`
`PHYSICIANS
`See
`RsrareNe=
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1023, p. 001
`
`

`

`2000
`
`
`
`
` PDR
`eh
`
`EDITION
`
`
`
`
`PHYSICIANS
`OK
`REFERENCE
`
`
`
`Senior Vice President, Directory Services: Paul Walsh
`
`Director of Product Management: Mark A. Friedman
`Associate Product Manager: Bill Shaughnessy
`Senior Business Manager: Mark S. Ritchin
`Financial Analyst: Wayne M. Soltis
`Director of Sales: Dikran N. Barsamian
`
`National Sales Manager, Pharmaceutical Sales: Anthony Sorce
`National Account Manager: Don Bruccoleri
`Senior Account Manager: Frank Karkowsky
`Account Managers:
`Marion Gray, RPh
`Lawrence C. Keary
`Jeffrey F. Pfohl
`Suzanne E. Yarrow, RN
`Electronic Sales Account Manager: Stephen M. Silverberg
`National Sales Manager, Medical Economics Trade Sales:Bill Gaffney
`Director of Direct Marketing: Michael Bennett
`List and Production Manager: Lorraine M. Loening
`Senior Marketing Analyst: Dina A. Maeder
`
`Director, New Business Development and
`Professional Support Services: Mukesh Mehta, RPh
`Manager, Drug Information Services: Thomas Fleming, RPh
`Drug Information Specialist: Maria Deutsch, MS, RPh, CDE
`Editor, Directory Services: David W. Sifton
`Senior Associate Editor: Lori Murray
`Director of Production: Carrie Williams
`Managerof Production: Kimberly H. Vivas
`Senior Production Coordinator: Amy B. Brooks
`Production Coordinators: Gianna Caradonna, Maria Volpati
`Data Manager: Jeffrey D. Schaefer
`Senior Format Editor: Gregory J. Westley
`Index Editors: Johanna M. Mazur, Robert N. Woerner
`Art Associate: Joan K. Akerlind
`
`Senior Digital Imaging Coordinator: Shawn W. Cahill
`Digital Imaging Coordinator: Frank J. McElroy,Ill
`Electronic Publishing Designer: Livio Udina
`Fulfillment Manager: Stephanie DeNardi
`
`
`
`oe Copyright©2000 and published by Medical Economics Company,Inc. at Montvale, NJ 07645-1742. All rights reserved. Noneofthe contentofthis publication may
`
`be reproduced, stored in a retrieval system, resold,redistributed, or transmitted in any form or by any means(electronic, mechanical, photocopying, recording, or
`otherwise) without the prior written permission of the publisher. PHYSICIANS' DESK REFERENCE®, PDR®, PDR For Ophthalmology®, Pocket PDR®, and The PDR® Family
`Guide to Prescription Drugs® are registered trademarks used herein underlicense. PDR For Nonprescription Drugs and Dietary Supplements™, PDR Companion Guide™,
`PDR?for Herbal Medicines™, PDR® Medical Dictionary™, PDR® Nurse's Drug Handbook™, PDR® Nurse's Dictionary™, The PDR® Family Guide Encyclopedia of Medical
`Care™, The PDR® Family Guide to Natural Medicines and Healing Therapies™, The PDR® Family Guide to CommonAilments™, The PDR® Family Guide to Over-the-
`Counter Drugs™, and PDR?® Electronic Library™ are trademarks used herein underlicense.
`
`Officers of Medical Economics Company: President and Chief Executive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDell; Vice President, Corporate Human
`Resources: Pamela M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Chief Financial Officer: Christopher Caridi; Vice President and Controller: Barry
`Gray; Vice President, New Business Planning: Linda G. Hope; Vice President, Business Integration: David A. Pitler; Vice President, Finance: Donna Santarpia; Senior Vice President,
`Directory Services: Paul Walsh; Senior Vice President, Operations: Jonn R. Ware; Senior Vice President, Internet Strategies: Raymond Zoeller
`
`3) Printed on recycled paper
`
`ISBN: 1-56363-330-2
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1023, p. 002
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1023, p. 002
`
`

`

`1968/MYLAN
`
`PHYSICIANS’ DESK REFERENCE®
`ageeeeeeneeRcrete
`Captopril—Cont.
