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`Metrics EX1030, Page 1
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`

`
`PRODUCT INFORMATION (cid:9)
`
`CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF
`FERTILITY
`No studies have been performed to evaluate carcinogenic or
`mutagenic potential of Diucardin or the potential of Diucar-
`din to impair fertility.
`PREGNANCY
`Teratogenic Effects.(cid:151)Pregnancy Categoiy C
`Animal reproduction studies have not been conducted with
`Diucardin. It is also not known whether Diucardin can
`cause fetal harm when administered to a pregnant woman
`or can affect reproduction capacity. Diucardin should be
`given to a pregnant woman only if clearly needed.
`Nonteratogenic Effects
`Fetal or neonatal jaundice, thrombocytopenia, and possibly
`other adverse reactions which have occurred in the adult.
`NURSING MOTHERS
`Thiazides appear in breast milk. If use of the drug is
`deemed essential, the patient may consider stopping nurs-
`ing.
`PEDIATRIC USE
`Safety and effectiveness in children have not been estab-
`lished.
`ADVERSE REACTIONS
`The following adverse reactions have been observed, but
`there is not enough systematic collection of data to support
`an estimate of their frequency.
`GASTROINTESTINAL SYSTEMS
`Anorexia, gastric irritation, nausea, vomiting, cramping, di-
`arrhea, constipation, jaundice (intrahepatic cholestatic
`jaundice), pancreatitis, sialadenitis.
`CENTRAL NERVOUS SYSTEM
`Dizziness, vertigo, paresthesias, headache, xanthopsia.
`HEMATOLOGIC
`Leukopenia, agranulocytosis, thrombocytopenia, aplastic
`anemia, hemolytic anemia.
`CARDIOVASCULAR
`Orthostatic hypotension (may be aggravated by alcohol,
`barbiturates, or narcotics).
`DERMATOLOGIC(cid:151)HYPERSENSITIVITY
`Purpura, photosensitivity, rash, urticaria, necrotizing angi-
`itis (vasculitis, cutaneous vasculitis), fever, respiratory dis-
`tress including pneumonitis, anaphylactic reactions.
`OTHER
`Hyperglycemia, glycosuria, hyperuricemia, muscle spasm,
`weakness, restlessness, transient blurred vision.
`Whenever adverse reactions are moderate or severe, thia-
`zide dosage should be reduced or therapy withdrawn.
`OVERDOSAGE
`SIGNS AND SYMPTOMS
`Diuresis, lethargy progressing to coma, with minimal car-
`diorespiratory depression and with or without significant
`serum electrolyte changes or dehydration; GI irritation; hy-
`permotility; transient elevation in BUN level.
`TREATMENT
`Empty stomach by gastric lavage, taking core to avoid aspi-
`ration. Monitor serum electrolyte levels and renal function,
`and institute supportive measures, as required to maintain
`hydration, electrolyte balance, respiration, and cardiovascu-
`lar and renal function, Treat GI effects symptomatically.
`DOSAGE AND ADMINISTRATION
`The average adult diuretic dose is 25 to 200 mg per day. The
`average adult antihypertensive dose is 50 to 100 mg per day.
`Therapy should be individualized according to patient re-
`sponse. This therapy should be titrated to gain maximal re-
`sponse as well as the minimal dose possible to maintain
`that therapeutic response.
`HOW SUPPLIED
`Diucardint%(cid:151)Each scored, white oval compressed tablet, in-
`scribed "DIUCARDIN 50," contains 50 mg hydroflumethiaz-
`ide, in bottles of 100 (NDC 0046-0702-81).
`Store at room temperature (approximately 25’ C)
`Dispense in a well-closed container as defined in the USP
`Caution: Federal law prohibits dispensing without pre-
`scription.
`Manufactured by:
`Ayerst Laboratories Inc.
