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`PHYSICIANS' DESK REFERENCB'
`
`
`nary circumstances (as in liver disease or renal dim
`chloride replacement may be required in the treatment 1
`metabolic alkalosis.
`Dilutional hyponatremia may occur in edematous pati.
`in hot weather; appropriate therapy is water restricth
`rather than administration of salt, except in rare install.
`when the hyponatremia is life threatening. In actual sfi
`depletion, appropriate replacement is the therapy of chi:
`Hyperuricemia may occur or acute gout may be precipit‘
`in certain patients receiving thiazides.
`In diabetic patients dosage adjustments of insulin or ad
`hypoglycemic agents may be required. Hyperglycemia I-_I
`occur with thiazide diuretics. Thus latent diabetes mell'n
`may become manifest during thiazide therapy.
`The antihypertensive effects of the drug may be enhanced n
`the post-sympathectomy patient.
`If progressive renal impairment becomes evident, cousihr
`withholding or discontinuing diuretic therapy.
`Thiazides have been shown to increase the urinary em
`tion of magnesium; this may result in hypomagnesemia.
`Thiazides may decrease urinary calcium excretion. Thin—
`ides may cause intermittent and slight elevation of serum
`calcium in the absence of known disorders of calcium D
`tabolisrn. Marked hypercalcemia may be evidence of hidri!
`hyperparathyroidism. Thiazides should be discontinued lu-
`fore carrying out tests for parathyroid function.
`Increases in cholesterol and triglyceride levels may be am
`ciated with thiazide diuretic therapy.
`Laboratory Tests
`Periodic determination of serum electrolytes to detect pm»
`sible electrolyte imbalance should be done at appropriate in-
`tervals.
`Drug Interactions
`When given concurrently the following drugs may intern:
`with thiazide diuretics.
`Alcohol, barbiturates, or narcotics —potentiation of ordain»
`static hypotension may occur.
`Antidiabetic drugs —(oral agents and insulin)——dosage ad-
`justment of the antidiabetic drug may be required.
`Other antihypertensive drugs —additive effect or potentia-
`tion.
`,
`Cholestyrarnine and colestipol resins—Absorption of hydro
`chlorothiazide is impaired in the presence of anionic ex
`change resins. Single doses of either cholestyramine (x
`colestipol resins bind the hydrochlorothiazide and reduce he
`absorption from the gastrointestinal tract by up to 85 and
`43 percent, respectively.
`Corticosteroids, ACTH —intensified electrolyte depletion
`particularly hypokalemia.
`Presser 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 1%
`laxant.
`Lithium —generally should not be given with diuretics Di-
`uretic agents reduce the renal clearance of lithium and add
`a high risk of lithium toxicity. Refer to the package insen
`for lithium preparations before use of such preparations
`with HydroDlURlL.
`Non—steroidal Anti-inflammatory Drugs —In some patients.
`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 HydroDlURlL and non—steroidal
`anti-inflammatory agents are used concomitantly, the pa-
`tient should be observed closely to determine if 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, Impairment of Fertility
`Two-year feeding studies in mice and rats conducted under
`the auspices of the National Toxicology Program (NTP) un-
`covered no evidence of a carcinogenic potential of hydrochlo-
`rothiazide in female mice (at doses of up to approximately
`600 mg/kg/day) or in male and female rats (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 1538 and in the Chin-
`ese Hamster Ovary (CHO) test for chromosomal aberra-
`tions, or in vivo in assays using mouse germinal cell 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 CHO Sis-
`ter Chromatid Exchange (clastogenicity) and in the Mouse
`Lymphoma Cell (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 adverse effects on the fertility
`of mice and rats of either sex in studies wherein these spe-
`cies were exposed, via their diet, to doses of up to 100 and 4
`mg/kg, respectively, prior to conception and throughout ges-
`tation.
`
`‘
`Pregnancy
`Teratogenic Effects—Pregnancy Category B: Studies in
`which hydrochlorothiazide was orally administered to preg-
`nant mice and rats during their respective periods of major
`organogenesis at doses up to 3000 and 1000 mg hydrochlo-
`rothiazide/kg, respectively, provided no evidence of harm to
`the fetus.
`
`
`
`‘
`
`'
`
`
`
`HydroDlURIL afl'ects the distal renal tubular mechanism of
`electrolyte reabsorption. At mam'mal therapeutic dosage all
`thiazides are approximately equal in their diuretic efficacy
`HydroDlURlL increases excretion of sodium and chloride in
`approximately equivalent amounts. Natriuresis may be ac-
`companied by some loss of potassium and bicarbonate.
`After oral use diuresis begins within 2 hours, peaks in about
`4 hours and lasts about 6 to 12 hours.
