`
`LUPIN EX 1062
`
`Page 1 of 7
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`PDT?
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`5 5
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`PHYSICIANS
`DESK
`PEEEPENCE
`
`
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`
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`Senior Vice President, Directory Services: Paul Walsh
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`MEDICAL ECONOMICS Copyright © 2001 and published by Medical Economics Company, Inc. at Montvale, NJ 07645-1742. All rights reserved. None of
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`ISBN: 1563638302
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`Page 2 of 7
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`Page 2 of 7
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`

`1946/MERCK
`
`Indomethacin exists in the plasma as the parent drug and ,
`INDOCIN is supplied in"three dosage forms. Capsules IN-
`DOCIN for oral administration contain either 25 mg or 50
`its desmethyl, desbenzoyl, and desmethyI-desbsnzoyl me-
`tabolites, all in the unconjugated form. About 60 percent of
`mg of indomethacin and the following inactive ingredients:
`colloidal silicon dioxide,- FD 85 C Blue 1, FD & C Red 3, gel—
`snow] dosage is recovered in urine as drug and metabolites
`(26 percent as indomethacin and its glucuronide), and 33
`atin, lactose, lecithin, magnesium stearate, and titanium di-
`percent is recovered in feces (1.5 percent as indomethacin).
`oxide. Suspension INDOCIN for oral use contains 25 mg of
`About 99% of indomethacin is bound to protein in plasma
`indomethacin per 5 mL, alcohol.1%, and sorbic acid 0.1%
`over the expected range of therapeutic plasma concen-
`added as a preservative and the following inactive ingredi-
`trations. Indomethacin has been found to cross the blood-
`- ents: antifoam AF emulsion, flavors, purified water, sodium
`brsin barrier and the placenta.
`hydroxide or hydrochloric acid to adjust pH, sorbitol solu-
`In a gastroscopic study in 45 healthy subjects, the number
`tion, tragacanth. Suppositories INDOCIN for rectal use con-
`of gastric mucosal abnormalities was significantly higher in
`tain 50 mg of indomethacin and the following inactive in-
`the group receiving Capsules INDOCIN than in the group
`gredients: butylated hydroxyanisols, butylated hydroxytolu-
`taking Suppositories INDOCIN or placebo.
`ene, edetic acid, glycerin, polyethylene glycol 3350,
`In a double~blind comparative clinical study involving 175
`polyethylene glycol 8000 and sodium chloride. Indometha-
`patients with rheumatoid arthritis, however, the incidence
`cin is a non-steroidal anti—inflammatory indole derivative
`of upper gastrointestinal adverse effects with Suppositories
`designated chemically as 1-(4-chlorobenzoyl)-5-methoxy-2~
`or Capsules INDOCIN was comparable. The incidence of
`methyl-1H —indole-3-acetic acid. Indomethacin is practically
`lower gastrointestinal adverse effects was greater in the
`insoluble in water and sparingly soluble in alcohol. It has a
`. suppository group.
`pKa of 4.5 and is stable in neutral or slightly acidic media
`and decomposes in strong alkali. The suspension has a pH
`of 4.0—5.0. The structural formula is:
`
`.
`
`
`
`Hyzaar—Cont.
`
`tients with a history of hepatic impairment (see WARN~
`INGS, Impaired Hepatic Function). Losartan can be admin-
`istered once or twice daily at total daily doses of 25 to 100
`. mg. If the antihypertensive efl‘ect measured at trough using
`once-a-day dosing is inadequate, a twice-a-day regimen at
`the same total daily dose or an increase in dose may give a
`more satisfactory response.
`Hydrochlorothiazide is effective in doses of 12.5 to 50 mg
`once daily and can be given at doses of 12.5 to 25 mg as
`HYZAAR.
`To minimize dose-independent side effects, it is usually ap-
`propriate to begin combination therapy only afier a patient
`has failed to achieve the desired effect with monotherapy.
`The side effects (see WARNINGS) of losartan are generally
`rare and apparently independent of dose; those of hydro-
`chlorothiazide are a mixture of dose-dependent (primarily
`hypokalemia) and dose-independent phenomena (e.g., pan-
`creatitis), the former much more common than the latter.
