Fenoprofen

1 INDICATIONS AND USAGE Fenoprofen calcium is indicated for: • Relief of mild to moderate pain in adults • Relief of the signs and symptoms of rheumatoid arthritis • Relief of the signs and symptoms of osteoarthritis Fenoprofen calcium is a nonsteroidal anti-inflammatory drug indicated for: • Relief of mild to moderate pain in adults. ( 1 ) • Relief of the signs and symptoms of rheumatoid arthritis. ( 1 ) • Relief of the signs and symptoms of osteoarthritis. ( 1 )

12.1 Mechanism of Action Fenoprofen has analgesic, anti-inflammatory, and antipyretic properties. The mechanism of action of fenoprofen calcium, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase (COX-1 and COX-2). Fenoprofen is a potent inhibitor of prostaglandin synthesis in vitro . Fenoprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because fenoprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.

2 DOSAGE AND ADMINISTRATION • Use the lowest effective dosage for shortest duration consistent with individual patient treatment goals ( 2.1 ) • Analgesia: For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed ( 2.1 ) • Rheumatoid Arthritis and Osteoarthritis: For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3,200 mg. 2.1 General Dosing Instructions Carefully consider the potential benefits and risks of fenoprofen calcium and other treatment options before deciding to use fenoprofen. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals. Use lowest effective dosage for the shortest duration consistent with individual patient treatment goals [ see Warnings and Precautions ( 5 ) ]. Fenoprofen calcium may be administered with meals or with milk. Although the total amount absorbed is not affected, peak blood levels are delayed and diminished. Patients with rheumatoid arthritis generally seem to require larger doses of fenoprofen calcium than do those with osteoarthritis. The smallest dose that yields acceptable control should be employed. Although improvement may be seen in a few days in many patients, an additional 2 to 3 weeks may be required to gauge the full benefits of therapy. 2.2 Analgesia For the treatment of mild to moderate pain, the recommended dosage is 200 mg given orally every 4 to 6 hours, as needed. 2.3 Rheumatoid Arthritis and Osteoarthritis For the relief of signs and symptoms of rheumatoid arthritis or osteoarthritis the recommended dose is 400 to 600 mg given orally, 3 or 4 times a day. The dose should be tailored to the needs of the patient and may be increased or decreased depending on the severity of the symptoms. Dosage adjustments may be made after initiation of drug therapy or during exacerbations of the disease. Total daily dosage should not exceed 3,200 mg.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: •Cardiovascular Thrombotic Events [ see Warnings and Precautions ( 5.1 ) ] •GI Bleeding, Ulceration and Perforation [ see Warnings and Precautions ( 5.2 ) ] •Hepatotoxicity [ 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 ) ] •Anaphylactic Reactions [ see Warnings and Precautions ( 5.7 ) ] •Serious Skin Reactions [ see Warnings and Precautions ( 5.9 ) ] •Hematologic Toxicity [ see Warnings and Precautions ( 5.12 ) ] Most common adverse reactions (incidence ≥ 5%) are Dyspepsia, headache, somnolence, nausea, dizziness, constipation, nervousness, asthenia, and peripheral edema.( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ( 6 ) 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. During clinical studies for rheumatoid arthritis, osteoarthritis, or mild to moderate pain and studies of pharmacokinetics, complaints were compiled from a checklist of potential adverse reactions, and the following data emerged. These encompass observations in 6,786 patients, including 188 observed for at least 52 weeks. For comparison, data are also presented from complaints received from the 266 patients who received placebo in these same trials. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies. Adverse Drug Reactions Reported in >1% of Patients During Clinical Trials Digestive System — During clinical trials with fenoprofen calcium, the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving fenoprofen calcium as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% fenoprofen calcium vs. 2.3% placebo), nausea (7.7% vs. 7.1%), constipation (7% vs. 1.5%), vomiting (2.6% vs. 1.9%), abdominal pain (2% vs. 1.1%), and diarrhea (1.8% vs. 4.1%). The drug was discontinued because of adverse gastrointestinal reactions in less than 2% of patients during premarketing studies. Nervous System — The most frequent adverse neurologic reactions were headache (8.7% vs. 7.5%) and somnolence (8.5% vs. 6.4%). Dizziness (6.5% vs. 5.6%), tremor (2.2% vs. 0.4%), and confusion (1.4% vs. none) were noted less frequently. Fenoprofen calcium was discontinued in less than 0.5% of patients because of these side effects during premarketing studies. Skin and Appendages — Increased sweating (4.6% vs. 0.4%), pruritus (4.2% vs. 0.8%), and rash (3.7% vs. 0.4%) were reported. Fenoprofen calcium was discontinued in about 1% of patients because of an adverse effect related to the skin during premarketing studies. Special Senses — Tinnitus (4.5% vs. 0.4%), blurred vision (2.2% vs. none), and decreased hearing (1.6% vs. none) were reported. Fenoprofen calcium was discontinued in less than 0.5% of patients because of adverse effects related to the special senses during premarketing studies. Cardiovascular — Palpitations (2.5% vs. 0.4%). Fenoprofen calcium was discontinued in about 0.5% of patients because of adverse cardiovascular reactions during premarketing studies. Miscellaneous — Nervousness (5.7% vs. 1.5%), asthenia (5.4% vs. 0.4%), peripheral edema (5.0% vs. 0.4%), dyspnea (2.8% vs. none), fatigue (1.7% vs. 1.5%), upper respiratory infection (1.5% vs. 5.6%), and nasopharyngitis (1.2% vs. none). Adverse Drug Reactions Reported in <1% of Patients Duri

