Diflunisal Information
Diflunisal ()
Diflunisal () Description
Diflunisal () is 2',4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid. Its structural formula is:
CHFO M.W. 250.20
Diflunisal () is a stable, white, crystalline compound with a melting point of 211° to 213°C. It is practically insoluble in water at neutral or acidic pH. Because it is an organic acid, it dissolves readily in dilute alkali to give a moderately stable solution at room temperature. It is soluble in most organic solvents including ethanol, methanol, and acetone.
Each tablet, for oral administration, contains 500 mg Diflunisal () . In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, FD&C Blue #2 aluminum lake, hypromellose, microcrystalline cellulose, pregelatinized starch, propylene glycol, sodium stearyl fumarate, and titanium dioxide.
Diflunisal () Clinical Pharmacology
Diflunisal () is a non-steroidal drug with analgesic, anti-inflammatory and antipyretic properties. It is a peripherally-acting non-narcotic analgesic drug. Habituation, tolerance, and addiction have not been reported.
Diflunisal () is a difluorophenyl derivative of salicylic acid. Chemically, Diflunisal () differs from aspirin (acetylsalicylic acid) in two respects. The first of these two is the presence of a difluorophenyl substituent at carbon 1. The second difference is the removal of the -acetyl group from the carbon 4 position. Diflunisal () is not metabolized to salicylic acid, and the fluorine atoms are not displaced from the difluorophenyl ring structure.
The precise mechanism of the analgesic and anti-inflammatory actions of Diflunisal () is not known. Diflunisal () is a prostaglandin synthetase inhibitor. In animals, prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain. Since prostaglandins are known to be among the mediators of pain and inflammation, the mode of action of Diflunisal () may be due to a decrease of prostaglandins in peripheral tissues.
Diflunisal () is rapidly and completely absorbed following oral administration with peak plasma concentrations occurring between 2 to 3 hours. The drug is excreted in the urine as two soluble glucuronide conjugates accounting for about 90% of the administered dose. Little or no Diflunisal () is excreted in the feces. Diflunisal () appears in human milk in concentrations of 2 to 7% of those in plasma. More than 99% of Diflunisal () in plasma is bound to proteins.
As is the case with salicylic acid, concentration-dependent pharmacokinetics prevail when Diflunisal () is administered; a doubling of dosage produces a greater than doubling of drug accumulation. The effect becomes more apparent with repetitive doses. Following single doses, peak plasma concentrations of 41 ± 11 mcg/mL (mean ± S.D.) were observed following 250 mg doses, 87 ± 17 mcg/mL were observed following 500 mg and 124 ± 11 mcg/mL following single 1000 mg doses. However, following administration of 250 mg b.i.d., a mean peak level of 56 ± 14 mcg/mL was observed on day 8, while the mean peak level after 500 mg b.i.d. for 11 days was 190 ± 33 mcg/mL. In contrast to salicylic acid which has a plasma half-life of 2 1/2 hours, the plasma half-life of Diflunisal () is 3 to 4 times longer (8 to 12 hours), because of a difluorophenyl substituent at carbon 1. Because of its long half-life and nonlinear pharmacokinetics, several days are required for Diflunisal () plasma levels to reach steady state following multiple doses. For this reason, an initial loading dose is necessary to shorten the time to reach steady-state levels, and 2 to 3 days of observation are necessary for evaluating changes in treatment regimens if a loading dose is not used.
Studies in baboons to determine passage across the blood-brain barrier have shown that only small quantities of Diflunisal () , under normal or acidotic conditions are transported into the cerebrospinal fluid (CSF). The ratio of blood/CSF concentrations after intravenous doses of 50 mg/kg or oral doses of 100 mg/kg of Diflunisal () was 100:1. In contrast, oral doses of 500 mg/kg of aspirin resulted in a blood/CSF ratio of 5:1.
Diflunisal () is a peripherally-acting analgesic agent with a long duration of action. Diflunisal () produces significant analgesia within 1 hour and maximum analgesia within 2 to 3 hours.