`
`the IV injection than after the tablet or oral solution. There
`are no significant differences between the two oral formule-
`tions in the amount of unchanged drugexcreted in urine.
`INDICATIONS AND USAGE
`Edema: Furosemide is indicated in adults, infants, and
`children for the treatment of edemaassociated with conges-
`tive heart failure, cirrhosis of the liver, and renal disease.
`including the nephrotic syndrome. Furosemide is particu-
`larly useful when an agentwith greaterdiuretic potential is
`desired.
`Hypertension: Oral furosemide may be used in adults for
`the treatment of hypertension aloneor in combination with
`other antihypertensive agents. Hypertensive patients who
`cannot be adequately controlled with thiazideswill probably
`also not be adequately controlled with furosemide alone.
`CONTRAINDICATIONS
`Furosemideis contraindicated in patients with anuria and
`in patients with a history of hypersensitivity to furosemide.
`WARNINGS
`
`oval tablets marked with M to theleft of the score and C1 to
`the right of the score on one side. They are available as
`follows:
`NDC 0378-3007-01
`bottles of 100 tablets
`NDC 0378-3007-10
`bottles of 1000 tablets
`The 25 mg tablets are white, quadrisect scored, round tab-
`lets marked with M over C2 on the non-scored side. They
`are available as follows:
`NDC 0378-3012-01
`bottles of 100 tablets
`NDC 0378-3012-10
`bottles of 1000 tablets
`The 50 mgtablets are white, scored, round tablets marked
`with M over C3 on the scored side. They are available as
`follows:
`NDC 0378-3017-01
`bottles of 100 tablets
`NDC 0378-3017-10
`bottles of 1000 tablets
`The 100 mgtablets are white, scored, round tablets marked
`with M over C4 on the scored side. They are available as
`follows:
`NDC 0378-3022-01
`bottles of 100 tablets
`Captopril tablets may exhibit a slight sulfurous odor.
`Bottles contain-a desiccant-charcoal canister.
`STORE AT CONTROLLED ROOM TEMPERATURE 15°-30°C
`(59°-86°F).
`PROTECT FROM MOISTURE.
`Dispensein a tight container using a child-resistantclosure.
`Rx only
`Mylan Pharmaceuticals Inc.
`Morgantown, WV 26505
`
`REVISED MARCH 1998
`CAPT:R7
`
`
`
`FUROSEMIDE TABLETS, USP
`20 mg, 40 mg and 80 mg
`
`R
`
`
`
` The 12.5 mgtablets are white, partially scored (both sides),
` Significantly more furosemide is excreted in urine following
`
`Initiation of therapy requires consideration
`Hypertension:
`of recent antihypertensive drug treatment, the extent of
`blood pressure elevation, salt restriction, and other clinical
`circumstances. If possible, discontinue the patient’s previ-
`ous antihypertensive drug regimen for one week before
`starting captopril.
`Theinitial dose of captopril is 25 mgbidortid. If satisfac-
`tory reduction of blood pressure has not been achieved after
`one.or two weeks, the dose maybe increased to 50 mg bid or
`tid. Concomitant sodium restriction may be beneficial when
`captopril is used alone.
`The dose of captopril in hypertension usually does not ex-
`ceed 50 mgtid. Therefore,if the blood pressure has not been
`satisfactorily controlled after one to two weeksat this dose,
`(and the patientis not already receiving a diuretic), a mod-
`est dose of a thiazide-type diuretic (e.g., hydrochlorothia-
`zide, 25 mgdaily), should be added. The diuretic dose may
`be increased at one- to two-week intervals until its highest
`usual antihypertensive dose is reached.
`If captopril is being started in a patient already receiving a
`diuretic, captopril therapy should be initiated under close
`medical supervision (see WARNINGS and PRECAUTIONS
`In patients with hepatic cirrhosis and ascites, furosemide
`{Drug Interactions] regarding hypotension), with dosage
`therapy is best initiated in the hospital. In hepatic coma
`and titration of captopril as noted above.
`andin statesof electrolyte depletion, therapy should not be
`If further blood pressure reduction is required, the dose of
`instituted until the basic condition is improved. Sudden al-
`captopril may be increased to 100 mgbid or tid and then,if
`terationoffluid and electrolyte balance in patients with cir-
`necessary, to 150 mgbid ortid (while continuingthe diuret-
`rhosis may precipitate hepatic coma; therefore,strict obser-
`ic). The usual dose rangeis 25 to 150 mg bid or tid. A max-
`vation is necessary during the period ofdiuresis. Supple-
`imum daily dose of 450 mgcaptopril should not be exceeded.