`A Wyeth-Ayerst Company
`Philadelphia, PA 19101
`Shown in Product Identification Guide, page 341
`
`DURACT’TM
`[nor ’diet]
`bromfenac sodium capsules
`
`DESCRIPTION
`Bromfenac sodium is benzene acetic acid, 2-amino-344-
`bromobenzyl)-, monosodium salt, sesquihydrate. It is an
`achiral compound with the following structural formula:
`[See chemical structure at top of next column]
`Its empirical formula is C 15H11BrNNa0.3 ’ 11/2H20, with a
`molecular weight of 383.17. The pKa is 4.3. Bromfenac so-
`
`0 (cid:9)
`
`NH5 (cid:9)
`
`0
`
`C,&CHSO0Na
`
`1 1 15H2O
`
`Or
`dium is a non-hygroscopic, yellow to orange crystalline pow -
`der. It is soluble in water, propylene glycol, PEG-400, and
`glycerin. DURACT (bromfenac sodium capsule) contains
`28.76 mg of bromfenac sodium sesquihydrate, equivalent to
`25 mg of bromfenac base and 1.73 mg of sodium, for oral
`administration.
`The inactive ingredients are: gelatin, lactose, magnesium
`stearate, silicon dioxide, titanium dioxide, and FD&C Blue
`#1, FD&C Red #40, D&C Yellow #10.
`CLINICAL PHARMACOLOGY
`DURACT is considered a peripherally acting analgesic that
`belongs to the nonsteroidal anti-inflammatory drug
`(NSA1D) class.
`PHARMACODYNAMICS
`Following single doses of 25 and 50 sag of DURACT, onset
`on analgesia was demonstrable in various pain models
`within 30 minutes, reaching peak effects between 2 and 3
`hours, and median duration of analgesia of 6 to 7 hours (see
`Clinical Studies).
`PHARMACOKINETICS
`The analgesic activity of bromfenac is due to the parent
`drug. Studies with radiolabeled drug have demonstrated
`that bromfenac administered orally as DURACT is ab-
`sorbed into systemic circulation with 80% of the radiolabel
`recovered in the urine. The median oral-dose clearance of
`bromfonac is 0.08 lJh/kg and the volume of distribution is
`0.15 L/kg. Elimination of bromfonac is due to hepatic me-
`tabolism with subsequent renal elimination of metabolites;
`no unchanged drug has been found in the urine. The termi-
`nal elimination half-life is approximately 1.3 hours. The ob-
`served plasma half-life of bromfenac does not correlate with
`the duration of action. Concomitant ingestion of food causes
`a significant decrease in bromfenac bioavailability (see Food
`Efllcts).
`Pharmacokinetic parameters for bromfonac are shown in
`the table below.
`[See table at top of next page]
`Absorption: Bromfenac is absorbed after oral administra-
`tion with peak plasma levels occurring approximately
`45 minutes after dosing. The absolute bioavailability of
`DURACT is approximately 67% in humans. The pharmaco-
`kinetics of bromfenac are best described by a one-compart-
`ment model with first-order absorption. Dose proportional-
`ity, based on AUC (area under the plasma-concentration
`time curve), has been demonstrated between single doses
`from 5 to 100 mg. There was no drug accumulation after
`administration of multiple doses using an every 8 or every
`12 hour dosing regimen.
`Antacid Effects: Following the concomitant administration
`of an aluminum hydroxide containing antacid with brom-
`fenac, peak plasma levels of bromfenac were reduced by
`36%. There was no effect on the overall extent of bromfenac
`absorption.
`Food Effects: The concomitant administration of a high-fat
`meal with bromfenao causes a 75% reduction in peak
`plasma concentrations and a 60% reduction in total AUC. In
`vivo pharmacokinetic studies have demonstrated that the
`absorption of bromfenac is greatly reduced if the drug is ad-
`ministered with, or up to 3 1/ hours after, a high fat stan-
`dardized meal (see Clinical Studies).
`Distribution: Bromfenac is more than 99% bound to hu-
`man plasma proteins. The unbound fraction is independent
`of concentration over the dose range studied.
