Froben (Flurbiprofen)

FROBEN® FROBEN SR®

Knoll

Flurbiprofen

Nonsteroidal Anti-inflammatory Agent

Action And Clinical Pharmacology: Flurbiprofen is a nonsteroidal anti-inflammatory drug with analgesic and antipyretic activity. Although its mechanism of action has not been completely elucidated it has been shown to be an inhibitor of prostaglandin synthesis, specifically cyclo-oxygenase, and to some extent lipoxygenase, and is not due to pituitary-adrenal stimulation.

Flurbiprofen is well absorbed and the rate of absorption is not altered with old age. Following a single oral dose of 100 mg, peak plasma levels are achieved in about 2 hours. Absorption may be delayed in some individuals when administered with food but the total amount of drug absorbed is not affected. The elimination half-life is approximately 4 hours. When the drug is administered daily, steady state concentrations are reached with no drug accumulation. Twenty to 25% of flurbiprofen is recovered from the urine as free and conjugated unchanged drug, with 60 to 80% being hydroxylated metabolites. At therapeutic blood levels, flurbiprofen is at least 99% bound to serum proteins. Excretion of flurbiprofen is completed 24 hours after the final dose.

Bioavailability for Froben SR is comparable to that of standard Froben with no evidence of dose dumping or excessive accumulation. Steady state is reached within 2 to 3 days. Froben SR is less rapidly absorbed than the conventional Froben tablet, reaching maximum plasma concentrations in a longer period of time.

Froben: Following a single 100 mg oral dose of flurbiprofen tablets to healthy volunteers, peak serum concentrations of 12.7±2.8 µg/mL were reached in 1.9±0.7 hours. The apparent elimination half-life was 3.8±0.4 hours. Multiple dose studies of 50 mg 3 times a day in volunteers resulted in no drug accumulation and steady state serum concentrations of 5 to 6 µg/mL. Administration of a single 50 mg dose of flurbiprofen to elderly men (age range 66 to 90 years) resulted in peak blood levels of 5 to 6 µg/mL, similar to those seen in young, healthy males.

Elderly females, however, (74 to 94 years) had higher mean peak concentrations of 8.7±0.8 µg/mL as compared to elderly and young males, however, this difference is not significant. These higher concentration levels are not related to a reduction in elimination of flurbiprofen since the half-life of elimination is similar to that found in young, healthy male volunteers. The mean volume of distribution is lower in elderly females than in elderly or young males. The total amount of drug absorbed or the time to reach peak levels does not differ between age groups indicating that the rate of absorption is not altered with old age and thus the onset of action in geriatric patients is not delayed.

Flurbiprofen absorption was delayed up to 2 hours in some individuals when administered with food resulting in lower maximum plasma levels, but the total amount of drug absorbed was not affected by concomitant food intake.

In man, 20 to 25% of a dose of flurbiprofen is recovered from the urine as free and conjugated unchanged drug. Three major urinary metabolites have been identified with the most abundant being hydroxylation products, representing about 60 to 80% of the administered dose. At therapeutic blood levels, flurbiprofen is at least 99% bound to serum proteins. Excretion of flurbiprofen is completed 24 hours after the last dose.

Froben SR: Comparison of the AUC values for the sustained release capsules and conventional tablets show that the capsule has adequate bioavailability in most volunteers with no evidence of dose dumping or excessive accumulation of flurbiprofen. A steady state is reached within 2 to 3 days. The elimination half-life for flurbiprofen is 3 to 4 hours and is not significantly different following long-term administration.

Pharmacokinetic parameters determined in elderly patients have been shown to be comparable with those seen in younger patients. Studies in which young and elderly patients received single daily doses of sustained release capsules resulted in a Cmax, Cmaxs AUC0-48 and AUC0-48s of 7.53 µg/mL, 10.33 µg/mL, 134 µg• h/mL and 192.7 µg• h/mL, respectively in elderly patients compared to 8.56 µg/mL, 10.78 µg/mL, 138.5 µg• h/mL and 195.5 µg• h/mL, respectively in young patients.

The effect of food on Froben SR causes a delay in Tmax (from 5.5 to 8.3 hours), increases Cmax significantly (to 10 µg/mL) and increases bioavailability. The AUC for the sustained release capsules increases to a figure close to that of conventional tablets (taken fasting).

Indications And Clinical Uses: For the symptomatic treatment of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.

Also indicated for the relief of pain associated with dysmenorrhea.