`mental potassium chloride and, if required, an aldosterone
`For patients with severe hypertension (e.g., accelerated or
`antagonist are helpful in preventing hypokalemia and met-
`abolic alkalosis.
`malignant hypertension), when temporary discontinuation
`of current antihypertensive therapy is not practical or de-
`If increasing azotemia andoliguria occur during treatment
`sirable, or when prompttitration to more normotensive
`of severe progressive renal disease, furosemide should be
`blood pressurelevels is indicated, diuretic should be contin-
`discontinued.
`ued but other current antihypertensive medication stopped
`Casesof tinnitus and reversible or irreversible hearing im-
`and captopril dosage promptly initiated at 25 mg bid or tid,
`pairment have been reported. Usually, reports indicate that
`underclose medical supervision.
`furosemide ototoxicity is associated with rapid injection, se-
`When necessitated by the patient’s clinical condition, the
`vere renal impairment, doses exceeding several times the
`daily dose of captopril may be increased every 24 hours or
`usual recommendeddose, or concomitant therapy with ami-
`less under continuous medical supervision until a satisfac-
`noglycoside antibiotics, ethacrynic acid, or other ototoxic
`tory blood pressure response is obtained or the maximum
`drugs. If the physician elects to use high dose parenteral
`dose of captopril is reached. In this regimen, addition of a
`therapy, controlled intravenous infusion is advisable (for
`more potent diuretic, e.g., furosemide, may also be indi-
`cated.
`adults, an infusion rate not exceeding 4 mg furosemide per
`minute has been used).
`Beta-blockers mayalso be used in conjunction with capto-
`PRECAUTIONS
`pril therapy (see PRECAUTIONS: Drug Interactions), but
`the effects of the two drugs are less than additive.
`General: Excessive diuresis may cause dehydration and
`Heart Failure:
`Initiation of therapy requires consideration
`blood volumereduction with circulatory collapse and possi-
`of recent diuretic therapy and the possibility of severe salt/
`ble vascular thrombosis and embolism, particularly in el-
`volume depletion. In patients with either normal or low
`derly patients. As with anyeffective diuretic, electrolyte de-
`blood pressure, who have been vigorously treated with di-
`pletion may occur during furosemide therapy, especially in
`uretics and who may be hyponatremic and/or hypovolemic,
`patients receiving higher doses anda restricted salt intake.
`a starting dose of 6.25 or 12.5 mg tid may minimize the
`Hypokalemia may develop with furosemide, especially with
`magnitudeor duration of the hypotensive effect (see WARN-
`brisk diuresis, inadequate oral electrolyte intake, whencir-
`INGS: Hypotension); for these patients, titration to the
`rhosis is present or during concomitant use ofcorticoster-
`usual daily dosage can then occur within the next several
`days.
`oids or ACTH.Digitalis therapy may exaggerate metabolic
`effects of hypokalemia, especially myocardial effects.
`For mostpatients the usual initial daily dosage is 25 mgtid.
`All patients receiving furosemide therapy should be ob-
`After a dose of 50 mgtid is reached, further increases in
`served for these signs or symptomsoffluid or electrolyte im-
`0
`dosage should be delayed, wherepossible, for at least two
`balance (hyponatremia, hypochloremic alkalosis, hypokale-
`weeks to determine if a satisfactory response occurs. Most
`LI
`I
`mia, hypomagnesemiaor hypocalcemia): dryness of mouth,
`patients studied have hadasatisfactory clinical improve-
`thirst, weakness,lethargy, drowsiness, restlessness, muscle
`nt
`ment at 50 or 100 mgtid. A maximum daily dose of 450 mg
`pains or cramps, muscular fatigue, hypotension, oliguria,
`of captopril should not be exceeded.
`O
`tachycardia, arrhythmia, or gastrointestinal disturbances
`Captopril should generally be used in conjunction with a di-
`such as nausea and vomiting.
`uretic and digitalis. Captopril therapy must beinitiated un-
`Increases in blood glucose and alterations in glucose toler-
`der very close medical supervision.
