CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of ActionThEt m~chanism 01 action of captopriJ has not yet been fully elucidated. lis-beneficial effects In hypertension and heart failure appear 10result primarily from suppression of the reninwangiolensln-aJdosterone system. However, there is no consistent correlallon betweenrenin levels and response 10 Ihe drug. Renin, an enzyme synthesized by Ihe kidneys, is released into the circulation where it acts on aplasma globulin ub~trate to produce angiotensinl, relatively inactive decapeptide. AngIotensin is then converted by angiotensinconverting enzyme (ACE) to angiotensin II, potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosteronesecretion from the adrenal cortex, thereby contributing to sodiumand fluid retenllon. .Caplopril prevents the conversion of angiotensin Ito angiotensin II by inhibition of ACE, peplidyldipeplide carboxy hydrolase. Thlsinhibition has been demonstrated in both heallhyhuman subjects and in animals by showing that the elevation of blood pressure causedby exogenously adminlstered angiotensin Iwas attenuated or abolished by captopril.lnanimal studies, captopril did notaltertha pressorlasponses to anumber 01 other agents, Including angiotensin II andnorepinephrine, Indicating specificity 01 action.ACE Is Identical to bradykinlnase, and captopril may also interfere with the degradation of tho vasodepressor peptide, bradykinin.IncreasedconcenlraUons of bradykinin Of prQstaglandin E2 mayalsohave arole In the therapeutic e~ecl ofCaptopril.Inhibition of ACE results In decreased plasma aogiolensln II and increased plasma renin activity (PRA), the laller resulting from loss ofnegative feedback on rennin release caused by reduction in angiotensin II. The reducllon 01 angiotensin II leads to decreasedaldosterone secretion, and, asaresull, small increases In serum potassium may occur along with sodium and fluid loss.The antihypertensive effects persist for longer period of time than does demonstrable inhibition of circulating ACE. It is not knownwhether the ACE present In vascular endothelium ls lnhlb~ed longer than the ACE In circulating blood.. Pharmacodynamics. After oral adminIstration of therapeutic doses 01 captopril, rapid absorption occurs with peak blood levels at about one hour. Thepresence of food in the gastrointeslinaltract reduces absorption by about 30 to 40percen~ captopril therefore should be given one hourbefore meals. Based on carbon-14 labeling, average minimal absorption Is approXimately 75.percenl.ln 24-hour period, Over ~5percentofthe absorbed doseis ellminaled In the urine; 40 to Opercent isunchanged drug; most01 the remainder Is the dIsulfidedimerofcaplopriland caplopril-oyslelne disulfide.Approximately 25 to 30 percentof the circulating drug Is bound to plasma proteins. The apparentelimination half-life for total radioactivityIn blood is probably lass Ihan 3hours. An accurala delanninaUon 01 half-lila 01 unchanged caplopnlls nol, al presenl, posslbie, bul<< Isprobably less than hours. In patients with renal Impairment, however, retention of captopril occurs .(sge .DOSAGE ANDADMINISTRATION).. Pharmacokinetics. Administration of captoprll results in reduction of peripheral arterial reslslance in hypertensive patients with either no change, or anIncrease, in cardiac o.ulpul. There Is an Increase irl renal blood now following administration of captopril and glomerular filtration rate Isusually unchanged.Reduclions of blood pressure are usually maximal 60. to 90 mInutes after oral administration of an individual dose of captopriJ. ,Theduration of effectIs dose related. The reduction in blood pressure maybe progressive, so to achieve maximal therapeutic effects, severalweeks of therapy may be required. The blood pressure lowering effects of caplopril and thlazldewlype cfiurellcs are addtllve.ln contrast,captopril and bela-blockers have aless than addRive effeclBlood pressure is kJwered to about the same extent in both standing and supine positions. Orthostatic effects and lachycardia areinfrequent but may occur in vo[umedepleled paUenls. Abrupt withdrawal of caplopril has not been associated wilh rapid Increase Inblood pressure.In patients with heart failure, significantly decreased peripheral (systemic vascular) resistance and blood pressure (after1oad), reducedpUlmonary capillary wedge pressure (preload) and pUlmonary vascular resistance, increased cardiac output, and Increased exercisetolerance time (En) have been demonstrated. These hemodynamic and clinical eUecls occur after the first dose and appear to persistfor the duration of therapy. Placebo controlled studies of 12 weeks duration in patients who did not respond adequately to diuretics anddigitalis show no tolerance to benefICial effects on En; open sludies, with exposure up to 16months in some cases, also Indicate IhatEnbenefit Is maintaIned. Clinical ImprovementhasbeenobseNed in some patienls where acutehemodynamic effects were minImal.The Survival and Ventricular Enlargement (SAVE) study was multicenter, randomized, double-blind. placebo-conlrolled trialconducted In 2,231 pallents (age21.79 years) who survived the acute phase of amy~rdlal infarction and did not have active Ischemia.PaUenls had left ventricular dysfunction (LVD), defined as resting left ventricular ejecllon fraction ~%, but at the time ofrandomization were not sUfriclently symplomallc to require ACE inhibitor therapy lor heart failure. About half 01 the palients hadsymptoms 01 heart failure in the past Pavents were given alest dose of 6.25 mg oralcaploprillablets and were randomized within 3-16days posllnfarctlon to receive either caplopriltablets or placebo in addition to conventional therapy. Captopril tablets ware inltiated at6.25 mg or 12.5 mg l.I.d. and after two weeks titrated to atarget maintenance dose of 50 mg .i.d. About 80% of pallenls were receivingthe target dose at the end of the study. Pallenls were followed fora minimum of two years and lorup to five years, vlith an average followupoI3.5years.oBaseline blood pressure was 113170 mm Hg and 112170 mm Hg lor Ihe placebo and captopril tablels groups, respectively. Bloodpressure iOCleased slighlly in botlltrealmenl groups during the studyand was somewhatlower in the caploprillablets group (119fl4 Vs.125177mmHgat1yr). oTherapy with captopril tablets improved 10rl9-lerm sUlVival and clinical outcomes compared to placebo. The risk reduction for all causemortality was 19%(P=O.02) and for cardiovascular dealh was 21% (P=0.014). Captopril trealed subjects had 22% (P=O.034) fewer firslhospitalizations for heart failure. Compared 10 placebo, 22% fewer patienls receiving captopril devekJped symptoms of overt heartfailure. There wasnoslgnmcant difference between groups1n total hospitalizations for all cause (2056 placebo; 2036captopriQ.Captopril tablets were well tolerated in the presence of other therapies such as aspirin, beta blockers, nitrates, vasodilators, calciumantagonists and diuretics.In amulticenter, doUble-blind, placebo controlled trial, 409 patients, age 18-49 of either gender, with or without hypertension, with type Iuwenile type, onset before age 30)Insulin-dependent diabetes mellitus, retinopathy, proteinuria 500 mg per day and serum creatinine;2.5 mg/dL, were randoml.ed to placebo or captoprillablels (25 mg t.I.d.) and followed forup to 4.6 years (median 3years). To achieveblood pressure control, additional antihypertensive agents (diurelics, bela blockers, centrallyaclfng agents or vasodnators) were addedas needed for patients In both groups.The captopnl tablets group had 51% reduction In risk of doubling of serum creatinine (P<o.01) and 51% reduction in risk for thecombined endpoint of end-stage renal disease (dialysis or transplantation) or death (Pd)o1). Captopril tablets treatment resulted in a30% reduction in urine prote in excretion within the first months (P<O.05), which was maintained throughout the trial. The captoprUtablets group had somewhat beUer blood pressurecontrol than the placebo group~but the effects 01 captoprlilablet on renal functionwere graaterthanwould be expected from the group differences In blood pressure reduction alone. Captopril tablets were well toleratedin this palienl population.In two multicenter, double-blind, placebo controlled studies, total of 235 normotensive patienls with inSUlin-dependent diabetesmellitus, reUnopathy and m~roalbumlnuria (20-200 meg/min) were randomized to placebo or Captopnl tablets (SO mg b.l.d.) andfollowad tor upto 2years. Captopril tabtats dalayed Ihe progression 10 overt nephropathy(protelriurla;,soD mg/day) In both sludles (riskreduction 67% to 76%; P<O.05). Captopriltablets also reduced the albumin excretion .rale. However, the long term clInical benefit 01reducing the progression from microalbuminuria to proteinuriahasnol been esl~blished,Studies in rats andcats indicate that captopril does notcross he blood-brain barrier to nyslgnmcant extent.

CONTRAINDICATIONS SECTION.

CONTRAINDICATIONS. Captopril tablets are contraindicatedin patients who are hypersensitive to this product or any other anglolensln. converting enzyme inhibitor(e.g., patient who has experienced angloedema during therapy with any other ACE inhibitor).