Contra-Indications: Peptic ulcer or active inflammatory disease of the gastrointestinal system. Known or suspected hypersensitivity to flurbiprofen. Flurbiprofen should not be used in patients in whom acute asthmatic attacks, urticaria, rhinitis or other allergic manifestations are precipitated by ASA or other nonsteroidal anti-inflammatory agents. Fatal anaphylactoid reactions have occurred in such individuals.

Manufacturers’ Warnings In Clinical States: Peptic ulceration, perforation and gastrointestinal bleeding, sometimes severe and occasionally fatal have been reported during therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) including flurbiprofen.

Flurbiprofen should be given under close medical supervision to patients prone to gastrointestinal tract irritation particularly those with a history of peptic ulcer, diverticulosis or other inflammatory disease of the gastrointestinal tract. In these cases the physician must weigh the benefits of treatment against the possible hazards.

Patients taking any NSAID including this drug should be instructed to contact a physician immediately if they experience symptoms or signs suggestive of peptic ulceration or gastrointestinal bleeding. These reactions can occur without warning symptoms or signs and at any time during the treatment.

Elderly, frail and debilitated patients appear to be at higher risk from a variety of adverse reactions from NSAIDs. For such patients, consideration should be given to a starting dose lower than usual, with individual adjustment when necessary and under close supervision (see Precautions).

Pregnancy and Lactation: Flurbiprofen should not be used during pregnancy, or in nursing mothers as its safety under these conditions has not been established. Although no teratogenic effects were seen in animal studies, parturition was delayed and prolonged and the number of stillbirths was increased. Flurbiprofen has been found to cross the placental barrier, but it is not known if it is secreted in breast milk.

Children: The safety and efficacy of flurbiprofen has not been established in children, and therefore its use in this age group is not recommended.

Precautions: General: Elderly patients, particularly women, should be carefully followed for the appearance of side effects and the dosage decreased accordingly.

Gastrointestinal: If peptic ulceration is suspected or confirmed, or if gastrointestinal bleeding or perforation occurs, flurbiprofen should be discontinued, an appropriate treatment instituted and patient closely monitored.

There is no definitive evidence that the concomitant administration of histamine H2-receptor antagonists and/or antacids will either prevent the occurrence of gastrointestinal side effects or allow continuation of therapy when and if these adverse reactions appear.

Renal: As with other nonsteroidal anti-inflammatory drugs (NSAIDs), long-term administration of flurbiprofen to animals has resulted in renal papillary necrosis and other abnormal renal pathology. In humans, there have been reports of acute interstitial nephritis with hematuria, proteinuria, and occasionally nephrotic syndrome.

A second form of renal toxicity has been seen in patients with prerenal conditions leading to the reduction in renal blood flow or blood volume, where the renal prostaglandins have a supportive role in the maintenance of renal perfusion. In these patients, administration of a NSAID may cause a dose-dependent reduction in prostaglandin formation and 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 the elderly. Discontinuation of nonsteroidal anti-inflammatory therapy is usually followed by recovery to the pre-treatment state.

Flurbiprofen and its metabolites are eliminated primarily by the kidneys, therefore the drug should be used with great caution in patients with impaired renal function. In these cases lower doses of flurbiprofen should be anticipated and patients carefully monitored.

During long-term therapy kidney function should be monitored periodically.

Hepatic: As with other NSAIDs, borderline elevations of one or more liver tests may occur. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. A patient with symptoms and/or signs suggesting liver dysfunction, or in whom an abnormal liver test has occurred, should be evaluated for evidence of the development of more severe hepatic reaction while on therapy with this drug. Severe hepatic reactions including jaundice and cases of fatal hepatitis have been reported with this drug as with other NSAIDs. Although such reactions are rare, if abnormal liver tests persist or worsen, if clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, etc.), this drug should be discontinued.

During long-term therapy, liver function tests should be monitored periodically. If this drug is to be used in the presence of impaired liver function, it must be done under strict observation.

Fluid and Electrolyte Balance: Fluid retention and edema have been observed in patients treated with flurbiprofen. Therefore, as with many other NSAIDs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be borne in mind. Flurbiprofen should be used with caution in patients with heart failure, hypertension or other conditions predisposing to fluid retention.

Serum electrolytes should be monitored periodically during long-term therapy, especially in those patients at risk.

Hematology: Drugs inhibiting prostaglandin biosynthesis do interfere with platelet function to some degree; therefore, patients who may be adversely affected by such an action should be carefully observed when flurbiprofen is administered.

Blood dyscrasias associated with the use of NSAIDs are rare, but could be with severe consequences.

Infection: In common with other anti-inflammatory drugs, flurbiprofen may mask the usual signs of infection.