`Metabolism: After the ingestion of ["Cl bromfenac so-
`dium, virtually all of the radioactivity in plasma is ac-
`counted for as unchanged drug. In the urine, a cyclic amide
`metabolite and four glucuronide conjugates of aglycone me-
`tabolites account for most of the radioactivity recovered in
`the urine. The precise iso-enzyme of cytochrome P.450 in-
`volved in the metabolism of bromfenac has not been identi-
`fied (see Precautions(cid:151)DRUG INTERACTIONS). Brom-
`fenac has no effect on the pharmacokinetics of digoxin, gly-
`buride, methotrexate, or phenytoin.
`In the same radiolabeled study referred to
`Elimination:
`above, an average of 80% of the radioactivity has been re-
`covered in the urine within 24 hours, Neither unchanged
`bromfenac nor bromfenac conjugates have been recovered
`from urine.
`Special Populations: A population pharmacokinotic analy-
`sis of the data from patients receiving bromfenac showed
`that the variability between patients was not linked to sex,
`weight, or calculated creatinine clearance. The observations
`in clinical trials were in agreement with those seen in
`healthy volunteers, and suggest that no dosage adjustment
`is required based on any of these patient characteristics.
`In a study with 24 subjects greater than 65 years
`Elderly:
`old, age was found to have an effect on the pharmacokinet-
`ics of bromfenac only in those subjects over 75 years old. In
`these 12 subjects, plasma clearance was decreased and vol-
`ume of distribution was increased, such that the terminal
`
`WYETH-AYERST LABORATORIES/3035
`
`half-life increased from 1.3 to 2.8 hrs (see Table). In these
`subjects, an increased time between doses should be consid-
`ered.
`Hepatic Impairment: While the disposition of total and un-
`bound bromfenac was not altered in patients with mild to
`moderate hepatic disease, the observed oral clearance was
`reduced by 40%. This reduction in clearance caused a pro-
`longation of the observed median plasma half-life to 3.1 bra
`(vs. 2 hrs in the appropriate control sample),
`In a study of the effects of mild to se-
`Renal Impairment:
`vere renal impairment (CrCl < 60 mL/mia), no significant
`differences were seen in the disposition of total and un-
`bound bromfenac. In subjects undergoing homodialysis, un-
`bound bromfenac clearance was not altered. No dosage ad-
`justment of DURACT is required in patients with mild to
`severe renal impairment; however, DURACT should be used
`with caution in such patients because NSAIDs may further
`decrease renal function in some patients with preexisting
`impairment.
`CLINICAL STUDIES
`Clinical trials for analgesic efficacy were conducted in fasted
`patients with moderate or severe acute pain following
`surgery (major abdominal, orthopedic, or oral surgery).
`DURACT 25 mg, given orally, was comparable to oral
`naproxen sodium 550 mg, and ibuprofen 400 mg. Doses of
`25 mg of DURACT were superior to aspirin 650 mg. In one
`oral surgery study, a 25 mg dose of DURACT, given with a
`high fat meal, was effective but inferior to 25 mg given to
`fasted patients.
`In repeat-dose postsurgical pain studios of acute pain,
`DURACT was administered every 6 to 8 hours, as needed,
`for up to 1 week. In these studies, DUR.ACT was comparable
`to naproxen sodium (550 mg followed by 275 mg).
`INDICATIONS AND USAGE
`DURACT is indicated for the short-term (generally less
`than 10 days) management of pain, DURACT is not indi-
`cated for the treatment of such conditions as osteoarthritis
`or rheumatoid arthritis.
`CONTRAINDICATIONS
`DURACT is contraindicated in patients who have known
`hypersensitivity to bromfenac. DURACT should not be
`given to patients who have experienced asthma, urticaria,
`or other allergic-type reactions after taking aspirin or other
`NSAIDs. Severe anaphylactic-like reactions to drugs in this
`class have been reported (see Warnings(cid:151)ANAPHYLAC-
`TOlD REACTIONS and Precautions(cid:151)GENERAL PRE-
`CAUTIONS, Pre-Existing Asthma). Such reactions may be
`fatal if not treated promptly. DURACT should be avoided in
`patients with known chronic hepatitis.