`ance tests (with abnormalities of the fasting and 2-hour
`Left Ventricular Dysfunction After Myocardial Infarction:
`postprandial sugar) have been observed, and rarely, precip-
`The recommendeddose for long-term use in patients follow-
`itation of diabetes mellitus has been reported.
`ing a myocardialinfarction is a target maintenance dose of
`50 mgtid.
`Asymptomatic hyperuricemia can occur and gout may
`rarely be precipitated.
`Therapy maybeinitiated as early as three days following a
`Patients allergic to sulfonamides mayalso be allergic to fu-
`rosemide.
`myocardial infarction. After a single dose of 6.25 mg, capto-
`pril therapy should be initiated at 12.5 mg tid. Captopril
`The possibility exists of exacerbation or activation of sys-
`should then beincreased to 25 mgtid during the next sev-
`temic lupus erythematosus.
`eral days andto a target dose of 50 mg tid over the next
`As with manyotherdrugs, patients should be observed reg-
`several weeksas tolerated (see CLINICAL PHARMACOL-
`OGY).
`ularly for the possible occurrence of blood dyscrasias, liver
`or kidney damageorotheridiosyncratic reactions.
`Captopril may be usedin patients treated with other post-
`Information for Patients: Patients receiving furosemide
`myocardial infarction therapies,e.g., thrombolytics, aspirin,
`beta-blockers.
`should be advised that they may experience symptoms from
`excessive fluid and/or electrolyte losses. The postural hypo-
`Dosage Adjustmentin Renal Impairment: Because capto-
`tension that sometimesoccurs can usually be managed by
`pril is excreted primarily by the kidneys,excretion rates are
`getting up slowly. Potassium supplements and/or dietary
`reduced in patients with impaired renal function. These pa-
`measures maybeneededto control or avoid hypokalemia.
`tients will take longer to reach steady-state captopril levels
`Patients with diabetes mellitus should be told that furose-
`and will reach higher steady-state levels for a given daily
`dose than patients with normalrenal function. Therefore,
`mide mayincrease blood glucose levels and thereby affect
`these patients may respond to smaller or less frequent
`urine glucosetests. The skin of some patients may be more
`doses.
`sensitive to the effects of sunlight while taking furosemide.
`Hypertensive patients should avoid medications that may
`increase blood pressure, including over-the-counter prod-
`ucts for appetite suppression and cold symptoms.
`Laboratory Tests: Serum electrolytes, (particularly potas-
`sium), COQp, creatinine and BUN should be determined fre-
`quently duringthe first few months of furosemide therapy
`andperiodically thereafter. Serum and urine electrolyte de-
`terminations are particularly important when the patient is
`vomiting profusely or receiving parenteral fluids. Abnormal-
`ities should be corrected or the drug temporarily with-
`drawn. Other medications mayalso influence serum electro-
`lytes.
`Reversible elevations of BUN mayoccur and are associated
`with dehydration which should be avoided, particularly in
`patients with renal insufficiency.
`
`WARNING: Furosemide.is a potent diuretic which, if
`given in excessive amounts,can lead to a profounddiuresis
`with water and electrolyte depletion. Therefore, careful
`medical supervision is required, and dose and dose sched-
`ule must be adjusted to theindividual patient's needs. (See
`“DOSAGE AND ADMINISTRATION”)
`DESCRIPTION
`Furosemideis a diuretic which is an anthranilic acid deriv-
`ative. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylan-
`thranilic acid. Furosemideis a white to slightly yellow odor-
`less, crystalline powder.It is practically insoluble in water,
`sparingly soluble in alcohol, freely soluble in dilute alkali
`solutions and insolublein dilute acids.
`The structural formulais as follows:
`COOH
`
`NHCH2
`
`clC42H;+CIN205S
`M.W.330.75
`
`Eachtablet for oral administration contains 20 mg, 40 mg
`or 80 mgof furosemide and thefollowing inactive ingredi-
`ents:’ colloidal silicon dioxide, lactose monohydrate, micro-
`crystalline cellulose, pregelatinized starch and stearic acid.
`Furosemide Tablets, USP 20 mg, 40 mg and 80 mg meet
`USP DISSOLUTION TEST1.
