FDA label 296775de-dbce-4fe0-bd83-b682134b57ca

Cardiovascular Risk • NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction (MI), 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 ). • Orudis and Oruvail are contraindicated for the 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 (GI) 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 Orudis and Oruvail, 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 Orudis and Oruvail, 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. Peripheral edema has been observed in approximately 2% of patients taking ketoprofen. Orudis and Oruvail should be used with caution in patients with fluid retention or heart failure. Gastrointestinal Effects: Risk of Ulceration, Bleeding and Perforation NSAIDs, including Orudis and Oruvail, 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 to 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 with neither of these risk factors. Other factors that increase the risk for 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 ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse 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 nonsteroidal anti-inflammatory drug may cause a dose-dependent reduction in prostaglandin formation and, secondarily, in renal blood flow, which may precipitate overt renal decompensation. Patients at greater 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. Advanced Renal Disease No information is available from controlled clinical studies regarding the use of Orudis or Oruvail in patients with advanced renal disease. Therefore, treatment with Orudis or Oruvail is not recommended in these patients with advanced renal disease. If Orudis or Oruvail therapy must be initiated, close monitoring of the patient's renal function is advisable. Anaphylactoid Reactions As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Orudis or Oruvail. Orudis or Oruvail should not be given to patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs (see CONTRAINDICATIONS and PRECAUTIONS – Preexisting Asthma ). Emergency help should be sought in cases where an anaphylactoid reaction occurs. Skin Reactions NSAIDs, including Orudis and Oruvail, can cause serious skin adverse events such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Patients should be informed about the signs and symptoms of serious skin manifestations and use of the drug should be discontinued at the first appearance of skin rash or any other sign of hypersensitivity. Pregnancy In late pregnancy, as with other NSAIDs, Orudis and Oruvail should be avoided because they may cause premature closure of the ductus arteriosus.

ADVERSE REACTIONS The incidence of common adverse reactions (above 1%) was obtained from a population of 835 Orudis-treated patients in double-blind trials lasting from 4 to 54 weeks and in 622 Oruvail-treated (200 mg/day) patients in trials lasting from 4 to 16 weeks. Minor gastrointestinal side effects predominated; upper gastrointestinal symptoms were more common than lower gastrointestinal symptoms. In crossover trials in 321 patients with rheumatoid arthritis or osteoarthritis, there was no difference in either upper or lower gastrointestinal symptoms between patients treated with 200 mg of Oruvail (ketoprofen) once a day or 75 mg of Orudis (ketoprofen) TID (225 mg/day). Peptic ulcer or GI bleeding occurred in controlled clinical trials in less than 1% of 1,076 patients; however, in open label continuation studies in 1,292 patients the rate was greater than 2%. The incidence of peptic ulceration in patients on NSAIDs is dependent on many risk factors including age, sex, smoking, alcohol use, diet, stress, concomitant drugs such as aspirin and corticosteroids, as well as the dose and duration of treatment with NSAIDs (see “ WARNINGS ” ). Gastrointestinal reactions were followed in frequency by central nervous system side effects, such as headache, dizziness, or drowsiness. The incidence of some adverse reactions appears to be dose-related (see “ DOSAGE AND ADMINISTRATION ” ). Rare adverse reactions (incidence less than 1%) were collected from one or more of the following sources: foreign reports to manufacturers and regulatory agencies, publications, U.S. clinical trials, and/or U.S. postmarketing spontaneous reports. Reactions are listed below under body system, then by incidence or number of cases in decreasing incidence. Incidence Greater than 1% (Probable Causal Relationship) Digestive: Dyspepsia (11%), nausea*, abdominal pain*, diarrhea*, constipation*, flatulence*, anorexia, vomiting, stomatitis. Nervous System: Headache*, dizziness, CNS inhibition (i.e., pooled reports of somnolence, malaise, depression, etc.) or excitation (i.e., insomnia, nervousness, dreams, etc.)*. Special Senses: Tinnitus, visual disturbance. Skin and Appendages: Rash. Urogenital: Impairment of renal function (edema, increased BUN)*, signs or symptoms of urinary-tract irritation. * Adverse events occurring in 3 to 9% of patients. Incidence Less than 1% (Probable Causal Relationship) Body as a Whole: Chills, facial edema, infection, pain, allergic reaction, anaphylaxis. Cardiovascular: Hypertension, palpitation, tachycardia, congestive heart failure, peripheral vascular disease, vasodilation. Digestive: Appetite increased, dry mouth, eructation, gastritis, rectal hemorrhage, melena, fecal occult blood, salivation, peptic ulcer, gastrointestinal perforation, hematemesis, intestinal ulceration, hepatic dysfunction, hepatitis, cholestatic hepatitis, jaundice. Hemic: Hypocoagulability, agranulocytosis, anemia, hemolysis, purpura, thrombocytopenia. Metabolic and Nutritional: Thirst, weight gain, weight loss, hyponatremia. Musculoskeletal: Myalgia. Nervous System: Amnesia, confusion, impotence, migraine, paresthesia, vertigo. Respiratory: Dyspnea, hemoptysis, epistaxis, pharyngitis, rhinitis, bronchospasm, laryngeal edema. Skin and Appendages: Alopecia, eczema, pruritus, purpuric rash, sweating, urticaria, bullous rash, exfoliative dermatitis, photosensitivity, skin discoloration, onycholysis, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome. Special Senses: Conjunctivitis, conjunctivitis sicca, eye pain, hearing impairment, retinal hemorrhage and pigmentation change, taste perversion. Urogenital: Menometrorrhagia, hematuria, renal failure, interstitial nephritis, nephrotic syndrome. Incidence Less than 1% (Causal Relationship Unknown) The following rare adverse reactions, whose causal relationship to ketoprofen is uncertain, are being listed to serve as alerting information to the physician. Body as a Whole: Septicemia, shock. Cardiovascular: Arrhythmias, myocardial infarction. Digestive: Buccal necrosis, ulcerative colitis, microvesicular steatosis, pancreatitis. Endocrine: Diabetes mellitus (aggravated). Nervous System: Dysphoria, hallucination, libido disturbance, nightmares, personality disorder, aseptic meningitis. Urogenital: Acute tubulopathy, gynecomastia.