`WARNINGS
`HEPATIC EFFECTS
`Elevations of one or more liver tests may occur during
`DURACT therapy. Those laboratory abnormalities may
`progress, may remain unchanged, or may be transient de-
`spite continued therapy. As with other NSAIDs, borderline
`elevations (i.e., less than 3 times the Upper Limit of Normal
`(IJLN[) or greater elevations of transaminasos occurred in
`clinical trials (n=926) at some time during treatment in ap-
`proximately 15% of DURACT-treated patients. Elevations
`to more than 3 times the ULN of AST (SGOT) or ALT
`(SGPT) occurred in 2.7% of those patients at some time dur-
`ing DURACT treatment, but the incidence of such eleva-
`tions during short-term therapy was less than 0.4%.
`Marked elevations (i.e., more than 8 times the ULN) oc-
`curred in 0.4% of patients in longer term trials. The enzyme
`elevations seen in clinical trials have been reversible after
`discontinuation of therapy (see Adverse Reactions).
`Short-term management of pain should generally be less
`than ten days duration. Because hepatotoxicity may develop
`without a prodroms of distinguishing symptoms, if a physi-
`cian chooses to administer DURACT for a longer duration,
`the patient’s transaminases, particularly ALT, should be
`monitored for evidence of hepatotoxicity after 4 weeks.
`DURACT should be avoided in patients with known severe
`hepatic disease and should be used with caution in patients
`with lees severe pro-existing liver impairment (see Precau-
`tions).
`GASTROINTESTINAL (GI) EFFECTS(cid:151)RISK OF GI UL-
`CERATION, 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 non-
`steroidal anti-inflammatory drugs (NSAIDe). Minor upper
`GI problems, such as dyspepsia, are common and may also
`occur at any time during NSAID therapy. Therefore, physi-
`cians and patients should remain alert for ulceration and
`bleeding, even in the absence of previous GI tract symp-
`toms. Only one in five patients, who develop a serious upper
`GI adverse event on NSAID therapy, is symptomatic. Pa-
`tients should he informed about the signs and/or symptoms
`
`Consult 1998 PDRe supplements and future editions for revisions
`
`Continued on next page
`
`Metrics EX1030, Page 2
`
`

`
`3036/WYETH-AYERST LABORATORIES
`Duract-Cont. (cid:9)
`
`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.
`The likelihood of developing a serious GI adverse reaction is
`directly related to the duration of DURACT treatment.
`Several factors have been identified that will, or may, in-
`crease the risk of an NSAID-treated patient to develop Se-
`rious GI events. Studies have shown that patients with a
`prior history of peptic ulcer disease and/or GI bleeding who
`use NSAIDs have an overall rate 14 to 17 times higher of
`developing a GI bleed than patients with neither of these
`risk factors. Conditions that may increase the risk for GI
`bleeding include: treatment with oral corticosteroids, treat-
`ment with anticoagulants, advanced age, smoking, alcohol-
`ism, and deteriorated general health status. Most Spontane-
`ous reports of fatal GI events are in elderly or debilitated
`patients and, therefore, special care should be taken in
`treating this population. High doses of any NSAID are also
`associated with a greater risk for GI bleeding. To minimize
`the potential risk for an adverse GI event, the lowest effec-
`tive dose should be used.
`ANAPHYLACTOID REACTIONS
`Anaphylactoid reactions may occur in patients without
`known prior exposure to bromfenac. DURACT should net 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 fa-
`tal bronchospasm after taking aspirin or other NSATDe. Fa-
`tal reactions to NSAIDs have been reported in such patients
`(see Contraindications and Precautions-GENERAL
`PRECAUTIONS, Pre-Existing Asthma). Emergency help
`should be sought when an anaphylactoid reaction occurs.
