`
`PHYSICIANS
`See
`RsrareNe=
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1025, 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. 1025, p. 002
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1025, p. 002
`
`

`

`1808/MERCK
`
`Hydrocortone Tablets—Cont.
`
`Ophthalmic
`Posterior subcapsular cataracts
`Increased intraocular pressure
`Glaucoma
`Exophthalmos
`Metabolic
`Negative nitrogen balance dueto protein catabolism
`Cardiovascular
`Myocardial rupture following recent myocardial infarc-
`tion (see WARNINGS)
`Other
`Hypersensitivity
`Thromboembolism
`Weight gain
`Increased appetite
`Nausea
`Malaise
`
`OVERDOSAGE
`
`Reports of acute toxicity and/or death following overdosage
`of glucocorticoids are rare. In the event of overdosage, no
`specific antidote is available; treatment is supportive and
`symptomatic.
`The intraperitoneal LD;, of hydrocortisone in female mice
`was 1740 mg/kg.
`
`DOSAGE AND ADMINISTRATION
`For oral administration
`DOSAGE REQUIREMENTS ARE VARIABLE AND MUST
`BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE
`AND THE RESPONSE OF THE PATIENT.
`Theinitial dosage varies from 20 to 240 mg a day depending
`on the disease being treated. In less severe diseases doses
`lower than 20 mg maysuffice, while in severe diseases doses
`higher than 240 mg maybe required. Theinitial dosage
`should be maintained or adjusted until the patient’s re-
`sponse is satisfactory. If satisfactory clinical response does
`not occur after a reasonable period of time, discontinue HY-
`DROCORTONEtablets and transfer the patient to other
`therapy.
`After a favorable initial response, the proper maintenance
`dosage should be determined by decreasing theinitial dos-
`age in small amounts to the lowest dosage that maintains
`an adequateclinical response.
`Patients should be observed closely for signs that might re-
`quire dosage adjustment,including changesin clinical sta-
`tus resulting from remissions or exacerbations of the dis-
`ease, individual drug responsiveness, and theeffectof stress
`(e.g, surgery, infection, trauma). During stress it may be
`necessary to increase dosage temporarily.
`If the drug is to be stopped after more than a few days of
`treatment, it usually should be withdrawn gradually.
`HOW SUPPLIED
`
`No. 7604—Tablets HYDROCORTONE,10 mgeach, are
`white, oval shaped compressedtablets, scored on one side,
`coded MSD 619, and are supplied asfollows:
`NDC 0006-0619-68 in bottles of 100.
`Shown in Product Identification Guide, page 323
`7920528 Issued February 1997
`
`HydroDIURIL® Tablets
`(Hydrochlorothiazide), U.S.P.
`
`DESCRIPTION
`
`BR
`
`HydroDIURIL* (Hydrochlorothiazide) is a diuretic and an-
`tihypertensive. It is the 3,4-dihydro derivative of chlorothi-
`azide. Its chemical nameis 6-chloro-3,4-dihydro-2H -1,2,4-
`benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical
`formula is C;H,CIN,;0,S, andits structural formulais:
`
`NH,SO.
`
`cl
`
`20
`\W
`SScHa
`
`iGH
`
`It is a white, or practically white, crystalline powder with a
`molecular weight of 297.74, whichis slightly soluble in wa-
`ter, but freely soluble in sodium hydroxidesolution.
`HydroDIURILis supplied as 25 mg and 50 mgtablets for
`oral use. Each tablet contains the following inactive ingre-
`Gents: calcium phosphate, FD&C Yellow 6, gelatin, lactose,
`magnesium stearate, starch andtale.
`
`*Registered trademark of MERCK & CO., Inc.
`
`CLINICAL PHARMACOLOGY
`
` HydroDIURILaffects the distal renal tubular mechanism of
`does not require specific treatment except under extraordi-
`
`Y
`Pregnancy
`Teratogenic Effects—Pregnancy Category B: Studies in
`whichhydrochlorothiazide wasorally administered to preg-
`nant mice and rats during their respective periods of major
`The mechanism of the antihypertensive effect of thiazides is
`organogenesis at doses up to 3000 and 1000-mg hydrochlo-
`unknown. HydroDIURIL does not usually affect normal
`rothiazide/kg, respectively, provided no evidence of harm to
`blood pressure.