Consistent with its long half-life, clinical effects of Diflunisal () mirror its pharmacokinetic behavior, which is the basis for recommending a loading dose when instituting therapy. Patients treated with Diflunisal () , on the first dose, tend to have a slower onset of pain relief when compared with drugs achieving comparable peak effects. However, Diflunisal () produces longer lasting responses than the comparative agents.
Comparative single dose clinical studies have established the analgesic efficacy of Diflunisal () at various dose levels relative to other analgesics. Analgesic effect measurements were derived from hourly evaluations by patients during eight and twelve hour postdosing observation periods. The following information may serve as a guide for prescribing Diflunisal () .
Diflunisal () 500 mg was comparable in analgesic efficacy to aspirin 650 mg, acetaminophen 600 mg or 650 mg, and acetaminophen 650 mg with propoxyphene napsylate 100 mg. Patients treated with Diflunisal () had longer lasting responses than the patients treated with the comparative analgesics.
Diflunisal () 1000 mg was comparable in analgesic efficacy to acetaminophen 600 mg with codeine 60 mg. Patients treated with Diflunisal () had longer lasting responses than the patients who received acetaminophen with codeine.
A loading dose of 1000 mg provides faster onset of pain relief, shorter time to peak analgesic effect, and greater peak analgesic effect than an initial 500 mg dose.
In contrast to the comparative analgesics, a significantly greater proportion of patients treated with Diflunisal () did not remedicate and continued to have a good analgesic effect eight to twelve hours after dosing. Seventy-five percent (75%) of patients treated with Diflunisal () continued to have a good analgesic response at four hours. When patients having a good analgesic response at four hours were followed, 78% of these patients continued to have a good analgesic response at eight hours and 64% at twelve hours.
The effectiveness of Diflunisal () for the treatment of osteoarthritis was studied in patients with osteoarthritis of the hip and/or knee. The activity of Diflunisal () was demonstrated by clinical improvement in the signs and symptoms of disease activity.
In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, Diflunisal () 500 or 750 mg daily was shown to be comparable in effectiveness to aspirin 2000 or 3000 mg daily. In open-label extensions of this study to 24 or 48 weeks, Diflunisal () continued to show similar effectiveness and generally was well tolerated.
In controlled clinical trials, the effectiveness of Diflunisal () was established for both acute exacerbations and long-term management of rheumatoid arthritis. The activity of Diflunisal () was demonstrated by clinical improvement in the signs and symptoms of disease activity.
In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient response, Diflunisal () 500 or 750 mg daily was comparable in effectiveness to aspirin 2600 or 3900 mg daily. In open-label extensions of this study to 52 weeks, Diflunisal () continued to be effective and was generally well tolerated.
Diflunisal () 500, 750, or 1000 mg daily was compared with aspirin 2000, 3000, or 4000 mg daily in a multicenter study of 8 weeks' duration in which dosages were adjusted according to patient response. In this study, Diflunisal () was comparable in efficacy to aspirin.
In a double-blind multicenter study of 12 weeks' duration in which dosages were adjusted according to patient needs, Diflunisal () 500 or 750 mg daily and ibuprofen 1600 or 2400 mg daily were comparable in effectiveness and tolerability.
In a double-blind multicenter study of 12 weeks' duration, Diflunisal () 750 mg daily was comparable in efficacy to naproxen 750 mg daily. The incidence of gastrointestinal adverse effects and tinnitus was comparable for both drugs. This study was extended to 48 weeks on an open-label basis. Diflunisal () continued to be effective and generally well tolerated.
In patients with rheumatoid arthritis, Diflunisal () and gold salts may be used in combination at their usual dosage levels. In clinical studies, Diflunisal () added to the regimen of gold salts usually resulted in additional symptomatic relief but did not alter the course of the underlying disease.
