`
`PHYSICIANS
`See
`RsrareNe=
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1026, p. 001
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`2000
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`REFERENCE
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1026, p. 002
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`Sermatinnbemepecreeaibyprimon endoweeeees**TOCON PHARMALTD (IPR2020-01263) Ex. 1026, p. 003 ae
`tion (e.g., extracellular volume depletion from any cause, congestive heart failure, sepsis, concomitant use of any
`dose of intravenous indomethacin, there wasa transient re- duction in cerebral blood flow velocity and cerebral blood
`
`General
`INDOCIN (indomethacin) may mask the usual signs and
`symptoms of infection. Therefore, the physician must b=
`continually on the alert for this and should use the drag
`with extra care in the presence of existing controlled inte
`tion.
`Severe hepatic reactions have been reported in adults
`treated chronically with oral indomethacin for arthritic G=
`orders. [For further information, see package circular far
`Capsules INDOCIN (Indomethacin)]. If clinical signs and
`symptomsconsistent with liver disease develop in the nex
`nate, or if systemic manifestations occur, INDOCIN L¥
`should be discontinued.
`INDOCIN I.V. may inhibit platelet aggregation. In ome
`small study, platelet aggregation was grossly abnormal a=
`ter indomethacin therapy (given orally to premature infants
`to close the ductus arteriosus). Platelet aggregation r=
`turned to.normal by the tenth day. Premature infants
`should be observed for signs of bleeding.
`The drug should be administered carefully to avoid extr=
`vascular injection or leakage as the solution may be irritat-
`ing to tissue.
`Drug Interactions
`Since renal function may be eidnoad by INDOCIN L-V., com
`sideration should’ be given to reduction in dosage of those
`medications that rely on adequate renal function for the
`elimination. Because the half-life of digitalis (given fre-
`quently to pre-term infants with patent ductus arteriosus
`and associated cardiac failure) may be prolonged when
`given concomitantly with indomethacin, the neonate should
`be observedclosely; frequent ECGs and serum digitalis ley-
`els may be required to prevent or detect digitalis toxicity
`early. Furthermore, in one study of premature infants
`treated with INDOCIN I.V. andalsoreceiving either genta-
`micin or amikacin, both peak and trough levels of these
`aminoglycosides were significantly elevated.
`Therapy with indomethacin maybluntthenatriuretic effect
`of furosemide. This response has been attributed to inhibi-
`tion of prostaglandin synthesis by non-steroidal anti-in-
`flammatory drugs. In a study of 19 premature infants with
`patent ductus arteriosus treated. with either INDOCIN LV.
`alone or a combination of INDOCINLV. and furosemide, re-
`sults showed that neonates receiving both INDOCIN LY.
`and furosemide hadsignificantly higher urinary output.
`higher levels of sodium and chloride excretion, and higher
`glomerular filtration rates than did those receiving INDO-
`CIN LV. alone. In this study, the data suggested that ther-
`apy with furosemide helped to maintain renal function in
`the premature infant when INDOCINL.V. was added to the
`treatment of patent ductus arteriosus.
`Neonatal Effects
`In rats and mice, oral indomethacin 4.0 mg/kg/day given
`during the last three days of gestation caused a.decrease in
`maternal weight gain and some maternal andfetal deaths.
`An.increased incidence of neuronal necrosis in the dienceph-
`alon in the live-born fetuses was observed. At 2.0 mg/kg/day,
`no increase in neuronal necrosis was.observed as compared
`to the control groups. Administration of 0.5 or 4.0. mg/kg/
`day during thefirst three daysof life did not cause an in-
`crease in neuronalnecrosis at. either dose level.
`Pregnantrats, given 2.0 mg/kg/day and 4.0 mg/kg/day dur-
`ingthelast trimesterof gestation, delivered offspring whose
`pulmonary blood vessels were both reduced in number and
`excessively muscularized,.. These findings are similar to
`those observed in the syndromeofpersistent pulmonary hy-
`pertension of the neonate.
`
`nephrotoxic drug, hepatic dysfunction); When significant
`suppression of urine volume occurs after a dose of INDO-
`CIN L-V., no additional dose should be given until the urime
`output returns to normal levels.