`the fetus.
`information will be superseded by supplements and subsequerSFYON PHARMA LTD (IPR2020-0 ] 263) Ex. ] 025 5 p. 003
`
`
`
`PHYSICIANS’ DESK REFERENCES
`
`|
`
`_
`
`nary circumstances (as in liver disease or renal disease
`chloride replacement may be required in the treatment =
`metabolic alkalosis.
`Dilutional hyponatremia may occur in edematous patient
`in hot weather; appropriate therapy is water restriction
`rather than administration of salt, except in rare instance:
`when the hyponatremia is life threatening. In actual sek
`depletion, appropriate replacementis the therapy of chim
`Hyperuricemia mayoccuror acute gout maybe precipitatet
`in certain patients receiving thiazides.
`In diabetic patients dosage adjustments of insulin or axa
`hypoglycemic agents may be required. Hyperglycemia may
`occur with thiazide diuretics: Thus latent diabetes mellitus
`may become manifest during thiazide therapy.
`The antihypertensiveeffects of the drug may be enhanced =
`the post-sympathectomypatient.
`If progressive renal impairment becomes evident, consider
`withholding or discontinuing diuretic therapy.
`Thiazides have been shown to increase the urinary exc
`tion of magnesium; this may result in hypomagnesemia.
`Thiazides may decrease urinary calcium excretion. This
`ides may cause intermittent and slight elevation of serum
`calcium in the absence of known disorders of calcium me
`tabolism. Marked hypercalcemia maybe evidence of hidde=
`hyperparathyroidism. Thiazides should be discontinued be
`fore carrying out tests for parathyroid function.
`Increasesin cholesterol and triglyceride levels may be asse
`ciated with thiazide diuretic therapy.
`Laboratory Tests
`Periodic determination of serum electrolytes to detect pas
`sible electrolyte imbalance should be done at appropriate i=
`tervals.
`Drug Interactions
`Whengiven concurrently the following drugs may interact
`with thiazide diuretics.
`Alcohol, barbiturates, or narcotics —potentiation of orthe
`static hypotension mayoccur.
`Antidiabetic drugs —(oral agents and insulin)—dosage ad-
`justmentof the antidiabetic drug may be required.
`Other antihypertensive drugs —additive effect or potentis-
`tion.
`é
`Cholestyramine andcolestipol resins—Absorption of hydre-
`chlorothiazide is impaired in the presence of anionic e=-
`change resins. Single doses of either cholestyramine or
`colestipol resins bind the hydrochlorothiazide and reduce its
`absorption from the gastrointestinal tract by up to 85 and
`43 percent, respectively.
`Corticosteroids, ACTH —intensified electrolyte depletion.
`particularly hypokalemia.
`Pressor amines (e.g., norepinephrine) —possible decreased
`response to pressor amines but not sufficient to preclude
`their use.
`Skeletal muscle relaxants, nondepolarizing (e.g., tubocura-
`rine) —possible increased responsiveness to the muscle re-
`laxant.
`Lithium —generally should not be given with diuretics. Di-
`uretic agents reduce the renal clearance of lithium and add
`a highrisk of lithium toxicity. Refer to the package insert
`for lithium preparations before use of such preparations
`with HydroDIURIL.
`Non-steroidal Anti-inflammatory Drugs —In somepatients.
`the administration of a non-steroidal anti-inflammatory
`agent can reduce the diuretic, natriuretic, and antihyper-
`tensive effects of loop, potassium-sparing and thiazide di-
`uretics. Therefore, when HydroDIURIL and non-steroidal
`anti-inflammatory agents are used concomitantly, the pa-
`tient should be observed closely to determineif the desired
`effect of the diuretic is obtained.
`Drug/Laboratory Test Interactions
`Thiazides should be discontinued before carrying out tests
`for parathyroid function (see PRECAUTIONS, General).
`Carcinogenesis, Mutagenesis, Impairmentof Fertility
`Two-year feeding studies in mice and rats conducted under
`the auspices of the National Toxicology Program (NTP) un-
`coverednoevidence ofa carcinogenic potential of hydrochlo-
`rothiazide in female mice (at doses of up to approximately
`600 mg/kg/day) or in male and femalerats (at doses of up to
`approximately 100 mg/kg/day). The NTP, however, found
`equivocal evidence for hepatocarcinogenicity in male mice.
