DRUGS & SUPPLEMENTS
1 INDICATIONS AND USAGE
Flurbiprofen tablets are indicated:
2 DOSAGE AND ADMINISTRATION
Carefully consider the potential benefits and risks of Flurbiprofen tablets and other treatment options before deciding to use Flurbiprofen tablets. Use the lowest effective dosage for the shortest duration consistent with individual patient treatment goals [see Warnings and Precautions (5) ].
After observing the response to initial therapy with Flurbiprofen tablets, 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 dosage 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.
3 DOSAGE FORMS AND STRENGTHS
Flurbiprofen Tablets, USP are available containing 50 mg or 100 mg of Flurbiprofen, USP.
Fluriprofen tablets: 50 mg and 100 mg (3)
Flurbiprofen tablets are contraindicated in the following patients:
5 WARNINGS AND PRECAUTIONS
5.1 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, 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 Flurbiprofen, increases the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2) ].
Status Post Coronary Artery Bypass Graft 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) ].
Observational studies conducted in the Danish National Registry have demonstrated that patients treated with NSAIDs in the post-MI period were at increased risk of reinfarction, CV-related death, and all-cause mortality beginning in the first week of treatment. In this same cohort, the incidence of death in the first year post-MI was 20 per 100 person years in NSAID-treated patients compared to 12 per 100 person years in non-NSAID exposed patients. Although the absolute rate of death declined somewhat after the first year post-MI, the increased relative risk of death in NSAID users persisted over at least the next four years of follow-up.
Avoid the use of Flurbiprofen tablets in patients with a recent MI unless the benefits are expected to outweigh the risk of recurrent CV thrombotic events. If Flurbiprofen tablets are used in patients with a recent MI, monitor patients for signs of cardiac ischemia.
5.2 Gastrointestinal Bleeding, Ulceration, and Perforation
NSAIDs, including Flurbiprofen tablets, cause serious gastrointestinal adverse events including inflammation, bleeding, ulceration, and perforation of the esophagus, 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. However, even short-term therapy is not without risk.
Risk Factors for GI Bleeding, Ulceration, and Perforation
Patients with a prior history of peptic ulcer disease and/or GI bleeding who used NSAIDs had a greater than 10-times increased risk for developing a GI bleed compared to patients without these risk factors. Other factors that increase the risk of GI bleeding in patients treated with NSAIDs include longer duration of NSAID therapy; concomitant use of oral corticosteroids, aspirin, anticoagulants, or selective serotonin reuptake inhibitors (SSRIs); smoking, use of alcohol, older age, and poor general health status. Most postmarketing reports of fatal GI events occurred in elderly or debilitated patients. Additionally, patients with advanced liver disease and/or coagulopathy are at increased risk for GI bleeding.
Strategies to Minimize the GI Risks in NSAID-Treated Patients
Elevations of ALT or AST (three or more times the upper limit of normal [ULN]) have been reported in approximately 1% of NSAID-treated patients in clinical trials. In addition, rare, sometimes fatal, cases of severe hepatic injury, including fulminant hepatitis, liver necrosis, and hepatic failure have been reported.
Elevations of ALT or AST (less than three times ULN) may occur in up to 15% of patients treated with NSAIDs including Flurbiprofen.
Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and "flu-like" symptoms). If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), discontinue Flurbiprofen tablets immediately, and perform a clinical evaluation of the patient.
NSAIDs, including Flurbiprofen tablets, can lead to new onset of hypertension or worsening of preexisting hypertension, either of which may contribute to the increased incidence of CV events. Patients taking angiotensin converting enzyme inhibitors, thiazide diuretics, or loop diuretics may have impaired response to these therapies when taking NSAIDs [see Drug Interactions (7) ].
Monitor blood pressure (BP) during the initiation of NSAID treatment and throughout the course of therapy.
5.5 Heart Failure and Edema
The Coxib and traditional NSAID Trialists’ Collaboration meta-analysis of randomized controlled trials demonstrated an approximately two-fold increase in hospitalizations for heart failure in COX-2 selective-treated patients and nonselective NSAID-treated patients compared to placebo-treated patients. In a Danish National Registry study of patients with heart failure, NSAID use increased the risk of MI, hospitalization for heart failure, and death.