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. Reported incidences are based on clinical trials involving approximately7000 patients.Renal: About one of100 pallenls develope<iprolelnuna (seeWARNINGS),About one of100 pallenls develope<iprolelnuna (seeWARNINGS),Each of the following has been reported in approximately 102 of 1000 patients and are of uncertain relationship 10 drug use: renalInsufficiency. r~nal faHure, nephrotic syndrome, polyuria, oliguria, andurinary frequency. . .Hematoldgic: Neutropenia/agranulocytosis has occurred (see WARNINGS). Cases of anemia, thrombocytopenia, and pancytopeniaNeutropenia/agranulocytosis has occurred (see WARNINGS). Cases of anemia, thrombocytopenia, and pancytopeniahavebeenreportedtDetmaf9foglc :R~h, otten Vvilh pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 410 (depending on:R~h, otten Vvilh pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 410 (depending onrenal status and-dose) 01100 patients, usually dUring the first four weeks of therapy. It is usually maCUlopapular, and rarely urUcarial. Therash is usually mild and disappears within few days of dosage ~eduction, short-tenn treatmenl with an anUhlstaminic agent, and/ordisconlinuing therapy; remission mayoccur even lfcaptoprills conllnued.Prurilus, without rash, occurs in about2 of 100patients. Between7and 10 percenl of patients with skin rash haveshown an eosinophilia and/or positive ANA titers. Areversible associated pemphigoid-likelesion, and photosensitivity, have alsobeen reported. Flushing orpallorhasMenreported In 2to5of1000patlenls.Cardiovascular: Hypotension may occur; see WARNINGS and PRECAUTIONS (Drug Interactions) for discussion of hypotension withHypotension may occur; see WARNINGS and PRECAUTIONS (Drug Interactions) for discussion of hypotension withcaptoprlilherapy,Tachycardia, Chest pain, andpalpitations have eachbeenobseNed in approximately1of100 patients.Angina pectoris, myocardiallnfarclion, Raynauds syndrome, and congestive heart failure have each occurred ln2lo of 1000patients.Dysgeusia: Approximately 2to 4(depending on renal status and dose) of 100pallents developed adiminution or loss of taste perception.Approximately 2to 4(depending on renal status and dose) of 100pallents developed adiminution or loss of taste perception.Taste impairment Is reversible and usually self.l1mited (2 to months) even with coolinued drug adminiStration. Weighlless-may beassoclatedwiththelossottasle.Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported inAngioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported inapproxImately one In 1000 patrents. AngIoedema Involving lheupperaiWiays lias caused fatal airway obstruction. (See WARNINGS:Head and NeckAngloedema Intestinal Angioedema and PRECAUTIONS: Information for Patients.)Cough:Cough has been reported In 0.5 -2% of patients treated with captopril inclinicat trlals(see PRECAUTIONS: General, Cough):Cough has been reported In 0.5 -2% of patients treated with captopril inclinicat trlals(see PRECAUTIONS: General, Cough)The following have been reported in about 0.5 to percent of patients but did not appear at Increased frequency compared to placebo orother treatments used In controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthousulcers, pepticulcer,dizziness, headache, malaise,1atigue, insomnia, drymouth, dyspnea, alopecla, parestheslas.Other clinical adverse effects reported sInce the drugwas marketed are listed below by body system, In this selting, an incidence or causalrelationship cannot be accurately determined.Body as whole: Anaphylactoid reactions (see WARNINGS: Anaphylactoid and possible related reactions and PRECAUTIONS:as whole: Anaphylactoid reactions (see WARNINGS: Anaphylactoid and possible related reactions and PRECAUTIONS:Hemodialysis),General:Asthenia, gynecomastia.Asthenia, gynecomastia.Cardiovascular: Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope.Cardiac arrest, cerebrovascular accident/insufficiency, rhythm disturbances, orthostatic hypotension, syncope.Dermafologic: Bullous pemphigus, erythemamulliforme (including Slevens-Johnson syndrome), exfoliative oormalitis,Gastrointestinal Pancreatitis, glossitis, dyspepsia,Hematologic:AnemIa, Including aplastic and hemolytic.AnemIa, Including aplastic and hemolytic.Hepatobi/lary:Jaundice, hepatitis, Including fare cases of necrosis, cholestasis.Jaundice, hepatitis, Including fare cases of necrosis, cholestasis.MelaboflC:Symplomatichyponatremla. Musculoskelela/:Myalgia, myasthenia,NelVouslPsychiatric: Ataxia, confusion, depression, nervousness, somnolence.Ataxia, confusion, depression, nervousness, somnolence.Respirafo/):Bronchospasm, eosinophilic pneumonitis, rhinitis.Bronchospasm, eosinophilic pneumonitis, rhinitis.Specla/Senses:Bfurredvlsion.Urogenital:lmpotence.As with otherACE inhibitors, asyndrome has been reported which may include; lever, myalgia, arthralgia, inlerstitial nephritis, vasculitis,rash or other dermatologicmanifestations, eosinophilia and an elevated ESA.FetallNeonatal Morbidityand MortalitySee WARNINGS: FataUNaonetat Morbldltyand Mortality,Altered Laboratory FindingsSewfTJ Elecfrolytes: HyperkafemJa: small increases in serum potassium, especially in patients with renal Impairment (seesmall increases in serum potassium, especially in patients with renal Impairment (seePRECAUTIONS),Hyponatremfa: Particularly in patients receiving alowsodium diet or concomitantdiuretics,Particularly in patients receiving alowsodium diet or concomitantdiuretics,BUN/Serum Creatinine: Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those withTransient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those withrenovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in theglomerular filtration rale and, In lum,lead to Increases inBUNor serum creatinine.Hemalologlc:AposKIv~ANAhasbeen reported,AposKIv~ANAhasbeen reported,UverFunctionTesls: Elevallons of liver transaminases, alkaline phosphatase, and serum biirubin have occurred.Elevallons of liver transaminases, alkaline phosphatase, and serum biirubin have occurred.

BOXED WARNING SECTION.

BOXED WARNING. USE IN PREGNANCY .When used In pregnancy during the second and third trimesters, ACE Inhibitors can cause Injury and even death to thedeveloping fetus. When pregnancy Is detected, captopriJ tablets USP should be disconlinued as. soon as possible. SeeWARNINGS: FelallNeonalal Morbidity and Mortalily.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis, MutagenasIsandImpaIrmental Fertl IllyTwo-year studies with doses of SOto 1350mglkgfdayln miceand rats failed to show any evidence of carcinogenic potential. The high doseIn these studies Is 150 limes the maximum recommended human dose of 450 mg, assuming a5O-kg subject. On body-surface-areabasis, the high doses formlce and rats are 13 and26times the maximum recommendedhumandose, respectively.Studies In rats have revealed noImpairmentoffertility.AnlmalToxlcologyChronic oralloXlclty sludies were conducted in rals (2 years), dogs (47 weeks; 1year), mlco (2 years), and monkeys (1 year). Signiflcanldrug related toxicity included effects On hematopoiesis, renal toxicity, erosion/ulceration of the stomach and variation of retinal bloodvessels.Reductions in hemoglofin and/or hematocril values were seen in mice, rats and monkeys at doses 50 to 150 limes the maximumrecommended human dose (MRHD) 01450 mg, assuming 50-kg subject. On abody-surface-area basis, these doses are 5to 25 timesmaximum recommended human dose (MRHD). Anemia, leUkopenia, thrombocytopenia, and bone marrow suppression occurred In dogsatdoses8to30timesMRHDon abody-weightbasis (4 to 15 times MRHDon asurface;area basis).The reductions in hemoglobin and hematocrit values In rats and mk;a were only slgnllicantat 1year and returned to normal with continueddosingby the endolthesludy.Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs, whereas moderate to marked leUkopenia was noted only at15and 30 times MRHD and thrombocytopenia at 30 times MAHD. The anemia GOuld be reversed upon discontinuation of dosing. Bonemarrow suppression occurred to avarying degree, being associated only with dogs that died or were sacrifICed in amoribund condition Inthe 1year study. However,ln the 47-weekstudy at adose 30 limes MRHD, bone marrow suppression was found to be reversible uponcontinued drug administration.captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys In mice and rals at doses 7to 2QO times MRHD on abodyweightbasis (O.6 to 35 limes MAHD on asurface-area basis); in monkeys at 20 10 60 times MRHDon abody.weight basis (7 to 20 limesMRHDonasUrface-araa basis): andin dogs at30 times MRHDonabody-weight basis (15limesMRHOon asurface-area basis).Gastric eroslonslulcerallons were increased in incidence in male rats at 20 to 200 limes MAHD on abody-weight basis (3.5 and 35 limesMRHD on asurface-area basis); In dogs at 30 limes MAHD on abody.weight basls(15llmes on MRHD on surface-area basis); and inmonkeys at 65 times MRHD on body-weiglll basis (20 times MRHD on asurt.ce-area bas~). Rabbits developed gaslric and Inlestinalulcerswhen given oral doses approximately 30 timesMRHDon abody-weight basIs (10 timesMRHD on asudaee-area basis) for only 5107days.In the two-year rat study, irreversible and progressive variatlons In the caliber of retinal vessels (focal sacculalions and constricllons)OCCIJrred at all doss levels (710 200 times MRHD) on abody y/eighl-basis; 11035 Urnes MRHDon asurtaco-area basis in adose.relaledfashion. The effect wCsfirst observed In Ihe ~th week of dosing, with aprogressivelyIncreased Incidence thereaer, even after cessationof dosing.