`Hydrochlorothiazide was not genotoxic in vitro in the Ames
`mutagenicity assay of Salmonella typhimurium strains TA
`98, TA 100, TA 1535, TA 1537, and TA 1538andin the Chin-
`ese Hamster Ovary (CHO) test for chromosomal aberra-
`tions, or in vivo in assays using mouse germinalcell chro-
`mosomes, Chinese hamster bone marrow chromosomes, and
`the Drosophila sex-linked recessive lethal trait gene. Posi-
`tive test results were obtained only in the in vitro CHOSis-
`ter Chromatid Exchange(clastogenicity) and in the Mouse
`LymphomaCell (mutagenicity) assays, using concentrations
`of hydrochlorothiazide from 43 to 1300 pg/mL, and in the
`Aspergillus nidulans non-disjunction assay at an unspeci-
`fied concentration.
`Hydrochlorothiazide had no adverseeffects on the fertility
`of mice andrats of either sex in studies wherein these spe-
`cies were exposed,via their diet, to doses of up to 100 and 4
`me/kg, respectively, prior to conception and throughout ges-
`tation.
`
`electrolyte reabsorption. At maximal therapeutic dosage all
`thiazides are approximately equal in their diuretic efficacy.
`HydroDIURILincreases excretion of sodium and chloride in
`approximately equivalent amounts. Natriuresis may be ac-
`companied by someloss of potassium and bicarbonate.
`After oral use diuresis begins within 2 hours, peaks in about
`4 hours andlasts about 6 to 12 hours.
`Pharmacokinetics and Metabolism
`HydroDIURILis not metabolized but is eliminated rapidly
`by the kidney. When plasmalevels have been followedfor at
`least 24 hours, the plasma half-life has been observed to
`vary between 5.6 and 14.8 hours. At least 61 percent of the
`oral doseis eliminated unchanged within 24 hours. Hydro-
`chlorothiazide crosses the placental but not the blood-brain
`barrier and is excreted in breast milk.
`
`INDICATIONS AND USAGE
`
`HydroDIURILis indicated as adjunctive therapy in edema
`associated with congestive heart failure, hepatic cirrhosis,
`and corticosteroid and estrogen therapy.
`HydroDIURIL hasalso been found useful in edema due to
`various forms of renal dysfunction such as nephrotic syn-
`drome, acute glomerulonephritis, and chronic renal failure.
`HydroDIURILis indicated in the managementof hyperten-
`sion either as the sole therapeutic agent or to enhance the
`effectiveness ofother antihypertensive drugsin the morese-
`vere forms of hypertension.
`:
`Use in Pregnancy. Routine use of diuretics during normal
`‘pregnancy is inappropriate and exposes mother andfetus to
`unnecessary hazard. Diuretics do not prevent development
`of toxemia of pregnancy andthereis no satisfactory evi-
`dencethat they are useful in the treatment of toxemia.
`Edemaduring pregnancy mayarise from pathologic causes
`or from the physiologic and mechanical consequences of
`pregnancy. Thiazides are indicated in pregnancy when
`edemais due to pathologic causes, just as they are in the
`absenceof pregnancy (see PRECAUTIONS,Pregnancy). De-
`pendent edema in pregnancy,resulting from restriction of
`venous return by the gravid uterus, is properly treated
`through elevation of the lower extremities and use of sup-
`port stockings. Use of diuretics to lower intravascular vol-
`umein this instance is illogical and unnecessary. During
`normal pregnancy there is hypervolemia which is not harm-
`ful to the fetus or the motherin the absenceof cardiovascu-
`lar disease. However, it may be associated with edema,
`rarely generalized edema.If such edemacauses discomfort,
`increased recumbencywill often provide relief. Rarely this
`edema maycause extreme discomfort whichis not relieved
`by rest. In these instances, a short course of diuretic ther-
`apy mayproviderelief and be appropriate.
`CONTRAINDICATIONS
`
`;
`Anuria.
`Hypersensitivity to this product or to other sulfonamide-
`derived drugs.
`
`WARNINGS
`
`Use with caution in severe renal disease. In patients with
`renal disease, thiazides may precipitate azotemia. Cumula-
`tive effects of the drug may develop in patients with im-
`paired renal function.
