FENOPROFEN CALCIUM TABLETS, USP
600 mg

Fenoprofen calcium is a non-steroidal, anti-inflammatory, antiarthritic drug. Chemically, fenoprofen calcium is an arylacetic acid derivative. The structural formula is as follows:

Benzeneacetic acid, α-methyl-3-phenoxy-, calcium salt (2:1)-(±)-, dihydrate

Fenoprofen calcium, USP is a white, crystalline powder, soluble in alcohol (95%) to the extent of approximately 15 mg/mL at 25°C, slightly soluble in water, and insoluble in benzene. The pKa of fenoprofen calcium is 4.5 at 25°C.

Film-coated fenoprofen calcium tablets for oral administration are available containing fenoprofen calcium as the dihydrate equivalent to 600 mg of fenoprofen and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, pregelatinized starch, sodium lauryl sulfate, titanium dioxide and FD&C Yellow #6 Aluminum Lake.

Fenoprofen calcium is a non-steroidal, anti-inflammatory, antiarthritic drug that also possesses analgesic and antipyretic activities. Its exact mode of action is unknown, but it is thought that prostaglandin synthetase inhibition is involved. Fenoprofen has been shown to inhibit prostaglandin synthetase isolated from bovine seminal vesicles. Reproduction studies in rats have shown fenoprofen to be associated with prolonged labor and difficult parturition when given during late pregnancy. Evidence suggests that this may be due to decreased uterine contractility resulting from the inhibition of prostaglandin synthesis. Its action is not mediated through the adrenal gland.

Fenoprofen shows anti-inflammatory effects in rodents by inhibiting the development of redness and edema in acute inflammatory conditions and by reducing soft-tissue swelling and bone damage associated with chronic inflammation. It exhibits analgesic activity in rodents by inhibiting the writhing response caused by the introduction of an irritant into the peritoneal cavities of mice and by elevating pain thresholds to pressure in edematous hindpaws of rats. In rats made febrile by the subcutaneous administration of brewer's yeast, fenoprofen produces antipyretic action. These effects are characteristic of non-steroidal, antiinflammatory, antipyretic, analgesic drugs.

The results in humans confirmed the anti-inflammatory and analgesic actions found in animals. The emergence and degree of erythemic response were measured in adult male volunteers exposed to ultraviolet irradiation. The effects of fenoprofen, aspirin, and indomethacin were compared separately with those of a placebo. All 3 drugs demonstrated antierythemic activity.

In patients with rheumatoid arthritis, the anti-inflammatory action of fenoprofen has been evidenced by relief of pain; by increase in grip strength; by reductions in joint swelling, duration of morning stiffness and disease activity (as assessed by both the investigator and the patient); and by increased mobility (a decrease in the number of joints having limited motion).

The use of fenoprofen in combination with gold salts or corticosteroids has been studied in patients with rheumatoid arthritis. The studies, however, were inadequate in demonstrating whether further improvement is obtained by adding fenoprofen to maintenance therapy with gold salts or steroids. Whether or not fenoprofen, used in conjunction with partially effective doses of a corticosteroid, has a "steroid-sparing" effect is unknown.

In patients with osteoarthritis, the anti-inflammatory and analgesic effects of fenoprofen have been demonstrated by reduction in tenderness on pressure; relief of pain with motion and at rest; reductions in night pain, stiffness, swelling, and overall disease activity (as assessed by both the patient and the investigator); and increased range of motion in involved joints.

In patients with rheumatoid arthritis and osteoarthritis, clinical studies have shown fenoprofen to be comparable to aspirin in controlling the aforementioned measures of disease activity, but mild gastrointestinal adverse reactions (nausea, dyspepsia) and tinnitus occurred less frequently than in aspirin-treated patients. It is not known whether fenoprofen calcium causes less peptic ulceration than does aspirin.

In patients with pain, the analgesic action of fenoprofen has produced a reduction in pain intensity, an increase in pain relief, improvement in total analgesia scores, and a sustained analgesic effect.

Under fasting conditions, fenoprofen is rapidly absorbed, and peak plasma levels are achieved within 2 hours after oral administration. Good dose proportionality was observed between 200 mg and 600 mg doses in fasting male volunteers. The plasma half-life is approximately 3 hours. About 90% of a single oral dose is eliminated within 24 hours as fenoprofen glucuronide and 4'-hydroxy-fenoprofen glucuronide, the major urinary metabolites of fenoprofen. Fenoprofen is highly bound (99%) to albumin.

The concomitant administration of antacid (containing both aluminum and magnesium hydroxide) does not interfere with absorption of fenoprofen.

There is less suppression of collagen-induced platelet aggregation with single doses of fenoprofen calcium than there is with aspirin.

Carefully consider the potential benefits and risks of fenoprofen calcium tablets and other treatment options before deciding to use fenoprofen calcium tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see WARNINGS).

Fenoprofen calcium tablets are indicated for relief of the signs and symptoms of rheumatoid arthritis and osteoarthritis. It is recommended for the treatment of acute flares and exacerbations and for the long-term management of these diseases.

Fenoprofen is also indicated for the relief of mild to moderate pain.

Controlled trials are currently in progress to establish the safety and efficacy of fenoprofen in children.

Fenoprofen calcium tablet is contraindicated in patients with known hypersensitivity to fenoprofen calcium.

