Ansaid (Flurbiprofen)

ANSAID®

Pharmacia & Upjohn

Flurbiprofen

Anti-inflammatory – Analgesic

Action And Clinical Pharmacology: Flurbiprofen, a phenylalkanoic acid derivative, is a nonsteroidal anti-inflammatory agent which also possesses analgesic and antipyretic activities. Its mode of action, like that of other nonsteroidal anti-inflammatory agents, is not known. However, its therapeutic action is not due to pituitary-adrenal stimulation. Flurbiprofen is an inhibitor of prostaglandin synthesis. The resulting decrease in prostaglandin synthesis may partially explain the drug’s anti-inflammatory effect at the cellular level.

Pharmacokinetics: In bioavailability studies in normal volunteers, flurbiprofen reached peak blood levels in about 1.5 hours (range of 0.5 to 4 hours). Its plasma half-life is 5.7 hours (range of 3 to 9 hours). Administration with food does not alter total drug availability but delays absorption. Excretion is 88 to 98% complete within 24 hours after the last dose.

Flurbiprofen is rapidly metabolized and excreted in the urine as free and unaltered intact drug (20%) and hydroxylated metabolites (50%). About 90% of the flurbiprofen in urine is present as conjugates. In animal models of inflammation the metabolites showed no activity. Flurbiprofen is extensively bound (99%) to human plasma protein such as albumin, but less than 10% of the primary albumin binding sites would be occupied by the drug. Flurbiprofen binds to a different primary site on albumin than do anticoagulants, sulfonamides and phenytoin. Mean peak serum concentrations of flurbiprofen were higher in the elderly female patients.

Indications And Clinical Uses: For the relief of signs and symptoms of rheumatoid arthritis, osteoarthritis and ankylosing spondylitis.

For the relief of pain associated with dysmenorrhea.

For the relief of mild to moderate pain accompanied by inflammation (e.g., bursitis, tendinitis, soft-tissue trauma).

Contra-Indications: Flurbiprofen should not be used in patients with active, or recent history of inflammatory diseases of the gastrointestinal tract such as peptic ulcer, gastritis, regional enteritis or ulcerative colitis.

It is contraindicated in patients with a history of hypersensitivity to the drug.

It 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: General: ulceration, perforation and bleeding of the stomach, small intestine, large intestine, 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 nonsteroidal anti-inflammatory drugs including flurbiprofen 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 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: Safe use in pregnancy and lactation has not been established. Although no teratogenic effects were seen in animal studies, parturition was delayed and prolonged, and there was an increase in the number of stillbirths. Flurbiprofen has been found to cross the placental barrier, and it is secreted in breast milk. Therefore, the use of this drug is not recommended during pregnancy and lactation.

Children: Safety and efficacy has not been established in children, and therefore the use in this age group is not recommended.

Pre-existing asthma: About 10% of patients with asthma may have ASA-sensitive asthma. The use of ASA in patients with ASA-sensitive Asthma has been associated with severe bronchospasm which can be fatal. Since cross-reactivity, including bronchospasm, between ASA and other NSAIDs has been reported in such ASA-sensitive patients, flurbiprofen should not be administered to patients with this form of ASA-sensitivity and should be used with caution in all patients with pre-existing asthma.

Precautions: As with all NSAIDs, flurbiprofen should be used with caution in the elderly particularly women and the dosage should be adjusted individually.

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 definite 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 flurbiprofen therapy when and if these adverse reactions appear.

Renal Function: As with other 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 pretreatment 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 Function: 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 nonsteroidal anti-inflammatory drugs, the possibility of precipitating congestive heart failure in elderly patients or those with compromised cardiac function should be born 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: NSAIDs, including flurbiprofen, can increase the risk of bleeding in patients receiving anticoagulants, and should be given with caution.

NSAIDs including flurbiprofen can cause reductions in hemoglobin and should be used with caution in patients who are anemic.

Flurbiprofen inhibits collagen-induced platelet aggregation, and patients who may be adversely affected by prolonged bleeding time 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: Anticoagulants, Sulfonamides, Phenytoin: Flurbiprofen affects bleeding parameters and serious clinical bleeding has been reported. Caution is advised.