`Thiazides should be used with caution in patients with im-
`paired hepatic function or progressive liver disease, since
`minoralterations offluid and electrolyte balance may pre-
`cipitate hepatic coma.
`Thiazides may add to or potentiate the action of other anti-
`hypertensive drugs.
`Sensitivity reactions may occur in patients with or without
`a history of allergy or bronchial asthma.
`Thepossibility of exacerbation or activation of systemic lu-
`pus erythematosus has been reported.
`Lithium generally should not be given with diuretics (see
`PRECAUTIONS,Drug Interactions).
`PRECAUTIONS
`General
`All patients receiving diuretic therapy should be observed
`for evidenceoffluid or electrolyte imbalance: namely, hypo-
`natremia, hypochloremic alkalosis, and hypokalemia.
`Serum andurine electrolyte determinations are particu-
`larly important whenthepatient is vomiting excessively or
`receiving parenteral fluids. Warning signs or symptoms of
`fluid and electrolyte imbalance, irrespective of cause, in-
`clude dryness of mouth, thirst, weakness, lethargy, drowsi-
`ness, restlessness, confusion, seizures, muscle pains or
`cramps, muscular fatigue, hypotension, oliguria, tachycar-
`dia, and gastrointestinal disturbances such as nausea and
`vomiting.
`-
`Hypokalemia may develop, especially with brisk diuresis,
`whenseverecirrhosis is present or after prolonged therapy.
`Interference with adequate oral electrolyte intake will also
`contribute to hypokalemia. Hypokalemia may cause cardiac
`arrhythmia and may also sensitize or exaggerate the re-
`sponseofthe heart to the toxic effects ofdigitalis (e.g., in-
`creased ventricular irritability). Hypokalemia may be
`avoided or treated by use of potassium sparing diuretics or
`potassium supplementssuch asfoods with a high potassium
`content.
`Although any chloride deficit is generally mild and usually
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1025, p. 003
`
`

`

`eebeessbeeeeee
`
`PRODUCT INFORMATION
`
` HOW SUPPLIED
`
`No. 3263—Tablets HydroDIURIL, 25 mg, are peach-colored,
`round, scored, compressed tablets, coded MSD 42 on one
`side and HydroDIURILon the other. They are supplied as
`follows:
`NDC 0006-0042-68 bottles of 100
`NDC 0006-0042-82 bottles of 1000.
`Shown in Product Identification Guide, page 323
`No. 3264—Tablets HydroDIURIL,50 mg, are peach-colored,
`round, scored, compressed tablets, coded MSD 105 on one
`side and HydroDIURILon the other. They are supplied as
`follows:
`NDC 0006-0105-68 bottles of 100
`NDC 0006-0105-86 bottles of 5000.
`Shown in Product Identification Guide, page 323
`Storage
`Keep container tightly closed. Protect from light, moisture,
`freezing, —20°C (—4°F) and store at room temperature, 15—
`30°C (59-86°F).
`7897450 Issued June 1998
`COPYRIGHT © MERCK & CO., Inc., 1986
`All rights reserved
`
`HYZAAR® 50-12.5
`(losartan potassium-hydrochlorothiazide tablets)
`HYZAAR® 100-25
`(losartan potassium-hydrochlorothiazide tablets)
`
`USE IN PREGNANCY
`When usedin pregnancy during the second andthird
`trimesters, drugs that act directly on the renin-angio-
`tensin system can cause injury and even death to the
`developing fetus. When pregnancy is detected, HYZ-
`AAR should be discontinued.as soon as possible. See
`
`WARNINGS:Fetal/Neonatal Morbidity and Mortality.
`
`DESCRIPTION
`
`HYZAAR* 50-12.5 (losartan potassium-hydrochlorothia-
`zide) and HYZAAR* 100-25 (losartan potassium-hydrochlo-
`rothiazide), combines an angiotensin II receptor (type AT,)
`antagonist and a diuretic, hydrochlorothiazide.
`Losartan potassium, a non-peptide molecule, is chemically
`described as 2-butyl-4-chloro-1-[p-(o-1H-tetrazol-5-ylphe-
`nyl)benzyllimidazole-5-methanol monopotassium salt. Its
`empirical formula is C..H,,CIKN,O, and its structural for-
`mula is:
`
`Cl
`
`Ld
`CH3CH2CH2CH, se ‘CHZOH. NSN
`ie
`rR Ke
`=
`
`Losartan potassium is a white to off-white free-flowing crys-
`talline powder with a molecular weightof 461.01.Itis freely
`soluble in water, soluble in alcohols, and slightly soluble in
`commonorganic solvents, such as acetonitrile and methyl
`ethyl ketone.