`Therapy with any combination of losartan and hydrochloro-
`thiazide will be asSociated with both sets of dose—indepen-
`dent side efi‘ccts.
`Replacement Therapy: The combination may be subti-
`tuted for the titrated components.
`Dose Titration by Clinical Effect: A patient whose blood
`pressure is not adequately controlled with losartan mono-
`therapy (see above) may be switched to HYZAAR 5042.5
`(losartan 50 mg/hydrochlorothiazide 12.5 mg) once daily. If
`blood pressure remains uncontrolled after about 3 weeks of
`therapy, the dose may be increased to two tablets of HYZ-
`AAR 5042.5 once daily or one tablet of HYZAAR 100-25
`(losartan 100 mg/hydrcchlorothiazide 25 mg) once daily.
`A patient whose blood pressure is inadequately controlled
`by 25 mg once daily of hydrochlorothiazide, or is controlled
`but who experiences hypokalemia with this regimen, may
`be switched to HYZAAR 5042.5 (losartan 50 mg/hy'drochlo-
`rothiazide 12.5 mg) once daily, reducing the dose of hydro-
`chlorothiazide without reducing the overall expected anti-
`hypertensive‘response. The clinical response to HYZAAR
`5042.5 should be subsequently evaluated and if blood pres
`sure remains uncontrolled after about 3 weeks of therapy,
`the dose may be increased to two tablets of HYZAAR
`5042.5 once daily or one tablet of HYZAAR 100-25 (losartan
`100 mg/hydrochlorothiazide 25 mg) once daily.
`The usual dose of HYZAAR is one tablet of HYZAAR 5042.5
`once daily. More than two tablets of HYZAAR 5042.5 once
`daily or more than one tablet of HYZAAR 100—25 once daily
`is not recommended. The maximal antihypertensive effect is
`attained, about 3 weeks after initiation of therapy.
`Use in Patients with"Renal Impairment: The usual regi-
`mens of therapy with HYZAAR may be followed as long as
`the patient’s creatinine clearance is >30 mL/min. In pa-
`tients with more severe renal impairment, loop diuretics are
`preferred to thiazides, so HYZAAR is not recommended.
`Patients with Hepatic Impairment:
`'HYZAAR is not recom-
`mended for titration in patients with hepatic impairment
`(see WARNINGS, Impaired Hepatic Function). because the
`appropriate 25 mg starting dose oflosartan cannot be given.
`HYZAAR may be administered with other antihypertensive
`agents.
`-
`HYZAAR may be administered with or without food.
`
`HOW SUPPLIED
`
`No. 3502—Tablets HYZAAR, 5042.5 are yellow, teardrop
`shaped, film-coated tablets, coded MR‘K 717 on one side and
`HYZAAR on the other. Each tablet contains 50 mg of loser-
`tan potassium and 12.5 mg ofhydrochlorothiazide. They are
`supplied as follows:
`NDC 0006-0717-31 unit of use bottles of 30
`NBC 0006-0717-54 unit of use bottles of 90
`NBC 0006-071'7—58 unit of use bottles of 100.
`N06 0006-0717-28 unit dose packages of 100
`N00 0006-0717—82 unit of use bottles of 1,000.
`Shown in Product Identification Guide, page 323
`No. 3793—Tablets HYZAAR 100-25 are light yellow, tear-
`drop shaped, film-coated tablets, coded MRK 747 on one
`side and HYZAAR on the other. Each tablet contains 100 mg
`of losartan potassium and 25 mg of hydrachlorothiazide.
`They are supplied as follows:
`‘
`NDC 0006-0747—31 unit of use bottles of 30
`NDC 0006-0747-58 unit of use bottles of 100
`NDC 0006-0747-28 unit dose packages of 100.'
`Shown in Product Identification Guide, page 323
`Storage
`Store at 25°C (77W); excursions permitted to 15—30°C (59—
`86°F) [see USP Controlled Room Temperature). Keep-con-
`tainer tightly closed. Protect from light.
