FENOPRON TM FENOPROFEN CALCIUM 300 mg Capsule, 100-count

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 )

5.1Cardiovascular 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 conducted in the D…

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.

To report SUSPECTED ADVERSE REACTIONS, contact Galt Pharmaceuticals, LLC at 1-855-965-2783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch ( 6 )

6.1Clinical 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 FENOPRON TM , the most common adverse reactions were gastrointestinal in nature and occurred in 20.8% of patients receiving FENOPRON TM as compared to 16.9% of patients receiving placebo. In descending order of frequency, these reactions included dyspepsia (10.3% FENOPRON TM 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.

FENOPRON TM 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. FENOPRON TM 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. FENOPRON TM 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%). FENOPRON TM 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 During Clinical Trials Digestive System —Gastritis, peptic ulcer with/without perforation, gastr…

7 DRUG INTERACTIONS See Table 1 for clinically significant drug interactions with fenoprofen. Table 1: Clinically Significant Drug Interactions with Fenoprofen Drugs That Interfere with Hemostasis Clinical Impact: Fenoprofen and anticoagulants such as warfarin have a synergistic effect on bleeding. The concomitant use of fenoprofen 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 FENOPRON TM 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 (5.2) ] . Intervention: Concomitant use of FENOPRON TM and analgesic doses of aspirin is not generally recommended because of the increased risk of bleeding [see Warnings and Precautions (5.12) ] .

FENOPRON TM 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 FENOPRON TM and ACE-inhibitors, ARBs, or beta-blockers, monitor blood pressure to ensure that the desired blood pressure is obtained. During concomitant use of FENOPRON TM , 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 FENOPRON TM with diuretics, observe patients for signs of worsening renal function, in addition to assuring diuretic efficacy including antihypertensive effects [see Warnings and Precautions (5.6) ] . Digoxin Clinical Impact: The concomitant use of fenoprofen with digoxin has been reported to increase the serum concentration and prolong the half-life of digoxin.

Intervention: During concomitant use of FENOPRON TM 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: Du…