Flurbiprofen is extensively protein bound (99%) to human serum albumin. Less than 10% of the primary binding sites were estimated to be occupied at therapeutic drug concentrations. In vitro studies suggest that it binds to a different primary site on albumin (Type II) than drugs such as anticoagulants, sulfonamides and phenytoin (Type I). However, patients with such combination therapy should be monitored.

ASA: Concomitant oral administration of flurbiprofen and ASA indicates that flurbiprofen has no significant effect on the pharmacokinetics and metabolism of ASA. However, concomitant administration of ASA decreases flurbiprofen peak serum levels, as well as the rate and amount of flurbiprofen absorbed.

Antacids: In geriatric subjects antacid suspensions caused a reduction in the rate but not the extent of flurbiprofen absorption.

B-adrenergic Blocking Agents: Flurbiprofen pretreatment attenuated the hypotensive effect of propranolol but did not appear to affect the b-blocker mediated reduction in heart rate.

Cimetidine, Ranitidine: A small but statistically significant increase in flurbiprofen serum concentration may result with administration of these agents.

Digoxin: Concurrent administration of digoxin with flurbiprofen did not reveal a change in steady-state serum levels of either drug.

Diuretics: Flurbiprofen can interfere with the effects of furosemide. NSAIDs have been shown to interfere with the action of thiazide diuretics and potassium-sparing diuretics.

Oral Hypoglycemic Agents: Concomitant administration of flurbiprofen and hypoglycemic agents revealed a slight reduction in blood sugar concentrations but no signs or symptoms of hypoglycemia.

Adverse Reactions: In clinical trials of flurbiprofen a total of 2 820 patients were treated. Gastrointestinal adverse reactions were those most commonly seen, the most severe of which were gastrointestinal bleeding and ulceration.

Gastrointestinal (24.3%): abdominal pain 6.8%; dyspepsia 6.0%; diarrhea 5.7%; nausea 4.5%; constipation 2.6%; gastrointestinal bleeding 1.7%; flatulence 1.4%; emesis 1.2%; elevated liver enzymes 1.4%. Incidence 0.1 to 1.0%: increased appetite, stomatitis, gastrointestinal distress, gastritis, gastroenteritis, ulcer (peptic, gastric or duodenal), melena (includes rectal bleed, bloody diarrhea), oral inflammation, eructation, dry mouth, esophagitis, hematemesis, colitis, hepatitis, rectal discomfort, periodontal abscess, gingivitis, glossitis, anorexia, vomiting. Incidence less than 0.1%: gums bleeding, cholecystitis.

CNS (8.0%): headache 2.6%; asthenia 1.0%. Incidence 0.1% to 1.0%: somnolence, hypertonia, insomnia, nervousness, paresthesia, depression, mood changes, tremors, anxiety, amnesia, migraine, ataxia, cerebrovascular accident, confusion, cerebral ischemia, malaise, increased reflex. Incidence less than 0.1%: EEG abnormalities, neuralgia, convulsions, meningitis, speech disorder, twitch, euphoria, decreased libido.

Respiratory (9.6%): pharyngitis 6.1%; infection 1.2%; rhinitis 1.3%; sinusitis 1.6%. Incidence 0.1 to 1.0%: bronchitis, epistaxis, increase in cough, dyspnea, laryngitis, lung disorder, asthma, voice alterations. Incidence less than 0.1%: hyperventilation, pleural distress, pulmonary infarct, pulmonary embolism, pneumonia.

General Body (6.7%): edema 2.6%; pain 1.9%; flu syndrome 2.0%. Incidence 0.1 to 1.0%: fever, abdominal enlargement, chills, infection, allergic reaction, death. Incidence less than 0.1%: injury.

Special Senses (5.2%): Ear: dizziness 1.5%; tinnitus 1.2%; vertigo 0.6%; pain 0.3%; disorder 0.2%. Incidence less than 0.1%: vestibular disturbances.