`Manufactured for:
`MERCK & CO., mo, West Point, PA 19486, USA
`by:
`'
`:
`DuPont Pharma, Wilmington, DE 19880 USA
`7892813
`Issued December 1999
`COPYRIGHT © MERCK & CO., Inc., 1995
`All rights reserved.
`
`INDOCIN® Capsules, Oral Suspension and
`Suppositories
`(Indornethacin)
`
`R
`
`DESCRIPTION
`
`INDOCIN* (Indomethacin) cannot be considered a simple
`analgesic and should not be used in conditions other than
`those recommended under INDICATIONS.
`
`Page 3 of 7
`
`PHYSICIANS’ DESK REFERENCE®
`
`
`
`INDICATIONS
`
`Indomethacin has been found effective in active” stages of
`the following:
`.
`1. Moderate to severe rheumatoid arthritis including acute
`flares of chronic disease.
`-
`2. Moderate to severe ankylosing spondylitis.
`3. Moderate to severe osteoarthritis.
`4. Acute painful'shoulder (bursitis and/or tendinitis).
`5. Acute gouty arthritis.
`'
`‘
`INDOCIN may enable the reduction of steroid dosage in pa-
`tients receiving steroids for the more severe forms of rheu-
`matoid arthritis. In such instances the steroid dosage
`should be reduced slowly and the patients followed'very
`closely for any possible adverse effects.
`'
`'
`The use of INDOCIN in conjunction with aspirin or other
`salicylates is not recommended. Controlled clinical studies
`have 'shown that the combined use ofINDOCIN and aspirin
`does not produce any greater therapeutic effect than the use
`of INDOCIN alone. Furthermore, in one of these clinical
`studies, the incidence'of gastrointestinal side effects was
`significantly increased with combined therapy (sec DRUG
`INTERACTIONS).
`_
`
`CONTRAINDICATIONS
`
`INDOCIN should not be used in:
`Patients who are hypersensitive to this product.
`Patients in whom acute asthmatic attacks, urticaria, or rhi-
`nitis are precipitated by aspirin or other non-steroidal anti-
`inflammatory agents.
`Suppositories INDOCIN are contraindicated in patients
`with a history of proctitis or recent rectal bleeding.
`'
`
`WARNINGS
`General:
`Because of the variability of the potential of INDOCIN to
`cause adverse reactions in the individual patient, the fol-
`lowing are strongly recommended:
`‘
`1. The lowest possible effective dose for the individual pa-
`tient should be prescribed. Increased dosage tends to in-
`crease adverse effects, particularly in doses over 150—200
`mg/day, without corresponding increase in clinical ben-
`efits.
`.
`-.
`2. Careful'instructionc to, and observations of, the individ-
`ual patient are essential to the prevention of serious ad-
`verse reactions. As advancing years appear to increase
`the possibility of adverse reactions, INDOCIN should be
`used with greater care in the elderly.
`3. Effectiveness of INDOCIN in pediatric patients has not
`been established. INDOCIN should not be prescribed for
`pediatric patients 14 years of age and younger unless tox-
`icity or lack of efficacy associated with other drugs war~
`rants the risk.
`.
`In experience with more than 900 pediatric patients re‘~
`ported in the literature or to the manufacturer who were
`treated with Capsules INDOCIN, side effects in pediatric
`patients were comparable to those reported in adults. Ex-
`perience in pediatric patients has been confined to the
`use of Capsules INDOCIN.
`.
`If a decisionlis made to use indomethacin for pediatric
`patients two years of age or older, such patients should be
`monitored closely and periodic assessment of liver func-
`tion is recommended. There have been cases ofhepatotox-
`icity reported in pediatric patients with juvenile rheuma~
`toid arthritis, including fatalities. If indomethacin treat-
`ment is instituted, a suggested starting dose is 2 mg/kg/
`day given in divided doses. Maximum daily dosage should
`not exceed 4 mg/kg/day or 150~200 mg/day, whichever is
`less. As’symptoms subside, the total daily dosage should
`be reduced to the lowest level required to control symp-
`toms, or the drug should be discontinued.