Ophthalmology: Blurred and/or diminished vision has been reported with the use of flurbiprofen and other NSAIDs. If such symptoms develop, this drug should be discontinued and an ophthalmologic examination performed; ophthalmic examination should be carried out at periodic intervals in any patient receiving this drug for an extended period of time.

Drug Interactions: ASA or other NSAIDs: The concomitant administration of ASA with flurbiprofen caused decreased serum levels and peak concentrations of flurbiprofen. The rates of absorption and elimination of flurbiprofen were not affected.

Digoxin: Flurbiprofen does not change the rate of elimination of digoxin and the rate of elimination of flurbiprofen is not altered by co-administration of digoxin. Although, digoxin absorption may be delayed during co-administration of flurbiprofen.

Coumarin Type Anticoagulants: In a short-term study flurbiprofen did not significantly affect prothrombin time but the bleeding time increased slightly, although it remained within the normal range. Flurbiprofen should therefore be administered with caution to patients on concomitant coumarin-type anticoagulant therapy. Such patients should be closely monitored.

Oral Hypoglycemic Drugs: Co-administration of flurbiprofen with glibenclamide, metformin, chlorpropamide or phenformin did not lead to interaction effects of any clinical significance. A tendency towards a reduction in blood sugar levels occurred over a 24 hour period however no hypoglycemic reactions occurred. No interaction in terms of blood sugar or immuno-reactive insulin occurred following the co-administration of flurbiprofen and tolbutamide.

Methotrexate: Caution is advised in the concomitant administration of flurbiprofen and methotrexate since nonsteroidal anti-inflammatory agents have been reported to increase the blood concentration of methotrexate, thereby possibly enhancing its toxicity.

Lithium: Nonsteroidal anti-inflammatory agents have been reported to increase the steady state plasma levels of lithium. It is recommended that lithium plasma levels be monitored when co-administering it with flurbiprofen.

Diuretics: Flurbiprofen antagonizes the action of i.v. or oral furosemide.

Antihypertensives: No significant alterations in the pharmacokinetics of either propranolol or atenolol followed pre-treatment with placebo or flurbiprofen. However, pre-treatment with flurbiprofen attenuated the effects of propranolol on blood pressure but not on heart rate. The hypotensive effect caused by atenolol was attenuated to a lesser degree following flurbiprofen pre-treatment.

Antacids: The pharmacokinetics of a single oral dose of flurbiprofen are not altered by the concomitant administration of a magnesium and aluminum hydroxide antacid formulation.

Clinical Laboratory Tests: Flurbiprofen and Thyroid Function Tests: Flurbiprofen does not modify the laboratory parameters of thyroid function. Flurbiprofen is extensively bound to plasma protein and thus patients receiving concomitant drugs such as oral diabetic agents, sulfonamides, anticoagulants, and phenytoin should be monitored closely for side effects and/or clinical effectiveness and dosage adjustments made, if necessary.

Adverse Reactions: The most common adverse reactions encountered with NSAIDs are gastrointestinal, of which peptic ulcer, with or without bleeding, is the most severe. Fatalities have occurred on occasion, particularly in the elderly.

Froben: The adverse reaction incidences were those reported during controlled clinical trials and include data from 2 141 patients on the conventional Froben tablets. Gastrointestinal adverse reactions were the most common, with ulceration and bleeding the most severe. The trials included 55 patients who received flurbiprofen for 3 months, 85 for 6 months at doses up to 300 mg daily, and 191 who received it for 3 years at a dose of 200 mg daily. The adverse report figures below represent the percent of treated patients reporting an adverse reaction.

Gastrointestinal (26.4%): dyspepsia (5.9%); nausea (with or without vomiting) (5.4%); gastrointestinal pain (4.5%); gastrointestinal bleeding (0.3%); diarrhea (2.3%); constipation (1.6%); gastritis (0.3%); flatulence (0.3%); anorexia (0.5%); peptic ulceration (0.3%); melena (0.1%); stomatitis (0.3%); others (4.7%). Although not reported in this series of clinical trials, glossitis and eructation have been observed.

CNS (7.2%): headache (2.0%); dizziness (1.6%); depression (0.6%); drowsiness (0.4%); insomnia (0.2%); confusion (0.2%); other (2.2%). Although not reported in this series of clinical trials, vertigo, paresthesia, nervousness, mood alteration, ataxia, and tremor have been observed.

Dermatological (1.8%): rash (0.9%); pruritus (0.6%); urticaria (0.1%) and dryness of skin (0.1%). Two cases of Stevens-Johnson syndrome have been reported.

Renal (0.9%): edema (0.6%); frequency (0.3%) and hematuria (0.1%). Although not reported in this series of trials, dysuria, urinary incontinence and urine abnormalities (decreased osmolality, albuminuria) have been reported.