Eye: ocular inflammations 0.3%; amblyopia 0.6%; vision disturbances 0.4%; blepharitis 0.1%; conjunctivitis 0.5%; keratoconjunctivitis 0.1%; photophobia 0.1%. Incidence less than 0.1%: diplopia, visual field problems, corneal opacity, lacrimal distress, glaucoma, pain, scleritis.

Others: taste changes 0.2%; parosmia
Urogenital (4.9%): urinary tract infections 1.5%. Incidence 0.1 to 1.0%: urine abnormalities, hematuria, cystitis, frequency, vaginitis, breast pain, kidney function abnormalities. Incidence less than 0.1%: dysuria, albuminuria, pyuria, pain, kidney stones, kidney failure, incontinence, ejaculatory abnormality, leukorrhea, urethritis, retention, dysmenorrhea, menstrual distress, impotence.

Cardiovascular (2.2%): Incidence 0.1 to 1.0%: hypertension, arrhythmias, inotropic problems, palpitations, vasodilatation, angina, phlebitis, vascular distress, extrasystoles, right heart failure, myocardial infarction, vasculitis. Incidence less than 0.1%: tachycardia, syncope.

Metabolic (1.1%): Incidence 0.1 to 1.0%: weight changes, hyperuricemia. Incidence less than 0.1%: electrolyte changes (Ca++, K+), increased CPK, thirst.

Musculoskeletal (0.7%): Incidence 0.1 to 1.0%: arthritis, injury, myalgia. Incidence less than 0.1%: myasthenia, tenosynovitis, joint disease.

Skin (3.5%): rash 1.9%. Incidence 0.1 to 1.0%: herpetic infections, alopecia, dry skin, eczema, nail discoloration, pruritus, sweating, skin ulcerations, urticaria. Incidence less than 0.1%: seborrhea, angioedema, exfoliation.

Hemic/Lymphatic (6.6%): Decrease in hemoglobin and hematocrit 4.6%. Incidence 0.1 to 1.0%: iron deficiency anemia, ecchymosis, eosinophilia, leukopenia, lymphadenopathy, neutropenia. Incidence less than 0.1%: anemia, leukocytosis, petechia, thrombocytopenia, WBC abnormality.

Rare events are derived principally from worldwide marketing experience and the literature. Accurate rate estimates are generally impossible. These include the following: cholestatic and non-cholestatic jaundice, exacerbation of inflammatory bowel disease, small intestine inflammation with loss of blood and protein, photosensitivity, toxic epidermal necrolysis, interstitial nephritis and anaphylaxis.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Information on flurbiprofen overdosage is available for 13 children and 12 adults; all persons receiving only a flurbiprofen overdose and all but one person exposed to more than 1 drug recovered. Manifestations of flurbiprofen overdose have included decreased mental status, coma, diminished muscle tone, headache, diplopia, elevated liver enzymes, respiratory depression, nausea, and epigastric pain.

Dosage And Administration: Rheumatoid Arthritis, Osteoarthritis, Ankylosing Spondylitis: 200 mg/day given in divided doses. Some patients may require up 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 (see Adverse Effects).

Dysmenorrhea: 50 mg given 4 times daily.

Mild to Moderately Severe Pain: 50 mg given every 4 to 6 hours as needed.

Availability And Storage: 50 mg: Each white, elliptical, film-coated tablet imprinted with Ansaid logo contains: flurbiprofen 50 mg. Nonmedicinal ingredients: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, film-coat white, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose. Gluten-free. Bottles of 100 and 500.

100 mg: Each blue, elliptical, film-coated tablet imprinted with Ansaid logo contains: flurbiprofen 100 mg. Nonmedicinal ingredients: carnauba wax, colloidal silicon dioxide, croscarmellose sodium, hydroxypropyl methylcellulose, lactose, magnesium stearate, microcrystalline cellulose, Opaspray blue. Gluten-free. Bottles of 100 and 500. (Shown in Product Recognition Section)

ANSAID® Pharmacia & Upjohn Flurbiprofen Anti-inflammatory – Analgesic

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