Flufenamic Acid
Adverse Effects and Precautions as for NSAIDs in general, like ibuprofen.
IBUPROFEN
WARNINGS
Gastrointestinal (GI) Effects - Risk of GI Ulceration, Bleeding and Perforation: Serious gastrointestinal toxicity, such as inflammation, bleeding, ulceration, and perforation of the stomach, small intestine or large intestine, can occur at any time, with or without warning symptoms, in patients treated with nonsteroidal anti-inflammatory drugs (NSAIDs). Minor upper GI problems, such as dyspepsia, are common and may also occur at any time during NSAID therapy. Therefore, physicians and patients should remain alert for ulceration and bleeding even in the absence of previous GI tract symptoms. Patients should be informed about the signs and/or symptoms of serious GI toxicity and what steps to take if they occur. The utility of periodic laboratory monitoring has not been demonstrated, nor has it been adequately assessed. Only one in five patients, who develop a serious upper GI adverse event of NSAID therapy, is symptomatic. 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. 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, the lowest effective dose should be used for the shortest possible duration. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Studies have shown that patients with a prior history of peptic ulcer disease and/or gastrointestinal bleeding and who use NSAIDs, have a greater than 10-fold risk for developing a GI bleed than patients with neither of these risk factors. In addition to a past history of ulcer disease, pharmaco-epidemiological studies have identified several other co-therapies or co-morbid conditions that may increase the risk for GI bleeding such as: treatment with oral corticosteroids, treatment with anticoagulants, longer duration of NSAID therapy, smoking, alcoholism, older age, and poor general health status.
Anaphylactoid Reactions: Anaphylactoid reactions may occur in patients without known prior exposure to BRUFEN. BRUFEN should not be given to patients with the aspirin triad. The triad 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. Fatal reactions to NSAIDs have been reported in such patients (see CONTRAINDICATIONS and PRECAUTIONS - Pre-existing Asthma ). Emergency help should be sought when anaphylactoid reaction occurs.
Advanced Renal Disease: In cases with advanced kidney disease, treatment with BRUFEN is not recommended. If NSAID therapy, however, must be initiated, close monitoring of the patient's kidney function is advisable (see PRECAUTIONS - Renal Effects ).
Pregnancy: As with other NSAID-containing products, BRUFEN should be avoided in late pregnancy because it may cause premature closure of the ductus arteriosus.
PRECAUTIONS
General Precautions
Special Risk Patients:
Effect on Diagnostic Signs: The antipyretic and anti-inflammatory activity of ibuprofen may reduce fever and inflammation, thus diminishing their utility as diagnostic signs in detecting complications of presumed noninfectious, noninflammatory painful conditions.
Hepatic Effects: As with other NSAIDs, ibuprofen has been reported to cause borderline elevations of one or more liver enzymes; this may occur in up to 15% of patients. These abnormalities may progress, may remain essentially unchanged, or may be transient with continued therapy. Notable (3 times the upper limit of normal) elevations of SGPT (ALT) or SGOT (AST) occurred in controlled clinical trials in less than 1% of patients. 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 reactions while on therapy with BRUFEN. Severe hepatic reactions, including jaundice and cases of fatal hepatitis, have been reported with ibuprofen 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.), BRUFEN should be discontinued.
Renal Effects: Caution should be used when initiating treatment with BRUFEN in patients with considerable dehydration. It is advisable to rehydrate patients first and then start therapy with BRUFEN. Caution is also recommended in patients with pre-existing kidney disease (see WARNINGS - Advanced Renal Disease ).
As with other NSAIDs, long-term administration of ibuprofen has resulted in renal papillary necrosis and other renal pathologic changes. Renal toxicity has also been seen in patients in which 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 nonsteroidal anti-inflammatory drug therapy is usually followed by recovery to the pretreatment state.
Ibuprofen metabolites are eliminated primarily by the kidneys. The extent to which the metabolites may accumulate in patients with renal failure has not been studied. Patients with significantly impaired renal function should be more closely monitored.
Hematological Effects: Ibuprofen, like other NSAIDs, can inhibit platelet aggregation but the effect is quantitatively less and of shorter duration than that seen with aspirin. Ibuprofen has been shown to prolong bleeding time in normal subjects. Because this prolonged bleeding effect may be exaggerated in patients with underlying hemostatic defects, BRUFEN should be used with caution in persons with intrinsic coagulation defects and those on anticoagulant therapy.
