`
`PHYSIOANS’
`
`#
`# DESK
`_
`PEEEEENCE‘
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1023, p. 001
`
`

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` 5g;
`5.3
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`BIOCON PHARMA LTD (IPR2020-01263) EX. 1023, p. 002
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1023, p. 002
`
`

`

`1968/MYLAN
`
`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.
`The initial dose of captopril is 25 mg bid or tid. If satisfac-
`tory reduction of blood pressure has not been achieved after
`one or two weeks, the dose may be 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 mg tid. Therefore, if the blood pressure has not been
`satisfactorily controlled alter one to two weeks at this dose,
`(and the patient is not already receiving a diuretic), a mod-
`est dose of a thiazide—type diuretic (e.g., hydrochlorothia-
`zide, 25 mg daily), 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
`[Drug Interactions] regarding hypotension), with dosage
`and titration of captopril as noted above.
`If further blood pressure reduction is required, the dose of
`captopril may be increased to 100 mg bid or tid and then, if
`necessary, to 150 mg bid or tid (while continuing the diuret-
`ic). The usual dose range is 25 to 150 mg bid or tid. A max-
`imum daily dose of 450 mg captopril should not be exceeded.
`For patients with severe hypertension (e.g., accelerated or
`malignant hypertension), when temporary discontinuation
`of current antihypertensive therapy is not practical or de-
`sirable, or when prompt titration to more normotensive
`blood pressure levels is indicated, diuretic should be contin-
`ued but other current antihypertensive medication stopped
`and captopril dosage promptly initiated at 25 mg bid or tid,
`under close medical supervision.
`When necessitated by the patient’s clinical condition, the
`daily dose of captopril may be increased every 24 hours or
`less under continuous medical supervision until a satisfac-
`tory blood pressure response is obtained or the maximum
`dose of captopril is reached. In this regimen, addition of a
`more potent diuretic, e.g., furosemide, may also be indi-
`cated.
`
`PHYSICIANS’ DESK REFERENCEO
`EM
`Captopril—Cont.
`The 12.5 mg tablets are white, partially scored (both sides),
`oval tablets marked with M to the left of the score and CI 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 CZ 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 mg tablets 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 mg tablets 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
`l59°—86°Fl.
`PROTECT FROM MOISTURE.
`Dispense in a tight container using a child-resistant closure.
`Rx only
`Mylan Pharmaceuticals Inc.
`Morgantown, WV 26505
`
`‘ FUROSEMIDE TABLETS, USP
`20 mg, 40 mg and 80 mg
`
`-
`
`R
`
`WARNING: Furosemide is a potent diuretic which, if
`given in excessive amounts, can lead to a profound diuresis
`with water and electrolyte depletion. Therefore, careful
`medical supervision is required, and dose and dose sched-
`ule must be adjusted to the individual patient's needs. (See
`"DOSAGE AND ADMINISTRATION".)
`DESCRIPTION
`Furosemide is a diuretic which is an anthram'lic acid deriv-
`ative. Chemically, it is 4-chloro-N-furfuryl-5-sulfamoylan-
`thranilic acid. Furosemide is 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 insoluble in dilute acids.
`The structural formula is as follows:
`COOH
`
`NHCHZ
`
`O
`U
`
`ClC12H11CIN2053
`M.W. 330.75
`
`O n
`
`HZNfi0
`
`Beta-blockers may also be used in conjunction with capto-
`pril therapy (see PRECAUTIONS: Drug Interactions), but
`the eifects of the two drugs are less than additive.
`Heart Failure:
`Initiation of therapy requires consideration
`of recent diuretic therapy and the possibility of severe salt/
`volume depletion. In patients with either normal or low
`blood pressure, who have been vigorously treated with di-
`uretics and who may be hyponatremic and/or hypovolemic,
`a starting dose of 6.25 or 12.5 mg tid may minimize the
`magnitude or duration of the hypotensive effect (see WARN-
`INGS: Hypotension); for these patients, titration to the
`usual daily dosage can then occur within the next several
`davs.
`
`For most patients the usual initial daily dosage is 25 mg tid.
`Afier a dose of 50 mg tid is reached, further increases in
`dosage should be delayed, where possible, for at least two
`weeks to determine if a satisfactory response occurs. Most
`patients studied have had a satisfactory clinical improve-
`ment at 50 or 100 mg tid. A maximum daily dose of 450 mg
`of captopril should not be exceeded.