`Oxidation of the 5-hydroxymethyl group on the imidazole
`ring results in the active metabolite of losartan.
`Hydrochlorothiazideis 6-chloro-3,4-dihydro-2H-1,2,4-benzo-
`thiadiazine-7-sulfonamide 1,1-dioxide. Its empirical for-
`mula is C;HgCIN,0,S, andits structural formulais:
`OS86.0:
`\JY
`na
`
`NHsSO2
`
`N
`ol
`Hydrochlorothiazide is a white, or practically white, crystal-
`line powder with a molecular weight of 297.74, which is
`slightly soluble in water, but freely soluble in sodium hy-
`droxide solution.
`HYZAAR is available for oral administration in two tablet
`combinationsof losartan and hydrochlorothiazide. HYZAAR
`50-12.5 contains 50 mgoflosartan potassium and 12.5 mg of
`hydrochlorothiazide. HYZAAR 100-25 contains 100 mg of
`losartan potassium and 25 mgof hydrochlorothiazide. Inac-
`tive ingredients are microcrystalline cellulose, lactose hy-
`drous, pregelatinized starch, magnesium stearate, hydroxy-
`propyl cellulose, hydroxypropyl methylcellulose, titanium
`dioxide and D&C yellow No. 10 aluminum lake.
`HYZAAR 50-12.5 contains 4.24 mg (0.108 mEq) of potas-
`sium and HYZAAR 100-25 contains 8.48 mg (0.216 mEq)of
`potassium.
`
`
`
`There are, however, no adequate and well-controlled studies
`in pregnant women. Because animal reproduction studies
`are not always predictice of human response, this drug
`should be used during pregnancyonly if clearly needed.
`Nonteratogenic Effects: Thiazides cross the placental bar-
`rier and appear in cordblood. Thereis a risk of fetal or neo-
`natal jaundice, thrombocytopenia, and possibly other ad-
`verse reactions that have occurred in adults.
`Nursing Mothers
`Thiazides are excreted in breast milk. Because ofthe poten-
`tial for serious adverse reactions in nursing infants, a deci-
`sion should be made whether to discontinue nursing or to
`discontinue hydrochlorothiazide, taking into account the
`importance of the drug to the mother.
`Pediatric Use
`There are no well-controlled clinical trials in pediatric pa-
`tients. Information on dosing in this age group is supported
`by evidence from empiric use in pediatric patients and pub-
`lished literature regarding the treatmentof hypertension in
`such patients. (See DOSAGE AND ADMIN:ISTRATION, In-
`fants and Children.)
`
`ADVERSE REACTIONS
`
`The following adverse reactions have been reported and,
`within each category, are listed in order of decreasing sever-
`ity.
`Body as a Whole: Weakness.
`Cardiovascular: Hypotension including orthostatic hypo-
`tension (may be aggravatedby alcohol, barbiturates, narcot-
`ies or antihypertensive drugs).
`Digestive: Pancreatitis, jaundice (intrahepatic cholestatic
`jaundice), diarrhea, vomiting, sialadenitis, cramping, con-
`stipation, gastric irritation, nausea, anorexia.
`Hematologic: Aplastic anemia, agranulocytosis, leukope-
`nia, hemolytic anemia, thrombocytopenia.
`Hypersensitivity: Anaphylactic reactions, necrotizing angi-
`itis (vasculitis and cutaneous vasculitis), respiratory dis-
`tress including pneumonitis and pulmonary edema,photo-
`sensitivity, fever, urticaria, rash, purpura.
`Metabolic: Electrolyte imbalance (see PRECAUTIONS),
`hyperglycemia, glycosuria, hyperuricemia.
`Musculoskeletal: Muscle spasm.
`Nervous System/Psychiatric: Vertigo, paresthesias, dizzi-
`mess, headache,restlessness.
`Renal: Renal failure, renal dysfunction, interstitial ne-
`phritis. (See WARNINGS.)