`PREGNANCY
`As with other NSAIDe, DURACT should be avoided in late
`pregnancy, because it may cause premature closure of the
`ductus arteriosus and delay parturition (see Precau-
`tions-PREGNANCY).
`PRECAUTIONS
`GENERAL PRECAUTIONS
`Renal Effects
`Renal toxicity associated with NSAIDs is seen in patients
`with conditions in which renal prostaglandins have a sup-
`portive role in the maintenance of renal perfusion. In these
`patients, administration of NSAIDs may cause a doss-de-
`pendent reduction in prostaglandin formation and, second-
`arily, in renal blood flow, which may precipitate overt renal
`decompensation.
`Patients at greatest risk of this reaction are those with vol-
`ume depletion, impaired renal function, heart failure, liver
`dysfunction, those taking diuretics, and the elderly. Discon-
`tinuation of NSAID therapy is usually followed by recovery
`to the pretreatment state.
`Pre-existing Asthma
`About 10% of patients with asthma have aspirin-sensitive
`asthma. The use of aspirin in patients suffering from aspi-
`rin-sensitive asthma has been associated with severe bron-
`chospaem which can be fatal. Since cross-reactivity, includ-
`ing bronchospasm, between aspirin and other NSAIDs has
`been reported, DURACT should not be administered to pa-
`tients with this form of aspirin sensitivity and should be
`used with caution in all patients with preexisting asthma.
`Hematological Effects
`All drugs that inhibit the biosynthesis of prostaglandin may
`interfere to some extent with platelet function and vascular
`responses to bleeding. DURACT inhibits platelet aggrega-
`tion and may prolong bleeding time. In contrast to aspirin’s
`prolonged effect on platelets, the inhibition of platelet func-
`tion by bromfenac sodium disappears within 24 hours.
`DURACT does not affect platelet counts, prothrombin time
`(PT), or partial thromboplaetin time (PIT). Patients receiv-
`ing DURACT who may be adversely affected by alterations
`in platelet function, such as those with coagulation disor-
`ders or patients receiving anticoagulants, should be care-
`fully monitored.
`Anemia is sometimes seen in patients receiving NSAIDs, in-
`cluding DURACTTM. This may be due to fluid retention, GI
`blood loss, or an incompletely described effect upon erythro-
`poiesis.
`Fluid Retention and Edema
`Fluid retention and edema have been observed in some pa-
`tients taking DURACT. Therefore, as with other NSAIDe.
`DIJRACT should be used with caution in patients with fluid
`retention, hypertension, or heart failure.
`INFORMATION FOR PATIENTS
`Analgesic treatment with DURACT should be guided by the
`patient’s response. The individual response to DURACT can
`be determined when the patient perceives a return of pain
`that necessitates the taking of the next dose. The time be-
`tween the first and second dose should be a guide to subse-
`quent doses, without exceeding the recommended total
`daily dose of 150 mg. Patients should take the lowest effec-
`tive total daily dose to minimize the potential for adverse
`events.
`
`Pharmacokinetic Parameters in Subjects Receiving Bromfenac Sodium
`MEDIAN (RANGE)
`
`PHYSICIANS’ DESK REFERENCEfi
`
`Peak concentration
`time
`t,,, (cid:9)
`(h)
`
`Oral dose
`clearance
`Cl/F (L/hlkg)
`
`Volume of
`distribution
`vkz/F (11kg)
`
`Terminal
`half-life
`t112 (Ii)
`
`0.75 (0.25-3.0)
`
`0.08 (0.04-0.19)
`
`0.15 (0.08-0.50)
`
`1.3 (0.7-3.4)
`
`0.5 (0.25-1.5)
`
`0.06 (0.03-0.11)
`
`0.20 (0.11-0.48)
`
`2.8 (1.443)
`
`0.6 (0.2-1.6)
`
`0.05 (0.02-0.15)
`
`0.22 (0.11-0.42)
`
`3.1 (1.1-5,6)
`
`0.6 (0.1-2.8)
`
`0.09 (0.04-0.27)
`
`0.18 (0.11-1.17)
`
`1.5 (0.7-3.1)
`
`Males and females (18-75 years)
`N=32 (16M/16F)
`
`Males and females (75+ years)
`N=12 (6M/6F)
`
`Hepatic impairment
`N=16 (12M/4F)
`
`Renal impairment
`(mild to moderate)
`N=12 (9M/3F)
`
`Patients should be alerted to the fact that food intake alters
`the absorption of DURACT. Patients should be instructed as
`to how DURACT is to be taken in relation to meals (see
`Clinical Pharmacology-PHARMACOKINETICS, Food
`Effects).