Anemia is sometimes seen in patients receiving NSAIDs, including ibuprofen. This may be due to fluid retention, GI loss, or an incompletely described effect upon erythropoiesis.
Fluid Retention and Edema: Fluid retention and edema have been reported in association with ibuprofen, therefore, the drug should be used with caution in patients with a history of cardiac decompensation, hypertension or heart failure.
Pre-existing Asthma: Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which may be fatal. Since cross-reactivity between aspirin and other NSAIDs has been reported in such aspirin-sensitive patients, BRUFEN should not be administered to patients with this form of aspirin sensitivity and should be used with caution in patients with pre-existing asthma.
Aseptic Meningitis: Aseptic meningitis with fever and coma has been observed on rare occasions in patients on ibuprofen therapy. Although it is probably more likely to occur in patients with systemic lupus erythematosus and related connective tissue diseases, it has been reported in patients who do not have an underlying chronic disease. If signs or symptoms of meningitis develop in a patient on BRUFEN, the possibility of its being related to ibuprofen should be considered.
Information for Patients
BRUFEN, like other opioid-containing analgesics, may impair mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery; patients should be cautioned accordingly.
Alcohol and other CNS depressants may produce an additive CNS depression, when taken with this combination product, and should be avoided.
BRUFEN may be habit-forming. Patients should take the drug only for as long as it is prescribed, in the amounts prescribed, and no more frequently than prescribed.
BRUFEN, like other drugs containing ibuprofen, is not free of side effects. The side effects of these drugs can cause discomfort and, rarely, there are more serious side effects, such as gastrointestinal bleeding, which may result in hospitalization and even fatal outcomes. Patients should be instructed to report any signs and symptoms of gastrointestinal bleeding, blurred vision or other eye symptoms, skin rash, weight gain, or edema.
Laboratory Tests
A decrease in hemoglobin may occur during BRUFEN® and elevations of liver enzymes may be seen in a small percentage of patients during BRUFEN therapy (see PRECAUTIONS - Hematological Effects and PRECAUTIONS - Hepatic Effects ).
In patients with severe hepatic or renal disease, effects of therapy should be monitored with liver and/or renal function tests.
Drug Interactions
ACE-Inhibitors: Reports suggest that NSAIDs may diminish the antihypertensive effect of ACE-inhibitors. This interaction should be given consideration in patients taking BRUFEN concomitantly with ACE-inhibitors.
Anticholinergics: The concurrent use of anticholinergics with hydrocodone preparations may produce paralytic ileus.
Antidepressants: The use of MAO inhibitors or tricyclic antidepressants with BRUFEN may increase the effect of either the antidepressant or hydrocodone.
Aspirin: As with other products containing NSAIDs, concomitant administration of BRUFEN and aspirin is not generally recommended because of the potential of increased adverse effects.
Furosemide Ibuprofen has been shown to 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 BRUFEN the patient should be observed closely for signs of renal failure (see PRECAUTIONS - Renal Effects ), as well as diuretic efficacy.
Lithium Ibuprofen has been shown to elevate plasma lithium concentration and reduce renal lithium clearance. This effect has been attributed to inhibition of renal prostaglandin synthesis by ibuprofen. Thus, when BRUFEN and lithium are administered concurrently, patients should be observed for signs of lithium toxicity.
Methotrexate: Ibuprofen, as well as other NSAIDs, has been reported to competitively inhibit methotrexate accumulation in rabbit kidney slices. This may indicate that ibuprofen could enhance the toxicity of methotrexate. Caution should be used when BRUFEN is administered concomitantly with methotrexate.
Warfarin: 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.
Carcinogenicity, Mutagenicity, and Impairment of Fertility
The carcinogenic and mutagenic potential of BRUFEN has not been investigated. The ability of BRUFEN to impair fertility has not been assessed.
Pregnancy: Pregnancy Category C.
Teratogenic Effects: BRUFEN, administered to rabbits of 95 mg/kg (5.72 and 1.9 times the maximum clinical dose based on body weight and surface area, respectively), a maternally toxic dose, resulted in an increase in the percentage of litters and fetuses with any major abnormality and an increase in the number of litters and fetuses with one or more nonossified metacarpals (a minor abnormality). BRUFEN, administered to rats at 166 mg/kg (10.0 and 1.66 times the maximum clinical dose based on body weight and surface area, respectively), a maternally toxic dose, did not result in any reproductive toxicity. There are no adequate and well-controlled studies in pregnant women. BRUFEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nonteratogenic Effects: Because of the known effects of nonsteroidal anti-inflammatory drugs on the fetal cardiovascular system (closure of the ductus arteriosus), use during pregnancy (particularly late pregnancy) should be avoided.