`Skin: Erythema multiforme including Stevens-Johnson
`syndrome, exfoliative dermatitis including toxic epidermal
`necrolysis, alopecia.
`Special Senses: Transient blurred vision, xanthopsia.
`Urogenital:
`Impotence.
`Whenever adverse reactions are moderate or severe, thia-
`tide dosage should be reduced or therapy withdrawn.
`OVERDOSAGE
`
`The most common signs and symptomsobserved are those
`eaused by electrolyte depletion (hypokalemia, hypochlore-
`mia, hyponatremia) and dehydration resulting from exces-
`seve diuresis. If digitalis has also been administered, hypo-
`Ealemia may accentuate cardiac arrhythmias.
`Is the event of overdosage, symptomatic and supportive
`measures should be employed. Emesis should be induced or
`gastric lavage performed. Correct dehydration, electrolyte
`=mbalance, hepatic coma and hypotension by established
`srocedures.If required, give oxygen orartificial respiration
`tor respiratory impairment. The degree to which hydrochlo-
`mathiazide is removed by hemodialysis has not been estab-
`ished.
`The oral LD,» of hydrochlorothiazideis greater than 10 g/kg
`=@ the mouse andrat.
`
`DOSAGE AND ADMINISTRATION
`
`Therapy should be individualized according to patient re-
`sponse. Use the smallest dosage necessary to achieve the
`mequired response.
`Adults
`For Edema
`The usual adult dosage is 25 to 100 mgdaily as a single or
`@rided dose. Many patients with edema respondto inter-
`mittenttherapy,i.e., administration on alternate days or on
`three to five days each week. With an intermittent schedule,
`=messive responseandtheresulting undesirable electrolyte
`‘balance are less likely to occur.
`Per Control of Hypertension
`The usual initial dose in adults is 25 mg daily given as a
`“mele dose. The dose maybeincreased to 50 mgdaily, given
`= = single or two divided doses. Doses above 50 mgareof-
`‘== associated with marked reductions in serum potassium
`= also PRECAUTIONS).
`Petients usually do not require doses in excess of 50 mg of
`Setrochlorothiazide daily when used concomitantly with
`wer antihypertensive agents.
`Uefeets and Children
`Wor Diuresis and For Control of Hypertension
`‘The usual pediatric dosage is 0.5 to 1 mg per pound (1 to 2
`emwke) per dayin singleor two divided doses, not to exceed
`3) 5 meg per day in infantsup to 2 years of age or 100 mg per
`‘Gey im children 2 to 12 years ofage. In infants less than 6
`menths of age, doses up to 1.5 mg per pound (3 mg/kg) per
`dey in two divided doses may be required. (See PRECAU-
`TOONS. Pediatric Use.)
`
`
`
`
`
`
`
`
`
`
`
`
`*Registered trademark of E.J. du Pont de Nemours and
`Company, Wilmington, Delaware, USA
`CLINICAL PHARMACOLOGY
`
`Mechanism ofAction
`Angiotensin II [formed from angiotensin I in a reaction cat-
`alyzed by angiotensin converting enzyme (ACE, kininase
`
`BIOCON PHARMA LTD (IPR20200THOSSERTOLS.8"OOd—
`
`MERCK/1809
`
`II)], is a potent vasoconstrictor, the primary vasoactive hor-
`mone of the renin-angiotensin system and an important
`component in the pathophysiology of hypertension. It also
`stimulates aldosterone secretion by the adrenal cortex.
`Losartan andits principal active metabolite block the vaso-
`constrictor and aldosterone-secreting effects of angiotensin
`II by selectively blocking the binding of angiotensinII to the
`AT, receptor found in manytissues, (e.g., vascular smooth
`muscle, adrenal gland). There is also an AT, receptor found
`in many tissues but it is not known to be associated with
`cardiovascular homeostasis. Both losartan andits principal
`active metabolite do not exhibit any partial agonist activity
`at the AT, receptor and have much greater affinity (about
`1000-fold) for the AT, receptor than for the AT, receptor. In
`vitro binding studies indicate that losartan is a reversible,
`competitive inhibitor of the AT, receptor. The active metab-
`olite is 10 to 40 times more potent by weight than losartan
`and appearsto be a reversible, nofi-competitive inhibitor of
`the AT, receptor.