`INDOCINLV. in pre-term infants may suppress water es
`cretion to a greater extent than sodium excretion. When
`this occurs, a significant reduction in serum sodium values
`(.e., hyponatremia) may result. Neonates should hawe
`serum electrolyte determinations done during therapy wat
`INDOCINI.V. Renal function and serum electrolytes shows
`be monitored (see PRECAUTIONS, Drug Interactions ant
`DOSAGE AND ADMINISTRATION).
`
`* Registered trademark of MERCK & CO., Inc.
`
`PRECAUTIONS
`
`emmeeeeoeAe
`
`ADVERSE REACTIONS
`
`In a double-blind placebo-controlled trial of 405 premature
`infants weighing less than or equal to.1750 g with evidence
`of large ductal shunting, in those neonates treated with in-
`domethacin (n =.206), there was a statistically significantly
`greater incidence of bleeding problems, including gross or
`microscopic bleeding into the gastrointestinal tract, oozing
`from the skin after needlestick, pulmonary hemorrhage,
`and disseminated intravascular coagulopathy. There was no
`statistically significant difference between treatment
`groups with reference to intracranial hemorrhage.
`The neonates treated with indomethacin sodium trihydrate
`also had.a significantly higher incidence oftransient oligu-
`ria and elevations of serum creatinine (greater than. or
`equal to 1.8 mg/dL) than did the neonates treated with pla-
`cebo.
`The incidencesof retrolental fibroplasia (grades III and IV)
`and pneumothorax in neonates treated with INDOCINLV.
`
`PHYSICIANS’ DESK REFERENCE®
`1816/MERCK
`
`
`indocin/iIndocin SR—Cont.
`
`HOW SUPPLIED
`
`No. 3316—Capsules INDOCIN,25 mg are opaque blue and
`white capsules, coded INDOCIN and MSD 25. They are sup-
`plied as follows:
`NDC 0006-0025-68 bottles of 100
`(6505-00-926-2154, 25 mg 100’s)
`NDC 0006-0025-82 bottles of 1000
`6505-00-931-0680, 25 mg 1000’s).
`Shown in Product Identification Guide, page 323
`No. 3317—Capsules INDOCIN,50 mg are opaque blue and
`white capsules, coded INDOCIN and MSD 50. Theyare sup-
`plied as follows:
`NDC 0006-0050-68 bottles of 100
`6505-01-049-6811, 50 mg 100’s).
`Shownin Product Identification Guide, page 323
`No. 3376—Oral Suspension INDOCIN, 25 mg per 5 mL,is
`an off-white suspension with a pineapple coconut mint fla-
`vor. It is supplied as follows: .
`NDC 0006-3376-66 in bottles of 237 mL.
`No. 3370—Capsules INDOCIN SR, 75 mg each, are cap-
`sules with an opaque blue cap andclear body containing a
`mixture of blue and white pellets, coded INDOCIN SR and
`MSD 693. They are supplied as follows:
`NDC 0006-0693-31unit of use bottles of 30
`6505-01-135-7391, 75 mg 30’s)
`NDC 0006-0693-61 unit of use bottles of 60
`6505-01-137-4629, 75 mg 60's).
`Shown in Product Identification Guide, page 323
`No. 3354—Suppositories INDOCIN,50 mgeach,are white,
`opaque, rectal suppositories and are supplied asfollows:
`NDC 0006-0150-30, boxes of 30
`6505-01-231-7284, 50 mg 30’s).
`Shownin ProductIdentification Guide, page 323
`Storage
`Store Oral Suspension INDOCINbelow 30°C (86°F). Avoid
`temperatures above 50°C (122°F). Protect from freezing.
`Stere Suppositories INDOCIN below 30°C (86°F). Avoid
`tramsient temperatures above 40°C (104°F).
`
`Suppositories INDOCINaredistributed by:
`MERCK SHARP & DOHME,Division of Merck & Co., Inc.
`West Point, Pa. 19486
`Manufactured by:
`MERCK SHARP & DOHME
`Ttalia) S.p.A.
