FLURBIPROFEN

STAT Rx USA LLC

FULL PRESCRIBING INFORMATION

The mean oral bioavailability of flurbiprofen 100 mg tablets is 96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed with peak plasma concentrations occurring at about 2 hours (see Table 1). Administration of flurbiprofen with either food or antacids may alter the rate but not the extent of flurbiprofen absorption. Ranitidine has been shown to have no effect on either the rate or extent of flurbiprofen absorption.

The apparent volume of distribution (Vz/F) of both R- and S-flurbiprofen is approximately 0.12 L/Kg. Both flurbiprofen enantiomers are more than 99% bound to plasma proteins, primarily albumin. Plasma protein binding is relatively constant for the typical average steady-state concentrations (≤ 10 mcg/mL) achieved with recommended doses. Flurbiprofen is poorly excreted into human milk. The nursing infant dose is predicted to be approximately 0.1 mg/day in the established milk of a woman taking flurbiprofen 200 mg/day (see PRECAUTIONS: Nursing Mothers).

Flurbiprofen plasma protein binding may be decreased in patients with liver disease and serum albumin concentrations below 3.1 g/dL (see PRECAUTIONS: General: Hepatic Effects).

Renal clearance is an important route of elimination for flurbiprofen metabolites, but a minor route of elimination for unchanged flurbiprofen (≤ 3% of total clearance). The unbound clearances of R- and S-flurbiprofen did not differ significantly between normal healthy volunteers (N = 6, 50 mg single dose) and patients with renal impairment (N = 8, inulin clearances ranging from 11 to 43 mL/min, 50 mg multiple doses). Flurbiprofen plasma protein binding may be decreased in patients with renal impairment and serum albumin concentrations below 3.9 g/dL. Elimination of flurbiprofen metabolites may be reduced in patients with renal impairment (see PRECAUTIONS: General: Renal Effects).

Flurbiprofen is not significantly removed from the blood into dialysate in patients undergoing continuous ambulatory peritoneal dialysis.

(see also PRECAUTIONS: Drug Interactions)

Concurrent administration of flurbiprofen and aspirin resulted in 50% lower serum flurbiprofen concentrations. This effect of aspirin (which is also seen with other non-steroidal anti-inflammatory drugs) has been demonstrated in patients with rheumatoid arthritis (n = 15) and in healthy volunteers (n = 16) (see PRECAUTIONS: Drug Interactions).

The effect of flurbiprofen on blood pressure response to propranolol and atenolol was evaluated in men with mild uncomplicated hypertension (n = 10). Flurbiprofen pretreatment attenuated the hypotensive effect of a single dose of propranolol but not atenolol. Flurbiprofen did not appear to affect the beta-blocker-mediated reduction in heart rate. Flurbiprofen did not affect the pharmacokinetic profile of either drug (see PRECAUTIONS: Drug Interactions).

Studies in healthy volunteers have shown that, like other non-steroidal anti-inflammatory drugs, flurbiprofen can interfere with the effects of furosemide. Although results have varied from study to study, effects have been shown on furosemide-stimulated diuresis, natriuresis, and kaliuresis. Other non-steroidal anti-inflammatory drugs that inhibit prostaglandin synthesis have been shown to interfere with thiazide and potassium-sparing diuretics (see PRECAUTIONS: Drug Interactions).

In a study of 11 women with bipolar disorder receiving lithium carbonate at a dosage of 600 mg to 1200 mg/day, administration of 100 mg flurbiprofen every 12 hours increased plasma lithium concentrations by 19%. Four of 11 patients experienced a clinically important increase (> 25% or > 0.2 mmol/L). Non-steroidal anti-inflammatory drugs have also been reported to decrease the renal clearance of lithium by about 20% (see PRECAUTIONS: Drug Interactions).

Uses

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

Flurbiprofen tablets are indicated:

• For relief of the signs and symptoms of rheumatoid arthritis.
• For relief of the signs and symptoms of osteoarthritis.

Flurbiprofen tablets are contraindicated in patients with known hypersensitivity to flurbiprofen tablets or the excipients (see DESCRIPTION).

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

Flurbiprofen is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery (see WARNINGS).

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).

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 (see CONTRAINDICATIONS).

NSAIDs, including flurbiprofen, can lead to onset of new hypertension or worsening of preexisting 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 flurbiprofen, 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.

Fluid retention and edema have been observed in some patients taking NSAIDs. Flurbiprofen should be used with caution in patients with fluid retention or heart failure.

NSAIDs, including flurbiprofen, 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 to 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.

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.

In clinical studies, the elimination half-life of flurbiprofen was unchanged in patients with renal impairment. Flurbiprofen metabolites are eliminated primarily by the kidneys. Elimination of 4'-hydroxy-flurbiprofen was reduced in patients with moderate to severe renal impairment. Therefore, treatment with flurbiprofen is not recommended in these patients with advanced renal disease. If flurbiprofen therapy must be initiated, close monitoring of the patients renal function is advisable (see CLINICAL PHARMACOLOGY).

As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to flurbiprofen. Flurbiprofen 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: General: Preexisting Asthma). Emergency help should be sought in cases where an anaphylactoid reaction occurs.

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

Flurbiprofen 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 flurbiprofen 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 non-steroidal anti-inflammatory drugs, including flurbiprofen. 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 non-steroidal anti-inflammatory drugs. In addition, rare cases of severe hepatic reactions, including jaundice, 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 with abnormal liver test values, should be evaluated for evidence of the development of a more severe hepatic reaction while on therapy with flurbiprofen. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), flurbiprofen should be discontinued.