Additionally, fluid retention and edema have been observed in some patients treated with NSAIDs. Use of Flurbiprofen may blunt the CV effects of several therapeutic agents used to treat these medical conditions (e.g., diuretics, ACE inhibitors, or angiotensin receptor blockers [ARBs]) [see Drug Interactions (7) ].
Avoid the use of Flurbiprofen tablets in patients with severe heart failure unless the benefits are expected to outweigh the risk of worsening heart failure. If Flurbiprofen tablets are used in patients with severe heart failure, monitor patients for signs of worsening heart failure.
5.6 Renal Toxicity and Hyperkalemia
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 an NSAID 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, dehydration, hypovolemia, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors or ARBs, 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 tablets is not recommended in these patients with advanced renal disease. If Flurbiprofen tablets therapy must be initiated, close monitoring of the patients renal function is advisable [see Clinical Pharmacology ].
Correct volume status in dehydrated or hypovolemic patients prior to initiating Flurbiprofen tablets. Monitor renal function in patients with renal or hepatic impairment, heart failure, dehydration, or hypovolemia during use of Flurbiprofen tablets [see Drug Interactions (7) ]. Avoid the use of Flurbiprofen tablets in patients with advanced renal disease unless the benefits are expected to outweigh the risk of worsening renal function. If Flurbiprofen tablets are used in patients with advanced renal disease, monitor patients for signs of worsening renal function.
Increases in serum potassium concentration, including hyperkalemia, have been reported with use of NSAIDs even in some patients without renal impairment. In patients with normal renal function, these effects have been attributed to a hyporeninemic-hypoaldosteronism state.
5.7 Anaphylactic Reactions
Flurbiprofen has been associated with anaphylactic reactions in patients with and without known hypersensitivity to Flurbiprofen and in patients with aspirin-sensitive asthma [see Contraindications and Warnings and Precautions (5.8) ].
Seek emergency help if an anaphylactic reaction occurs.
5.8 Exacerbation of Asthma Related to Aspirin Sensitivity
A subpopulation of patients with asthma may have aspirin-sensitive asthma which may include chronic rhinosinusitis complicated by nasal polyps; severe, potentially fatal bronchospasm; and/or intolerance to aspirin and other NSAIDs. Because cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, Flurbiprofen tablets are contraindicated in patients with this form of aspirin sensitivity [see Contraindications (4) ]. When Flurbiprofen tablets are used in patients with preexisting asthma (without known aspirin sensitivity), monitor patients for changes in the signs and symptoms of asthma.
5.9 Serious Skin Reactions
NSAIDs, including Flurbiprofen, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome, and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin reactions, and to discontinue the use of Flurbiprofen tablets at the first appearance of skin rash or any other sign of hypersensitivity. Flurbiprofen tablets are contraindicated in patients with previous serious skin reactions to NSAIDs [see Contraindications (4) ].
5.10 Premature Closure of Fetal Ductus Arteriosus
Flurbiprofen may cause premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Flurbiprofen tablets, in pregnant women starting at 30 weeks of gestation (third trimester) [see Use in Specific Populations (8.1) ].
5.11 Hematologic Toxicity
Anemia has occurred in NSAID-treated patients. This may be due to occult or gross blood loss, fluid retention, or an incompletely described effect on erythropoiesis. If a patient treated with Flurbiprofen tablets have any signs or symptoms of anemia, monitor hemoglobin or hematocrit.
NSAIDs, including Flurbiprofen tablets, may increase the risk of bleeding events. Co-morbid conditions such as coagulation disorders of concomitant use of warfarin, other anticoagulants, antiplatelet agents, serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs) may increase this risk. Monitor these patients for signs of bleeding [see Drug Interactions (7) ].
5.12 Masking of Inflammation and Fever
The pharmacological activity of Flurbiprofen tablets in reducing inflammation, and possibly fever, may diminish the utility of diagnostic signs in detecting infections.
5.13 Laboratory Monitoring
Because serious GI bleeding, hepatotoxicity, and renal injury can occur without warning symptoms or signs, consider monitoring patients on long-term NSAID treatment with a CBC and a chemistry profile periodically [see Warnings and Precautions ].