As with other drugs known to inhibit prostaglandin synthesis, an increased incidence of dystocia and delayed parturition occurred in rats. Administration of BRUFEN is not recommended during labor and delivery.
Nursing Mothers
It is not known whether hydrocodone is excreted in human milk. In limited studies, an assay capable of detecting 1 mcg/mL did not demonstrate ibuprofen in the milk of lactating mothers. However, because of the limited nature of the studies, and the possible adverse effects of protaglandin-inhibiting drugs on neonates, BRUFEN is not recommended for use in nursing mothers.
Pediatric Use
The safety and effectiveness of BRUFEN in pediatric patients below the age of 16 have not been established.
Geriatric Use
ADVERSE REACTIONS
BRUFEN was administered to approximately 300 pain patients in a safety study that employed dosages and a duration of treatment sufficient to encompass the recommended usage (see DOSAGE AND ADMINISTRATION ). Adverse event rates generally increased with increasing daily dose. The event rates reported below are from approximately 150 patients who were in a group that received one tablet of BRUFEN an average of three to four times daily. The overall incidence rates of adverse experiences in the trials were fairly similar for this patient group and those who received the comparison treatment, acetaminophen 600 mg with codeine 60 mg.
The following lists adverse events that occurred with an incidence of 1% or greater in clinical trials of BRUFEN, without regard to the causal relationship of the events to the drug. To distinguish different rates of occurrence in clinical studies, the adverse events are listed as follows:
name of adverse event = less than 3%
adverse events marked with an asterisk * = 3% to 9%
adverse event rates over 9% are in parentheses.
Body as a Whole: Abdominal pain*; Asthenia*; Fever; Flu syndrome; Headache (27%); Infection*; Pain.
Cardiovascular: Palpitations; Vasodilation.
Central Nervous System: Anxiety*; Confusion; Dizziness (14%); Hypertonia; Insomnia*; Nervousness*; Paresthesia; Somnolence (22%); Thinking abnormalities.
Digestive Anorexia; Constipation (22%); Diarrhea*; Dry mouth*; Dyspepsia (12%); Flatulence*; Gastritis; Melena; Mouth ulcers; Nausea (21%); Thirst; Vomiting*.
Metabolic and Nutritional Disorders: Edema*.
Respiratory: Dyspnea; Hiccups; Pharyngitis; Rhinitis.
Skin and Appendages: Pruritus*; Sweating*.
Special Senses: Tinnitus.
Urogenital: Urinary frequency.
Incidence less than 1%
Body as a Whole: Allergic reaction.
Cardiovascular: Arrhythmia; Hypotension; Tachycardia.
Central Nervous System: Agitation; Abnormal dreams; Decreased libido; Depression; Euphoria; Mood changes; Neuralgia; Slurred speech; Tremor, Vertigo.
Digestive: Chalky stool; "Clenching teeth"; Dysphagia; Esophageal spasm; Esophagitis; Gastroenteritis; Glossitis; Liver enzyme elevation.
Metabolic and Nutritional: Weight decrease.
Musculoskeletal Arthralgia; Myalgia.
Respiratory: Asthma; Bronchitis; Hoarseness; Increased cough; Pulmonary congestion; Pneumonia; Shallow breathing; Sinusitis.
Skin and Appendages: Rash; Urticaria.
Special Senses: Altered vision; Bad taste; Dry eyes.
Urogenital Cystitis; Glycosuria; Impotence; Urinary incontinence; Urinary retention.
Effects on the gastro-intestinal tract. Acute proctocoli-
tis associated with oral Flufenamic acid in one patient.
Porphyria. Flufenamic acid has been associated with acute
attacks of porphyria and is considered unsafe in patients with
acute porphyria.
Uses and Administration
Flufenamic acid an anthranilic acid derivative related to
mefenamic acid , is an NSAID . Flufenamic acid
is mainly used topically in a concentration of 2.5 to 3.5% for
the relief of pain and inflammation associated with muscu-
loskeletal, joint, and soft-tissue disorders. It has also been
given by mouth.