`27100—Pavia,Italy
`Capsules and Oral Suspension INDOCIN® and Capsules
`DYDOCIN®SRare distributed and manufactured by:
`MERCK SHARP & DOHME,Division of Merck & Co., Inc.
`West Point, Pa. 19486
`Issued July 1998
`7873326
`COPYRIGHT © MERCK & CO.,Inc., 1988
`All rights reserved
`
`INDOCING® I.V.
`‘indomethacin Sodium Trihydrate)
`
`RB
`
`DESCRIPTION
`
`Sterile INDOCIN* IV. (Indomethacin Sodium Trihydrate)
`for intravenous administration is lyophilized indomethacin
`sodium trihydrate. Each vial contains indomethacin sodium
`trihydrate equivalent to 1 mg indomethacin as a white to
`yellow lyophilized powderor plug. Variations in the size of
`the lyophilized plug and the intensity of color have norela-
`tsonship to the quality or amount of indomethacin present
`im the vial.
`Indomethacin sodium trihydrate is designated chemically
`2s 1-(4-chlorobenzoyl) -5- methoxy-2-methyl-1H -indole-3-
`eetic acid, sodium salt, trihydrate. Its molecular weight is
`433.82. Its empirical formula is Ci9H,sCINNaO,:3H,O and
`is structural formulais:
`
`wo\—
`NW
`CH,
`
`CH}
`
`‘CHyCOONa
`
`* Registered trademark of MERCK & CO., Inc.
`
`CLINICAL PHARMACOLOGY
`
`Although the exact mechanism ofaction through which in-
`d@emethacin causes closure of a patent ductus arteriosus is
`mot known,it is believed to be through inhibition ofprosta-
`elendin synthesis. Indomethacin has been shown tobe a po-
`tent inhibitor of prostaglandin synthesis, both in vitro and
`im vivo. In human newbornswith certain congenital heart
`malformations, PGE 1 dilates the ductusarteriosus.In fetal
`and newborn lambs, E type prostaglandins have also been
`shown to maintain the patency of the ductus, and as in hu-
`man newborns, indomethacin causesits constriction.
`Studies in healthy young animals and in premature infants
`with patent ductus arteriosus indicated that, after the first
`
`flow. Similar decreasesin mesenteric blood flow and velocity
`have been observed. Theclinical significance of theseeffects
`has not been established.
`In double-blind placebo-controlled studies of INDOCINL.V.
`in 460 small pre-term infants, weighing 1750 g orless, the
`neonates treated with placebo had a ductusclosure rate af-
`ter 48 hoursof 25 to 30 percent, whereasthose treated with
`INDOCIN LV.had a 75 to 80 percent closure rate. In one of
`these studies, a multicenter study, involving 405 pre-term
`infants, later re-opening ofthe ductus arteriosus occurred in
`26 percent of neonates treated with INDOCINL.V., however,
`70 percent ofthese closed subsequentlywithout the ——for
`surgery or additional indomethacin.
`Pharmacokinetics and Metabolism
`The disposition of indomethacin following intravenous ad-
`ministration (0.2 mg/kg) in pre-term neonates with patent
`ductus arteriosus has not been extensively evaluated. Even
`though the plasma half-life of indomethacin was variable
`among premature infants, it was shown to vary inversely
`with postnatal age and weight. In one study, of 28 neonates
`who could be evaluated, the plasmahalf-life in those less
`than 7 days old averaged 20 hours (range: 3-60 hours, n =
`18). In neonates older than 7 days, the mean plasmahalf-
`life of indomethacin was 12 hours (range: 4-38 hours, n =
`10). Grouping the neonates by weight, mean plasma half-
`life in those weighing less than 1000 g was 21 hours (range:
`9-60 hours, n = 10); in those neonates weighing more than
`1000 g, the mean plasmahalf-life was 15 hours (range: 3-52
`hours, n = 18).
`Following intravenous administration iin adults; indometh-
`acin is eliminated via renal excretion, metabolism, andbil-
`iary excretion. Indomethacin undergoes appreciable entero-
`hepatic circulation. The mean plasmahalf-life of indometh-
`acin is 4.5 hours.
`In the absence of enterohepatic
`circulation, it is 90 minutes. Indomethacin has been found
`to cross the blood-brain barrier and the placenta.