5.14 Vision Changes
Blurred and/or diminished vision has been reported with the use of Flurbiprofen tablets and other nonsteroidal anti-inflammatory drugs. Patients experiencing eye complaints should have ophthalmologic examinations.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Most common adverse reactions (incidence > 3% from clinical trials) are: abdominal pain, dyspepsia, nausea, diarrhea, constipation, headache, edema, signs and symptoms suggesting urinary tract infection (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical 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.
Incidence of 1% or greater
Body as a Whole: edema
Digestive System: GI bleeding, abdominal pain, constipation, diarrhea, dyspepsia/heartburn, flatulence, nausea, vomiting, elevated liver enzymes
Metabolic and Nutritional System: body weight changes
Nervous System: headache, nervousness, anxiety, insomnia, increased reflexes, tremor, amnesia, asthenia, depression, malaise, somnolence
Respiratory System: rhinitis
Skin and Appendages: rash
Special Senses: changes in vision, dizziness, tinnitus
Urogenital System: signs and symptoms suggesting urinary tract infection
Incidence < 1%
Body as a Whole: anaphylactic reaction, chills, fever
Cardiovascular System: myocardial infarction, congestive heart failure, hypertension, vascular diseases, vasodilation
Digestive System: gastric/peptic ulcer disease, hematemesis, bloody diarrhea, hepatitis, esophageal disease, gastritis, stomatitis/glossitis, dry mouth
Hemic and Lymphatic System: iron deficiency anemia, decrease in hemoglobin and hematocrit, purpura, eosinophilia
Metabolic and Nutritional System: hyperuricemia
Nervous System: cerebrovascular ischemia, convulsion, ataxia, confusion, hypertonia, paresthesia, twitching, emotional lability
Respiratory System: asthma, dyspnea, epistaxis, bronchitis, laryngitis
Skin and Appendages: angioedema, urticaria, eczema, pruritus, herpes simplex, alopecia, dry skin
Special Senses: vertigo, corneal opacity, parosmia, conjunctivitis
Urogenital System: renal failure, vaginal hemorrhage, hematuria
6.2 Postmarketing Experience
The following adverse reactions have been identified during post approval use of Flurbiprofen tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiovascular System: angina pectoris, arrhythmias
Digestive System: jaundice (cholestatic and noncholestatic), colitis, small intestine inflammation with loss of blood and protein, exacerbation of inflammatory bowel disease, cholecystitis, periodontal abscess, appetite changes
Hemic and Lymphatic System: aplastic anemia (including agranulocytosis or pancytopenia), hemolytic anemia, leukopenia, thrombocytopenia, ecchymosis, lymphadenopathy
Metabolic and Nutritional System: hyperkalemia
Nervous System: cerebrovascular accident, subarachnoid hemorrhage, meningitis, myasthenia
Respiratory System: pulmonary infarct, pulmonary embolism, hyperventilation
Skin and Appendages: toxic epidermal necrolysis, exfoliative dermatitis, zoster, photosensitivity, nail disorder, sweating
Special Senses: retinal hemorrhage, glaucoma, retrobulbar neuritis, transient hearing loss, changes in taste, ear disease
Urogenital System: interstitial nephritis, uterine hemorrhage, menstrual disturbances, prostate disease, vulvovaginitis
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
Pregnancy: Use of NSAIDs during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs in pregnant women starting at 30 weeks gestation
Infertility: NSAIDs are associated with reversible infertility. Consider withdrawal of Flurbiprofen tablets in women who have difficulties conceiving (8.3)
Use of NSAIDs, including Flurbiprofen tablets, during the third trimester of pregnancy increases the risk of premature closure of the fetal ductus arteriosus. Avoid use of NSAIDs, including Flurbiprofen tablets, in pregnant women starting at 30 weeks of gestation.