Diflunisal () Indications And Usage
Carefully consider the potential benefits and risks of Diflunisal () tablets and other treatment options before deciding to use Diflunisal () tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
Diflunisal () tablets are indicated for acute or long-term use for symptomatic treatment of the following:
Diflunisal () Contraindications
Diflunisal () tablets are contraindicated in patients with known hypersensitivity to Diflunisal () or the excipients (see ).
Diflunisal () tablets should not be given to patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal, anaphylactic/analphylactoid reactions to NSAIDs have been reported in such patients (see , and ,).
Diflunisal () tablets are contraindicated for the treatment of peri-operative pain in the setting of coronary artery bypass graft (CABG) surgery (see ).
Diflunisal () Warnings
NSAIDs, including Diflunisal () tablets, can cause serious gastrointestinal (GI) adverse events including inflammation, bleeding, ulceration, and perforation of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients, who develop a serious upper GI adverse event on NSAID therapy, is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3 to 6 months, and in about 2 to 4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. However, even short-term therapy is not without risk.
NSAIDs should be prescribed with extreme caution in those with a prior history of ulcer disease or gastrointestinal bleeding. Patients with a who use NSAIDs have a greater than 10 fold increased risk for developing a GI bleed compared to patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most spontaneous reports of fatal GI events are in elderly or debilitated patients and therefore, special care should be taken in treating this population.
To minimize the potential risk for an adverse GI event in patients treated with an NSAID, the lowest effective dose should be used for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulceration and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered.
Diflunisal () Precautions
Diflunisal () tablets cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to disease exacerbation. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids.
The pharmacological activity of Diflunisal () tablets in reducing fever and inflammation may diminish the utility of these diagnostic signs in detecting complications of presumed noninfectious, painful conditions.
Borderline elevations of one or more liver tests may occur in up to 15% of patients taking NSAIDs including Diflunisal () tablets. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continuing therapy. Notable elevations of ALT or AST (approximately three or more times the upper limit of normal) have been reported in approximately 1% of patients in clinical trials with NSAIDs. In addition, rare cases of severe hepatic reactions, including jaundice and fatal fulminant hepatitis, liver necrosis and hepatic failure, some of them with fatal outcomes have been reported.
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 a more severe hepatic reaction while on therapy with Diflunisal () tablets. If clinical signs and symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g., eosinophilia, rash, etc.), Diflunisal () tablets should be discontinued.
Anemia is sometimes seen in patients receiving NSAIDs, including Diflunisal () tablets. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. Patients on long-term treatment with NSAIDs, including Diflunisal () tablets, should have their hemoglobin or hematocrit checked if they exhibit any signs or symptoms of anemia.
NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Patients receiving Diflunisal () tablets who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants, should be carefully monitored.
Patients should be informed of the following information before initiating therapy with an NSAID and periodically during the course of ongoing therapy. Patients should also be encouraged to read the NSAID Medication Guide that accompanies each prescription dispensed.
Diflunisal () did not affect the type or incidence of neoplasia in a 105 week study in the rat given doses up to 40 mg/kg/day (equivalent to approximately 1.3 times the maximum recommended human dose), or in long-term carcinogenic studies in mice given Diflunisal () at doses up to 80 mg/kg/day (equivalent to approximately 2.7 times the maximum recommended human dose). It was concluded that there was no carcinogenic potential for Diflunisal () .
Diflunisal () passes the placental barrier to a minor degree in the rat. Diflunisal () had no mutagenic activity after oral administration in the dominant lethal assay, in the Ames microbial mutagen test or in the V-79 Chinese hamster lung cell assay.
No evidence of impaired fertility was found in reproduction studies in rats at doses up to 50 mg/kg/day.
Safety and effectiveness of Diflunisal () in pediatric patients below the age of 12 have not been established. Use of Diflunisal () tablets in pediatric patients below the age of 12 is not recommended.