`DURACT, like other NSAIDs, is not free of side effects. The
`side effects of these drugs can cause discomfort and, rarely,
`there may be serious side effects, such as drug-induced hep-
`atitis and gastrointestinal bleeding, that may result in hos-
`pitalization and even fatal outcomes. Patients should be in-
`structed to report any flu-like symptoms (that may be an
`early signal of hepatic damage), as well as signs and symp-
`toms of gastrointestinal bleeding.
`As with other NSATDs, DURACT should be avoided in late
`pregnancy, because it may cause premature closure of the
`ductus arteriosus and delay parturtion.
`LABORATORY TESTS
`Elevations of one or more liver tests may occur during
`DURACT therapy (see Warnings-HEPATIC EFFECTS).
`DRUG INTERACTIONS
`Cimetidine
`The concomitant administration of cimetidine caused a
`moderate increase in bromfenac concentrations. The clear-
`ance of bromfenac was decreased by 17% in patients taking
`cimetidine, but bromfenac has no effect on the pharmacoki-
`netics of cimetidine.
`Lithium
`The interaction between lithium and bromfenac has not
`been studied. However, other NSAIDs are known to cause
`an increase in blood lithium concentrations, thus increasing
`the possibility of toxic events to lithium when concomitantly
`administered with DURACT.
`Phenytoin
`As with other drugs metabolized by the cytochrome P450
`pathways, phenytoin reduced the plasma levels of brom-
`fenac by about 50%. Bromfenac has no effect on the phar-
`macokinetics of phenytoin.
`Warfarin
`Coadministration of bromfenac has no effect on warfarin
`pharmacokinetics or its anticoagulant effect. Warfarin has
`no effect on the pharmacokinetics of bromfenac. Neverthe-
`less, caution should be exercised when adding any drug that
`affects platelet function, such as DURACT, to patients re-
`ceiving oral anticoagulants.
`CARCINOGENESIS, MUTAGENESIS, AND IMPAIR-
`MENT OF FERTILITY
`No carcinogenic effect of bronafenac was observed in rats
`given oral dosages of up to 0.60 mg/kg (3.6 mg/m2/day), or in
`mice given oral dosages of up to 7.5 mg/kg (22.5 mg/m 2/day)
`for two years.
`Bromfenac was not mutagenic in in vitro tests performed
`with S. typhimurium, mouse lymphoma cells and Chinese
`hamster ovary cells, an in vitro micronucleus test, and an in
`vivo unscheduled DNA synthesis assay. Bromfenac showed
`no impairment of fertility in male and female rats up to oral
`dosages of 0.9 mg/kg (5.4 mg/m 2/day).
`PREGNANCY: TERATOGENIC EFFECTS: PREGNANCY
`CATEGORY C
`No toratogenic potential was demonstrated in rats up to an
`oral dosage of 0.9 mg/kg (5.4 mg/m 2/day) or in rabbits up to
`an oral dosage of 7.5 nag/kg (82.5 mg/m 2/day). Maternal and
`fetal effects (reduced embryo/fetal survival) occurred at an
`oral dosage of 7.5 mg/kg in rabbits.