`Captopril should generally be used in conjunction with a di-
`uretic and digitalis. Captopril therapy must be initiated un-
`der very close medical supervision.
`Left Ventricular Dysfunction After Myocardial infarction:
`The recommended dose for long-term use in patients follow
`ing a myocardial infarction is a target maintenance dose of
`50 mg tid.
`Therapy may be initiated as early as three days following a
`myocardial infarction. After a single dose of 6.25 mg, capto-
`pril therapy should be initiated at 12.5 mg tid. Captopril
`should then be increased to 25 mg tid during the next sev-
`eral days and to a target dose of 50 mg tid over the next
`several weeks as tolerated (see CLINICAL PHARMACOL-
`OGY).
`Captopril may be used in patients treated with other post-
`myocardial infarction therapies, e.g., thrombolytics, aspirin,
`beta-blockers.
`Dosage Adjustment in Renal Impairment: Because capto-
`pril is excreted primarily by the kidneys, excretion rates are
`reduced in patients with impaired renal function. These pa-
`tients will take longer to reach steady-state captopril levels
`and will reach higher steady-state levels for a given daily
`dose than patients with normal renal function. Therefore,
`these patients may respond to smaller or less frequent
`doses.
`
`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 minimal effective
`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 mg of captopril.
`
`Each tablet for oral administration contains 20 mg, 40 mg
`or 80 mg of furosemide and the following inactive ingredi-
`entsrcolloidal 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 TEST 1.
`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-
`mansand 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 degree of effi-
`cacy is largely due to this unique site of action. The action
`on the distal tubule is independent of any inhibitory efl‘ect
`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
`plasma proteins, mainly to albumin. Plasma concentrations
`ranging from 1 to 400 ug/mL are 91 to 99% bound in healthy
`individuals. The unbound fraction averages 23 to 4.1% at
`therapeutic concentrations.
`The onset of diuresis following oral 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 furosemide oral solution
`has been shown to 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 approximawa 2 hours.
`information will be superseded by supplements and subsequeniloBdiiiajs
`
`CON PHARMA LTD (IPR2020-01263) EX. 1023, p. 003
`
`
`
`REVISED MARCH 1998
`CAPT2R7
`
`
`
`Significantly more furosemide is excreted in urine followirg
`the IV injection than after the tablet or oral solution. That
`are no significant differences between the two oral formula-
`tions in the amount of unchanged drug excreted in urine.
`INDICATIONS AND USAGE
`Edema: Furosemide is indicated in adults, infants, and
`children for the treatment of edema associated with oonges
`tive heart failure, cirrhosis of the liver, and renal disease.
`including the nephrotic syndrome. Furosemide is particu-
`larly useful when an agent with greater diuretic potential is
`desired.
`Hypertension: Oral furosemide may be used in adults for
`the treatment of hypertension alone or in combination with
`other antihypertensive agents. Hypertensive patients who
`cannot be adequately controlled with thiazides will probably
`also not be adequately controlled with furosemide alone.
`CONTRAINDICATIONS
`Furosemide is contraindicated in patients with anuria and
`in patients with a history of hypersensitivity to furosemide.
`WARNINGS
`
`In patients with hepatic cirrhosis and ascites, furosemide
`therapy is best initiated in the hospital. In hepatic coma
`and in states of electrolyte depletion, therapy should not be
`instituted until the basic condition is improved. Sudden al-
`teration of fluid and electrolyte balance in patients with cir-
`rhosis may precipitate hepatic coma; therefore, strict obser-
`vation is necessary during the period of diuresis. Supple-
`mental potassium chloride and, if required, an aldosterone
`antagonist are helpful in preventing hypokalemia and met-
`abolic alkalosis.
`If increasing azotemia and oliguria occur during treatment
`of severe progressive renal disease, furosemide should be
`discontinued.
`Cases of tinnitus and reversible or irreversible hearing im-
`pairment have been reported. Usually, reports indicate that
`furosemide ototoxicity is associated With rapid injection, se-
`vere renal impairment, doses exceeding several times the
`usual recommended dose, or concomitant therapy with ami-
`noglycoside antibiotics, ethacrynic acid, or other ototoxic
`drugs. If the physician elects to use high dose parenteral
`therapy, controlled intravenous infusion is advisable (for
`adults, an infusion rate not exceeding 4 mg furosemide per
`minute has been used).