The adverse effects observed following Diflunisal () administration to neonatal animals appear to be species, age, and dose-dependent. At dose levels approximately 3 times the usual human therapeutic dose, both aspirin (200 to 400 mg/kg/day) and Diflunisal () (80 mg/kg/day) resulted in death, leukocytosis, weight loss, and bilateral cataracts in neonatal (4 to 5-day-old) beagle puppies after 2 to 10 doses. Administration of an 80 mg/kg/day dose of Diflunisal () to 25-day-old puppies resulted in lower mortality, and did not produce cataracts. In newborn rats, a 400 mg/kg/day dose of aspirin resulted in increased mortality and some cataracts, whereas the effects of Diflunisal () administration at doses up to 140 mg/kg/day were limited to a decrease in average body weight gain.
As with any NSAID, caution should be exercised in treating the elderly (65 years and older) since advancing age appears to increase the possibility of adverse reactions. Elderly patients seem to tolerate ulceration or bleeding less well than other individuals and many spontaneous reports of fatal GI events are in this population (see , ).
This drug is known to be substantially excreted by the kidney and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (see , ).
Diflunisal () Adverse Reactions
The adverse reactions observed in controlled clinical trials encompass observations in 2,427 patients.
Listed below are the adverse reactions reported in the 1,314 of these patients who received treatment in studies of two weeks or longer. Five hundred thirteen patients were treated for at least 24 weeks, 255 patients were treated for at least 48 weeks, and 46 patients were treated for 96 weeks. In general, the adverse reactions listed below were 2 to 14 times less frequent in the 1,113 patients who received short-term treatment for mild to moderate pain.
Diflunisal () Overdosage
Cases of overdosage have occurred and deaths have been reported. Most patients recovered without evidence of permanent sequelae. The most common signs and symptoms observed with overdosage were drowsiness, vomiting, nausea, diarrhea, hyperventilation, tachycardia, sweating, tinnitus, disorientation, stupor, and coma. Diminished urine output and cardiorespiratory arrest have also been reported. The lowest dosage of Diflunisal () at which a death has been reported was 15 grams without the presence of other drugs. In a mixed drug overdose, ingestion of 7.5 grams of Diflunisal () resulted in death.
In the event of overdosage, the stomach should be emptied by inducing vomiting or by gastric lavage, and the patient carefully observed and given symptomatic and supportive treatment. Because of the high degree of protein binding, hemodialysis may not be effective.
The oral LD of the drug is 500 mg/kg and 826 mg/kg in female mice and female rats, respectively.
Diflunisal () Dosage And Administration
Carefully consider the potential benefits and risks of Diflunisal () tablets and other treatment options before deciding to use Diflunisal () tablets. Use the lowest effective dose for the shortest duration consistent with individual patient treatment goals (see ).
After observing the response to initial therapy with Diflunisal () tablets, the dose and frequency should be adjusted to suit an individual patient's needs.
Concentration-dependent pharmacokinetics prevail when Diflunisal () is administered; a doubling of dosage produces a greater than doubling of drug accumulation. The effect becomes more apparent with repetitive doses.
For mild to moderate pain, an initial dose of 1000 mg followed by 500 mg every 12 hours is recommended for most patients. Following the initial dose, some patients may require 500 mg every 8 hours.
A lower dosage may be appropriate depending on such factors as pain severity, patient response, weight, or advanced age; for example, 500 mg initially, followed by 250 mg every 8 to 12 hours.
For osteoarthritis and rheumatoid arthritis, the suggested dosage range is 500 mg to 1000 mg daily in two divided doses. The dosage of Diflunisal () may be increased or decreased according to patient response.
Maintenance doses higher than 1500 mg a day are not recommended.
Tablets should be swallowed whole, not crushed or chewed.
Diflunisal () How Supplied
Diflunisal () tablets USP are supplied as follows:
500 mg tablets: blue, unscored, oblong, film-coated tablets, debossed "755"-"93". Packaged in bottles of 100, 500 and unit of use 60's.
Dispense in a well-closed container as defined in the USP, with a child-resistant closure (as required).
Keep tightly closed.
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].
Manufactured In Israel By:
Jerusalem, 91010, Israel
Manufactured For:
Sellersville, PA 18960
Rev. N 5/2008
Diflunisal ()
Diflunisal ()