`In adults, about 99 percent of indomethacin is boundto pro-
`tein in plasma over the expected range of therapeutic
`plasmaconcentrations. The percent bound in neonates has
`not been studied. In controlled trials in premature infants,
`however, no evidenceofbilirubin displacement has been ob-
`served as evidenced by increased incidenceofbilirubin en-
`cephalopathy (kernicterus).
`
`INDICATIONS AND USAGE
`
`INDOCINLY. is indicated to close a hemodynamically sig-
`nificant patent ductus arteriosus in premature infants
`weighing between 500 and 1750 g when after 48 hours
`usual medical management(e.g., fluid restriction, diuretics,
`digitalis, respiratory support, etc.) is ineffective. Clear-cut
`clinical evidence of a hemodynamically significant patent
`ductusarteriosus shouldbe present, such as respiratory dis-
`tress, a continuous murmur, a hyperactive precordium,car-
`diomegaly and pulmonary plethora on chest x-ray.
`CONTRAINDICATIONS
`
`INDOCIN LV. is contraindicated in: neonates with proven
`or suspected infection that is untreated; neonates who are
`bleeding, especially those with active intracranial hemor-
`rhage or gastrointestinal bleeding; neonates with thrombo-
`cytopenia; neonates with coagulation defects; neonates with
`or who aresuspected of having necrotizing enterocolitis;
`neonates with significant impairmentof renal function; neo-
`nates with congenital heart disease in whom patency of the
`ductus arteriosus is necessary for satisfactory pulmonary or
`systemic blood flow (e.g., pulmonary atresia, severe tetral-
`ogy of Fallot, severe coarctation of the aorta).
`
`WARNINGS
`
`Gastrointestinal Effects:
`In the collaborative study, major gastrointestinal bleeding
`was no more commonin those neonates receiving indometh-
`acin than in those neonates on placebo. However, minor gas-
`trointestinal bleeding (i.e., chemical detection of blood in
`the stool) was more commonly noted in those neonates
`treated with indomethacin. Severe gastrointestinal effects
`have been reported in adults with various arthritic disor-
`ders treated chronically with oral indomethacin. [For fur-
`ther information, see package circular for Capsules INDO-
`CIN* (Indomethacin)].
`Central Nervous System Effects:
`Prematurity per se, is associated with an increased inci-
`dence of spontaneousintraventricular hemorrhage. Because
`indomethacin may inhibit platelet aggregation, the poten-
`tial for intraventricular bleeding may be increased. How-
`ever, in the large multi-center study of INDOCIN LV. (see
`CLINICAL PHARMACOLOGY),the incidence of intraven-
`tricular hemorrhagein neonates.treated with INDOCIN I.V.
`wasnot significantly higher than in the control neonates.
`Renal Effects:
`INDOCIN L.V. maycausesignificant reductioniin urine out-
`put (50 percent or more) with concomitant elevations of
`blood urea nitrogen and creatinine, and reductionsin glo-
`merularfiltration rate and creatinine clearance. These ef-
`fects in most neonatesare transient, disappearing with ces-
`sation of therapy with INDOCIN I.V. However, because ad-
`equate renal function can depend upon renal prostaglandin
`synthesis, INDOCIN I.V. may precipitate renal insuffi-
`ciency, including acute renal failure, especially in neonates
`with other conditions that may adversely affect renal func-
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1026, p. 003
`
`

`

`
`
`OOEEE
`PRODUCT INFORMATION
`
`No. 3406—Sterile INDOCIN LV. is a lyophilized white to
`yellow powderor plug supplied as single dosevials contain-
`ing indomethacin sodium trihydrate, equivalent to 1 mg in-
`domethacin.
`NDC 0006-3406-17
`(6505-01-209-1192, 3 single dose vials).
`Storage
`Store below 30°C (86°F). Protect from light. Store container
`in carton until contents have been used.
`
`ADDITIONAL ADVERSE REACTIONS—ADULTS
`
`The following adverse reactions have been reported in
`adults treated with oral indomethacin for moderate to se-
`vere rheumatoidarthritis, osteoarthritis, ankylosing spon-
`dylitis, acute painful shoulder and acute gouty arthritis.