There are no adequate and well-controlled studies of Flurbiprofen tablets in pregnant women. Data from observational studies regarding potential embryo-fetal risks of NSAID use in women in the first or second trimesters of pregnancy are inconclusive. In the general U.S. population, all clinically recognized pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. In animal reproduction studies, delayed parturition, prolonged labor, stillborn fetuses, and the presence of retained fetuses at necropsy occurred following treatment of pregnant rats treated with oral Flurbiprofen throughout gestation until labor at less than 1-time the human dose of 300 mg/day. Embryofetal lethality was seen in pregnant rats and rabbits administered oral Flurbiprofen during the period of organogenesis at exposures 0.03-times and 0.5-times, respectively, the human dose of 300 mg. No evidence of malformations were noted in rats, rabbits, or mice treated with Flurbiprofen during the period of organogenesis at doses that were 0.8-, 0.5-, and 0.2-times the maximum human daily dose [see Data]. Based on animal data, prostaglandins have been shown to have an important role in endometrial vascular permeability, blastocyst implantation, and decidualization. In animal studies, administration of prostaglandin synthesis inhibitors such as Flurbiprofen, resulted in increased pre- and post-implantation loss.
Labor or Delivery
There are no studies on the effects of Flurbiprofen tablets during labor or delivery. In animal studies, NSAIDs, including Flurbiprofen, inhibit prostaglandin synthesis, cause delayed parturition, and increase the incidence of stillbirth.
Pregnant rats were treated with oral doses of 0.05 mg/kg, 1 mg/kg, and 3 mg/kg Flurbiprofen 14 days prior to mating through Gestation Day 16. Embryofetal lethality was seen at 1 mg/kg and above (0.03 times the maximum recommended human dose [MRHD] of 300 mg on a mg/m2 basis). No maternal toxicity was evident at this dose. No malformations were seen in fetuses from pregnant rats administered Flurbiprofen during the period of organogenesis at doses up to 25 mg/kg (0.8 times the MRHD on a mg/m2 basis). Maternal toxicity (uterine hemorrhage, gastric ulcers) was observed at this dose.
Pregnant rabbits were administered oral doses of 0.675 mg/kg, 2.25 mg/kg, and 7.5 mg/kg Flurbiprofen from GD 1 through GD 29. Embryofetal lethality, but no evidence of teratogenicity, was seen at 7.5 mg/kg (0.5 times the MRHD of 300 mg on a mg/m2 basis). Maternal toxicity (gastric ulcers and lethality) was observed at this dose.
Pregnant mice were treated with oral doses of 2 mg/kg, 5 mg/kg, and 12 mg/kg Flurbiprofen from GD 3 to 18. An increased incidence of fetal lethality occurred in the 12 mg/kg group (0.2 times the MRHD). All doses were associated with some evidence of maternal toxicity (placental hemorrhage).
Pregnant rats were treated with oral doses of 0.2 mg/kg, 0.675 mg/kg, 2.25 mg/kg, 7.5 mg/kg, and 25 mg/kg Flurbiprofen from GD 1 until labor. Delayed delivery, the incidence of stillborn pups, and decreased pup viability, were noted at doses of 2.25 mg/kg and higher (0.07 times the MRHD). These doses were associated with maternal toxicity (uterine hemorrhage, gastrointestinal ulceration, decreased body weight).
Pregnant rats treated with oral doses of 0.4 mg/kg, 4 mg/kg, and 10 mg/kg Flurbiprofen from GD 16 to labor, delayed parturition was seen at 0.4 mg/kg and above and stillborn pups were seen at 4 mg/kg and above (0.01-times and 0.13-times, respectively, the MRHD on mg/m2 basis). Uterine hemorrhage, ulceration, and mortality were noted in dams at 0.4 mg/kg and above.
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 tablets 200 mg/day. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Flurbiprofen tablets and any potential adverse effects on the breastfed infant from Flurbiprofen tablets or from the underlying maternal condition.
8.3 Females and Males of Reproductive Potential
Based on the mechanism of action, the use of prostaglandin-mediated NSAIDs, including Flurbiprofen tablets, may delay or prevent rupture of ovarian follicles, which has been associated with reversible infertility in some women. Published animal studies have shown that administration of prostaglandin synthesis inhibitors has the potential to disrupt prostaglandin-mediated follicular rupture required for ovulation. Small studies in women treated with NSAIDs have also shown a reversible delay in ovulation. Consider withdrawal of NSAIDs, including Flurbiprofen tablets, in women who have difficulties conceiving or who are undergoing investigation of infertility.