`Pharmacokinetics and Metabolism
`HydroDlURIL is not metabolized but is eliminated rapidly
`by the kidney. When plasma levels have been followed for 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 dose is eliminated unchanged within 24 hours. Hydro-
`chlorothiazide crosses the placental but not the blood-brain
`barrier and is excreted in breast milk.
`
`1808/MERCK
`
`ydrocortone Tablets—Cont.
`
`Ophthalmic
`Posterior subcapsular cataracts
`Increased intraocular pressure
`Glaucoma
`Exophthalmos
`Metabolic
`Negative nitrogen balance due to 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 LD50 of hydrocortisone in female mice
`was 1740 mg/kg.
`
`DOSAGE AND ADMJNISTRATION
`For oral administration
`DOSAGE REQUIREMENTS ARE VARIABLE AND MUST
`BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE
`AND THE RESPONSE OF THE PATIENT
`The initial dosage varies from 20 to 240 mg a day depending
`on the disease being treated. In less severe diseases doses
`lower than 20 mg may suffice, while in severe diseases doses
`higher than 240 mg may be required. The initial dosage
`should be maintained or adjusted until the patient’s re“
`spouse is satisfactory. If satisfactory clinical response does
`not occur after a reasonable period of time, discontinue HY-
`DROCORTONE tablets and transfer the patient to other
`therapy.
`After a favorable initial response, the proper maintenance
`dosage should be determined by decreasing the initial dos-
`age in small amounts to the lowest dosage that maintains
`an adequate clinical response.
`Patients should be observed closely for signs that might re-
`quire dosage adjustment, including changes in clinical sta-
`tus resulting from remissions or exacerbations of the dis-
`ease, individual drug responsiveness, and the effect of 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 mg each, are
`white, oval shaped compressed tablets, scored on one side,
`coded MSD 619, and are supplied as follows:
`NDC 0006-0619-68 in bottles of 100.
`Shown in Product Identification Guide, page 323
`7920528 Issued February 1997
`
`HydroDlURlL® Tablets
`(Hydrochlorothiazidol, U.S.P.
`
`DESCRIPTION
`
`R
`
`HydeIURIL* (Hydrochlorothiazide) is a diuretic and an-
`xihypertensive. It is the 3,4—dihydro derivative of chlorothi—
`azide. Its chemical name is 6-chloro—3,4-dihydro—2H—1,2,4-
`benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical
`formula is C7HBCIN3O4SZ and its structural formula is:
`
`o o
`\\ I
`5 \NH
`N/l
`H
`
`NH2502
`Cl
`
`It is a white, or practically white, crystalline powder with a
`molecular weight of 297.74, which is slightly soluble in wa‘
`ter. but freely soluble in sodium hydroxide solution.
`HydroDIURIL is supplied as 25 mg and 50 mg tablets for
`oral use. Each tablet contains the following inactive ingre-
`clients: calcium phosphate, FD&C Yellow 6, gelatin, lactose,
`magnesium stearate, starch and talc.
`
`‘Registered trademark of MERCK & CO., INC.
`
`CLINICAL PHARMACOLOGY
`
`The mechanism of the antihypertensive effect of thiazides is
`unknown. HydroDlURIL does not usually affect normal
`blood pressure.
`
`
`
`INDICATIONS AND USAGE
`
`HydroDl'URlL is indicated as adjunctive therapy in edema
`associated with congestive heart failure, hepatic cirrhosis,
`and corticosteroid and estrogen therapy.
`HydroDlURIL has also been found useful in edema due to
`various forms of renal dysfunction such as nephrotic syn-
`drome, acute glomerulonephritis, and chronic renal failure.
`HydroDlURIL is indicated in the management of hyperten-
`sion either as the sole therapeutic agent or to enhance the
`efl‘ectiveness ofother antihypertensive drugs in the more se-
`vere forms of hypertension.
`.
`Use in Pregnancy. Routine use of diuretics during normal
`pregnancy is inappropriate and exposes mother and fetus to
`unnecessary hazard. Diuretics do not prevent development
`of toxemia of pregnancy and there is no satisfactory evi-
`dence that they are useful in the treatment of toxemia.
`Edema during pregnancy may arise from pathologic causes
`or from the physiologic and mechanical consequences of
`pregnancy. Thiazides are indicated in pregnancy when
`edema is due to pathologic causes, just as they are in the
`absence of 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-
`ume in this instance is illogical and unnecessary During
`normal pregnancy there is hypervolemia which is not harm-
`ful to the fetus or the mother in the absence of cardiovascu-
`lar disease. However, it may be associated with edema,
`rarely generalized edema. If such edema causes discomfort,
`increased recumbency will often provide relief. Rarely this
`edema may cause extreme discomfort which is not relieved
`by rest. In these instances, a short course of diuretic ther-
`apy may provide relief 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
`minor alterations of fluid and electrolyte balance may pre-
`cipitate hepatic coma.