Hematological (0.3%): epistaxis (0.2%) and anemia (0.1%). Although not seen in this series of clinical trials, aplastic anemia, thrombocytopenia, granulocytopenia, leukopenia, purpura, and petechia have been observed.

Respiratory (1.2%): dry mouth/nose (0.4%); chest pain (0.3%) and dyspnea (0.1%). Although not seen in this series of clinical trials, asthma has been observed.

Cardiovascular (0.3%): cramps (0.1%) and palpitations (0.1%).

Miscellaneous (3.6%): weight gain/loss (0.2%); exhaustion (0.6%); sweating (0.4%); hot flushes (0.3%) and others (2.1%). Although not seen in this series of clinical trials, vaginal hemorrhage has been reported.

Hepatic: Although not reported in this series of clinical trials, increased AST and alkaline phosphatase and hepatitis have been reported.

Special Senses: One case of tinnitus was reported. Although not reported in this series of studies, blurred vision, conjunctivitis, photophobia, abnormal accommodation, corneal opacity and taste alteration have been reported.

Froben SR: Reports from clinical trials involving a total of 2 231 patients on both the conventional tablets and the sustained release capsules (1 787 patients were administered the sustained release capsules) showed similar adverse reactions for both dosage forms.

Symptoms And Treatment Of Overdose: Symptoms: No fatal cases of overdosage have been reported in conjunction with flurbiprofen ingestion and those suffering with overdosage recovered without sequelae.

Treatment: No specific antidote is known. Stomach emptying is advisable and supportive and symptomatic treatment with maintenance of electrolytes and acid balance is recommended.

Dosage And Administration: Froben: Rheumatoid Arthritis: The usual recommended initial dose is 150 to 200 mg/day given in 3 or 4 divided doses. Some patients may initially require 250 to 300 mg/day. The dose should be adjusted until the minimum effective maintenance dose is established. During the course of treatment the maximum daily dose of 300 mg should be used only during symptom exacerbations and not for maintenance therapy.

Osteoarthritis: The usual recommended initial dose is 100 to 150 mg/day given in 2 or 3 divided doses. Some patients may initially require 200 to 300 mg/day. The dose should be adjusted until the minimum effective maintenance dose is established. During the course of treatment, the maximum daily dose of 300 mg should be used only during symptom exacerbations and not for maintenance therapy.

Ankylosing Spondylitis: The usual recommended initial dose is 200 mg/day given in 4 divided doses. Some patients may initially require 250 to 300 mg/day. The dose should be adjusted until the minimum effective maintenance dose is established. During the course of treatment, the maximum daily dose of 300 mg should be used only during symptom exacerbations and not for maintenance therapy.

Dysmenorrhea: The usual recommended dosage is 50 mg given 4 times daily, beginning with the onset of dysmenorrhea and ending with the cessation of pain.

Froben SR: This dosage form is recommended for maintenance therapy of patients whose dose has been previously adjusted to 200 mg daily. The recommended daily dose of Froben SR is one 200 mg capsule, taken in the evening after food. The capsule should be swallowed whole.

Children: The safety and efficacy of flurbiprofen has not been established in children and therefore its use in this group is not recommended.

Availability And Storage: Froben: Each white, sugar coated tablet contains: flurbiprofen 50 mg (overprinted F50 in black) or 100 mg (overprinted F100 in black). Nonmedicinal ingredients: carnauba wax, colloidal silicon dioxide, cornstarch, dimethylpolysiloxane, gum juniper (sandarac), iron oxide black, lactose, liquid glucose, magnesium stearate, povidone, shellac, sodium benzoate, soya lecithin, stearic acid, sucrose, talc and titanium dioxide. Bottles of 100.

Froben SR: Each hard gelatin capsule with a yellow opaque cap and a transparent yellow body containing white to off-white beads, printed FSR in black, contains: flurbiprofen 200 mg in sustained release form. Nonmedicinal ingredients: avicel PH101 microcrystalline cellulose, colloidal silicon dioxide, eudragit RS100, magnesium stearate B.P. and polyethylene glycol 6 000. Capsule shell: Nonmedicinal ingredients: erythrosine, gelatin, glycerin, quinoline yellow, red iron oxide, sodium metabisulfate, titanium dioxide. Printing ink: nonmedicinal ingredients: black iron oxide, polydimethylsiloxane, soya lecithin and shellac. Bottles of 100.

FROBEN® FROBEN SR® Knoll Flurbiprofen Nonsteroidal Anti-inflammatory Agent

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