`PRECAUTIONS
`General: Excessive diuresis may cause dehydration and
`blood volume reduction with circulatory collapse and possi-
`ble vascular thrombosis and embolism, particularly in el-
`derly patients. As with any effective diuretic, electrolyte de-
`pletion may occur during furosemide therapy, especially in
`patients receiving higher doses and a restricted salt intake.
`Hypokalemia may develop with furosemide, especially with
`brisk diuresis, inadequate oral electrolyte intake, when cir-
`rhosis is present or during concomitant use of corticoster-
`oids or ACTH. Digitalis therapy may exaggerate metabolic
`effects of hypokalemia, especially myocardial effects.
`All patients receiving furosemide therapy should be ob
`served for these signs or symptoms of fluid or electrolyte im-
`balance (hyponatremia, hypochloremic alkalosis, hypokale—
`mia, hypomagnesemia or hypocalcemia): dryness of mouth,
`thirst, weakness, lethargy, drowsiness, restlessness, muscle
`pains or cramps, muscular fatigue, hypotension, oliguria,
`tachycardia, arrhythmia, or gastrointestinal disturbances
`such as nausea and vomiting.
`Increases in blood glucbse and alterations in glucose toler-
`ance tests (with abnormalities of the fasting and 2-hour
`postprandial sugar) have been observed, and rarely, precip-
`itation of diabetes mellitus has been reported.
`Asymptomatic hyperuricemia can occur and gout may
`rarely be precipitated.
`Patients allergic to sulfonamides may also be allergic to fu-
`rosemide.
`
`The possibility exists of exacerbation or activation of sys-
`temic lupus erythematosus.
`As with many other drugs, patients should be observed reg-
`ularly for the possible occurrence of blood dyscrasias, liver
`or kidney damage or other idiosyncratic reactions.
`Information for Patients: Patients receiving furosemide
`should be advised that they may experience symptoms from
`excessive fluid and/or electrolyte losses. The postural hypo-
`tension that sometimes occurs can usually be managed by
`getting up slowly. Potassium supplements and/or dietary
`measures may be needed to control or avoid hypokalemia.
`Patients with diabetes mellitus should be told that furose-
`mide may increase blood glucose levels and thereby afl’ect
`urine glucose tests. The skin of some patients may be more
`sensitive to the eflects 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), (302, creatinine and BUN should be determined fre~
`quently during the first few months of furosemide therapy
`and periodically 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 may also influence serum electro-
`lytes.
`Reversible elevations of BUN may occur and are associated
`with dehydration which should be avoided, particularly in
`patients with renal insufficiency
`
`
`
`
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1023, p. 003
`
`

`

`flfi
`
`MYLAN/1969
`PRODUCT INFORMATION
`___—_—_____—_____.___..—._———————————-———-—-——-——————
`
`Urine and blood glucose should be checked periodically in
`diabetics receiving furosemide, even in those suspected of
`latent diabetes.
`Furosemide may lower serum levels of calcium (rarely cases
`of tetany have been reported) and magnesium. Accordingly,
`serum levels of these electrolytes should be determined pe-
`riodically.
`Drug Interactions: Furosemide may increase the ototoxic
`potential of aminoglycoside antibiotics, especially in the
`presence of impaired renal function. Except in life threaten-
`ing situations, avoid this combination.
`Furosemide should not be used concomitantly with etha-
`crynic acid because of the possibility of ototoxicity.
`Patients receiving high doses of salicylates concomitantly
`with furosemide, as in rheumatic disease, may experience
`salicylate toxicity at lower doses because of competitive re-
`nal excretory sites.
`Furosemide has a tendency to antagonize the skeletal mus-
`cle relaxing eflects of tubocurarine and may potentiate the
`action of succinylcholine.
`Lithium generally should not be given with diuretics be—
`cause they reduce lithium's renal clearance and add a high
`risk of lithium toxicity.
`Furosemide may add to or potentiate the therapeutic effect
`of other antihypertensive drugs. Potentiation occurs with
`ganglionic or peripheral adrenergic blocking drugs.