`Complaints not of relevance in the treatment of the prema-
`ture infant, such as anorexia, psychic disturbances, and
`blurredvision, are not listed.
`
`Incidence
`1% to 3%
`
`Incidence less than 1%
`
`0.1 mL;if 2 mL ofdiluent are used, the concentration of the
`solution will equal approximately 0.05 mg/0.1 mL. Any un-
`used portion of the solution should be discarded because
`there is no preservative containedin the vial: A fresh solu-
`tion should be prepared just prior to each administration.
`Once reconstituted, the indomethacin solution maybe in-
`jected intravenously. While the optimalrate ofinjection has
`not beenestablished, published literature suggests an infu-
`sion rate over 20-30 minutes.
`Furtherdilution with intravenousinfusion solutions is not
`recommended. INDOCINLV. is not buffered, and reconsti-
`tution with solutions at pH values below 6.0 may result in
`precipitation ofthe insoluble indomethacinfree acid moiety.
`HOW SUPPLIED
`
`were no greater than in placebo controls and werestatisti-
`cally significantly lower than in surgically-treated neonates.
`The following additional adverse reactions in neonates have
`been reported from the collaborative study, anecdotal case
`reports, from other studies usingrectal, oral, or intravenous
`indomethacin for treatment of patent ductus arteriosus or
`im marketed use. The rates are calculated from a database
`which contains experienceof 849 indomethacin-treated neo-
`nates reported in the medical literature, regardless of the
`route of administration. One year follow-up is available on
`175 neonates and shows no long-term sequelae which could
`be attributed to indomethacin.In controlled clinical studies,
`enly electrolyte imbalance and renal dysfunction(of the re-
`actions listed below) occurred statistically significantly
`more frequently after INDOCIN LV. than after placebo. Re-
`actions marked with a single asterick (*) occurred in 3-9
`percent of indomethacin-treated neonates: those marked
`with a double asterisk (**) occurred in 3-9 percent of both
`indomethacin- and placebo-treated neonates. Unmarkedre-
`actions occurred in less than 3 percent of neonates.
`Renal:
`renal dysfunction in 41 percent ofneonates, includ-
`mg one or more of the following: reduced urinary output;
`reduced urine sodium, chloride, or potassium urine osmolal-
`uty, free waterclearance,or glomerular filtration, rate; ele-
`vated serum creatinine or BUN;uremia.
`Cardiovascular:
`intracranial bleeding**, pulmonary hy-
`pertension.
`Gastrointestinal: gastrointestinal bleeding*, vomiting, ab-
`dominaldistention, transient ileus, localized perforation(s)
`of the small and/or large intestine.
`Metabolic: hyponatremia*, elevated serum potassium*,re-
`duction in blood sugar, including hypoglycemia, increased
`weightgain (fluid retention).
`Coagulation: decreased platelet aggregation (see PRE-
`CAUTIONS).
`The following adverse reactions have also been reported in
`neonates treated with indomethacin, however, a causal re-
`‘tionship to therapy with INDOCIN LV. has not been es-
`tablished:
`Cardiovascular: bradycardia.
`Respiratory:
`apnea, exacerbation of pre-existing pulmo-
`mary infection.
`GASTROINTESTINAL
`Metabolic:
`acidosis/alkalosis.
`gastrointestinal
`diarrhea
`bloating (includes
`Sematologic: disseminated intravascular coagulation.
`bleeding without
`constipation distention)
`Gastrointestinal: necrotizing enterocolitis.