DESCRIPTION SECTION.

DESCRIPTION. Captoprills specific competitive inhibitor of angioerlSln I-converting enzyme (ACE), the enzyme responsible for the conversion ofanglolensln Iloanglolensin II.eaploprills deslgnaled chemically as j-[(2S)-3-mercaplo-2-malhylpropionylj-L-prolina. Moler:ular fonnul. e,HNO,S [MW 217.29) andhas the folloNIngstruclural.formula:Captoprills white to off-white crystalline powder that may have slight sulfurous odor; it is soluble in waler (approx. 160 m9fml),malhanol, and alhanol and sparingly soluQleln chIorolonn and alhyl acelala.Each scored tablet, for oral administration, contains 12.5 mg, 25 mg, 50 mg or 100 mg of captopril.ln add~ion, each lablet contains thefollowing inactive ingredients: microcf)stalline cellulose,comstarch, anhydrous ladose, coHoidalsilicon dioxide, talc andpalmilic acid.. Captopril structural formula.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION. Caplopril tablets should be taken one ho.ur before meals. Dosage mustbe individualized.Hypertension. Inlliation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressureelevation, salt restriction, and other clinical circumstances. Ifpossible, discontinue the paUenfs prfvious antihypertensive drug regimen forone weekbefore starting captopril.The initial dose of captopril tablels USis 25mgb.l.d. orUd.1f satisfactory reduction of blood pressure has not been achieved after one ortwo weeks, the dose may be increased 10 50 ffig b.l.d. or t.l.d. Concomitant sodium restrictfon may be beneficial when caploprills usedalone.The dose of caplopril in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the blood pressure has not been satisfactorilycontrolled after one to two weeks at this dose, (and the patrent is nol already receiving adiuretic), modest dose of thIazide-type diuretlc(e.g., hydrochlorolhiazide, 25 mg daily), should beadded. The diureticdose may be increased at one-Io two-week intervals untilits highestusual antihypertensive dose isreached.. .If capopril is beIng starte~ in patient already receiving adiuretic, captopriliherapy should be iniUaled under close medical supervision(see WARNINGS and PRECAUTIONS: Drug Interactions regarding hypotension), wiih dosageandtilration of caplopol as notedabove.l further blood pressure reduction Is required, the dose of captopril may be Increased to 100mgb.l.d. orUd. aodthen, if necessary, to 150mg b.l.d. or t.l.d (while continuing the diuretic). The usual dose range Is 25 10 150 mg b.l.d. or t.l.d. Amaximum daily dose of 450 mgcaplopril should notbe exceeded.For patients vlith severe hypertension (e.g., accelerated or malignant hypertension), when temporary discontinualion of currenantihypertensive therapy Is not practical or desirable, or when prompt titration to more normotensive blood pressure levels ls Indicaled,c;liureUc should be continued but other current antihypertensive medication slopped and captopril dosage promptly Initialed at 25 mgb.l.d.orUd., underdose medical supervision.When necessitated bylhe patients clinical condition, the dallydose of captopril maybeincreased every 24 hours or less undercontinuousmedical supervision until asatisfaclo/y blood pressure response is oblalned or the maximum dose of captoprills reached. In his regimen.addition of amore potent diureUc, e.g., furosemide, may alsobe Indicated.Bela-blockers mayalso be used inconjuncUon with caplopril therapy (see PRECAUTIONS: Drug Interactions), butthe effecls of the twodrugs are less than additive.Heart Failure -Initiation ollherapv requiles consideration of recent diuretic therapy and the possibility of severe salVvolume depletion. Inpatients with either normal or low blood pressure, who have been vigorously lrealed with diuretics and who may be hyponalremic and/orhypoVolemic, aslarting dose of 6.25 or 12.5mg l.i.d. may minimize the magnitude or duration of the hypotensive effect (see WARNINGS:Hypotension); for lhese patients, titration 10 the usual daily dosagecan then occur within the next several days.For most patients the usual initial daily dosage Is 25 mg ti.d, After adose of 50 mg t.l,d. is reached, further Increases in dosage should bedelayed, whete possible, for at least two weeks to determine Ha satisfactory response occurs. Most patients studied have had asallsfactol) clinical improvementat50or 100mgIJ.d.Amaximumdaily dose of 450mg of captopril should nol be exceeded.Captopril shouW generally be used In conjunction with adiuretic and digitalis. Captopriltherapymust be initiated under vel) close medical supervision.Left Ventrlcular Dysfunction After Myocardlallnfarctlon The recommended dose for long-term use In patients following amyocardialinfarction is atarget maintenance dOje of 50mgU.d.Therapy may be Initiated as early as three days following amyocardial infarction. After asingle dose of 6.25lng, caploprillablets therapyshould belnltialed at 12.5 mg t.i.d. Captoprillablets should then be Increased to 25 mg t.l.d. during Ihe next several days and to atargetdose 0150 mg tid. over the next several weeks as toleraled (seeClINICALPHARMACOLOGY).CaplopriJ tablets maybe used in patlenls treated wHh other posl.myocardiallnfarcllon therapies, e.g.lhrombolyllcs, aspirin, beta blockers.Dla belle Nephropathy:The recommended dose of Captoprll tablets for long term use 10 treat diabeticnephropathyis 25mgl.l.d.Other antihypertensives such as diuretics, bela blockers, centrally acllng agents orvasodilalors may be used in conjuctlon with Captoprillablelsit additiqnal therapyIS reqUired 10 further lowerblood pressure.Dosage Adjustment In Renal Impairment Because captopril is excreled primarily by the kidneys, excretion rates are reduced inpatients with Impaired renal function.These paUenls will take longer. 10 reach steady-state capoprtllevels and will reach higher steady.stale levels for agiven daily dose Ihanpatients with normal renal function. Therefore, these patientsmayrespond to smaller or less frequent doses.AcCordingly, for patlents with significant renal Impairment, Initial dailY dosage of caplopril should be reduced, and smaller Incremenlsutilized fortltration, Yihich should be quiteslow (one-Io two-week intelVals). After the desired therapeutic effect has been achIeved, thedose should be slowlyback titrated to determine the minimal effective dose. When concomitant diurellc-therapy Is required, aloOp diuretic(e.g., furosemide), ratherlhan athiazidediuretlp, Is preferredln palienlswlthsevere renal Impairment. (Sea WARNINGS: Anaphylactoidreactions during membrane exposure Bnd PRECAUTIONS: Hemodialysis.).

DRUG INTERACTIONS SECTION.