8.4 Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
8.5 Geriatric Use
Elderly patients, compared to younger patients, are at greater risk for NSAID-associated serious cardiovascular, gastrointestinal, and/or renal adverse reactions. If the anticipated benefit for the elderly patient outweighs these potential risks, start dosing at the low end of the dosing range, and monitor patients for adverse effects [see Warnings and Precautions (5.1, 5.2, 5.3, 5.6, 5.13) ].
Symptoms following acute NSAID overdosages have been typically limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding has occurred. Hypertension, acute renal failure, respiratory depression and coma have occurred, but were rare [see Warnings and Precautions (5.1, 5.2, 5.4, 5.6) ].
Manage patients with symptomatic and supportive care following an NSAID overdosage. There are no specific antidotes. Consider emesis and/or activated charcoal (60 to 100 grams in adults, 1 to 2 grams per kg of body weight in pediatric patients) and/or osmotic cathartic in symptomatic patients seen within four hours of ingestion or in patients with a large overdosage (5 to 10 times the recommended dosage). Forced diuresis, alkalinization of urine, hemodialysis, or hemoperfusion may not be useful due to high protein binding.
For additional information about overdosage treatment contact a poison control center (1-800-222-1222).
Flurbiprofen Tablets, USP are a member of the phenylalkanoic acid derivative group of nonsteroidal anti-inflammatory drug, available as 50 mg beige, film-coated, round, debossed with M over 76 on one side of the tablet and blank on the other side and 100 mg beige, film-coated, round, unscored tablets debossed with M over 93 on one side of the tablet and blank on the other side, 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 C15H13FO2 and it has the following structural formula:
The inactive ingredients in Flurbiprofen tablets (both strengths) include: black iron oxide, colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose (anhydrous), magnesium stearate, microcrystalline cellulose, polydextrose, propylene glycol, sodium lauryl sulfate, titanium dioxide, triacetin, and yellow iron oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Flurbiprofen has analgesic, anti-inflammatory, and antipyretic properties.
The mechanism of action of Flurbiprofen tablets, like that of other NSAIDs, is not completely understood but involves inhibition of cyclooxygenase.
Flurbiprofen is a potent inhibitor of prostaglandin (PG) synthesis in vitro. Flurbiprofen concentrations reached during therapy have produced in vivo effects. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Prostaglandins are mediators of inflammation. Because Flurbiprofen is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandins in peripheral tissues.
General Pharmacokinetic Characteristics
The pharmacokinetics of Flurbiprofen have been characterized in healthy subjects, special populations and patients. The pharmacokinetics of Flurbiprofen are linear, and there is little accumulation of Flurbiprofen following multiple doses of Flurbiprofen tablets.
The mean oral bioavailability of Flurbiprofen from Flurbiprofen tablets 100 mg is 96% relative to an oral solution. Flurbiprofen is rapidly and non-stereoselectively absorbed from Flurbiprofen tablets, with peak plasma concentrations occurring at approximately 2 hours.
Administration of Flurbiprofen tablets 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 tablets.
The apparent volume of distribution 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 μg/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 tablets 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 (e.g., ibuprofen), metabolism of R-flurbiprofen to S-flurbiprofen is minimal.
In vitro studies have demonstrated that cytochrome CYP2C9 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. In vitro studies also demonstrated glucuronidation of both enantiomers of Flurbiprofen and 4’-hydroxy-flurbiprofen. UGT2B7 is the predominant UGT isozyme responsible for the glucuronidation. Flurbiprofen does not induce enzymes that alter its metabolism.
Following dosing with Flurbiprofen tablets, less than 3% of Flurbiprofen is excreted unchanged in the urine, with about 70% of the dose eliminated in the urine as Flurbiprofen, 4’-hydroxy-flurbiprofen, and their acylglucuronide conjugates. 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 elimination half-lives of R- and S-flurbiprofen are similar, about 4.7 and 5.7 hours, respectively.
The pharmacokinetics of Flurbiprofen have not been investigated in pediatric patients.
No pharmacokinetic differences due to race have been identified.
Flurbiprofen pharmacokinetics were similar in geriatric arthritis patients, younger arthritis patients, and young healthy volunteers receiving Flurbiprofen tablets 100 mg as either single or multiple doses.
