Flurbiprofen 100 MG Oral Tablet
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 : 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 ).
Hypertension 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.
Congestive Heart Failure and Edema 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.
Gastrointestinal Effects Risk of Ulceration, Bleeding, and Perforation 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.
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 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.
Advanced Renal Disease 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 ).
Anaphylactoid Reactions 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.
Pregnancy In late pregnancy, as with other NSAIDs, flurbiprofen should be avoided because it may cause premature closure of the ductus arteriosus.
DRUG INTERACTIONS
Drug Interactions ACE Inhibitors 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.
Anticoagulants 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.
Aspirin 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.
Beta-Adrenergic Blocking Agents 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.
Diuretics 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.
Lithium 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.
Methotrexate 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.
OVERDOSAGE
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.
DESCRIPTION
Flurbiprofen is a member of the phenylalkanoic acid derivative group of non-steroidal anti-inflammatory drugs.
Flurbiprofen tablets are beige, round, film-coated tablets for oral administration.
Flurbiprofen is a racemic mixture of (+)S- and (-)R-enantiomers.
Flurbiprofen, USP is a white or slightly yellow crystalline powder.
It is slightly soluble in water at pH 7.0 and readily soluble in most polar solvents.
The chemical name is [1,1’-biphenyl]-4-acetic acid, 2-fluoro-alpha-methyl-, (±)-.
The molecular weight is 244.26.
Its molecular formula is C 15 H 13 FO 2 and it has the following structural formula: Each tablet, for oral administration, contains 50 mg or 100 mg flurbiprofen, USP.
Inactive ingredients are colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose (anhydrous), magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide, triacetin, yellow iron oxide and black iron oxide.
Structural Formula
HOW SUPPLIED
Flurbiprofen tablets, USP are available containing 50 mg or 100 mg of flurbiprofen, USP.
The 50 mg tablets are film-coated beige, round, unscored tablets debossed with M over 76 on one side of the tablet and blank on the other side.
They are available as follows: NDC 0378-0076-01 bottles of 100 tablets The 100 mg tablets are film-coated beige, round, unscored, tablets debossed with M over 93 on one side of the tablet and blank on the other side.
They are available as follows: NDC 0378-0093-01 bottles of 100 tablets NDC 0378-0093-05 bottles of 500 tablets Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] Protect from light.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
PHARMACIST: Dispense a Medication Guide with each prescription.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 REVISED JUNE 2009 FRB:R9mc
GERIATRIC USE
Geriatric Use 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 ).
INDICATIONS AND USAGE
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.
PEDIATRIC USE
Pediatric Use Safety and effectiveness in pediatric patients have not been established.
PREGNANCY
Pregnancy Teratogenic Effects.
Pregnancy Category C 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 .
Nonteratogenic Effects 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.
NUSRING MOTHERS
Nursing Mothers 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.
BOXED WARNING
Cardiovascular Risk NSAIDs may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, 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 ).
Flurbiprofen is contraindicated for the treatment of perioperative 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 events (see WARNINGS ).
INFORMATION FOR PATIENTS
Information for Patients 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.
DOSAGE AND ADMINISTRATION
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.