Drug Interactions. Hypotension. Patienls on Diurelic Therapy:Palienfs on diuretics and especially lhose iowhom diuretic therapy was recently Instituted, asPatienls on Diurelic Therapy:Palienfs on diuretics and especially lhose iowhom diuretic therapy was recently Instituted, aswell as lhose 00 severe dietary salt restriction or dialysis, may occasionally experience aprecipitous reduction of blood pressure usuallywithin the first hour after receiving the lorua dose of captopril.The possibility of hypotensive effects with captopril can be minimized by either disconlilluing the diuretic or Increasing the salt Intakeapproximately one week prior to initiation of trealment with caploprillablets USP or initiating therapy with small doses (6.25 or 12.5 mg).Alternatively, provide medical supervision for alleasl onehouralter the initial dose. Ifhypolenslon occurs, the palient shoUld be placed In asupine posi1lon and, II necessal), receive an Inlravenous Infusion of normal saline. This transient hypotensive response Is nol acontraindication 10furtherdoseswhich can be given without diffiCUltyonce the blood pressurehasincreased alter volume expansion.Agents Having Vasodilator Activity: Dala on Ute effect of concomllant use of other vasodilators In patienls receiving captopril for heartDala on Ute effect of concomllant use of other vasodilators In patienls receiving captopril for heartfailure are nol available; therelore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilatoractivily should, If possible. be discontinued before slarllng caplopnl. II resumed dunng caplopnllsblellherapy, such agenls should baadmlnlslered cautiously, and perhaps alJowerdosage.Agents Causing Renin Release: Captoprirs effect will be augmented by antihypertensive agents that cause renin release. For example,Captoprirs effect will be augmented by antihypertensive agents that cause renin release. For example,diuretics (e,g., thiazides) mayactivale the renin-angiotensln.aldosterone syslem.Agents Affecting Sympathetic Activity: The sympathetic nelVous system may be especially Important I.n supporting blood pressure inThe sympathetic nelVous system may be especially Important I.n supporting blood pressure inpaUenlS receMng captopnl alone or with dluretfcs Therefore, aganls affecUng sympathetic activity (e.g.; gangUonlc blocking agents oradrenergic n.euron blocking agents) should be used with caution. Beta.adrenergic blocking drugs addsome further antihyp~rtensive effect10caplopril, bul the overall response Isless than additive.Agents Increasing Sem Pota~i~m: ~ince.caplopri~ ec~eases aldosl~.ro~~ produclioo, elevatio~ of seru~ po.t~~slu~ may ~r.Pota~i~m: ~ince.caplopri~ ec~eases aldosl~.ro~~ produclioo, elevatio~ of seru~ po.t~~slu~ may ~r.Potassium-sparing diuretics such as spironolactone, tnamterene, or amiloride, or potassium supplements should be giVen only lordocumented hypokalemia, and then with caution, since they may lead 10 significant increase of serum polassium. Salt sUbstitutescont~.Inlng potassium sllould also be used with caulion.Inhibitors Of Endogenous Prostaglandin Synthesis: It has been reported that indomethacin may reduge the anlihypertensive effect ofIt has been reported that indomethacin may reduge the anlihypertensive effect ofcaptopril, especially in cases of low renIn hypertension. Other nonsteroidal anli-inflammatory agElnlse.g., aspirin) may.also have thiseffectUlhium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomUa.nt lithium andIncreased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomUa.nt lithium andACE Inhibitor therapy. These drugs shook: be coadmlnistered with caution and frequent monitoring of serum lithium levels Isrecommended. Ita di~retic Is alsq used, II may increase the risk oftllhium toxicity.Cardiac Glycosides: In asludy 01 young heallhy maJe subjects no evidence 01adlrecl phannacoklnetic captopril-digoxln interaction couldIn asludy 01 young heallhy maJe subjects no evidence 01adlrecl phannacoklnetic captopril-digoxln interaction couldbefound.Loop Diuretics: Furosemide administered concurrently with caplopril does not aller the pharmacokinetiQS of caploprilln renally impairedFurosemide administered concurrently with caplopril does not aller the pharmacokinetiQS of caploprilln renally impairedhypertensive patients.Allopurinol: In astudy of hc.althy male volunteers no significant pharmacokinetic InteractiOn oIXured when captopril and allopurinol wereIn astudy of hc.althy male volunteers no significant pharmacokinetic InteractiOn oIXured when captopril and allopurinol wereadmlnlslered concom~anlly for6days.Gold: Nitritoid reactions (symptoms Include facialllushing, nausea, vomiting and hypotension) have been reported rarely in patients onNitritoid reactions (symptoms Include facialllushing, nausea, vomiting and hypotension) have been reported rarely in patients ontherapywith injectable gold (sodium aurothiomaJate) and concomitantACEinhibitor therapy including captoprn.Drug andor LaboratoryTest InteractionCaptoprUmaycauseafalse-positive urine test foracetone.

GENERAL PRECAUTIONS SECTION.

General. ImpairedRena/FunctionHypertension -Some patients with renal disease, particularly those with severe renal artery stenosis. have developed increases InnUNand serum creatinIne after reduct10n of blood pressure with captopril..Captopril dosage reduction and/or discontlnuation of diurelic maybe require d. Forsomeof these patlents, It may notbeposslble to oonnalize blood pressure and maintain adequate renal perfusion.Heart Failure About 20 percent or patients develop stable etevations of BUN and serum creatinIne grealer than 20 percent abovenormal or baseline uponlong-term treatment with captopril. Less than 5percent 01 patients, generally those with severe preexisting renaldisease, reqUired discontinuation of treatment due 10 progressively increasing creatinine; subsequent improvement probably dependsupon the severity of the underlyingrenal disease. .Sea CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRAnON,ADVERSEREACTIONS: Altered Laboratory Findings.Hypeikalemia: Elevations in serum potassium have been observed in some patlents treated with ACE Inhibitors, including, caplopril.Elevations in serum potassium have been observed in some patlents treated with ACE Inhibitors, including, caplopril.When treated with ACE Inhibitors, patients at risk for the development of hyperkalemia include those with: renallnsufflClency; diabetesmellitus; and those using concomitant potassium-sparing diureUes, polassium supplements or potassium-rontalntng salt substitutes; or o.ther drugs associated with increases in serumpotassiumIna trialnf type Idiaqeticpatients with prolelnuria, the Incidence of withdrawalof treatment with captopril for hyperkalemIawas 2% 41207).ln two lrials of normotensIve type Idiabellc patients with mlcroalbumlnuria,no caplopnl group subJeels had hyperkalemia (01116). (Sae PRECAUTIONS: Informallon for Pallenls and Drug Inlersellons;ADVERSE REACTIONS: Altered Laboralory Findings.)Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persislent nonproductive cough has beenPresumably due to the inhibition of the degradation of endogenous bradykinin, persislent nonproductive cough has beenreported with all ACEinhibitors, always resotving after disconlivuation of therapy. ACE Inhibitor-induced cough should be considered in the. differentialdiagnosis of cough.Valvular Stenosis: There 15 concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreasedThere 15 concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreasedcoronal) perfusion when treated with vasodilators because they donot develop as much afterload reduction as others.Surgery/Anesthesia: In patients undergoIng major surgery or during anesthesia with agents that produce hypotension, captopril will blockIn patients undergoIng major surgery or during anesthesia with agents that produce hypotension, captopril will blockangiotensin II fannalion secondary to compensatOlY renin release. If hypotension occurs and is considered 10 be due to this mechanism, itcan be corrected by volume expansion.HemodialysisRecent clinical observations have shown an association of hypersensitivity.like (anaphylactoid) reactions during hemodiafyis with high.flux dialysis membranes (e.g., AN69) in patients receiving ACE Inhibitors. In these patients, consideration should be given to using adifferent type 01 dialysis membrane or different class medkation. (See WARNINGS: Anaphylactoid Reactions DUring MembraneExposure.)Information for PatientsPatients should be advised 10 Immediately report to their physician any signs orsymptoms suggesting angioedema (e.g., swelling of face,eyes, lips, tongue,larynxand extremities; diHicultyinswallowing or breathing; hoarseness) and 10 discontinue therapy. (See WARNINGS:Headand Neck Angioedema and Intestinal Angioedema.) PaUe~ls should be lold to report promptly any Indication of Infecll~ (~g., sore throal, fever), which may be asIgn on neutropenia, or ofprogressive edemawhich might be related 10proteinuriaandnephrotic syndrome. All patients should be cautioned that excessive perspiration and dehydration may lead an excessive lallin blood pressure because 01reduction in fluid volume. Other causes 01 volume depletion such as vomltlng or diarrhea may also lead to afall in blood pressure; patientsshould be advised 10consul with the physician.PaUenls shOUld be advised not to use potassium.sparing diuretics, potassium supplements or polassium-containing salt subsUMeswilhouiconsulllng th.eirphysi~an. (See PRECAUTIONS: General and Drug Inferactlon; ADVERSE REACTIONS.)Patients should be warned agaInstInterruption or disconUnualion of medication unlessinstructedbyIhephysician.Heart failure patients on captoprillherapy shouldbe cauUoned against rapid Increasesin physical activity.Patienls should be Informedlhalcaplopnllabisls USP shouldbe laken one hourbefore meals (see DOSAGE AND ADMINISTRAnoN).Pregnancy: Female palienls of childbearing age should belold about the ~nsequences of second. and third-lrimester exposure to ACElnhlbilors, and they should also be told that these consequences do not appear to have resulted from inlrauterine ACE.lnhibilor exposurethat hasbeen limited to the firsl trimester. These patients shouldbe asked to report pregnancies 10 their physicians as soon as possible.

HOW SUPPLIED SECTION.

HOW SUPPLIED. Captopril Tablets USP12.5 mg tabtets in blisterpacks 30 (NDC 0615-4519-39).25 mg tablets In blisterpacks 30(NDC 0615-4520-39).50 mg tablets In blisterpacks 30 (NDC 0615-4521-39).Bottle contains desiccant.The 12.5 mg tablet is white, flat bevelled-edge round with bisect bar on one side and W;902 on the other side; the 25mg Captopril tablet is white, flat vevelled-edge round with quadrisect bar on one side and W;903 on the other side; the 50mg Captopril tablet is white, flat vevelled-edge round with bisect bar on one side and W;904 on the other side.

INDICATIONS & USAGE SECTION.