`Gastrointestinal Efi‘ects:
`Single or multiple ulcerations, including perforation and
`hemorrhage of the esophagus, stomach, duodenum or small
`and large intestine, have been reported to occur with INDO~
`CIN. Fatalities have been reported in some instances.
`Rarely, intestinal ulceration has been associated with ste-
`nosis and obstruction.
`Gastrointestinal bleeding without obvious ulcer formation
`and perforation of pre-existing sigmoid lesions (diverticu-
`lum, carcinoma, etc.) have occurred. Increased abdominal
`
`50‘"
`
`CHJO
`
`CH2COOH_
`
`*Registered trademark of MERCK & CO., INC.
`
`CLINICAL PHARMACOLOGY
`
`INDOCIN is a non-steroidal drug with anti-inflammatory.
`’antipyretic and analgesic properties. Its mode of action, like
`that of other. anti-inflammatory drugs, is not known. How-
`ever, its therapeutic action is not due to pituitary-adrenal
`stimulation.
`INDOCIN is a potent inhibitor of prostaglandin synthesis in.
`vitro. Concentrations are reached during therapy which
`have been demonstrated to have an effect in viva as well.
`Prostaglandins sensitize afl'erent nerves and potentiate the
`action of bradykinin in inducing pain in animal models.
`Moreover, prostaglandins areknown to be among the me-
`diators of inflammation. Since indomethacin is an inhibitor
`of prostaglandin synthesis, its made of action may be due to
`a decrease of prostaglandins in peripheral tissues.
`’
`INDOCIN has been shown to be an effective anti-inflamma-
`tory agent, appropriate for long-term use in rheumatoid ar-
`thritis, ankylosing spondylitis, and osteoarthritis.
`INDOCIN afi‘ords relief of symptoms; it does not alter the
`progressive course of the underlying disease.
`-
`..
`INDOCIN suppresses inflammation in rheumatoid arthritis
`as demonstrated by relief of pain, and reduction of fever,
`swelling and tenderness. Improvement in patients treated
`with INDOCIN for rheumatoid arthritis has been demon-
`strated by a reduction in joint swelling, average number of
`joints involved, and morning stiffness; by increased mobility
`as demonstrated by a decrease in walking time; and by im-
`proved functional capability as demonstrated by an increase
`in grip strength.
`-
`Indomethacin has been reported to diminish basal and 002
`stimulated cerebral blood flow in healthy volunteers follow:
`ing acute oral and intravenous administration. In one study
`after one week of treatment with orally administered indo-
`methacin, this effect on basal cerebral blood flow had disap-
`peared. The clinical significance of this effect has not been
`established.
`Capsules INDOCIN have been found effective in relieving
`the pain, reducing the fever, swelling, redness, and tender-
`ness of acute gouty arthritis—see INDICATIONS.
`Following single oral doses of Capsules INDOCIN 25 mg or-
`50 mg, indomethacin. is readily absorbed, attaining peak
`plasma concentrations of about 1 and 2 mcg/mL, respec-
`tively, at about 2 hours. Orally administered Capsule-s IN-
`DOCIN are virtually 100% bioavailable, with 90% of the
`dose absorbed within 4 hours. A single 50 mg dose of Oral
`Suspension INDOCIN was found to be bioequivalent to a 50
`mg INDOCIN capsule when each was administered with
`food.
`\.
`.
`Indomethacin is eliminated via renal excretion, metabolism,
`and biliary excretion. Indomethacin undergoes appreciable
`enterohepatic circulation. The mean half-life of indometha-
`cin is estimated to be about 4.5 hours. With a typical ther-
`apeutic regimen of 25 or 50 mg t.i.d., the steady-state
`plasma concentrations of indomethacin are an average 1.4
`times those following the first dose.