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity: Inform patients of warning signs and symptoms of hepatotoxicity. Discontinue if abnormal liver tests persist or worsen or if clinical signs and symptoms of liver disease develop ( 5.3 ) • Hypertension: Patients taking some antihypertensive medications may have impaired response to these therapies when taking NSAIDs. Monitor blood pressure ( 5.4 , 7 ) • Heart Failure and Edema: Avoid use of fenoprofen calcium in patients with severe heart failure unless benefits are expected to outweigh risk of worsening heart failure ( 5.5 ) • Renal Toxicity: Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia. Avoid use of fenoprofen calcium in patients with advanced renal disease unless benefits are expected to outweigh risk of worsening renal function ( 5.6 ) • Anaphylactic Reactions: Seek emergency help if an anaphylactic reaction occurs ( 5.7 ) • Exacerbation of Asthma Related to Aspirin Sensitivity: Fenoprofen calcium is contraindicated in patients with aspirin-sensitive asthma. Monitor patients with preexisting asthma (without aspirin sensitivity) ( 5.8 ) • Serious Skin Reactions: Discontinue fenoprofen calcium 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 NSAIDs, including fenoprofen calcium, between about 20 to 30 weeks in pregnancy due to the risk of oligohydramnios/fetal renal dysfunction. Avoid use of NSAIDs 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 , 8.1 ) • Hematologic Toxicity: Monitor hemoglobin or hematocrit in patients with any signs or symptoms of anemia ( 5.12 , 7 ) 5.1 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 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 fenoprofen, increases the risk of serious gastrointestinal (GI) events [ see Warnings and Precautions ( 5.2 ) ]. 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 to 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 conduc

4 CONTRAINDICATIONS Fenoprofen calcium is contraindicated in the following patients: • Known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to fenoprofen or any components of the drug product [ see Warnings and Precautions ( 5.7 , 5.9 ) ] • 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 [ see Warnings and Precautions ( 5.7 , 5.8 ) ] • In the setting of coronary artery bypass graft (CABG) surgery [ see Warnings and Precautions ( 5.1 ) ] • Known hypersensitivity to fenoprofen or any components of the drug product ( 4 ) • History of asthma, urticaria, or other allergic-type reactions after taking aspirin or other NSAIDs ( 4 ) • In the setting of CABG surgery ( 4 )

10 OVERDOSAGE 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 , 5.4, 5.6) ]. Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. 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 osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding. For additional information about overdosage treatment contact a poison control center (1-800-222-1222).