INDICATIONS AND USAGE. Hypertension: Captopril tablets USare indicated for the Teatment of hypertension.tn using captopril, conslderallon should be gtven to the risk of neutropeniaagranutocytosls (seeWARNINGS).Captoprll maybe used as Initial therapy for patientswilh normal renal function, In whomthe rlskls relatively low. In patients with impairedrenal function, particularly those wfth collagen vascular olSeas6, captopril should be reseNed for,hypertenslves who have eitherdeveloPed unacceptable side effecls on otherdrugs, orhave failed to responq satislactorily 10drug cOmbinations.Captopril is effective alone and in combination with other antihypertensive agents, ~peclally thiazide-type diuretics. The blood pressurelowering effecls of captoprif and thlazldes are approximalaly a<dlltva.Heart Failure:Captopril tabletsare indicated in the treatmentof congestive heart failure usually in cornblnatlpn withdiuretics anddi9italls The beneficial effect 01 captopril in~eart failure does notrequl.re the presence 01 digllaUs, however, most controlled cliniCal trialexperience with captopril has been in paUentsreceMng digitalis, as well as dluretlctrealmen. .Left V~ntrlcular Dysfunction After MYQcar~lal tnlarctlon Gaplopril tablels are indicated to Improve survival following myocardialfnfarclion In clinically stable patients with left ventriCUlardysfUnction manlfesled as an ejection fraction ::;40% and 10 reduce the Incidence01 overt heart failure and subsequenthospitalizations forcongesUve heart failure In these patients.Diabetic Nephropathy: Captopril lablels are indicated fortha trealment ot diabetic nephropathy (proteinuria> 500 mg/day) in paUentswith type Ilnsulin-dependenl diabetes mellitus and retinopathy. Caplopriltablets decreases the rate of progression of renallns.uffJcienCyand development of serious adverse clinical outcomes death or need for renallransplantation or dialysisl.In considering use of caplopril tablets, it should be noted that In controlled trtals ACE inhibllors have an effect on blogd pressure that isless in black patients than In nonblacks. In addition, ACE Inhibitors (for which adequate data are available) cause higher rate ofangioedema in black than In non-black palients seeWARNINGS: Head and NeckAngloedema and Intestinal AngIQedema.

NURSING MOTHERS SECTION.

Nursing Mothers. Concenlraions of captoprilln human milk are apprOXimately one percent of those In maternal blood. Because of the polential for seriousadverse reactlons in nursing infants1rom captopril, adecision should be made whether to discontinue nursing or to discontinue the drug,laldnglntoaccountlhelmportanceof caploprlltabfel to Ihe molher. (See PRECAUTIONS: PediatricUse.).

OVERDOSAGE SECTION.

OVERDOSAGE. Correction of hypotension would beof primary concern. Volume expansion with an intravenous infusIon of normal saline Is the treatment ofchoice for restoration of blood pressure.While captopril may be remOved from theadult cIrculation by hemodialysis, there is Inadequate data concerning the effectiveness ofhemodialysis for removing it from the circulation of neonates or chfldren. Peritoneal dialysIs is not effeclive for removing captopril; there isno information concerning exchange transfusion for removing captopril from the general circulation.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. Captopril Tablets,USP 12.5 mg. Principal Display Panel-Captopril 12.5mg.

PEDIATRIC USE SECTION.

Pediatric Use. Safety and effec,tiveness in pediatric patlents have not been established. There Is limited experience reported In Ihe lit~rature with ~e useof caplopril in the pediatric population; dosage, on aweight basis, was generally rsported to be comparabfe 10 or less than that used inadults.Infants, especially newborns, may be more susceptible to tpe adverse hemodynamic etfects of eaptopril. Ex~essive. prolonged andunpredictable decreases In blood pressure and associated compllcaUons, Including oliguria and seizures, havebeenreported.Captopril tablets should be usedin pediatrlc paleints only if othermeasures for conlrolling blood pressure have not beeneffective.

PHARMACODYNAMICS SECTION.

Pharmacodynamics. After oral adminIstration of therapeutic doses 01 captopril, rapid absorption occurs with peak blood levels at about one hour. Thepresence of food in the gastrointeslinaltract reduces absorption by about 30 to 40percen~ captopril therefore should be given one hourbefore meals. Based on carbon-14 labeling, average minimal absorption Is approXimately 75.percenl.ln 24-hour period, Over ~5percentofthe absorbed doseis ellminaled In the urine; 40 to Opercent isunchanged drug; most01 the remainder Is the dIsulfidedimerofcaplopriland caplopril-oyslelne disulfide.Approximately 25 to 30 percentof the circulating drug Is bound to plasma proteins. The apparentelimination half-life for total radioactivityIn blood is probably lass Ihan 3hours. An accurala delanninaUon 01 half-lila 01 unchanged caplopnlls nol, al presenl, posslbie, bul<< Isprobably less than hours. In patients with renal Impairment, however, retention of captopril occurs .(sge .DOSAGE ANDADMINISTRATION).

PHARMACOKINETICS SECTION.

Pharmacokinetics. Administration of captoprll results in reduction of peripheral arterial reslslance in hypertensive patients with either no change, or anIncrease, in cardiac o.ulpul. There Is an Increase irl renal blood now following administration of captopril and glomerular filtration rate Isusually unchanged.Reduclions of blood pressure are usually maximal 60. to 90 mInutes after oral administration of an individual dose of captopriJ. ,Theduration of effectIs dose related. The reduction in blood pressure maybe progressive, so to achieve maximal therapeutic effects, severalweeks of therapy may be required. The blood pressure lowering effects of caplopril and thlazldewlype cfiurellcs are addtllve.ln contrast,captopril and bela-blockers have aless than addRive effeclBlood pressure is kJwered to about the same extent in both standing and supine positions. Orthostatic effects and lachycardia areinfrequent but may occur in vo[umedepleled paUenls. Abrupt withdrawal of caplopril has not been associated wilh rapid Increase Inblood pressure.In patients with heart failure, significantly decreased peripheral (systemic vascular) resistance and blood pressure (after1oad), reducedpUlmonary capillary wedge pressure (preload) and pUlmonary vascular resistance, increased cardiac output, and Increased exercisetolerance time (En) have been demonstrated. These hemodynamic and clinical eUecls occur after the first dose and appear to persistfor the duration of therapy. Placebo controlled studies of 12 weeks duration in patients who did not respond adequately to diuretics anddigitalis show no tolerance to benefICial effects on En; open sludies, with exposure up to 16months in some cases, also Indicate IhatEnbenefit Is maintaIned. Clinical ImprovementhasbeenobseNed in some patienls where acutehemodynamic effects were minImal.The Survival and Ventricular Enlargement (SAVE) study was multicenter, randomized, double-blind. placebo-conlrolled trialconducted In 2,231 pallents (age21.79 years) who survived the acute phase of amy~rdlal infarction and did not have active Ischemia.PaUenls had left ventricular dysfunction (LVD), defined as resting left ventricular ejecllon fraction ~%, but at the time ofrandomization were not sUfriclently symplomallc to require ACE inhibitor therapy lor heart failure. About half 01 the palients hadsymptoms 01 heart failure in the past Pavents were given alest dose of 6.25 mg oralcaploprillablets and were randomized within 3-16days posllnfarctlon to receive either caplopriltablets or placebo in addition to conventional therapy. Captopril tablets ware inltiated at6.25 mg or 12.5 mg l.I.d. and after two weeks titrated to atarget maintenance dose of 50 mg .i.d. About 80% of pallenls were receivingthe target dose at the end of the study. Pallenls were followed fora minimum of two years and lorup to five years, vlith an average followupoI3.5years.oBaseline blood pressure was 113170 mm Hg and 112170 mm Hg lor Ihe placebo and captopril tablels groups, respectively. Bloodpressure iOCleased slighlly in botlltrealmenl groups during the studyand was somewhatlower in the caploprillablets group (119fl4 Vs.125177mmHgat1yr). oTherapy with captopril tablets improved 10rl9-lerm sUlVival and clinical outcomes compared to placebo. The risk reduction for all causemortality was 19%(P=O.02) and for cardiovascular dealh was 21% (P=0.014). Captopril trealed subjects had 22% (P=O.034) fewer firslhospitalizations for heart failure. Compared 10 placebo, 22% fewer patienls receiving captopril devekJped symptoms of overt heartfailure. There wasnoslgnmcant difference between groups1n total hospitalizations for all cause (2056 placebo; 2036captopriQ.Captopril tablets were well tolerated in the presence of other therapies such as aspirin, beta blockers, nitrates, vasodilators, calciumantagonists and diuretics.In amulticenter, doUble-blind, placebo controlled trial, 409 patients, age 18-49 of either gender, with or without hypertension, with type Iuwenile type, onset before age 30)Insulin-dependent diabetes mellitus, retinopathy, proteinuria 500 mg per day and serum creatinine;2.5 mg/dL, were randoml.ed to placebo or captoprillablels (25 mg t.I.d.) and followed forup to 4.6 years (median 3years). To achieveblood pressure control, additional antihypertensive agents (diurelics, bela blockers, centrallyaclfng agents or vasodnators) were addedas needed for patients In both groups.The captopnl tablets group had 51% reduction In risk of doubling of serum creatinine (P<o.01) and 51% reduction in risk for thecombined endpoint of end-stage renal disease (dialysis or transplantation) or death (Pd)o1). Captopril tablets treatment resulted in a30% reduction in urine prote in excretion within the first months (P<O.05), which was maintained throughout the trial. The captoprUtablets group had somewhat beUer blood pressurecontrol than the placebo group~but the effects 01 captoprlilablet on renal functionwere graaterthanwould be expected from the group differences In blood pressure reduction alone. Captopril tablets were well toleratedin this palienl population.In two multicenter, double-blind, placebo controlled studies, total of 235 normotensive patienls with inSUlin-dependent diabetesmellitus, reUnopathy and m~roalbumlnuria (20-200 meg/min) were randomized to placebo or Captopnl tablets (SO mg b.l.d.) andfollowad tor upto 2years. Captopril tabtats dalayed Ihe progression 10 overt nephropathy(protelriurla;,soD mg/day) In both sludles (riskreduction 67% to 76%; P<O.05). Captopriltablets also reduced the albumin excretion .rale. However, the long term clInical benefit 01reducing the progression from microalbuminuria to proteinuriahasnol been esl~blished,Studies in rats andcats indicate that captopril does notcross he blood-brain barrier to nyslgnmcant extent.

