`
`PHYSIOANS’
`
`#
`# DESK
`_
`PEEEEENCE‘
`
`_
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1025, p. 001
`
`

`

`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1025, p. 002
`
`

`

`
`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
`
`

`

`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1025, p. 004
`
`