`CLINICAL PHARMACOLOGY
`Investigations into the mode of action of furosemide have
`utilized micropuncture studies in rats, stop flow experi-
`ments in dogs, and various clearance studies in both hu-
`mans:and experimental animals. It has been demonstrated
`that furosemide inhibits primarily the reabsorption of so-
`dium and chloride not only in the proximal and distal tu-
`bules but also in the loop of Henle. The high degreeof effi-
`cacy is largely due to this unique site of action. The action
`on the distal tubule is independentof any inhibitory effect
`on carbonic anhydrase and. aldosterone.
`Recent evidence suggests that furosemide glucuronide is the
`only or at least the major biotransformation product of fu-
`rosemide in man. Furosemide is extensively bound to
`plasmaproteins, mainly to albumin. Plasma concentrations
`ranging from 1 to 400 pg/mL are 91 to 99% boundin healthy
`individuals. The unbound fraction averages 2.3 to 4.1% at
`therapeutic concentrations.
`Theonsetof diuresis followingoral administration is within
`one hour. The peak effect occurs within the first or second
`hour. The duration of diuretic effect is 6 to 8 hours.
`In fasted normal men, the mean bioavailability of furose-
`mide from furosemide tablets and furosemideoral solution
`has been shownto be about 60% of that from an intravenous
`injection of the drug. Although furosemide is more rapidly
`absorbed from the oral solution than from the tablet, peak
`plasma levels and area under the plasma concentration-
`time curves do not differ significantly. Peak plasma concen-
`trations of furosemide increase with increasing dose but
`times-to-peak do not differ among doses. The terminal half-
`life of furosemide is approximately 2 hours.
`
`Accordingly, for patients with significant renal impairment,
`initial daily dosage of captopril should be reduced, and
`smaller increments utilized for titration, which should be
`quite slow (one- to two-week intervals). After the desired
`therapeutic effect has been achieved, the dose should be
`slowly back-titrated to determine the minimaleffective
`dose. When concomitant diuretic therapy is required, a loop
`diuretic (e.g., furosemide), rather than a thiazide diuretic, is
`preferred in patients with severe renal impairment. (See
`WARNINGS: Anaphylactoid Reactions During Membrane
`Exposure and PRECAUTIONS: Hemodialysis.)
`HOW SUPPLIED
`
`Captopril tablets are available containing 12.5 mg, 25 mg,
`50 mg or 100 mgof captopril.
`
`informationwill be superseded by supplements andBtOOCON PHARMALTD(IPR2020-01263) Ex. 1023, p. 003
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1023, p. 003
`
`

`

`TEieeeayaeaeganeaetEaagESOSaeegeESRT
`
`MYLAN/1969
`PRODUCT INFORMATION
`eee
`
`tion should be exercised when furosemide is administered to
`a nursing mother.
`ADVERSE REACTIONS
`Adverse reactions are categorized below by organ system
`andlisted by decreasing severity.
`Gastrointestinal System
`Reactions
`
`$909.1>OtBe09.BObe
`
`. pancreatitis
`jaundice (intrahepatic cholestatic jaundice)
`anorexia
`oral and gastric irritation
`cramping
`diarrhea
`constipation
`nausea
`vomiting
`
`Systemic Hypersensitivity
`Reactions
`
`mide in infants and children is 2 mg/kg body weight, given as a single dose. If the diuretic response is not satisfactory
` Nursing Mothers: Because it appears in breast milk, cau-
`
`Urine and blood glucose should be checked periodically in
`after the initial dose, dosage may be increased by 1 or 2
`diabetics receiving furosemide, even in those suspected of
`latent diabetes.
`mg/kg no sooner than6 to 8 hoursafter the previous dose.
`Doses greater than 6 mg/kg body weight are not recom-
`Furosemide may lower serum levels of calcium (rarely cases
`mended. For maintenance therapy in infants and children,
`of tetany have been reported) and magnesium. Accordingly,
`the dose should be adjusted to the minimumeffective level.
`serum levels of these electrolytes should be determined pe-
`For ease of administration, and to allow maximum flexibil-
`riodically.
`ity in dosing, the use of Furosemide Oral Solution is sug-
`Drug Interactions: Furosemide may increase the ototoxic
`gested.