`The rate of absorption is more rapid from the rectal suppos-
`itory than from Capsules INDOCIN. Ordinarily, therefore,
`the total amount absorbed from the suppositoryrwould be
`expected -to be at least equivalent to the capsule. In con-
`trolled clinical trials, however, the amount of indomethacin
`absorbed was found to-ba somewhat less (80—90%) than that
`absorbed from Capsules INDOCIN. This is probably be«
`cause some subjects did not retain the material from the
`suppository for the one hour necessary to assure complete
`absorption. Since the suppository dissolves rather quickly
`rather than melting slowly, it is seldom recovered in recog«
`nizable form if the patient retains the suppository for more
`than a few minutes.
`
`Page 3 of 7
`
`

`

`PRODUCT INFORMATION
`
`.
`
`MERCK/194‘I
`
`Incidence greater than 1%
`GASTROINTESTINAL
`nausea* with or
`without vomiting
`dyspepsia“ ,
`(including »
`indigestion,
`hemtburn' and
`epigastric pain)
`diarrhea
`abdominal distress
`or pain
`constipation
`
`-
`
`Incidence less than 1%
`
`anorexia
`bloating (includes
`distention)
`flatulence
`peptic ulcer
`gastroenteritis
`rectal bleeding
`proctitis
`'
`single or
`3multiple ulcerations,
`including
`perforation and
`hemorrhage of
`the esophagus,
`stomach,
`duodenum or
`small and large
`intestines
`intestinal ulceration
`associated with
`stenosis and
`obstruction
`
`'
`
`anxiety (includes
`nervousness)
`muscle weakness
`involuntary muscle
`movements
`insomnia
`muzziness
`psychic distur—
`bances including
`psychotic
`episodes
`mental confusion
`drowsiness
`‘
`ocular-corneal
`deposits and
`retinal distur—
`bances, including
`those of the
`macula, have been
`reported in some
`patients on pro—
`longed therapy
`with INDOCIN .
`
`gastrointestinal
`bleeding without
`obvious ulcer
`formation and
`perforation of pre-
`existing sigmoid
`lesions
`(diverticulum,
`carcinoma, etc.)
`development of
`ulcerative colitis
`and regional ileitis
`' ulcerative stomatitis
`toxic hepatitis and
`jaundice (some
`fatal cases have
`been reported)
`intestinal strictures
`(diaphragms)
`
`,_
`
`~~
`
`_
`
`,
`
`.-
`
`'
`
`.
`.
`light~headedness
`syncope
`'
`- paresthesia
`. aggravation of epilepsy ,
`and parkinsonism
`depersonalization
`.
`. coma
`‘
`_
`.
`peripheral neuropathy
`convulsions
`dysarthria
`
`blurred visibn '
`diplopia .
`hearing disturbances,
`deafness
`
`,
`
`..
`
`pain-in ulcerative colitis patients or the development of ul-
`cerative colitis and regional ileitis have been reported to oc-
`cur rarer
`Because of the occurrence, and at times severity, of gastro-
`intestinal reactions to INDOCIN, the prescribing physician
`must be continuously alert for any sign or symptom signal—
`ing a possible gastrointestinal reaction. The risks of con-
`tinuing therapy with INDOCIN in the face of such symp4
`toms must be weighed against the possible benefits to the
`individual patient.
`’
`'
`INDOCIN should not be given ‘to patients with active gas~
`trointestinal lesions or with a history of recurrent gastroin-
`testinal lesions except under ciiéumstances which warrant
`c ose y.
`the vlery high risk and where patients canbe monitoredvery
`The gastrointestinal effects may be reduced by giving Cap-
`sules INDOCIN immediately after meals, with food, or with
`antacids.
`.
`Risk of GI Ulcerations, Bleeding and Perforation with
`NSAID Therapy
`-
`.
`Serious gastrointestinal toxicity such as bleeding, ulcer-
`ation, and perforation, can occur at any time, with or with-
`out warning symptoms, in patients treated chronically with
`NSAID therapy. Although minor upper gastrointestinal
`problems, such as dyspepsia, are common, usually develop-
`ing early in therapy, physicians should remain alert for ul-
`ceration and bleeding in patients treated chronically with
`NSAIDs even in the absence of previous GI tract symptoms.