Hepatic metabolism may account for > 90% of Flurbiprofen elimination, so patients with hepatic disease may require reduced doses of Flurbiprofen tablets compared to patients with normal hepatic function. The pharmacokinetics of R- and S-flurbiprofen were similar, however, in alcoholic cirrhosis patients and young healthy volunteers (N = 8) following administration of a single 200 mg dose of Flurbiprofen tablets. Flurbiprofen plasma protein binding may be decreased in patients with liver disease and serum albumin concentrations below 3.1 g/dL.
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 mL/min 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.
Flurbiprofen is not significantly removed from the blood into dialysate in patients undergoing continuous ambulatory peritoneal dialysis.
Drug Interaction Studies
Administration of Flurbiprofen tablets to volunteers under fasting conditions or with antacid suspension yielded similar serum flurbiprofen-time profiles in young adult subjects. In geriatric subjects (n = 7), there was a reduction in the rate but not the extent of Flurbiprofen absorption.
Concurrent administration of Flurbiprofen tablets and aspirin resulted in 50% lower serum Flurbiprofen concentrations. This effect of aspirin (which is also seen with other NSAIDs) has been demonstrated in patients with rheumatoid arthritis (n = 15) and in healthy volunteers (n = 16) [see Drug Interactions (7) ].
Beta-adrenergic Blocking Agents
The effect of Flurbiprofen on blood pressure response to propranolol and atenolol was evaluated in men with mild uncomplicated hypertension. 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 Drug Interactions (7) ].
In normal volunteers (n = 9), pretreatment with cimetidine or ranitidine did not affect Flurbiprofen pharmacokinetics, except for a small (13%) but statistically significant increase in the area under the serum concentration curve of Flurbiprofen in subjects who received cimetidine.
In studies of healthy males, concomitant administration of Flurbiprofen and digoxin did not change the steady state serum levels of either drug [see Drug Interactions (7) ].
Studies in healthy volunteers have shown that, like other NSAIDs, 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 [see Drug Interactions (7) ].
In a study of 11 women with bipolar disorder receiving lithium carbonate at a dosage of 600 mg/day to 1200 mg/day, administration of 100 mg Flurbiprofen tablets every 12 hours increased plasma lithium concentrations by 19%. Four of 11 patients experienced a clinically important increase [see Drug Interactions (7) ].
In a study of six adult arthritis patients, coadministration of methotrexate (10 mg/dose to 25 mg/dose) and Flurbiprofen tablets (300 mg/day) resulted in no observable interaction between these two drugs [see Drug Interactions (7) ].
Oral Hypoglycemic Agents
In a clinical study, Flurbiprofen was administered to adult diabetics who were already receiving glyburide, metformin (n = 2), chlorpropamide with phenformin (n = 3), or glyburide with phenformin (n = 6). Although there was a slight reduction in blood sugar concentrations during concomitant administration of Flurbiprofen and hypoglycemic agents, there were no signs or symptoms of hypoglycemia.
Poor Metabolizers of CYP2C9 Substrates
In patients who are known or suspected to be poor CYP2C9 metabolizers based on genotype or previous history/experience with other CYP2C9 substrates (such as warfarin and phenytoin), reduce the dose of Flurbiprofen to avoid abnormally high plasma levels due to reduced metabolic clearance.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Flurbiprofen was not carcinogenic in long-term studies in Fischer-344 and CD rats at doses up to 5 mg/kg/day and in CFLP mice at doses up to 12 mg/kg/day.
Flurbiprofen was not genotoxic in an in vivo micronucleus assay in rats.
Impairment of Fertility
No effect on male or female fertility in rats was observed after oral administration of 3 mg/kg Flurbiprofen for 65 days prior to mating in males and 14 days prior to mating through Gestation Day 16 in females (equivalent to 0.1-times the human dose of 300 mg/day on a mg/m2 basis). This dose was not associated with significant toxicity in the dams or sires.
16 HOW SUPPLIED/STORAGE AND HANDLING
Flurbiprofen Tablets, USP are available containing 50 mg or 100 mg of Flurbiprofen, USP.
The 50 mg tablets are beige, film-coated, 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:
bottles of 100 tablets
The 100 mg tablets are beige, film-coated, 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:
bottles of 100 tablets
Store at 20° to 25°C (68° to 77°F).
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.