`potential of aminoglycoside antibiotics, especially in the
`Hypertension: Therapy shouldbe individualized according
`presenceof impaired renal function. Exceptin life threaten-
`to the patient’s response to gain maximal therapeutic re-
`ing situations, avoid this combination.
`sponse and to determine the minimal dose needed to main-
`Furosemide should not be used concomitantly with etha-
`tain that therapeutic response.
`crynic acid becauseof thepossibility of ototoxicity.
`Adults: The usualinitial dose of furosemide for hyperten-
`Patients receiving high doses of salicylates concomitantly
`sion is 80 mg, usually divided into 40 mg twice a day. Dos-
`with furosemide, as in rheumatic disease, may experience
`age should then be adjusted according to response. If re-
`salicylate toxicity at lower doses because of competitive re-
`sponse is not satisfactory, add other antihypertensive
`nal excretory sites.
`agents.
`Furosemide has a tendency to antagonize the skeletal mus-
`Changes in blood pressure must be carefully monitored
`cle relaxing effects of tubocurarine and may potentiate the
`whenfurosemideis used with other antihypertensive drugs,
`action of succinylcholine.
`especially during initial therapy. To prevent excessive drop
`Lithium generally should not be given with diuretics be-
`in blood pressure, the dosage of other agents should bere-
`cause they reducelithium’s renal clearance and add a high
`duced by at least 50 percent when furosemide is added to
`risk oflithium toxicity.
`the regimen.As the blood pressure falls under the potenti-
`Furosemide may addto or potentiate the therapeutic effect
`ating effect of furosemide, a further reduction in dosage or
`of other antihypertensive drugs. Potentiation occurs with
`even discontinuation of other antihypertensive drugs may
`ganglionic or peripheral adrenergic blocking drugs.
`be necessary.
`Furosemide maydecrease arterial responsiveness to norep-
`HOW SUPPLIED
`inephrine. However, norepinephrine maystill be used effec-
`tively.
`The 20 mg tablets are white, round, unscored, flat-bevel-
`Simultaneous administration of sucralfate and furosemide
`edged tablets marked with M2. They are available as fol-
`tablets may reducethe natriuretic and antihypertensive ef-
`lows:
`fects of furosemide. Patients receiving both drugs should be
`NDC 0378-0208-01 bottles of 100 tablets
`Hematologic Reactions
`observed closely to determineif the desired diuretic and/or
`NDC 0378-0208-10 bottles of 1000 tablets
`1. aplastic anemia (rare)
`antihypertensive effect of furosemide is achieved. The in-
`The 40 mgtablets are white, round, scored,flat-bevel-edged
`2. thrombocytopenia
`take of furosemide and sucralfate should be separated by at
`tablets marked with MYLAN over 216 0noneside and 40 on
`3. agranulocytosis (rare)
`least two hours.
`the other side. They are available as follows:
`4. hemolytic anemia
`One study in six subjects demonstrated that the combina-
`NDC 0378-0216-01 bottles of 100 tablets
`5. leukopenia
`tion of furosemide and acetylsalicylic acid temporarily re-
`NDC 0378-0216-10 bottles of 1000 tablets
`6. anemia
`duced creatinine clearancein patients with chronic renalin-
`The 80 mgtablets are white, round, scored,flat-bevel-edged
`Dermatologic-Hypersensitivity Reactions
`sufficiency. There are case reportsof patients who developed
`tablets marked with MYLAN over 232 on one side and 80 on
`exfoliative dermatitis
`increased BUN,serum creatinine and serum potassium lev-
`the other side. They are available as follows:
`erythema multiforme
`els, and weight gain when furosemide wasused in conjunc-
`NDC 0378-0232-01 bottles of 100 tablets
`purpura
`tion with NSAIDs.
`NDC 0378-0232-05 bottles of 500 tablets
`photosensitivity
`Literature reports indicate that coadministration of indo-
`STORE AT CONTROLLED ROOM TEMPERATURE 15°-30°C
`urticaria
`methacin may reduce the natriuretic and antihypertensive
`rash
`(59°-86°F).
`effects of furosemide in some patients by inhibiting prosta-
`PROTECT FROM LIGHT.
`pruritus
`glandin synthesis. Indomethacin mayalso affect plasma re-
`Cardiovascular Reaction
`Dispense inatight, light-resistant container using a child-
`nin levels, aldosterone excretion and renin profile evalua-
`resistant closure. Exposureto light may causeslight discol-
`Orthostatic hypotension may occur and maybe aggravated
`tion. Patients receiving both indomethacin and furosemide
`oration. Discolored tablets should not be dispensed.