`In patients observed in clinical'trials of several months to
`two years duration, symptomatic upper GI ulcers, gross
`bleeding or perforation appear to occur in approximately 1%
`of patients treated for 3-6 months, and in about 2—4% .of
`patients treated for one year. Physicians should inform pa-
`tients about the signs and/or symptoms of serious GI toxic~
`ity and what steps to take if they occur.
`Studies to date have not identified any subset of patients
`not at risk of developing peptic ulceration and bleeding. Ex-
`cept for a prior history of serious Gl events and other risk
`factors known to be associated with peptic ulcer disease,
`such as alcoholism, smoking, etc., no risk factors (e.g., age,
`sex) have been associated with increased risk. Elderly or de-
`bilitated patients seem to tolerate ulceration or bleeding
`less well than other individuals and most spontaneous re-
`ports of fatal GI events are in‘ this population. Studies to
`date are inconclusive concerning the relative risk of various
`NSAIDs' in causing such reactions. High doses of any
`NSAID probably carry a greater risk of these reactions, al-
`though controlled clinical trials showing this do not exist in ‘
`most cases. In considering the use of relatively large doses
`(within the recommended dosage range), sufficient benefit
`should be anticipated to offset the potential increased risk of
`GI toxicity.
`Renal Effects:
`As with other non-steroidal anti-inflammatory drugs, long
`term administration of indomethacin to animals has re-
`sulted in renal papillary necrosis and other abnormal renal
`pathology. In humans, there have been reports of acute in-
`terstitial nephritis with hematuria, proteinuria, and occa-
`sionally nephrotic syndrome.
`-
`'
`A second form of renal toxicity has been seen in patients
`with prerenal and renal conditions leading to a'reduction in
`renal blood flow or blood volume, where the renal prosta-
`glandins have ajsupportive role in the maintenance” of renal
`perfusion. In these patients administration of an’NSAID
`may cause a dose dependent reduction in prostaglandin for—
`mation and may precipitate overt renal decompensation.
`Patients at greatest risk of this reaction are those with con-
`ditions such 'as renal or hepatic dysfunction, diabetes mel-
`litus, advanced age, extracellular volume depletion from
`any cause, congestive'heart failure, septicemia, pyelone-
`phritis, or concomitant use of any nephrotoxic drug. INDO-
`CIN or other NSAIDs should be given with caution and re-
`nal function should be monitored in any patient who may
`have reduced renal reserve. Discontinuation of NSAID ther-
`apy is typically followed by recovery to the pretreatment
`state.
`‘
`Increases in serum potassium concentration, including hy—
`perkalemia, have been reported, even in some patients
`without renal impairment. In patients with normal renal
`function, these effects have been attributed to a hyporenine-
`mic-hypoaldosteronism state (see PRECAUTIONS, Drug
`Interactions).
`Since INDOCIN is eliminated primarily by the kidneys, pa-
`tients with significantly impaired renal function should be
`closely monitored; a lower daily dosage should be antici—
`pated to avoid excessive drug accumulation.
`Ocular Effects:
`Corneal deposits and retinal disturbances, including those
`of the macula, have been observed in some patients who had
`received prolonged therapy with INDOCIN. The prescribing
`physician should be alert to the possible association be-
`tween the changes noted and INDOCIN. It is advisable to
`discontinue therapy if such changes are observed. Blurred
`vision may be a significant symptom and warrants a thor-
`ough ophthalmological examination. Since these changes
`may be asymptomatic, ophthalmologic examination at peri-
`odic intervals is desirable in patients wherevtherapy is pro-
`longed.
`»
`,
`-
`.
`.
`Central Nervous System Effects:
`INDOCIN may aggravate depression or other psychiatric
`disturbances, epilepsy, and parkinsonism, and should be
`used with considerable caution in patients with these con‘
`ditions. If severe CNS adverse reactions develop, INDOCIN
`should be discontinued.
`INDOCIN may cause drowsiness; therefore, patients should
`be cautioned about engaging in activities requiring mental
`alertness and motor coordination, such as driving a car. IN-
`
`Page 4 of 7
`
`
`
`CENTRAL NERVOUS SYSTEM
`headache (11.7%)
`dizziness*
`vertigo
`somnolence
`depression and
`fatigue (including
`malaise and .