PRECAUTIONS SECTION.

PRECAUTIONS. General. ImpairedRena/FunctionHypertension -Some patients with renal disease, particularly those with severe renal artery stenosis. have developed increases InnUNand serum creatinIne after reduct10n of blood pressure with captopril..Captopril dosage reduction and/or discontlnuation of diurelic maybe require d. Forsomeof these patlents, It may notbeposslble to oonnalize blood pressure and maintain adequate renal perfusion.Heart Failure About 20 percent or patients develop stable etevations of BUN and serum creatinIne grealer than 20 percent abovenormal or baseline uponlong-term treatment with captopril. Less than 5percent 01 patients, generally those with severe preexisting renaldisease, reqUired discontinuation of treatment due 10 progressively increasing creatinine; subsequent improvement probably dependsupon the severity of the underlyingrenal disease. .Sea CLINICAL PHARMACOLOGY, DOSAGE AND ADMINISTRAnON,ADVERSEREACTIONS: Altered Laboratory Findings.Hypeikalemia: Elevations in serum potassium have been observed in some patlents treated with ACE Inhibitors, including, caplopril.Elevations in serum potassium have been observed in some patlents treated with ACE Inhibitors, including, caplopril.When treated with ACE Inhibitors, patients at risk for the development of hyperkalemia include those with: renallnsufflClency; diabetesmellitus; and those using concomitant potassium-sparing diureUes, polassium supplements or potassium-rontalntng salt substitutes; or o.ther drugs associated with increases in serumpotassiumIna trialnf type Idiaqeticpatients with prolelnuria, the Incidence of withdrawalof treatment with captopril for hyperkalemIawas 2% 41207).ln two lrials of normotensIve type Idiabellc patients with mlcroalbumlnuria,no caplopnl group subJeels had hyperkalemia (01116). (Sae PRECAUTIONS: Informallon for Pallenls and Drug Inlersellons;ADVERSE REACTIONS: Altered Laboralory Findings.)Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persislent nonproductive cough has beenPresumably due to the inhibition of the degradation of endogenous bradykinin, persislent nonproductive cough has beenreported with all ACEinhibitors, always resotving after disconlivuation of therapy. ACE Inhibitor-induced cough should be considered in the. differentialdiagnosis of cough.Valvular Stenosis: There 15 concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreasedThere 15 concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreasedcoronal) perfusion when treated with vasodilators because they donot develop as much afterload reduction as others.Surgery/Anesthesia: In patients undergoIng major surgery or during anesthesia with agents that produce hypotension, captopril will blockIn patients undergoIng major surgery or during anesthesia with agents that produce hypotension, captopril will blockangiotensin II fannalion secondary to compensatOlY renin release. If hypotension occurs and is considered 10 be due to this mechanism, itcan be corrected by volume expansion.HemodialysisRecent clinical observations have shown an association of hypersensitivity.like (anaphylactoid) reactions during hemodiafyis with high.flux dialysis membranes (e.g., AN69) in patients receiving ACE Inhibitors. In these patients, consideration should be given to using adifferent type 01 dialysis membrane or different class medkation. (See WARNINGS: Anaphylactoid Reactions DUring MembraneExposure.)Information for PatientsPatients should be advised 10 Immediately report to their physician any signs orsymptoms suggesting angioedema (e.g., swelling of face,eyes, lips, tongue,larynxand extremities; diHicultyinswallowing or breathing; hoarseness) and 10 discontinue therapy. (See WARNINGS:Headand Neck Angioedema and Intestinal Angioedema.) PaUe~ls should be lold to report promptly any Indication of Infecll~ (~g., sore throal, fever), which may be asIgn on neutropenia, or ofprogressive edemawhich might be related 10proteinuriaandnephrotic syndrome. All patients should be cautioned that excessive perspiration and dehydration may lead an excessive lallin blood pressure because 01reduction in fluid volume. Other causes 01 volume depletion such as vomltlng or diarrhea may also lead to afall in blood pressure; patientsshould be advised 10consul with the physician.PaUenls shOUld be advised not to use potassium.sparing diuretics, potassium supplements or polassium-containing salt subsUMeswilhouiconsulllng th.eirphysi~an. (See PRECAUTIONS: General and Drug Inferactlon; ADVERSE REACTIONS.)Patients should be warned agaInstInterruption or disconUnualion of medication unlessinstructedbyIhephysician.Heart failure patients on captoprillherapy shouldbe cauUoned against rapid Increasesin physical activity.Patienls should be Informedlhalcaplopnllabisls USP shouldbe laken one hourbefore meals (see DOSAGE AND ADMINISTRAnoN).Pregnancy: Female palienls of childbearing age should belold about the ~nsequences of second. and third-lrimester exposure to ACElnhlbilors, and they should also be told that these consequences do not appear to have resulted from inlrauterine ACE.lnhibilor exposurethat hasbeen limited to the firsl trimester. These patients shouldbe asked to report pregnancies 10 their physicians as soon as possible.. Drug Interactions. Hypotension. Patienls on Diurelic Therapy:Palienfs on diuretics and especially lhose iowhom diuretic therapy was recently Instituted, asPatienls on Diurelic Therapy:Palienfs on diuretics and especially lhose iowhom diuretic therapy was recently Instituted, aswell as lhose 00 severe dietary salt restriction or dialysis, may occasionally experience aprecipitous reduction of blood pressure usuallywithin the first hour after receiving the lorua dose of captopril.The possibility of hypotensive effects with captopril can be minimized by either disconlilluing the diuretic or Increasing the salt Intakeapproximately one week prior to initiation of trealment with caploprillablets USP or initiating therapy with small doses (6.25 or 12.5 mg).Alternatively, provide medical supervision for alleasl onehouralter the initial dose. Ifhypolenslon occurs, the palient shoUld be placed In asupine posi1lon and, II necessal), receive an Inlravenous Infusion of normal saline. This transient hypotensive response Is nol acontraindication 10furtherdoseswhich can be given without diffiCUltyonce the blood pressurehasincreased alter volume expansion.Agents Having Vasodilator Activity: Dala on Ute effect of concomllant use of other vasodilators In patienls receiving captopril for heartDala on Ute effect of concomllant use of other vasodilators In patienls receiving captopril for heartfailure are nol available; therelore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilatoractivily should, If possible. be discontinued before slarllng caplopnl. II resumed dunng caplopnllsblellherapy, such agenls should baadmlnlslered cautiously, and perhaps alJowerdosage.Agents Causing Renin Release: Captoprirs effect will be augmented by antihypertensive agents that cause renin release. For example,Captoprirs effect will be augmented by antihypertensive agents that cause renin release. For example,diuretics (e,g., thiazides) mayactivale the renin-angiotensln.aldosterone syslem.Agents Affecting Sympathetic Activity: The sympathetic nelVous system may be especially Important I.n supporting blood pressure