`obvious ulcer
`flatulence
`Ophthalmic:
`retrolentalfibroplasia.**
`formation and
`peptic ulcer
`4 variety of additional adverse experiences have been re-
`perforation of
`gastroenteritis
`ported in adults treated with oral indomethacin for moder-
`Mecamylamine reduces blood pressure in both normoten-
`pre-existing sigmoid
`rectal bleeding
`te to severe rheumatoidarthritis, osteoarthritis, ankylos-
`lesions
`‘proctitis
`sive and hypertensiveindividuals. It has a gradual onset of
`= spondylitis, acute painful shoulder and acute gouty ar-
`single or multiple
`action ('/, to 2 hours) and a long-lasting effect (usually 6 to
`development of
`‘hritis
`(see
`section
`ADDITIONAL
`ADVERSE
`ulcerative stomatitis
`ulcerations, includ-
`12 hours or more). A small oral dosage often produces 2
`REACTIONS—ADULTS). Their relevance to the pre-term
`ing perforation and
`toxic hepatitis and
`smooth and predictable reduction of blood pressure. Al-
`“fant receiving indomethacin for patent ductus arteriosus
`jaundice (some fatal
`hemorrhageofthe
`thoughthis antihypertensive effect is predominantly orthe-
`cases have been
`= unknown,however, the possibility exists that these expe-
`esophagus, stomach,
`static, the supine blood pressure is also significantly re-
`duced.
`mences may beassociated with the use of INDOCIN LV. in
`uodenum or small__reported)
`pre-term infants.
`Pharmacokinetics and Metabolism
`and large intestines
`intestinal strictures
`Mecamylamineis almost completely absorbed from the gas-
`intestinal ulceration—(diaphragms)
`associated with
`DOSAGE AND ADMINISTRATION
`trointestinaltract, resulting in consistent lowering of blood
`stenosis and
`pressure in most patients with hypertensive cardiovascular
`obstruction
`disease. Mecamylamineis excreted slowly in the urine in
`FOR INTRAVENOUS ADMINISTRATION ONLY.
`CENTRAL NERVOUS SYSTEM
`the unchanged form. Therateofits renal eliminationis in-
`Dosage recommendationsfor closure of the ductus arterio-
`fluenced markedly by urinary pH. Alkalinization of the
`
`none involuntary muscle—_aggravation of
`sus dependsonthe ageof the infant at the time of therapy.
`movements
`epilepsy coma
`urine reduces, and acidification promotes,renal excretion of
`A course of therapy is defined as three intravenous doses of
`mecamylamine.
`peripheral neuropathy
`INDOCIN LV. given at 12-24 hour intervals, with careful
`convulsions
`Mecamylaminecrosses the blood-brain and placental barri-
`ers.
`sttention to urinary output. If anuria or marked oliguria
`sminary output < 0.6 mL/kg/hr)is evident at the scheduled
`Sme of the secondor third dose of INDOCIN LV., no addi-
`Genal doses should be given until laboratory studies indi-
`este that renal function has returned to normal (see WARN-
`ONGS, Renal Effects).
`,
`Desage accordingto ageis as follows:
`
`MERCK/18197
`
`MISCELLANEOUS
`none
`epistaxis
`breast changes,
`including en-
`largement and
`tenderness, or
`gynecomastia
`
`See package circular for Capsules INDOCIN (Indometha-
`cin) for additional information concerning adverse reactions
`and other cautionary statements.
`7414815 Issued June 1998
`COPYRIGHT © MERCK& CO., Inc., 1985
`All rights reserved
`
`
`INVERSINE®Tablets
`(Mecamylamine HCl), U.S.P.
`
`DESCRIPTION
`
`B
`
`INVERSINE* (Mecamylamine HC) is a potent,oral antihy-
`pertensive agent and ganglion blocker, and is a secondary
`amine. It is N, 2,3,3-tetramethylbicyclo[2.2.1] heptan-2-
`aminehydrochloride. Its empirical formulais C,,H,;N -HCl
`andits structural formulais:
`
`NHCH, * HCI
`CHg
`CH3
`CH;
`
`It is a white, odorless, or practically odorless, crystalline
`powder, is highly stable, soluble in water and has a molec-
`ular weight of 203.75.
`INVERSINEis supplied as tablets for oral use, each con-
`taining 2.5 mg mecamylamine HCl. Inactive ingredients are
`acacia, calcium phosphate, D&C Yellow 10, FD&CYellow 6,
`lactose, magnesium stearate, starch, andtalc.
`
`*Registered trademark of MERCK & CO., Inc.
`CLINICAL PHARMACOLOGY
`
`INDICATIONS AND USAGE
`
`For the managementof moderately severe to severe essen-
`tial hypertension and in uncomplicated cases of malignant
`hypertension.