`There are no adequate or well-controlled studies of
`DURACT in pregnant women. DURACT should be used
`during pregnancy only if the potential benefit justifies the
`potential risk to the fetus. Since NSAIDs are known to de-
`lay parturition or cause premature closure of the ductus ar-
`teriosus, DURACT should be avoided during late pregnancy.
`LABOR AND DELIVERY
`As with other NSAIDs, the effects of bromfenac on labor and
`delivery in pregnant women are unknown. Because of the
`known effects of prostaglandin-inhibiting drugs on uterine
`contractions, DURACT may cause secondary uterine dysto-
`cia and delay parturition. In rat studies with bromfenac, as
`
`with other drugs known to inhibit prostaglandin synthesis.
`dystocia, delayed parturition, and increased pup mortality
`occurred.
`NURSING MOTHERS
`Bronsfenac is excreted in the milk of lactating rats. It is not
`known whether this drug is excreted in human milk. Be-
`cause many drugs are-excreted in human milk, and became
`of the potential for serious adverse reactions in nursing in-
`fonts from DURACT, a decision should be made whether to
`discontinue nursing or to discontinue this drug, taking into
`account the importance of the drug to the mother.
`PEDIATRIC USE
`Safety and effectiveness in pediatric patients have not been
`established.
`GERIATRIC POPULATION
`In volunteers greater than 75 years of age, the terminal
`half-life of bromfenac is increased from 1.3 to 2.8 hours. The
`dosing interval may need to be adjusted (increased) for pa-
`tients older than 75. (See Clinical Pharmacology and
`Dosage and Administration).
`ADVERSE REACTIONS
`Adverse reaction data were derived from approximately
`2400 patients who received DURACT in single- and multi.
`pie-dose studies. As with other NSAIDs, the incidence sl’ad.
`verse drug reactions attributed to DURACT was lower in
`single-dose studies than the incidence associated with re-
`peated dosing. The adverse event rates listed below meter to
`the incidence of treatment-emergent symptoms avon ill 926
`patients in those repeated-dose clinical trials that involved
`a course of therapy sufficient to include the recommended
`duration of use (see Indications and Usage and Dosage
`and Administration). To distinguish different motes of oc-
`currence in clinical studies, the adverse events are listed as
`follows:
`name of adverse event = < 3%
`adverse events/ marked with an asterisk" = 3 to 911
`adverse event rates over 9% are in parenthesis
`INCIDENCE GREATER THAN 1%
`Body as a w/mcmie: Asthenia, headache"
`Digestive system: Abdominal pain", constipation, diarrhea,
`dyspepsia (12%), eructation, flatulence, liver enzyme eleva-
`tions (< 3X upper limit of normal)", nausea", vonmittag.
`Nervous meystern.: Dizziness", somnolence*.
`INCIDENCE LESS THAN 1%
`Body as a ic/mole: Back pain, chest pain, chills, face edema,
`fever, flu syndrome, generalized edema, infection, mmmslaise.
`Cardiovascular system: Arrhythinias, hemorrhage, hyper-
`tension, migraine myocardial infarction, palpitations, phle-
`bitis, syncope, vaeodiIation.
`Digestive system: Anorexia, colitis, dry mouth, gastritis,
`gastroenteritis, gastrointestinal hemorrhage, increased ap-
`petite, liver test abnormalities w 3 x upper haul of nor.
`real), pancreatitis, peptic ulcer, periodontal abscess, pssmtiso
`focal occult blood test, rectal disorder, stonaatitis, tenesinos.
`Endocrine: Glycosurin.
`Hemic and lymphatic system: Anemia, ecchymosis, leaks.
`psnia.
`Metabolic and nutritional: Blood area nitrogen increased,
`edema, hypoglycemia, hypokalemia, hyponati-omia, serums
`creatinine increased, thirst, weight gain, weight lose.
`Musculoskeletal: Leg cramps, inyalgia.