`Furosemide may decrease arterial responsiveness to norep-
`inephrine. However, norepinephrine may still be used effec-
`tively.
`Simultaneous administration of sucralfate and furosemide
`tablets may reduce the natriuretic and antihypertensive ef»
`fects of furosemide. Patients receiving both drugs should be
`observed closely to determine if the desired diuretic and/or
`antihypertensive effect of furosemide is achieved. The in-
`take of furosemide and sucralfate should be separated by at
`least two hours.
`One study in six subjects demonstrated that the combina-
`tion of furosemide and acetylsalicylic acid temporarily re-
`duced creatinine clearance in patients with chronic renal in«
`sufficiency. There are case reports of patients who developed
`increased BUN, serum creatinine and serum potassium lev-
`els, and weight gain when furosemide was used in conjunc-
`tion with NSAIDs.
`Literature reports indicate that coadministration of indo-
`methacin may reduce the natriuretic and antihypertensive
`effects of furosemide in some patients by inhibiting prosta-
`glandin synthesis. Indomethacin may also aflect plasma re-
`nin levels, aldosterone excretion and renin profile evalua-
`tion. Patients receiving both indomethacin and furosemide
`should be observed closely to determine if the desired di-
`uretic and/or antihypertensive effect of furosemide is
`achieved.
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Fu-
`rosemide was tested for carcinogenicity by oral administra-
`tion in one strain of mice and one strain of rats. A small but
`significantly increased incidence of mammary gland carcin-
`omas occurred in female mice at a dose 17.5 times the max-
`imum human dose of 600 mg. There were marginal in—
`creases in uncommon tumors in male rats at a dose of 15
`mg/kg (slightly greater than the maximum human dose) but
`not at 30 mg/kg.
`Furosemide was devoid of mutagenic activity in various
`strains of Salmonella typhimurium when tested in the pres-
`ence or absence of an in vitro metabolic activation system,
`and questionably positive for gene mutation in mouse lym—
`phoma cells in the presence of rat liver SE) at the highest
`dose tested. Furosemide did not induce sister chromatid ex-
`change in human cells in vitro, but other studies on chro-
`mosomal aberrations in human cells in vitro gave conflict-
`ing results. In Chinese hamster cells it induced chromo-
`somal damage but was questionably positive for sister
`chromatid exchange. Studies on the induction by furose-
`mide of chromosomal aberrations in mice were inconclusive.
`The urine of rats treated with this drug did not induce gene
`conversion in Saccharomyces cerevisiae.
`Furosemide produced no impairment of fertility in male or
`female rats at 100 mg/kg/day (the maximum effective di-
`uretic dose in the rat and 8 times the maximal human dose
`of 600 mg/day).
`Pregnancy: Teratagenic Effects: Pregnancy Category C:
`Furosemide has been shown to cause unexplained maternal
`deaths and abortions in rabbits at 2, 4 and 8 times the max-
`imal recommended human dose. There are no adequate and
`tell-controlled studies in pregnant women. Furosemide
`should be used during pregnancy only if the potential ben-
`efit justifies the potential risk to the fetus.
`Ihe effects of furosemide on embryonic and fetal develop-
`ment and on pregnant dams were studied in mice, rats, and
`rabbits.
`‘
`Furosemide caused unexplained maternal deaths and abor-
`tions in the rabbit at the lowest dose of 25 mg/kg (two times
`the maximal recommended human dose of 600 mg/day). In
`another study, a dose of 50 mg/kg (four times the maximal
`recommended human dose of 600 mg/day) also caused ma-
`ternal deaths and abortions when administered to rabbits
`between Days 12 and 17 of gestation. In a third study, none
`of the pregnant rabbits survived a dose of 100 mg/kg. Data
`from the above studies indicate fetal lethality that can pre-
`sede maternal deaths.
`The results of the mouse study and one of the three rabbit
`studies also showed an increased incidence and severity of
`hydmnephrosis (distention of the renal pelvis and in some
`cases of the meters) in fetuses derived from the treated
`hmsascomparedwiththeinddminfitnseafromthe
`alm'ol group.
`
`
`
`Nursing Mothers: Because it appears in breast milk, cau-
`tion should be exercised when furosemide is administered to
`a nursing mother.