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide) that accompanies each prescription dispensed. Inform patients, families, or their caregivers of the following information before initiating therapy with Flurbiprofen tablets and periodically during the course of ongoing therapy.
Cardiovascular Thrombotic Events: Advise patients to be alert for the symptoms of cardiovascular thrombotic events, including chest pain, shortness of breath, weakness, or slurring of speech, and to report any of these symptoms to their health care provider immediately [see Warnings and Precautions (5.1) ].
Gastrointestinal Bleeding, Ulceration, and Perforation: Advise patients to report symptoms of ulcerations and bleeding, including epigastric pain, dyspepsia, melena, and hematemesis to their health care provider. In the setting of concomitant use of low-dose aspirin for cardiac prophylaxis, inform patients of the increased risk for and the signs and symptoms of GI bleeding [see Warnings and Precautions (5.2) ].
Hepatotoxicity: Inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, pruritus, diarrhea, jaundice, right upper quadrant tenderness, and “flu-like” symptoms). If these occur, instruct patients to stop Flurbiprofen tablets and seek immediate medical therapy [see Warnings and Precautions (5.3) ].
Heart Failure and Edema: Advise patients to be alert for the symptoms of congestive heart failure including shortness of breath, unexplained weight gain, or edema and to contact their healthcare provider if such symptoms occur [see Warnings and Precautions (5.5) ].
Anaphylactic Reactions: Inform patients of the signs of an anaphylactic reaction (e.g., difficulty breathing, swelling of the face or throat). Instruct patients to seek immediate emergency help if these occur [see Contraindications (4) and Warnings and Precautions (5.7) ].
Serious Skin Reactions: Advise patients to stop Flurbiprofen tablets immediately if they develop any type of rash and to contact their healthcare provider as soon as possible [see Warnings and Precautions (5.9) ].
Female Fertility: Advise females of reproductive potential who desire pregnancy that NSAIDs, including Flurbiprofen tablets, may be associated with a reversible delay in ovulation [see Use in Specific Populations (8.3) ].
Fetal Toxicity: Inform pregnant women to avoid use of Flurbiprofen tablets and other NSAIDs starting at 30 weeks gestation because of the risk of the premature closing of the fetal ductus arteriosus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.1) ].
Avoid Concomitant Use of NSAIDs: Inform patients that the concomitant use of Flurbiprofen tablets with other NSAIDs or salicylates (e.g., diflunisal, salsalate) is not recommended due to the increased risk of gastrointestinal toxicity, and little or no increase in efficacy [see Warnings and Precautions (5.2) and Drug Interactions (7) ]. Alert patients that NSAIDs may be present in “over the counter” medications for treatment of colds, fever, or insomnia.
Use of NSAIDs and Low-Dose Aspirin: Inform patients not to use low-dose aspirin concomitantly with Flurbiprofen tablets until they talk to their healthcare provider [see Drug Interactions (7) ].
Medication Guide for Nonsteroidal Anti-inflammatory Drugs
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.
Flurbiprofen pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Flurbiprofen available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Flurbiprofen destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Flurbiprofen Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Flurbiprofen pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Flurbiprofen?
Depending on the reaction of the Flurbiprofen after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Flurbiprofen not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Flurbiprofen addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
ReviewsDrugs.com conducted a study on Flurbiprofen, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Flurbiprofen consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
One visitor reported dosesWhat is the dose of Flurbiprofen drug you are taking?
According to the survey conducted among sDrugs.com website users, the maximum number of people are using the following dose 6-10mg. Few medications come in only one or two doses. Few are specific for adult dose and child dose. The dose of the medicine given to the patient depends on the severity of the symptom/disease. There can be dose adjustments made by the doctor, based on the progression of the disease. Follow-up is important.
One visitor reported time for resultsWhat is the time duration Flurbiprofen drug must be taken for it to be effective or for it to reduce the symptoms?
Most chronic conditions need at least some time so the dose and the drug action gets adjusted to the body to get the desired effect. The stastistics say sDrugs.com website users needed 2 weeks to notice the result from using Flurbiprofen drug. The time needed to show improvement in health condition after using the medicine Flurbiprofen need not be same for all the users. It varies based on other factors.
The information was verified by Dr. Arunabha Ray, MD Pharmacology