Flurbiprofen (oral)

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# Black Box Warning

# Overview
Flurbiprofen (oral) is an analgesic, NSAID, propionic acid that is FDA approved for the treatment of rheumathoid arthritis and osteoarthritis. There is a Black Box Warning for this drug as shown here.  Common adverse reactions include body fluid retention, edema, rash, weight change finding, abdominal pain, constipation, diarrhea, flatulence, heartburn, indigestion, nausea, vomiting, increased liver function test, central nervous system depression, central nervous system stimulation, dizziness, headache, abnormal vision, tinnitus, feeling nervous and rhinitis.

# Adult Indications and Dosage

## FDA-Labeled Indications and Dosage (Adult)
- Carefully consider the potential benefits and risks of Flurbiprofen tablet, USP and other treatment options before deciding to use Flurbiprofen tablet, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
- After observing the response to initial therapy with Flurbiprofen tablet, USP, 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 tablet, USP is 200 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.

## Off-Label Use and Dosage (Adult)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Flurbiprofen in adult patients.

### NonGuideline-Supported Use
- Dosage: 200mg q24h PO
- Dosage: 50mg q24h PO 
- Dosage: 50 mg PO 

# Pediatric Indications and Dosage

## FDA-Labeled Indications and Dosage (Pediatric)
- Carefully consider the potential benefits and risks of Flurbiprofen tablet, USP and other treatment options before deciding to use Flurbiprofen tablet, USP. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals.
- After observing the response to initial therapy with Flurbiprofen tablet, USP, 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 tablet, USP is 200 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.

## Off-Label Use and Dosage (Pediatric)

### Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Flurbiprofen in pediatric patients.

### NonGuideline-Supported Use
There is limited information regarding Off-Label NonGuideline-Supported Use of Flurbiprofen in pediatric patients.

# Contraindications
- Flurbiprofen tablets, USP are contraindicated in patients with known hypersensitivity to flurbiprofen. Flurbiprofen tablet, USP should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other nonsteroidal anti-inflammatory drugs. Severe, rarely fatal, anaphylactic-like reactions to nonsteroidal anti-inflammatory drugs have been reported in such patients.
- Flurbiprofen tablet, USP is contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery.

# Warnings

### Cardiovascular Effects
- 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.
- Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke.
- NSAIDs including Flurbiprofen tablet, USP, can lead to onset of new hypertension or worsening of pre-existing 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 tablet, USP, 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 tablet, USP should be used with caution in patients with fluid retention or heart failure.

### Gastrointestinal Effects - Risk of Ulceration, Bleeding, and Perforation
- NSAIDs, including Flurbiprofen tablet, USP, 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 3-6 months, and in about 2-4% 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 nonsteroidal 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 tablet, USP is not recommended in these patients with advanced renal disease. If Flurbiprofen tablet, USP therapy must be initiated, close monitoring of the patients renal function is advisable.

### Anaphylactoid Reactions
- As with other NSAIDs, anaphylactoid reactions may occur in patients without known prior exposure to Flurbiprofen tablet, USP. Flurbiprofen tablet, USP 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. Emergency help should be sought in cases where an anaphylactoid reaction occurs.

### Pregnancy
- In late pregnancy, as with other NSAIDs, Flurbiprofen tablet, USP should be avoided because it may cause premature closure of the ductus arteriosus.

# Adverse Reactions

## Clinical Trials Experience

## Postmarketing Experience
There is limited information regarding Flurbiprofen (oral) Postmarketing Experience in the drug label.

# Drug Interactions
- Reports suggest that nonsteroidal anti-inflammatory drugs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking nonsteroidal 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 tablet, USP to patients taking warfarin or other anticoagulants.
- Concurrent administration of aspirin lowers serum flurbiprofen concentrations. 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. 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 tablet, USP 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, 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 nonsteroidal anti-inflammatory drug. Thus, when nonsteroidal anti-inflammatory drugs and lithium are administered concurrently, subjects should be observed carefully for signs of lithium toxicity.
- Nonsteroidal 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 nonsteroidal anti-inflammatory drugs are administered concomitantly with methotrexate.

# Use in Specific Populations

### Pregnancy
Pregnancy Category (FDA): 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 tablet, USP should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.
Pregnancy Category (AUS): 
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Flurbiprofen (oral) in women who are pregnant.

### Labor and Delivery
- In rat studies with nonsteroidal 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 tablet, USP on labor and delivery in pregnant women are unknown.

### 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 tablet, USP 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.

### Pediatric Use
- The pharmacokinetics of flurbiprofen have not been investigated in pediatric patients.

### Geriatic Use
- Flurbiprofen pharmacokinetics were similar in geriatric arthritis patients, younger arthritis patients, and young healthy volunteers receiving Flurbiprofen tablet, USP 100 mg as either single or multiple doses.