`ADVERSE REACTIONS
`Adverse reactions are categorized below by organ system
`and listed by decreasing severity.
`Gastrointestinal System
`Reactions
`
`. pancreatitis
`. jaundice (intrahepatic cholestatic jaundice)
`anorexia
`oral and gastric irritation
`cramping
`diarrhea
`constipation
`nausea
`vomiting
`
`99°F¢WPWNH
`
`Systemic Hypersensitivity
`Reactions
`
`1. systemic vasculitis
`2. interstitial nephritis
`3. necrotizing angiitis
`Central Nervous System
`Reactions
`1. tinnitus and hearing loss
`2. paresthesias
`3. vertigo
`4. dizziness
`5. headache
`6. blurred vision
`7. xanthopsia
`
`Hematologic Reactions
`1. aplastic anemia (rare)
`2. thrombocytopenia
`3. agranulocytosis (rare)
`4. hemolytic anemia
`5. leukopenia
`6. anemia
`Dermatologic—Hypersensitivity Reactions
`. exfoliative dermatitis
`erythema multiforme
`purpura
`photosensitivity
`urticaria
`rash
`pruritus
`
`>193P‘FP‘JN"
`
`Cardiovascular Reaction
`Orthostatic hypotensi'on may occur and may be aggravated
`by alcohol, barbiturates, or narcotics.
`Other Reactions
`
`‘DE’DHP‘F‘S‘F’JE‘DH
`
`. hyperglycemia
`glycosuria
`hyperuricemia
`muscle spasm
`weakness
`restlessness
`urinary bladder spasm
`thrombophlebitis
`. fever
`Whenever adverse reactions are moderate or severe, furose-
`mide dosage should be reduced or therapy withdrawn.
`OVERDOSAGE
`The principal signs and symptoms of overdosage with furov
`semide are dehydration, blood volume reduction, hypoten-
`sion, electrolyte imbalance, hypokalemia and hypochloremic
`alkalosis, and are extensions of its diuretic action.
`The acute toxicity of furosemide has been determined in
`mice, rats, and dogs. In all three, the oral LD50 exceeded
`1000 mg/kg body weight while the intravenous LD50 ranged
`from 300 to 680 mg/kg. The acute intragastric toxicity in
`neonatal rats is 7 to 10 times that of adult rats.
`The concentration of furosemide in biological fluid associ-
`ated with toxicity or death is not known.
`Treatment of overdosage is supportive and consists of re-
`placement of excessive fluid and electrolyte losses. Serum
`electrolytes, carbon dioxide level and blood pressure should
`be determined frequently. Adequate drainage must be as-
`sured in patients with urinary bladder outlet obstruction
`(such as prostatic hypertrophy).
`Hemodialysis does not accelerate furosemide elimination.
`DOSAGE AND ADMINISTRATION
`Edema: Therapy should be individualized according to pa—
`tient response to gain maximal therapeutic response and to
`determine the minimal dose needed to maintain that re-
`sponse.
`Adults: The usual initial dose of furosemide is 20 to 80 mg
`given as a single dose. Ordinarily a prompt diuresis ensues.
`If needed, the same dose can be administered 6 to 8 hours
`later or the dose may be increased. The dose may be raised
`by 20 to 40 mg and given not sooner than 6 to 8 hours after
`the previous dose until the desired diuretic efiect has been
`obtained. This individually determined single dose should
`then be given once or twice daily (e.g., at 8 am and 2 pm).
`The dose of furosemide may be carefully titrated up to 600
`mg/day in patients with clinically severe edematous states.
`Edema may be most efficiently and safely mobilized by giv-
`ing furosemide on 2 to 4 consecutive days each week.
`When doses exceeding 80 mg/day are given for prolonged
`periods, careful clinical observation and laboratory monitor-
`ing are particularly advisable. (See PRECAUTIONS: Labo-
`ratory Tests.)
`Infants and Children: The usual initial dose of oral furose-
`mide in infants and children is 2 tog/kg body weight, given
`
`as a single dose. If the diuretic response is not satisfactory
`after the initial dose, dosage may be increased by 1 or 2
`mg/kg no sooner than 6 to 8 hours after the previous dose.
`Doses greater than 6 mg/kg body weight are not recom-
`mended. For maintenance therapy in infants and children,
`the dose should be adjusted to the minimum effective level.