Fenoprofen should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic-like reactions to NSAIDs have been reported in such patients (see WARNINGS: Anaphylactoid Reactions, and PRECAUTIONS: Preexisting Asthma).

Fenoprofen is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

Since the safety of fenoprofen has not been established in patients with impaired hearing, these patients should have periodic tests of auditory function during prolonged therapy with fenoprofen.

Studies to date have not shown changes in the eyes attributable to the administration of fenoprofen. However, adverse ocular effects have been observed with other anti-inflammatory drugs. Eye examinations, therefore, should be performed if visual disturbances occur in patients taking fenoprofen.

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 non-steroidal 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 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.

No information is available from controlled clinical studies regarding the use of fenoprofen in patients with advanced renal disease. Therefore, treatment with fenoprofen is not recommended in these patients with advanced renal disease. If fenoprofen therapy must be initiated, close monitoring of the patient's renal function is advisable.

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to fenoprofen. Fenoprofen 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.

NSAIDs, including fenoprofen, 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.

In late pregnancy, as with other NSAIDs, fenoprofen should be avoided because it may cause premature closure of the ductus arteriosus.

Fenoprofen cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.

The pharmacological activity of fenoprofen in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.

Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including fenoprofen. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.

A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with fenoprofen. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), fenoprofen should be discontinued.

Anemia is sometimes seen in patients receiving NSAIDs, including fenoprofen. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including fenoprofen, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.

NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving fenoprofen who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.

Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm which can be fatal. Since cross reactivity, including bronchospasm, between aspirin and other non-steroidal anti-inflammatory drugs has been reported in such aspirin-sensitive patients, fenoprofen should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.

• Fenoprofen, like other NSAIDs, may cause serious CV side effects, such as MI or stroke, which may result in hospitalization and even death. Although serious CV events can occur without warning symptoms, patients should be alert for the signs and symptoms of chest pain, shortness of breath, weakness, slurring of speech, and should ask for medical advice when observing any indicative sign or symptoms. Patients should be apprised of the importance of this follow-up (see WARNINGS: Cardiovascular Effects).
• Fenoprofen, like other NSAIDs, can cause GI discomfort and, rarely, serious GI side effects, such as ulcers and bleeding, which may result in hospitalization and even death. Although serious GI tract ulcerations and bleeding can occur without warning symptoms, patients should be alert for the signs and symptoms of ulcerations and bleeding, and should ask for medical advice when observing any indicative sign or symptoms including epigastric pain, dyspepsia, melena, and hematemesis. Patients should be apprised of the importance of this follow-up (see WARNINGS: Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation).
• Fenoprofen, like other NSAIDs, can cause serious skin side effects such as exfoliative dermatitis, SJS, and TEN, which may result in hospitalizations and even death. Although serious skin reactions may occur without warning, patients should be alert for the signs and symptoms of skin rash and bulers, fever, or other signs of hypersensitivity such as itching, and should ask for medical advice when observing any indicative signs or symptoms. Patients should be advised to stop the drug immediately if they develop any type of rash and contact their physicians as soon as possible.
• Patients should promptly report signs or symptoms of unexplained weight gain or edema to their physicians.
• Patients should be informed of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If these occur, patients should be instructed to stop therapy and seek immediate medical therapy.
• Patients should be informed of the signs of an anaphylactoid reaction (e.g. difficulty breathing, swelling of the face or throat). If these occur, patients should be instructed to seek immediate emergency help (see WARNINGS).
• In late pregnancy, as with other NSAIDs, fenoprofen should be avoided because it will cause premature closure of the ductus arteriosus.

Because serious GI tract ulcerations and bleeding can occur without warning symptoms, physicians should monitor for signs or symptoms of GI bleeding. Patients on long-term treatment with NSAIDs, should have their CBC and a chemistry profile checked periodically. If clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash, etc.) or if abnormal liver tests persist or worsen, fenoprofen should be discontinued.

Amerlex-M kit assay values of total and free triiodothyronine in patients receiving fenoprofen have been reported as falsely elevated on the basis of a chemical cross-reaction that directly interferes with the assay. Thyroid-stimulating hormone, total thyroxine and thyrotropin-releasing hormone response are not affected.

In vitro studies have shown that fenoprofen, because of it's affinity for albumin, may displace from their binding sites other drugs that are also albumin bound, and this may lead to drug interaction. Theoretically, fenoprofen could likewise be displaced. Patients receiving hydantoins, sulfonamides, or sulfonylureas should be observed for increased activity of these drugs and, therefore, signs of toxicity from these drugs.

In rat studies with NSAIDs, as with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia, delayed parturition, and decreased pup survival occurred. The effects of fenoprofen on labor and delivery in pregnant women are unknown.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fenoprofen, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness in pediatric patients have not been established.

As with any NSAIDs, caution should be exercised in treating the elderly (65 years and older).

During clinical studies for rheumatoid arthritis or osteoarthritis, complaints were compiled from a checkul of potential adverse reactions, from which the following data emerged. These encompass observations in 3,391 patients, including 188 observed for at least 52 weeks. During short-term studies for analgesia, the incidence of adverse reactions was markedly lower than that seen in longer-term studies.

INCIDENCE LESS THAN 1%