`Neither losartan nor its active metabolite inhibits ACE
`(kininaseII, the enzyme that converts angiotensin I to an-
`giotensin II and degrades bradykinin); nor do they bind to
`or block other hormonereceptors or ion channels known to
`be important in cardiovascular regulation.
`Hydrochlorothiazide is a thiazide diuretic. Thiazides affect
`the renal tubular mechanisms of electrolyte reabsorption,
`directly increasing excretion of sodium and chloride in ap-
`proximately equivalent amounts. Indirectly, the diuretic ac-
`tion of hydrochlorothiazide reduces plasma volume, with
`consequent increases in plasma renin activity, increases in
`aldosterone secretion, increases in urinary potassium loss,
`and decreases in serum potassium. The renin-aldosterone
`link is mediated by angiotensinII, so coadministration of an
`angiotensin II receptor antagonist tends to reverse the po-
`tassium loss associated with these diuretics.
`The mechanismofthe antihypertensiveeffect of thiazides is
`unknown.
`Pharmacokinetics
`General
`Losartan Potassium
`Losartan is an orally active agent that undergoes substan-
`tial first-pass metabolism by cytochrome P450 enzymes.It
`is converted, in part, to an active carboxylic acid metabolite
`that is responsible for most of the angiotensin II receptor
`antagonism that follows losartan treatment. The terminal
`half-life of losartan is about 2 hours andof the metaboliteis
`about 6-9 hours. The pharmacokinetics of losartan andits
`active metabolite are linear with oral losartan doses up to
`200 mg and do not change over time. Neither losartan nor
`its metabolite accumulate in plasma upon repeated once-
`daily dosing.
`Following oral administration, losartan is well absorbed
`(based on absorption of radiolabeled losartan) and under-
`goes substantial first-pass metabolism; the systemic bio-
`availability of losartan is approximately 33%. About 14% of
`an orally-administered dose of losartan is converted to the
`active metabolite. Mean peak concentrations of losartan
`and its active metabolite are reached in 1 hour and in 3-4
`hours, respectively. While maximum plasmaconcentrations
`of losartan and its active metabolite are approximately
`equal, the AUC of the metabolite is about 4 times as great
`as that of losartan. A meal slows absorption of losartan and
`decreases its C,,,, but has only minoreffects on losartan
`AUC or on the AUCof the metabolite (about 10% de-
`creased).
`Both losartan andits active metabolite are highly bound to
`plasmaproteins, primarily albumin, with plasmafree frac-
`tions of 1.3% and 0.2% respectively. Plasma protein binding
`is constant over the concentration range achieved with rec-
`ommended doses. Studies in rats indicate that losartan
`crosses the blood-brain barrierpoorly,if at all.
`Losartan metabolites have been identified in human plasma
`and urine. In addition to the active carboxylic acid metabo-
`lite, several inactive metabolites are formed. Following oral
`and intravenous administration of '4C-labeled losartan po-
`tassium, circulating plasma radioactivity is primarily at-
`tributed to losartan andits active metabolite. In vitro stud-
`ies indicate that cytochrome P450 2C9 and 3A4are involved
`in the biotransformation of losartan to its metabolites. Min-
`imal conversion of losartan to the active metabolite (less
`than 1% of the dose compared to 14% of the dose in normal
`subjects) was seen in aboutone percentof individuals stud-
`ied.
`The volumeofdistribution of losartan is about 34 liters and
`of the active metabolite is about 12 liters. Total plasma
`clearance of losartan and the active metabolite is about 600
`mL/min and 50 mL/min,respectively, with renal clearance
`of about 75 mL/min and 25 mL/min,respectively. When
`losartan is administered orally, about 4% of the dose is ex-
`creted unchangedin the urine and about 6% is excreted in
`urine as active metabolite. Biliary excretion contributes to
`the elimination of losartan and its metabolites. Following
`oral C-labeled losartan, about 35% of radioactivity is re-
`covered in the urine and about 60% in the feces. Following
`an intravenous dose of ‘4C-labeled losartan, about 45% of
`radioactivity is recovered in the urine and 50% in the feces.
`
`Continued on next page
`
`Information on the Merck & Co., Inc. products listed on
`these pagesis the full prescribing information from product
`circulars in use August 31, 1999. For information, pleasecall
`1-800-NSC MERCK[1-800-672-6372].
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1025, p. 004
`
`