`listlessness)
`
`SPECIAL SENSES
`tinnitus
`
`
`
`DOCIN may also cause headache. Headache which persists
`despite dosage reduction requires cessation of.therapy with
`INDOCIN.
`Use in Pregnancy and the Neonatal Period
`INDOCIN is not recommended for use in pregnant women,
`sincesafety for use has not been established. The known
`effects of indomethacin and other drugs of this class on the
`human fetus, during the thirdtrimester of pregnancy in—
`clude: constriction of-the ductus arteriosus prenatally, tri-
`cuspid incompetence, and-pulmonary hypertension; non~
`closure of the ductus arteriosus postnatally.which may be
`resistant to medical management; myocardial degenerative
`changes, platelet dysfunction with resultant bleeding, intra«
`cranial bleeding, renal dysfunction or failure,.renal injury/
`dysgenesis which may result in prolonged or permanent re-
`nal failure, oligohydramnios, gastrointestinal bleeding or .
`perforation, and increased risk of necrotizing enterocolitis.
`Teratogenic studies were conductedin mice and rats at dos-
`ages of 0.5, 1.0, 2.0, and 4.0 mg/kg/day. Except for retarded
`fetal ossification at 4 mg/kg/day considered secondary to the
`decreased average fetal weights, no increase in fetal malfor-
`mations was observed as compared with control groups.
`Other studies in mice reported in the literature using
`higher doses (5 to 15 mg/kglday) have described maternal
`toxicity and death, increased fetal resorptions, and fetal
`malformations. Comparable studies in rodents using high
`doses of aspirin have shown similar maternal and fetal ef-
`fects.
`As with other non-steroidal anti-inflammatory agents which;
`inhibit prostaglandin synthesis, indomethacin has been
`found to delay parturition in rats.
`-
`In rats and mice, 4.0 mg/kg/day given during the last three
`days of gestation caused a decrease in maternal weight gain
`and some maternal and fetal deaths. An increased incidence
`of neuronal necrosis in the diencephalon in the live-born fe-
`tuses was observed. At 2.0 mg/kg/day, no increase in neuro-
`nal necrosis was observed as compared to the control
`groups. Administration of 0.5 or 4.0 mg/kg/day during the
`first three days of life did not cause an increase in neuronal
`necrosis at either dose level.
`Use in Nursing Mothers
`INDOCIN is excreted in the milk of lactating mothers. IN—
`DOCIN is not recommended for use in nursing mothers.
`PRECAUTIONS
`General
`Non-steroidal anti-inflammatdry drugs, including INDO-
`CIN, may mask the usual signs and symptoms of infection.
`Therefore, the physician must be continually on the alert for
`this and should use the drug with extra care in the presence
`.of existing infection.
`_ Fluid retention and peripheral edema have been observed
`in some patients taking lNDOCIN. Therefore, as with other
`
`-
`
`non~steroidal anti-inflammatory drugs, INDOCIN should-be
`used with caution in patients with cardiac dysfunction, hy-
`pertension, or other conditionspredisposing to fluid reten-
`tion.
`'
`‘
`'
`In a study of patients with severe heart failure and hypona-
`tremia_,'lNDOClN was associated with.significant deterio-
`ration of circulatory hemodynamics, presumably due to in1
`hibition of prostaglandin dependent’compensatory mecha-
`nisms.
`.
`
`like" other non-steroidal anti-inflammatory
`INDOCIN,
`agents, can inhibit platelet aggregation. This effect is of
`shorter duration than that seen with aspirin and usually
`disappears within 24 hours after discontinuation of,lNDO—
`CIN. INDOCIN has been shown to prolong bleeding time
`(but within the normal range) in normal subjects. Because
`this effect may be exaggerated in patients with underlying
`hemostatic defects, INDOCIN should be used with caution
`in persons with coagulation defects.