`Thiazides may add to or potentiate the action of other anti-
`hyper'tensive drugs.
`Sensitivity reactions may occur in patients with or without
`a history of allergy or bronchial asthma.
`The possibility 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 evidence of fluid or electrolyte imbalance: namely, hypo-
`natremia, hypochloremic alkalosis, and hypokalemia.
`Serum and urine electrolyte determinations are particu-
`larly important when the patient 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,
`when severe cirrhosis 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-
`sponse of the heart to the toxic effects of digitalis (e.g., in-
`creased ventricular irritability). Hypokalemia may be
`avoided or treated by use of potassium sparing diuretics or
`potassium supplements such as foods with a high potassium
`content.
`Although any chloride deficit is generally mild and usually
`does not require specific treatment except under extraordi»
`
`% H
`
`inflation will be superseded by supplements and subsequeleCON PHARMA LTD (IPR2020—01263) EX, 1 025 , p.003
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1025, p. 003
`
`

`

`PRODUCT lNFORMATION
`
`MERCK/1809
`
`, —____‘-
`
`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 pregnancy only if clearly needed.
`Nonteratogenic Efiects: Thiazides cross the placental bar-
`rier and appear in cord blood. There is 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 of the 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 treatment of hypertension in
`such patients. (See DOSAGE AND ADMINISTRATION, In-
`fants and Children.)
`
`ADVERSE REACTIONS
`
`The following adverse reactions have been reported and,
`within each category, are listed in order of decreasing sever-
`1ty.
`Body as a Whole: Weakness.
`Cardiovascular: Hypotension including orthostatic hypo-
`tension (may be aggravated by alcohol, barbiturates, narcot-
`ics or antihypertensive drugs).
`Digestive: Pancreatitis, jaundice (intrabepatic cholestatic
`iaundice), 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-
`iress 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-
`ness, headache, restlessness.
`Renal: Renal failure, renal dysfunction, interstitial ne-
`phritis. (See WARNINGS.)
`Skin: Erythema multiforme including Stevens-Johnson
`syndrome, exfoliative dermatitis including toxic epidermal
`merelysis, alopecia.
`Special Senses: Transient blurred vision, xanthopsia.
`Urogenital:
`Impotence.
`Whenever adverse reactions are moderate or severe, thia-
`zide dosage should be reduced or therapy withdrawn.
`OVERDOSAGE
`
`The most common signs and symptoms observed are those
`caused by electrolyte depletion (hypokalemia, hypochlore—
`nia, hyponatremia) and dehydration resulting from exces-
`xve diuresis. If digitalis has also been administered, hypo-
`kalemia may accentuate cardiac arrhythmias
`In the event of overdosage, symptomatic and supportive
`neasures should be employed. Emesis should be induced or
`gastric lavage performed. Correct dehydration, electrolyte
`Imbalance, hepatic coma and hypotension by established
`zocedures. If required, give oxygen or artificial respiration
`it respiratory impairment. The degree to which hydrochlo-
`rmhiazide1s removed by hemodialysis has not been estab-
`mhed.
`1‘1 oral LD50 of hydrochlorothiazide1s greater than 10 g/kg
`z. the mouse and rat.
`
`DOSAGE AND ADMINISTRATION
`
`hmpy should be individualized according to patient re—
`mse. Use the smallest dosage necessary to achieve the
`xquired response.
`Adults
`.72? Edema
`The usual adult dosage is 25 to 100 mg daily as a single or
`frnded dose. Many patients with edema respond to inter-
`ment therapy, i.e., administration on alternate days or on
`tree to five days each week. With an intermittent schedule,
`msive response and the resulting undesirable electrolyte
`melance are less likely to occur.
`Ft? Control of Hypertension
`The usual initial dose in adults is 25 mg daily given as a
`5:519 dose. The dose may be increased to 50 mg daily, given
`5 a single or two divided doses. Doses above 50 mg are of-
`: asociated with marked reductions in serum potassium
`me also PRECAUTIONS).
`Paients usually do not require doses in excess of 50 mg of
`Whlorothiazide daily when used concomitantly with
`I22! antihypertensive agents.
