="Lrule Rrule" valign="top"> Dry eyes and mouth, gingival ulcer, rhinitis </td> <td styleCode="Lrule Rrule"> </td> </tr> <tr> <td colspan="3"> <paragraph styleCode="Footnote"> ^*Reactions are classified under &#x201C;Probable Causal Relationship (PCR)&#x201D; if there has been one positive rechallenge or if three or more cases occur which might be causally related. Reactions are classified under &#x201C;Causal Relationship Unknown&#x201D; if seven or more events have been reported but the criteria for PCR have not been met. </paragraph> <paragraph styleCode="Footnote"> ^&#x2020;Reactions occurring in 3% to 9% of patients treated with ibuprofen tablets. (Those reactions occurring in less than 3% of the patients are unmarked). </paragraph> </td> </tr> </tbody> </table>