`by alcohol, barbiturates, or narcotics.
`should be observed closely to determine if the desired di-
`MYLAN®
`Other Reactions
`uretic and/or antihypertensive effect of furosemide is
`Mylan Pharmaceuticals Inc.
`. hyperglycemia
`achieved.
`Morgantown, WV 26505
`glycosuria
`Carcinogenesis, Mutagenesis, Impairmentof Fertility: Fu-
`hyperuricemia
`rosemide wastested for carcinogenicity by oral administra-
`muscle spasm
`tion in one strain of mice and onestrain of rats. A small but
`weakness
`significantly increased incidence of mammaryglandcarcin-
`. restlessness
`omasoccurred in female mice at a dose 17.5 times the max-
`. urinary bladder spasm
`imum human dose of 600 mg. There were marginal in-
`. thrombophlebitis
`creases in uncommon tumors in male rats at a dose of 15
`. fever
`mg/kg (slightly greater than the maximum human dose) but
`Wheneveradverse reactions are moderateor severe, furose-
`not at 30 mg/kg.
`mide dosage should be reduced or therapy withdrawn.
`Furosemide was devoid of mutagenic activity in various
`OVERDOSAGE
`strains of Salmonella typhimurium whentested in the pres-
`ence or absence of an in vitro metabolic activation system,
`The principal signs and symptomsof overdosage with furo-
`and questionably positive for gene mutation in mouse lym-
`semide are dehydration, blood volume reduction, hypoten-
`phomacells in the presence of rat liver S9 at the highest
`sion, electrolyte imbalance, hypokalemia and hypochloremic
`dose tested. Furosemide did not inducesister chromatid ex-
`alkalosis, and are extensionsof its diuretic action.
`change in human cells in vitro, but other studies on chro-
`The acute toxicity of furosemide has been determined in
`mosomalaberrations in humancells in vitro gave conflict-
`mice, rats, and dogs. In all three, the oral LD;) exceeded
`ing results. In Chinese hamster cells it induced chromo-
`1000 mg/kg body weight while the intravenous LD;ranged
`somal damage but was questionably positive for sister
`from 300 to 680 mg/kg. The acute intragastric toxicity in
`neonatalrats is 7 to 10 times that of adult rats.
`chromatid exchange. Studies on the induction by furose-
`mide of chromosomal aberrations in mice were inconclusive.
`The concentration of furosemidein. biological fluid associ-
`The urine of rats treated with this drug did not induce gene
`ated with toxicity or death is not known.
`conversion in Saccharomyces cerevisiae.
`Treatment of overdosage is supportive and consists. of re-
`Furosemide produced no impairmentoffertility in male or
`placementof excessive fluid and electrolyte losses. Serum
`female rats at 100 mg/kg/day (the maximum effective di-
`electrolytes, carbon dioxide level and blood pressure should
`uretic dose in the rat and 8 times the maximal human dose
`be determined frequently. Adequate drainage must be as-
`of 600 mg/day).
`CigH16CINgO3S
`sured in patients with urinary bladder outlet obstruction
`Pregnancy: Teratogenic Effects: Pregnancy Category C:
`(such as prostatic hypertrophy).
`Eachtablet, for oral administration, contains 1.25 mgor 2.5
`Furosemide has been shownto cause unexplained maternal
`Hemodialysis does not accelerate furosemide elimination.
`deaths and abortionsin rabbits at 2, 4 and 8 times the max-
`mg of indapamide and the following inactive ingredients:
`DOSAGE AND ADMINISTRATION
`imal recommended human dose. There are no adequate and
`anhydrouslactose, colloidal silicon dioxide, hydroxypropyl
`Edema: Therapy should be individualized according to pa-
`well-controlled studies in pregnant women. Furosemide
`methylcellulose, magnesium stearate, microcrystalline cel-
`tient response to gain maximal therapeutic response and to
`lulose, polydextrose, polyethylene glycol, pregelatinized
`should be used during pregnancyonlyif the potential ben-
`determine the minimal dose needed to maintain that re-
`starch, sodium lauryl sulfate, and titanium dioxide. Addi-
`efit justifies the potential risk to the fetus.