`For ease of administration, and to allow maximum flexibil-
`ity in dosing, the use of Furosemide Oral Solution is sug-
`gested.
`Hypertension: Therapy should be individualized according
`to the patient’s response to gain maximal therapeutic re-
`sponse and to determine the minimal dose needed to main-
`tain that therapeutic response.
`Adults: The usual initial dose of furosemide for hyperten-
`sion is 80 mg, usually divided into 40 mg twice a day. Dos-
`age should then be adjusted according to response. If re-
`sponse is not satisfactory, add other antihypertensive
`agents.
`Changes in blood pressure must be carefully monitored
`when furosemide is used with other antihypertensive drugs,
`especially during initial therapy. To prevent excessive drop
`in blood pressure, the dosage of other agents should be re-
`duced by at least 50 percent when furosemide is added to
`the regimen. As the blood pressure falls under the potenti-
`ating efl‘ect of furosemide, a further reduction in dosage or
`even discontinuation of other antihypertensive drugs may
`be necessary.
`HOW SUPPLIED
`The 20 mg tablets are white, round, unscored, flat-bevel-
`edged tablets marked with M2. They are available as fol-
`lows:
`NDC 0378-0208-01 bottles of 100 tablets
`NDC 0378-0208-10 bottles of 1000 tablets
`The 40 mg tablets are white, round, scored, flat—bevel-edged
`tablets marked with MYLAN over 216 on one side and 40 on
`the other side. They are available as follows:
`NDC 0378-0216-01 bottles of 100 tablets
`NDC 0378-0216-10 bottles of 1000 tablets
`The 80 mg tablets are white, round, scored, flatvbevel-edged
`tablets marked with MYLAN over 232 on one side and 80 on
`the other side. They are available as follows:
`NDC 0378-0232-01 bottles of 100 tablets
`NDC 0378-0232—05 bottles of 500 tablets
`STORE AT CONTROLLED ROOM TEMPERATURE 15°-30°c
`(ST-86°F).
`PROTECT FROM LIGHT.
`Dispense in a tight, light-resistant container using a child-
`resistant closure. Exposure to light may cause slight discol-
`oration. Discolored tablets should not be dispensed.
`MYLAN®
`Mylan Pharmaceuticals Inc.
`Morgantown, WV 26505
`
`REVISED MARCH 1998
`FURzR24
`
`INDAPAMIDE TABLETS, USP
`1.25 mg and 2.5 mg
`
`R
`
`DESCRIPTION
`Indapamide is 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 name of indapamide is 1-(4-chloro-3-
`sulfamoylbenzamido)-2-methylindoline, and its molecular
`weight is 365.83. The compound is a weak acid, pKa=8.8,
`and is soluble in aqueous solutions of strong bases. It is a
`white to yellow-white crystalline (tetragonal) powder.
`H3C
`
`SOZNHQ
`
`C‘5H1ECIN3038
`Each tablet, for oral administration, contains 1.25 mg or 2.5
`mg of indapamide and the following inactive ingredientsz'
`anhydrous lactose, colloidal silicon dioxide, hydroxypropyl
`methylcellulose, magnesium stearate, microcrystalline cel-
`lulose, polydextrose, polyethylene glycol, pregelatinized
`starch, sodium lauryl sulfate, and titanium dioxide. Addi-
`tionally, the 1.25 mg product contains glyceryl triacctate
`and D&C Red No. 30 Aluminum Lake and the 2.5 mg prod-
`uct contains triacetin.
`CLINICAL PHARMACOLOGY
`Indapamide is the first of a new class of antihypertensive/
`diuretics, the indolines. It has been reported that the oral
`administration of 5 mg (two 2.5 mg tablets) of indapamide
`to healthy male subjects produced peak concentrations of
`approximately 260 ng/mL of the drug in the blood within
`two hours. A minimum of 70% of a single oral dose is elim-
`inated by the kidneys and an additional 23% by the gastro—
`intestinal tract, probably including the biliary route. The
`half—life of indapamide in whole blood is approximately 14
`hours.
`Indapamide is preferentially and reversibly taken up by the
`erythrocytes in the peripheral blood. The whole blood!
`Continued on next page
`
`
`
`BIOCON PHARMA LTD (Ipmozoememmesaywmm
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1023, p. 004
`
`