Anemia is sometimes seen in patients receiving non-steroidal anti-inflammatory drugs, including flurbiprofen. This may be due to fluid retention, GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with non-steroidal anti-inflammatory drugs, including flurbiprofen, should have their hemoglobin or hematocrit checked periodically even if they do not exhibit any signs or symptoms of anemia.

Non-steroidal anti-inflammatory drugs 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. Flurbiprofen does not generally affect platelet counts, prothrombin time (PT), or partial thromboplastin time (PTT). Patients receiving flurbiprofen 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, flurbiprofen should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with preexisting asthma.

Blurred and/or diminished vision has been reported with the use of flurbiprofen and other non-steroidal anti-inflammatory drugs. Patients experiencing eye complaints should have ophthalmologic examinations

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.

• Flurbiprofen, like other NSAIDs, may cause 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).
• Flurbiprofen, 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).
• Flurbiprofen, 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 blisters, 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, flurbiprofen should be avoided because it may 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 non-steroidal anti-inflammatory drugs should have their CBC and 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 abnormal liver tests persist or worsen, flurbiprofen should be discontinued.

Reports suggest that non-steroidal anti-inflammatory drugs may diminish the antihypertensive effect of ACE inhibitors. These interactions should be given consideration in patients taking non-steroidal anti-inflammatory drugs concomitantly with ACE inhibitors.

The effects of warfarin and NSAIDs on GI bleeding are synergistic, such that users of both drugs together have a risk of serious GI bleeding higher than users of either drug alone. The physician should be cautious when administering flurbiprofen to patients taking warfarin or other anticoagulants.

Concurrent administration of aspirin lowers serum flurbiprofen concentrations (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). The clinical significance of this interaction is not known; however, as with other NSAIDs, concomitant administration of flurbiprofen and aspirin is not generally recommended because of the potential for increased adverse effects.

Flurbiprofen attenuated the hypotensive effect of propranolol but not atenolol (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions). The mechanism underlying this interference is unknown. Patients taking both flurbiprofen and a beta-blocker should be monitored to ensure that a satisfactory hypotensive effect is achieved.

Clinical studies, as well as post-marketing observations, have shown that flurbiprofen can reduce the natriuretic effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis. During concomitant therapy with NSAIDs, the patient should be observed closely for signs of renal failure (see WARNINGS: Renal Effects), as well as diuretic efficacy.

NSAIDs have produced an elevation of plasma lithium levels and a reduction in renal lithium clearance. The mean minimum lithium concentration increased 15% and the renal clearance was decreased by approximately 20%.

These effects have been attributed to inhibition of renal prostaglandin synthesis by the non-steroidal anti-inflammatory drugs. Thus, when non-steroidal anti-inflammatory drugs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.

Non-steroidal anti-inflammatory drugs have been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that they could enhance the toxicity of methotrexate. Caution should be used when non-steroidal anti-inflammatory drugs are administered concomitantly with methotrexate.

Reproductive studies conducted in rats and rabbits have not demonstrated evidence of developmental abnormalities. However, animal reproduction studies are not always predictive of human response. There are no adequate and well controlled studies in pregnant women. Flurbiprofen should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Because of the known effects of non-steroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of ductus arteriosus), use during late pregnancy should be avoided.

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

Concentrations of flurbiprofen in breast milk and plasma of nursing mothers suggest that a nursing infant could receive approximately 0.10 mg flurbiprofen per day in the established milk of a woman taking flurbiprofen 200 mg/day. Because of possible adverse effects of prostaglandin-inhibiting drugs on neonates, 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 NSAID, caution should be exercised in treating the elderly (65 years and older). Clinical experience with flurbiprofen suggests that elderly patients may have a higher incidence of gastrointestinal complaints than younger patients, including ulceration, bleeding, flatulence, bloating, and abdominal pain. To minimize the potential risk for gastrointestinal events, the lowest effective dose should be used for the shortest possible duration (see WARNINGS, Gastrointestinal Effects). Likewise, elderly patients are at greater risk of developing renal decompensation (see WARNINGS: Renal Effects).

The pharmacokinetics of flurbiprofen do not seem to differ in elderly patients from those in younger individuals (see CLINICAL PHARMACOLOGY, Special Populations). The rate of absorption of flurbiprofen was reduced in elderly patients who also received antacids, although the extent of absorption was not affected (see CLINICAL PHARMACOLOGY: Drug-Drug Interactions).

Symptoms following acute overdoses with non-steroidal anti-inflammatory drugs are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. Anaphylactoid reactions have been reported with therapeutic ingestion of non-steroidal anti-inflammatory drugs, and may occur following an overdose.

Patients should be managed by symptomatic and supportive care following overdose with a non-steroidal anti-inflammatory drug. There are no specific antidotes. Emesis and/or activated charcoal (60 g to 100 g in adults, 1 to 2 g/kg in children) and/or osmotic cathartic may be indicated in patients seen within 4 hours of ingestion with symptoms, or following a large overdose (5 to 10 times the usual dose). Forced diuresis, alkalization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.

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

After observing the response to initial therapy with flurbiprofen, the dose and frequency should be adjusted to suit an individual patient's needs.

For relief of the signs and symptoms of rheumatoid arthritis or osteoarthritis, the recommended starting dose of flurbiprofen is 200 mg to 300 mg per day, divided for administration two, three, or four times a day. The largest recommended single dose in a multiple-dose daily regimen is 100 mg.

     FLURBIPROFEN 100MG LABEL IMAGE