inThe sympathetic nelVous system may be especially Important I.n supporting blood pressure inpaUenlS receMng captopnl alone or with dluretfcs Therefore, aganls affecUng sympathetic activity (e.g.; gangUonlc blocking agents oradrenergic n.euron blocking agents) should be used with caution. Beta.adrenergic blocking drugs addsome further antihyp~rtensive effect10caplopril, bul the overall response Isless than additive.Agents Increasing Sem Pota~i~m: ~ince.caplopri~ ec~eases aldosl~.ro~~ produclioo, elevatio~ of seru~ po.t~~slu~ may ~r.Pota~i~m: ~ince.caplopri~ ec~eases aldosl~.ro~~ produclioo, elevatio~ of seru~ po.t~~slu~ may ~r.Potassium-sparing diuretics such as spironolactone, tnamterene, or amiloride, or potassium supplements should be giVen only lordocumented hypokalemia, and then with caution, since they may lead 10 significant increase of serum polassium. Salt sUbstitutescont~.Inlng potassium sllould also be used with caulion.Inhibitors Of Endogenous Prostaglandin Synthesis: It has been reported that indomethacin may reduge the anlihypertensive effect ofIt has been reported that indomethacin may reduge the anlihypertensive effect ofcaptopril, especially in cases of low renIn hypertension. Other nonsteroidal anli-inflammatory agElnlse.g., aspirin) may.also have thiseffectUlhium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomUa.nt lithium andIncreased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomUa.nt lithium andACE Inhibitor therapy. These drugs shook: be coadmlnistered with caution and frequent monitoring of serum lithium levels Isrecommended. Ita di~retic Is alsq used, II may increase the risk oftllhium toxicity.Cardiac Glycosides: In asludy 01 young heallhy maJe subjects no evidence 01adlrecl phannacoklnetic captopril-digoxln interaction couldIn asludy 01 young heallhy maJe subjects no evidence 01adlrecl phannacoklnetic captopril-digoxln interaction couldbefound.Loop Diuretics: Furosemide administered concurrently with caplopril does not aller the pharmacokinetiQS of caploprilln renally impairedFurosemide administered concurrently with caplopril does not aller the pharmacokinetiQS of caploprilln renally impairedhypertensive patients.Allopurinol: In astudy of hc.althy male volunteers no significant pharmacokinetic InteractiOn oIXured when captopril and allopurinol wereIn astudy of hc.althy male volunteers no significant pharmacokinetic InteractiOn oIXured when captopril and allopurinol wereadmlnlslered concom~anlly for6days.Gold: Nitritoid reactions (symptoms Include facialllushing, nausea, vomiting and hypotension) have been reported rarely in patients onNitritoid reactions (symptoms Include facialllushing, nausea, vomiting and hypotension) have been reported rarely in patients ontherapywith injectable gold (sodium aurothiomaJate) and concomitantACEinhibitor therapy including captoprn.Drug andor LaboratoryTest InteractionCaptoprUmaycauseafalse-positive urine test foracetone.. Carcinogenesis, Mutagenesis, Impairment of Fertility. Carcinogenesis, MutagenasIsandImpaIrmental Fertl IllyTwo-year studies with doses of SOto 1350mglkgfdayln miceand rats failed to show any evidence of carcinogenic potential. The high doseIn these studies Is 150 limes the maximum recommended human dose of 450 mg, assuming a5O-kg subject. On body-surface-areabasis, the high doses formlce and rats are 13 and26times the maximum recommendedhumandose, respectively.Studies In rats have revealed noImpairmentoffertility.AnlmalToxlcologyChronic oralloXlclty sludies were conducted in rals (2 years), dogs (47 weeks; 1year), mlco (2 years), and monkeys (1 year). Signiflcanldrug related toxicity included effects On hematopoiesis, renal toxicity, erosion/ulceration of the stomach and variation of retinal bloodvessels.Reductions in hemoglofin and/or hematocril values were seen in mice, rats and monkeys at doses 50 to 150 limes the maximumrecommended human dose (MRHD) 01450 mg, assuming 50-kg subject. On abody-surface-area basis, these doses are 5to 25 timesmaximum recommended human dose (MRHD). Anemia, leUkopenia, thrombocytopenia, and bone marrow suppression occurred In dogsatdoses8to30timesMRHDon abody-weightbasis (4 to 15 times MRHDon asurface;area basis).The reductions in hemoglobin and hematocrit values In rats and mk;a were only slgnllicantat 1year and returned to normal with continueddosingby the endolthesludy.Marked anemia was seen at all dose levels (8 to 30 times MRHD) in dogs, whereas moderate to marked leUkopenia was noted only at15and 30 times MRHD and thrombocytopenia at 30 times MAHD. The anemia GOuld be reversed upon discontinuation of dosing. Bonemarrow suppression occurred to avarying degree, being associated only with dogs that died or were sacrifICed in amoribund condition Inthe 1year study. However,ln the 47-weekstudy at adose 30 limes MRHD, bone marrow suppression was found to be reversible uponcontinued drug administration.captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys In mice and rals at doses 7to 2QO times MRHD on abodyweightbasis (O.6 to 35 limes MAHD on asurface-area basis); in monkeys at 20 10 60 times MRHDon abody.weight basis (7 to 20 limesMRHDonasUrface-araa basis): andin dogs at30 times MRHDonabody-weight basis (15limesMRHOon asurface-area basis).Gastric eroslonslulcerallons were increased in incidence in male rats at 20 to 200 limes MAHD on abody-weight basis (3.5 and 35 limesMRHD on asurface-area basis); In dogs at 30 limes MAHD on abody.weight basls(15llmes on MRHD on surface-area basis); and inmonkeys at 65 times MRHD on body-weiglll basis (20 times MRHD on asurt.ce-area bas~). Rabbits developed gaslric and Inlestinalulcerswhen given oral doses approximately 30 timesMRHDon abody-weight basIs (10 timesMRHD on asudaee-area basis) for only 5107days.In the two-year rat study, irreversible and progressive variatlons In the caliber of retinal vessels (focal sacculalions and constricllons)OCCIJrred at all doss levels (710 200 times MRHD) on abody y/eighl-basis; 11035 Urnes MRHDon asurtaco-area basis in adose.relaledfashion. The effect wCsfirst observed In Ihe ~th week of dosing, with aprogressivelyIncreased Incidence thereaer, even after cessationof dosing.. Pregnancy. PregnMcy C.tegories C(lirsl trimester) and (second and third trimesters)SeeWARNINGS: Felell Neonetal Morbldityand Mortality.. Nursing Mothers. Concenlraions of captoprilln human milk are apprOXimately one percent of those In maternal blood. Because of the polential for seriousadverse reactlons in nursing infants1rom captopril, adecision should be made whether to discontinue nursing or to discontinue the drug,laldnglntoaccountlhelmportanceof caploprlltabfel to Ihe molher. (See PRECAUTIONS: PediatricUse.). Pediatric Use. Safety and effec,tiveness in pediatric patlents have not been established. There Is limited experience reported In Ihe lit~rature with ~e useof caplopril in the pediatric population; dosage, on aweight basis, was generally rsported to be comparabfe 10 or less than that used inadults.Infants, especially newborns, may be more susceptible to tpe adverse hemodynamic etfects of eaptopril. Ex~essive. prolonged andunpredictable decreases In blood pressure and associated compllcaUons, Including oliguria and seizures, havebeenreported.Captopril tablets should be usedin pediatrlc paleints only if othermeasures for conlrolling blood pressure have not beeneffective.