`harms and Children
`.lll’ Diuresis and For Control of Hypertenswn
`The Lual pediatric dosage1s 0.5 to 1 mg per pound (1 to 2
`mg'Lg per dayin single or two divided doses, not to exceed
`37 .3 mg per day in infants up to 2 years of age or 100 mg per
`my in children 2 to 12 years of age. In infants less than 6
`Mths of age, doses up to 1.5 mg per pound (3 rug/kg) per
`It“ in two divided doses may be required. (See PRECAU-
`TEOSS. Pediatric Use.l
`
`
`
`
`
`HOW SUPPLIED
`
`No. 3263—Tablets HydroDIURIL, 25 mg, are peach-colored,
`round, scored, compressed tablets, coded MSD 42 on one
`side and HydroDIURIL on 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 HydroDIURIL on 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, W20°C (41°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® 5042.5
`(losartan potassium-hydrochlorothiazide tabletsl
`HYZAAR® 1 00-25
`(losartan potassium-hydrochlorothiazide tablets)
`
`R
`
`B
`
`USE IN PREGNANCY
`When used in pregnancy during the second and third
`trimesters, drugs that act directly on the renin-angio-
`tensin system can cause iniury 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 ATl)
`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)benzyl]imidazole—S-inethanol monopotassium salt. Its
`empirical formula is CZZHZZClKNGO, and its structural for-
`mula is:
`
`N
`i- I
`N
`
`CH30H2CH2CH2
`
`Cl
`
`CHZOH
`
`N-——N
`
`CHZO NHGN
`
`Losartan potassium is a white to off-white free-flowing crys—
`talline powder with a molecular weight of 461.01. It is freely
`soluble in water, soluble in alcohols, and slightly soluble in
`common organic 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.
`Hydrochlorothiazide is 6—chloro—3,4-dihydro-2H—1,2,4-benzo-
`thiadiazine-7-sulfonamide 1,1-dioxide. Its empirical for-
`mula is C7H8ClN304S2 and its structural formula is:
`
`Nsto2
`
`Cl
`
`0V0
`J
`
`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
`combinations of losartan and hydrochlorothiazide. HYZAAR
`50-125 contains 50 mg oflosartan potassium and 12.5 mg of
`hydrochlorothiazide. HYZAAR 100-25 contains 100 mg of
`losartan potassium and 25 mg of hydrochlorothiazide. Inac-
`tive ingredients are microcrystalline cellulose, lactose hy-
`drous, pregelatinized starch, magnesium stearate, hydroxy-
`propyl cellulose, hydroxypropyl methylcellulose, titanium
`dioxide and D820 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.
`
`*Registered trademark of 13.1. du Pont de Nemours and
`Company, Wilmington, Delaware, USA
`CLINICAL PHARMACOLOGY
`
`
`
`ID], 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 and its principal active metabolite block the vaso-
`constrictor and aldosterone-secreting effects of angiotensin
`II by selectively blocking the binding of angiotensin II to the
`AT1 receptor found in many tissues, (e.g., vascular smooth
`muscle, adrenal gland). There is also an AT2 receptor found
`in many tissues but it is not known to be associated with
`cardiovascular homeostasis. Both losartan and its principal
`active metabolite do not exhibit any partial agonist activity
`at the AT1 receptor and have much greater affinity (about
`1000-fold) for the AT1 receptor than for the AT2 receptor. In
`vitro binding studies indicate that losartan is a reversible,
`competitive inhibitor of the AT1 receptor. The active metab-
`olite is 10 to 40 times more potent by weight than losartan
`and appears to be a reversible, non-competitive inhibitor of
`the AT1 receptor.
`Neither losartan nor its active metabolite inhibits ACE
`(kininase II, the enzyme that converts angiotensin I to an-
`giotensin II and degrades bradykinin); nor do they bind to
`or block other hormone receptors 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 angiotensin 11, so coadministration of an
`angiotensin II receptor antagonist tends to reverse the po-
`tassium loss associated with these diuretics.
`The mechanism ofthe antihypertensive effect 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 and of the metabolite is
`about 6—9 hours. The pharmacokinetics of losartan and its
`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 plasma concentrations
`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 Cmax but has only minor effects on losartan
`AUC or on the AUC of the metabolite (about 10% de—
`creased).
`Both losartan and its active metabolite are highly bound to
`plasma proteins, primarily albumin, with plasma free 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 barrier poorly, 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 1“C-labeled losartan po-
`tassium, circulating plasma radioactivity is primarily at-
`tributed to losartan and its active metabolite. In vitro stud-
`ies indicate that cytochrome P450 209 and 3A4 are 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 about one percent of individuals stud-
`ied.
`The volume of distribution of losartan is about 34 liters and
`of the active metabolite is about 12 liters. 'Ibtal 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 unchanged in 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 14C<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 pages is the full prescribing information from product
`circulars in use August 31, 1999. For information, please call
`1-800-NSC MERCK [1-800-672-6372].
`
`Mechanism ofAction
`Angiotensin II [formed from angiotensin I in a reaction cat-
`alyzed by angiotensin converting enzyme (ACE, kininase
`BIOCON PHARMA LTD (1PR2020‘30TE6WWUUZW "m“
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1025, p. 004
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