`. As with other non-steroidal anti-inflammatory drugs, bor—
`derline elevations of one or more liver tests may occur in up
`to 15% of patients. These abnormalities may progress, may
`remain essentially unchanged, or may be transient with
`continued therapy. The SGP’I‘ (ALT) test is probably the
`most sensitive indicator of liver dysfunction. Meaningful (3
`’times the upper limit of normal) elevations of SGPT or
`SGOT (AST) occurred in controlledclinical trials in less
`than 1% of patients. A patient with symptoms and/or signs
`suggesting liver dysfunction, or in whom an abnormalliver
`test has occurred, should be evaluated for evidence of the
`development of more severe hepatic reaction while on ther-
`apy with INDOCIN, Severe hepatic reactions, including
`jaundice and cases of fatal hepatitis, have been reported
`with INDOCIN as with other non-steroidal anti-inflamma-
`tory .drugs. 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 mani-
`festations occur (e.g., eosi‘nophilia, rash, etc), INDOCIN
`should be discontinued.
`,
`Information for Patients
`INDOCIN, like other drugs of its class, is not free of side
`effects. The side effects ofthese drugs can cause discomfort
`and, rarely, there are more serious side effects such as gas-
`trointestinal bleeding, which may result in hospitalization
`and even fatal outcomes.
`
`Continuedgon next page
`__________________..._.__———-——-—---
`Information on the Merck & Co., Inc. products listed on
`these pages is the full prescribing information from product
`circulars in use September 30, 2000. For information, please
`call 1-800-NSC MERCK [1-8007672-63721.
`______________......—.—-—-—-———-———-—
`
`Consult 200 1 PDRo supplements and future editions for revif
`
`
`
`Page 4 of 7
`
`

`

`
`. Incidence greater than 1%
`Incidence less than 1%
`’
`.
`CARDIOVASCULAR
`.
`none
`hypertension
`hypotension -
`tachycardia
`chest pain
`-
`edema
`weight gain
`fluid retention
`flushing or sweating
`pruritus
`rash; urticaria
`petechiae or
`ecchymosis
`
`PHYSICIANS’ DESK REFERENCE®
`
`(-
`
`congestive heart failure
`arrhythmia;
`palpitations -
`
`hyperglycemia
`_ glycosuria
`hyperkalemia
`
`exfoliative dermatitis
`erythema nodosum
`loss of hair
`,.
`Stevens-Johnson
`syndrome"
`erythema multiforme
`toxic epidermal
`necrolysis
`
`aplastic anemia
`hemolytic anemia
`agranulocytosis
`, thrombocytopenic
`purpura
`disseminated intravascular
`coagulation
`
`dyspnea
`asthma
`purpura
`’ angiitis
`fever
`' pulmonary edema
`
`BUN elevation
`renal insufficiency,
`including renal
`failure
`
`-
`
`METABOLIC
`none
`
`INTEGUMENTARY
`none
`
`HEMATOLOGIC
`none
`
`‘
`.
`'
`HYPERSENSITIVITY
`none
`
`GENITOURINARY
`none
`
`MISCELLANEOUS
`none
`
`leukopenia
`bone marrow
`depression
`anemia secondary
`to obvious or
`occult
`gastrointestinal
`bleeding
`.
`acute anaphylaxis
`acute respiratory
`distress
`rapid fall in blood
`pressure
`resembling a
`shock-like state
`angioedema
`hematuria
`- vaginal bleeding
`proteinuria
`nephrotic syndrome
`interstitial nephritis
`epistaxis
`breast changes,
`including
`enlargement and
`tenderness, or
`‘ gynecomastia
`
`1948/MERCK
`
`l
`
`-
`ndocIn—ant.
`
`NSAIDs (Non—steroidal Anti-inflammatory Drugs) are often
`essential agents in the management of arthritis; but they
`also may be commonly employed for conditions which are
`less serious.
`Physicians may wish to discuss with their patients the po-
`tential risks (see WARNINGS, PRECAUTIONS and AD-
`VERSE REACTIONS) and likely benefits of NSAID treat-
`ment, particularlywhen the drugs are used for less serious
`conditions where treatment withoutNSAIDs may represent
`an acceptable alternative to both the patient and phy