PREGNANCY SECTION.

Pregnancy. PregnMcy C.tegories C(lirsl trimester) and (second and third trimesters)SeeWARNINGS: Felell Neonetal Morbldityand Mortality.

REFERENCES SECTION.

REFERENCES. All caplopril tablets are while and may exhlblt slight sulfurous odor.Dispensein light container as defined in the USP.StorageDo nol store above 30C (86F) Keep bottles tIghtly closed (protect from moisture).Manufaclured by:Wockhardt LimitedMumbal, India.Distributed by:Wockhardt USA LLC.20 Walervlew Blvd.Parsippany, NJ 07054USA.Rev.220709.

WARNINGS SECTION.

WARNINGS. Anaphylaclold and Possibly Related ReactionsPresumably because angiotensln.converting enzyme inhibitors affect the metabolism of elcosanoids and polypeptides, inclUdingendogenous bradykinin, patients receiving ACEnhibitors (including caplopril) may be subject to avariety 01 adverse reactions, some ofthem serious.Headand Neck Angioedema: AngioedemaInvolving the extremities, face, Ij~, mucous membranes, longue, glottis or larynx has beenseen In patients Irealed with ACE inhibitors, Including captopril. If angioedema Involves the tongue, glottis or larynx, airway obstructionmay occur and be falal. Emergencytherapy, including but not necessarily limited 10, sUbculaneous administration of a1:1000 solution ofepinephrine should be prompUyinsUtuted.Swelling confined to ~e face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuatJon ofcaptopril; some cases required medlcallherapy. (See PRECAUTIONS: Information for Patients and ADVERSE REACTIONS.)Intestinal Angioedema: Intestinal angioedema has been reported in patients trealed wah ACE lnhibil.ors. These patients presenledwith abdominal pain (with or without naUSeaorvomiting); in somecasesIherewas noprior history of facial angioedemaandC.l esteraselevels were normal. Thf angioedema Vias diagnosed by procedures Including abdominal CT scan or ultrasound, or at surgery, andsymploms resolved after slopping the ACE inhibitor.lnlestinal angioedema shouldbe Included In the dillerential diagnosis of patlents onACEInhibitorspresenting with abdominal pain.Anaphylactoid reactions during desensitization: Two patienls undergoing desensitizing lreatment wilh hymenoplera venom whilereceiving ACE Inhibitors suslained liIe-threatenlng anaphylactoid reactions. In the same patients, these reacUonswere avoided WhenACE inhibilors were temporarity wHhheld, butthey reappeared uponinadvertentrechallenge.Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in pauenls dIalyzed with highfluxmembranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patienlsundergoing low-densitylipoproleln apheresls with dextran sulfate absorption.Neutropenia/AgranulocytosisNeutropenia <<1OOOmm~ with myeloid hypoplasia has resulted from use of caplopril. About hal( of the neutropenic patients developedsyslemic or oral cavity inlecUons or other features Qf the syndrome of agranUlocytosis.The risk of neutropeniais dependenton the clinical status of the paUent :In clinical trials inpatients with hypertension who have normal renat function (serum creatinine less than 1.6 mldL and no collagenvascular disease), neutropenia hasbeen seenin one patient oul of over 8,600 exposed.In patienls with some degree of renal failure (serum creatinine at least 1.6 mgldl) but no collagen vascular disease, the risk ofneutropenia in clnicallrials was about 1per 500, afrequency over 15 times that for uncomplicated hYpertension. Dally doses ofcaplopril were relatively highin these patients, p~rticulartyln view of Ihelrdiminished renal function. In foreign markeling experienceIn patients wilh renal fallure, use of allopUrinol concomitantly with caplopril has been assoclaled with neutropenIa but thisassociation has notappeared in U.S. reports.In patient& with collagen vascular diseases (e.g systemic lupus el)thematosus, scleroderma) and impaired renal function,.neutropenia occurred in 3.7 percent oipalients In c1inicat trials.While f1pne of the over 750 patlents In formal clinlcallrials of heart failure .developed neulropenla, it has occurred during thesubsequent clinical experience. About half of the reported cases had &erurn creatinine ~1.6 mgldL and more than 75 percent were Inpatlenls also receiving procainamide.ln heart failure, itappears thatlhe same risk factors for neutropenia are present.The neutropenia has usually been detected within three months alter caplopril was started. Bone marrow examinations in palienls withneutropenia consistently showed myeloId hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers ofmegakaryocytes (e,g hypoplasticbone marrowand pancytopenia); anemia and thrombocytopenia were sometimes seen.In general, neutrophlls returried to normal in about two weeks after captopril was discontinued,.and serious infections Were limned toclinically complex patients. About 13 percent oIlhe cases of neutropenia have eooed fatally, but afmostall falalitles were In patients withserious illness, having collagen vascular disease, renalfaHure, heart failure or immunosuppressant therapy, or acombination of thesecomplicalingfactors.Evaluation of the hypertensive orheart failure pallent should always Include assessmenl of renal function.If captoprills used In patients with ImpaIred renal function, white blood cell and differenllal counts shoUld be evalualedpnorto startingtreatment and at approxlmalely two.weekIntelvels foraboul three monlhs, Ihen periodically.In patients with collagen vascular disease or Who are exposed to other drugs known to affect the while cells or Immune response.particularly when there is impaired renal function, captopril should be used only after an assessment of benefit and risk, and then withcaution.All patients Ireated wilh capt~ shouldbe told to report any signs of Infection (e.g., sore Ihroat, fever). infection Is susPected, white cellcounts should be performed without delay,~ince discontinuation of captopril and other drugs has genera/ly led to prompt relurn of the white count to normal, upon confirmation ofneutropenia(neutrophil count<1OOOImm~ Ihe physlcien should wilhdraw captopol and closely follow the patienrs course.ProteinuriaTotal urinary proteins greater than 1gperday were seen in about 0.7 percentaf patients receiving captopril. Aboul90 petcentofaffectedpatlents had evidence of prior renal disease or received relatively high doses of captopril (in excess 01150 rng/day), or both. Thenephrotic syndrome occurred In aboul one.fifth of protelnuric patients. In most cases, proteinuria subsided or cleared within six monthswhether or not captopril was continued. Parameters of renal function, such as BUN and creatinIne, were s~ldom altered In the patientswith proteinuria.HypotensionExcessive hypotension was rarely seen in hypertensive paUenls but is apossible consequence of captopril use in salVvolume depletedpersons (such as those treated vigorously with diurelics), patients with heart faflure or those paUenls undergoing renal dialysis (seePRECAUTIONS: Drug Interactions.)In heart failure, where the blood pressure was elther nonnal or low, lranslentdecreases In mean blood pressure greater than 20 percentwere recorded in about half of the patients. This transient hypotension is more likely 10 occur after any of the first several doses and Isusually welliolerated, producingeither no symptoms or brief mUd IIghUleadedness although,In rare Instances it has been assoclaled with arrhythmia or conduction defects. Hypotension was the reason for discontinuation of drug in 3.6 patients with heart failure.BECAUSE OFTHE POTENTIAL FALL IN BLOOD PRESSURE IN THESE PATIENTS, THERAPY SHOULD BE STARTED UNDERVERY CLOSE MEDlCA~ SUPERVISION.Astarting dosa of 6.25 or 12.5mg t.i.d. may minimize the hypotensive effectPellents shouldbe followed closely for the first two weeks of treatment and whenever the dose of captopril and/or diurelic Is increased. In patients withhearffailure, reducing the dose of diuretic, if feasible, mayminimize the fall in blood pressure.Hypotension is not per se reason to disconlinue captoprll. Some decrease of systemic blood pressure is acommon and desirableobservation upon initiation of caploprillablets, USP treatment in heart failure. The magnItude of the decrease Is greatesl earty in thecourse of treatment; this effect stabHizes within week or two, and generally relums to prelreatmentlevels, without decrease intherapeutic efficacy, wilhlntwomonlhs.FetallNeonatal MorbiditY and MortalityACE inhibitors can cause fetal and neonalal morbidity and death when admlnlslered to pregnant women. Several dozen cases havebeen reported In the world literature.WhenpregnancyIs delected,ACE inhibitors should bediscontinuedas soon as possible.The use of ACE InhIbitors during the second and third trimeslers of pregnancy has been associated with fetal and neonatal injury,Including hypolension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure. and death. OligohydramnIos has alsobeen reported, presumably resulling from decreased fetal renal function; oligohydramniosin this selling has been assoclated with fetallimb cootraclures, craniofacial defonnalfon, and hypoplastic lung developmenl. Premalunty, Intrauterine growth retardation, and patentductus. arteriosus havEl alsobeen reported, althougbJt Is notdearYheth.er ~~~e opcurrences were dueto the ACE.inhlbltor exposure.These adverse effects do notappear to have resulted from Intraulerine ACE.inhibitor exposure that has been limited to the first trimester.Mothers whose embryos and fetuses are exposed to ACE inhlbilors only during the first trimester should be so Informed Nonetheless,when patients becomepregnant, physicians shouldmake every effort to discontinue the use 01 captopril as soon a~ possible.Rarely (probably less often than once In everylhousand pregnancies), no alternative toACE lnhlbll6ts will be found. In these rare cases,the molhers should be apprised of the potential hazatds to their feluses, and serial ultrasOund examinations should be peJfOlmed toassess the Intraamnlotlcenvironment.If oligohydramnios is obselVed, caploprilshould be discon~nued unless it is considered life.saving for lhe mother. Contraction stresslestingCST, non-stress tosl (NST), or biophysical profiling (BPP) may be approprtate, depending upon the weak 01 pregnency.Patients and physldans should be aware, however,that oligohydramnios may nol appear unl after the fetus has sustained IrreversibleInJury.Infants with histories of in utero expOsure to ACE inhibitors should be closely observed for hypolension, oliguria, and hyperkalemia. Ifoliguria occurs. atlention.should be directed toward support of blood pressure and renal perfusion. Exchangetransfusion or dialysis maybe required as ameans of reversing hypotension and/or sUbsliutingIor disordered renal fuoction. While captopril maybe removed fromthe adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from theclrculalion ofneonates orchildren. Peritoneal dialysis is not effective for removing captopril; there is no Informationconcerning exchangetransfusion for removing captopril from the general circulation. .When caplopril was given to rabbits at doses about 0.8 to 70 Urnes (on amglkg basis) the maximum recommended human dose, lowincidences of craniofacial malformations were seen. No teratogenic effects of captopril were seen In studies of pregnant rats andhamsters. On amgk:g basts, the doses used were up to 150 times (in hamsters) and 625 times ~n rats the maximum recommendedhumandose.Hepatic FailureRarely, ACE inhibitors have been associated with asyndrome that starts with cholestaUc Jaundice and progresses to fulminant h3psllcnecrosis and sometimes death. The mechanism of this syndrome Is not understood. Patienls receMng ACE inhibitors who developJaundice or marked elevations of hepaticenzymesshould discontinue theACEinhlbllorand receive appropriate medical follOW-Up.