`sponse.
`The effects of furosemide on embryonic and fetal develop-
`tionally, the 1.25 mg product contains glyceryl triacetate
`Adults: The usual initial dose of furosemide is 20 to 80 mg
`and D&C Red No. 30 Aluminum Lake andthe 2.5 mg prod-
`ment and on pregnant damswerestudied in mice, rats, and
`rabbits.
`:
`uct containstriacetin.
`given as a single dose. Ordinarily a prompt diuresis ensues.
`If needed, the same dose can be administered 6 to 8 hours
`Furosemide caused unexplained maternal deaths and abor-
`CLINICAL PHARMACOLOGY
`later or the dose may be increased. The dose maybe raised
`tions in the rabbit at the lowest dose of 25 mg/kg (two times
`Indapamideis the first of a new class of antihypertensive/
`by 20 to 40 mg andgiven not soonerthan6to 8 hours after
`the maximal recommended humandose of 600 mg/day). In
`diuretics, the indolines. It has been reported that the oral
`the previous dose until the desired diuretic effect has been
`another study, a dose of 50 mg/kg (four times the maximal
`administration of 5 mg (two 2.5 mgtablets) of indapamide
`obtained. This individually determined single dose should
`recommended human dose of 600 mg/day) also caused ma-
`to healthy male subjects produced peak concentrations of
`ternal deaths and abortions when administered to rabbits
`then be given onceor twice daily (e.g., at 8 am and 2 pm).
`The dose of furosemide maybe carefully titrated up to 600
`approximately 260 ng/mL of the drug in the blood within
`between Days 12 and 17ofgestation. In a third study, none
`two hours. A minimum of 70% of a single oral dose is elim-
`mg/dayin patients with clinically severe edematous states.
`of the pregnantrabbits survived a dose of 100 mg/kg. Data
`inated by the kidneys and an additional 23% by the gastro-
`Edema maybe mostefficiently and safely mobilized by giv-
`from the above studies indicate fetal lethality that can pre-
`cede maternal deaths.
`intestinal tract, probably including the biliary route. The
`ing furosemide on 2 to 4 consecutive days each week.
`half-life of indapamide in whole blood is approximately 14
`When doses exceeding 80 mg/day are given for prolonged
`The results of the mouse study andone ofthe three rabbit
`hours.
`studies also showed an increased incidence and severity of
`periods,careful clinical observation and laboratory monitor-
`Indapamideis preferentially and reversibly taken up by the
`ingare particularly advisable. (See PRECAUTIONS: Labo-
`hydronephrosis (distention of the renal pelvis and in some
`ratory Tests.)
`erythrocytes in the peripheral blood. The whole blood/
`cases of the ureters) in fetuses derived from the treated
`Infants and Children: The usual initial dose of oral furose-
`dams as compared with the incidence im fetuses from the
`Continued on next page
`control group.
`BIOCON PHARMALTD(IPR2020-04:268oEx294:023pid forrevsone
`
`ete
`
`systemic vasculitis
`interstitial nephritis
`necrotizing angiitis
`Central Nervous System
`Reactions
`1. tinnitus and hearing loss
`2. paresthesias
`3. vertigo
`4. dizziness
`5. headache
`6. blurred vision
`7. xanthopsia
`
`otS)SNeeGetebee
`
`REVISED MARCH 1998
`FUR:R24
`
`INDAPAMIDE TABLETS, USP
`1.25 mg and 2.5 mg
`
`R
`
`DESCRIPTION
`Indapamideis an oral antihypertensive/diuretic. Its mole-
`cule contains both a polar sulfamoyl chlorobenzamide moi-
`ety and a lipid-soluble methylindoline moiety. It differs
`chemically from the thiazides in that it does not possess the
`thiazide ring system and contains only one sulfonamide
`group. The chemical nameof indapamideis 1-(4-chloro-3-
`sulfamoylbenzamido)-2-methylindoline, and its molecular
`weight is 365.83. The compound is a weak: acid, pK,=8.8,
`and is soluble in aqueoussolutions of strong bases. It is a
`white to yellow-white crystalline (tetragonal) powder.
`H3C.
`
`cl
`
`CO-NH—N
`
`SO2NH2
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1023, p. 004
`
`