`
`CONTRAINDICATIONS
`
`WARNINGS
`
`Mecamylamine, a secondary amine, readily penetrates into
`the brain and thus may produce central nervous sytem ef-
`fects. Tremor, choreiform movements, mental aberrations,
`and convulsions mayoccur rarely. These have occurred most
`often when large doses ofINVERSINE were used, especially
`in patients with cerebral or renal insufficiency.
`When ganglion blockers or other potent antihypertensive
`drugs are discontinued suddenly, hypertensive levels re-
`
`Continued on next page ;
`——SeSSeSSFeFFFFFFSSSSeSeSFSFsSeseFe
`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].
`
`including renal
`
`arrhythmia
`congestive heart
`failure
`thrombophlebitis
`:
`METABOLIC
`DOSAGE(mg/kg)
`none
`edema
`hyperglycemia
`3rd
`2nd
`1st
`weight gain
`glycosuria
`INVERSINE should not be used in mild, moderate, labile
`
`
`
`
`0.2 0.1Less than 48 hours 0.1eseeToromaiohaesinseSes
`flushing
`hyperkalemia
`hypertension and may prove unsuitable in uncooperative
`INTEGUMENTARY
`patients. It is contraindicated in coronary insufficiency or
`recent myocardialinfarction.
`
`
`
`0.2 0.227 days "720.2ee
`none
`rash; urticaria
`exfoliative dermatitis
`‘petechiae or
`erythema nodosum
`INVERSINE should be given with great discretion,if at all
`ecchymosis
`loss of hair
`
`
`
`0.2 0.25over 7 days 0.25ee
`whenrenal insufficiency is manifested by a rising or ele
`Stevens-Johnson
`vated BUN.Thedrugis contraindicated in uremia. Patients
`syndrome
`receiving antibiotics and sulfonamides should generally not
`erythema multiforme
`‘be treated with ganglion blockers. Other contraindications
`toxic epidermal
`are glaucoma,organic pyloric stenosis or hypersensitivity to
`the product.
`necrolysis
`
`SPECIAL SENSES
`none
`hearing disturbances,
`deafness
`CARDIOVASCULAR
`none
`hypertension
`hypotension
`tachycardia
`
`AGEat 1st dose
`
`© the ductus arteriosuscloses or is significantly reduced in
`"ze after an interval of 48 hours or more from completion of
`‘he first course of INDOCIN LYV., no further doses are nec-
`=ssary. If the ductus arteriosus re-opens, a second course of
`1-3 doses may be given, each dose separated by a 12-24
`‘eur interval as described above.
`© the infant remains unresponsiveto therapy with INDO-
`CIN LV. after 2 courses, surgery maybe necessary for clo-
`sare of the ductus arteriosus. If severe adverse reactions oc-
`ear, STOP THE DRUG.
`Directions for Use
`Parenteral drug products should be inspected visually for
`particulate matter and discoloration prior to administration
`whenever solution andcontainer permit.
`The solution should be prepared only with 1 to 2 mL ofpre-
`servative-free sterile Sodium Chloride Injection, 0.9 percent
`& preservative-free Sterile Water for Injection. Benzyl alco-
`Sel as a preservative has been associated with toxicity in
`neonates. Therefore, all diluents should be preservative-
`See. If 1 mL of diluent is used, the concentration of indo-
`methacin in the solution will equal approximately 0.1 mg/
`BIOCON PHARMA LTD
`
`HEMATOLOGIC
`none
`leukopenia
`bone marrow
`depression
`anemia secondary to
`obvious oroccult
`gastrointestinal
`bleeding
`HYPERSENSITIVITY
`dyspnea
`none
`acute anaphylaxis
`asthma
`acute respiratory
`purpura
`distress
`angiitis
`rapid fall in blood
`pressure resembling pulmonary edema
`a shock-like state
`GENITOURINARY
`none
`hematuria
`vaginal bleeding
`
`aplastic anemia
`hemolytic anemia
`agranulocytosis
`thrombocytopenic
`purpura
`
`renal insufficiency,
`failure
`(IPR2020-01
`
`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1026, p. 004
`
`