`Nervous syotecms: Abnormal dreams, amnesia, anxiety, con-
`fusion, depression, emotional lability, euphoria, hallucina-
`tion, incoordination, insomnia, libido increased, aei’m’ess
`ness, parosthesia, psychosis, tremor, twitching.
`Respiratory system: Asthma, cough increased, dyspn, a.
`epistaxis, hiccup, hyperventilation, pharyngitis, rhimoitis. or
`nusitis.
`Skin and appendages: Alopecia, pruritue, ruoh, setserbea,
`skin infections, skin ulcer, sweating, urticaria.
`Special senses: Abnormal vision, blephaiitio, cataract, ion.
`junctivitis, dry eyes, ear disorder, lacrimation, photaphobmu,
`taste perversion, tinnitus.
`
`Information will be superseded by supplements and subsequent editions
`
`Metrics EX1030, Page 3
`
`(cid:9)
`

`
`PRODUCT INFORMATION (cid:9)
`
`Urogenital: Albuminuria, breast pain, dysuria, hesnaturia,
`impotence, menstrual disorder, nocturia, oliguria, orchitis,
`polyuria, pyuria, uterine fibroids enlarged, urinary fre-
`quency, uterine hemorrhage, urinary incontinence, urinary
`tract infection.
`OVERDOSAGE
`No cases of DURACT overdose have been reported. Symp-
`toms following acute NSAID overdose are usually limited to
`lethargy, drowsiness, nausea, vomiting, and epigastric pain
`which are generally reversible with supportive care. Gastro-
`intestinal bleeding can occur and coma has occurred follow-
`ing massive NSAID overdose. Hypertension, acute renal
`failure, and respiratory depression may occasionally occur.
`Patients should be managed by symptomatic and support-
`ive care following an NSAID overdose. There are no specific
`antidotes. Emesis and/or activated charcoal (60 to 100 g in
`adults, 1 to 2 g/kg in children) and/or an osmotic cathartic
`may be indicated in patients seen within 4 hours with
`symptoms or following a large overdose (5-10 times the
`usual dose). Dialysis is not likely to be effective for removal
`of bromfenac because it is more than 99% bound to plasma
`proteins.
`DOSAGE AND ADMINISTRATION
`For the short-term (generally less than 10 days) manage-
`ment of pain, the recommended dose of DURACT is 25 rug
`every 6 to 8 hours, as necessary, except when taken with
`high-fat food, when a 50 mg dose may be needed (see below).
`The total daily dose should not exceed 150 mg.
`Bronifenac sodium, like other NSAJDs, shows considerable
`inter-individual variation in patient response, but the bio-
`availability of bromfenac was shown to be especially sensi-
`tive to the effect of a high-fat meal (see Clinical Pharma-
`cology(cid:151)PHARMACOKINETICS, Food Effects). The effects
`of light, low-fat meals on the absorption of bromfenac have
`not been investigated.
`As with other NSAIDs, the lowest effective dose or the lon-
`gest dosing interval should be sought for each patient, es-
`pecially in the elderly. After observing the initial response to
`therapy with DURACT, the dose and ilequency of dosing
`should be adjusted to suit each individual patient’s needs,
`without exceeding the maximum total daily dose recom-
`mended (150 mg).
`HOW SUPPLIED
`DURACTu Capsules are available as:
`25 rag of bromfenac (as bromfenac sodium), opaque light
`yellow body with two 300(cid:176) blue bands, opaque red cap,
`branded "DURACT" in blue ink.
`- Bottles of 100 capsules (NDC 0008-0909-01)
`- Redipakfi cartons each containing 10 blister strips of
`10 capsules (NDC 0008-0909-03)
`Store at controlled room temperature. 20’ to 25(cid:176)C (68’ to
`77(cid:176)F), protected from moisture and light.
`Dispense in a tight, light-resistant container.
`Caution: Federal law prohibits dispensing without prescrip-
`tion.
`The appearance of those capsules is a trademark of Wyeth.
`Ayerst Laboratories.
`Manuf