### Gender
There is no FDA guidance on the use of Flurbiprofen (oral) with respect to specific gender populations.

### Race
- No pharmacokinetic differences due to race have been identified.

### Renal Impairment
- 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

### Hepatic Impairment
- Hepatic metabolism may account for >90% of flurbiprofen elimination, so patients with hepatic disease may require reduced doses of Flurbiprofen tablets, USP compared to patients with normal hepatic function. The pharmacokinetics of R- and S-flurbiprofen were similar, however, in alcoholic cirrhosis patients (N=8) and young healthy volunteers (N=8) following administration of a single 200 mg dose of Flurbiprofen tablets, USP.
- Flurbiprofen plasma protein binding may be decreased in patients with liver disease and serum albumin concentrations below 3.1 g/dL

### Females of Reproductive Potential and Males
There is no FDA guidance on the use of Flurbiprofen (oral) in women of reproductive potentials and males.

### Immunocompromised Patients
There is no FDA guidance one the use of Flurbiprofen (oral) in patients who are immunocompromised.

# Administration and Monitoring

### Administration
There is limited information regarding Flurbiprofen (oral) Administration in the drug label.

### Monitoring
There is limited information regarding Flurbiprofen (oral) Monitoring in the drug label.

# IV Compatibility
There is limited information regarding the compatibility of Flurbiprofen (oral) and IV administrations.

# Overdosage
- Symptoms following acute overdoses with nonsteroidal 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 nonsteroidal anti-inflammatory drugs, and may occur following an overdose.
- Patients should be managed by symptomatic and supportive care following overdose with a nonsteroidal anti-inflammatory drug. There are no specific antidotes. Emesis and/or activated charcoal (60 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.

# Pharmacology

## Mechanism of Action
There is limited information regarding Flurbiprofen (oral) Mechanism of Action in the drug label.

## Structure
- The chemical name is -4-acetic acid, 2-fluoro-alphamethyl-, ()-. The molecular weight is 244.26. Its molecular formula is C15H13FO2 and it has the following structural formula:

## Pharmacodynamics
- Flurbiprofen tablet, USP contain flurbiprofen, a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Flurbiprofen tablet, USP, like that of other nonsteroidal anti-inflammatory drugs, is not completely understood but may be related to prostaglandin synthetase inhibition.

## Pharmacokinetics

### Pharmacokinetics
- The mean oral bioavailability of flurbiprofen from Flurbiprofen tablet, USP 100 mg is 96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed from Flurbiprofen tablet, USP, with peak plasma concentrations occurring at about 2 hours. Administration of Flurbiprofen tablet, USP 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 from Flurbiprofen tablet, USP.
- 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 g/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 tablet, USP 200 mg/day.
- Several flurbiprofen metabolites have been identified in human plasma and urine. These metabolites include 4'-hydroxy-flurbiprofen, 3', 4'-dihydroxy-flurbiprofen, 3'-hydroxy-4'-methoxy-flurbiprofen, their conjugates, and conjugated flurbiprofen. Unlike other arylpropionic acid derivatives (eg, ibuprofen), metabolism of R-flurbiprofen to S-flurbiprofen is minimal. In vitro studies have demonstrated that cytochrome P450 2C9 plays an important role in the metabolism of flurbiprofen to its major metabolite, 4'-hydroxy-flurbiprofen. The 4'-hydroxy-flurbiprofen metabolite showed little anti-inflammatory activity in animal models of inflammation. Flurbiprofen does not induce enzymes that alter its metabolism.
- The total plasma clearance of unbound flurbiprofen is not stereoselective, and clearance of flurbiprofen is independent of dose when used within the therapeutic range.
- Following dosing with Flurbiprofen tablet, USP, less than 3% of flurbiprofen is excreted unchanged in the urine, with about 70% of the dose eliminated in the urine as parent drug and metabolites. Because renal elimination is a significant pathway of elimination of flurbiprofen metabolites, dosing adjustment in patients with moderate or severe renal dysfunction may be necessary to avoid accumulation of flurbiprofen metabolites. The mean terminal disposition half-lives (t12) of R- and S-flurbiprofen are similar, about 4.7 and 5.7 hours, respectively. There is little accumulation of flurbiprofen following multiple doses of Flurbiprofen tablet, USP.

## Nonclinical Toxicology
There is limited information regarding Flurbiprofen (oral) Nonclinical Toxicology in the drug label.

# Clinical Studies
There is limited information regarding Flurbiprofen (oral) Clinical Studies in the drug label.

# How Supplied

## Storage
- Store at controlled room temperature 15 - 30C (59 - 86F)

# Images

## Drug Images

## Package and Label Display Panel

# Patient Counseling Information
There is limited information regarding Flurbiprofen (oral) Patient Counseling Information in the drug label.

# Precautions with Alcohol
- Alcohol-Flurbiprofen interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

# Brand Names
- Ansaid

# Look-Alike Drug Names
There is limited information regarding Flurbiprofen (oral) Look-Alike Drug Names in the drug label.

# Drug Shortage Status

# Price