Captopril by NCS HealthCare of KY, Inc dba Vangard Labs CAPTOPRIL tablet

Drug Details [pdf]

BOXED WARNING (What is this?)

BOXED WARNING

USE IN PREGNANCY .

When used In pregnancy during the second and third trimesters, ACE Inhibitors can cause Injury and even death to the

developing fetus. When pregnancy Is detected, captopriJ tablets USP should be disconlinued as_. soon as possible. See

WARNINGS: FelallNeonalal Morbidity and Mortalily.
DESCRIPTION

Captoprills a specific competitive inhibitor of angio!erlSln I-converting enzyme (ACE), the enzyme responsible for the conversion of

anglolensln Iloanglolensin II.

eaploprills deslgnaled chemically as j-[(2S)-3-mercaplo-2-malhylpropionylj-L-prolina. Moler:ular fonnul. e,H'NO,S [MW 217.29) and

has the follo"NIngstruclural.formula:

Captoprills a white to off-white crystalline powder that may have a 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 the

following inactive ingredients: microcf)"stalline cellulose,comstarch, anhydrous ladose, coHoidalsilicon dioxide, talc andpalmilic acid.
CLINICAL PHARMACOLOGY

Mechanism of Action

ThE"t m~chanism 01 action of captopriJ has not yet been fully elucidated. lis-beneficial effects In hypertension and heart failure appear 10

result primarily from suppression of the reninwangiolensln-aJdosterone system. However, there is no consistent correlallon between

renin levels and response 10 Ihe drug. Renin, an enzyme synthesized by Ihe kidneys, is released into the circulation where it acts on a

plasma globulin $ub~trate to produce angiotensinl, a relatively inactive decapeptide. AngIotensin I is then converted by angiotensin

converting enzyme (ACE) to angiotensin II, a potent endogenous vasoconstrictor substance. Angiotensin II also stimulates aldosterone

secretion from the adrenal cortex, thereby contributing to sodiumand fluid retenllon. .

Caplopril prevents the conversion of angiotensin Ito angiotensin II by inhibition of ACE, a peplidyldipeplide carboxy hydrolase. Thls

inhibition has been demonstrated in both heallhyhuman subjects and in animals by showing that the elevation of blood pressure caused

by exogenously adminlstered angiotensin Iwas attenuated or abolished by captopril.lnanimal studies, captopril did notaltertha pressor

lasponses 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 of

negative feedback on rennin release caused by reduction in angiotensin II. The reducllon 01 angiotensin II leads to decreased

aldosterone secretion, and, asaresull, small increases In serum potassium may occur along with sodium and fluid loss.

The antihypertensive effects persist for a longer period of time than does demonstrable inhibition of circulating ACE. It is not known

whether 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. The

presence of food in the gastrointeslinaltract reduces absorption by about 30 to 40percen~ captopril therefore should be given one hour

before meals. Based on carbon-14 labeling, average minimal absorption Is approXimately 75.percenl.ln a 24-hour period, Over ~5

percentofthe absorbed doseis ellminaled In the urine; 40 to ?Opercent isunchanged drug; most01 the remainder Is the dIsulfidedimerof

caplopriland caplopril-oyslelne disulfide.

Approximately 25 to 30 percentof the circulating drug Is bound to plasma proteins. The apparentelimination half-life for total radioactivity

In blood is probably lass Ihan 3hours. An accurala delanninaUon 01 half-lila 01 unchanged caplopnlls nol, al presenl, posslbie, bul« Is

probably less than 2 hours. In patients with renal Impairment, however, retention of captopril occurs ·(sge .DOSAGE AND

ADMINISTRATION).

Pharmacokinetics

Administration of captoprll results in a reduction of peripheral arterial reslslance in hypertensive patients with either no change, or an

Increase, in cardiac o·ulpul. There Is an Increase irl renal blood now following administration of captopril and glomerular filtration rate Is

usually unchanged.

Reduclions of blood pressure are usually maximal 60. to 90 mInutes after oral administration of an individual dose of captopriJ. ,The

duration of effectIs dose related. The reduction in blood pressure maybe progressive, so to achieve maximal therapeutic effects, several

weeks 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 effecl

Blood pressure is kJwered to about the same extent in both standing and supine positions. Orthostatic effects and lachycardia are

infrequent but may occur in vo[umedepleled paUenls. Abrupt withdrawal of caplopril has not been associated wilh a rapid Increase In

blood pressure.

In patients with heart failure, significantly decreased peripheral (systemic vascular) resistance and blood pressure (after1oad), reduced

pUlmonary capillary wedge pressure (preload) and pUlmonary vascular resistance, increased cardiac output, and Increased exercise

tolerance time (En) have been demonstrated. These hemodynamic and clinical eUecls occur after the first dose and appear to persist

for the duration of therapy. Placebo controlled studies of 12 weeks duration in patients who did not respond adequately to diuretics and

digitalis show no tolerance to benefICial effects on En; open sludies, with exposure up to 16months in some cases, also Indicate Ihat

Enbenefit Is maintaIned. Clinical ImprovementhasbeenobseNed in some patienls where acutehemodynamic effects were minImal.

The Survival and Ventricular Enlargement (SAVE) study was a multicenter, randomized, double-blind. placebo-conlrolled trial

conducted 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 a resting left ventricular ejecllon fraction ~%, but at the time of

randomization were not sUfriclently symplomallc to require ACE inhibitor therapy lor heart failure. About half 01 the palients had

symptoms 01 heart failure in the past Pavents were given alest dose of 6.25 mg oralcaploprillablets and were randomized within 3-16

days posllnfarctlon to receive either caplopriltablets or placebo in addition to conventional therapy. Captopril tablets ware inltiated at

6.25 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 receiving

the 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.

Baseline blood pressure was 113170 mm Hg and 112170 mm Hg lor Ihe placebo and captopril tablels groups, respectively. Blood

pressure iOCl"eased slighlly in botlltrealmenl groups during the studyand was somewhatlower in the caploprillablets group (119fl4 Vs.

125177mmHgat1yr).

Therapy with captopril tablets improved 10rl9-lerm sUlVival and clinical outcomes compared to placebo. The risk reduction for all cause

mortality was 19%(P=O.02) and for cardiovascular dealh was 21% (P=0.014). Captopril trealed subjects had 22% (P=O.034) fewer firsl

hospitalizations for heart failure. Compared 10 placebo, 22% fewer patienls receiving captopril devekJped symptoms of overt heart

failure. 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, calcium

antagonists and diuretics.

In amulticenter, doUble-blind, placebo controlled trial, 409 patients, age 18-49 of either gender, with or without hypertension, with type I

uwenile 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 achieve

blood pressure control, additional antihypertensive agents (diurelics, bela blockers, centrallyaclfng agents or vasodnators) were added

as needed for patients In both groups.

The captopnl tablets group had a 51% reduction In risk of doubling of serum creatinine (P<o.01) and a 51% reduction in risk for the

combined endpoint of end-stage renal disease (dialysis or transplantation) or death (Pd)"o1). Captopril tablets treatment resulted in a

30% reduction in urine prote in excretion within the first 3 months (P<O.05), which was maintained throughout the trial. The captoprU

tablets group had somewhat beUer blood pressure'control than the placebo group~but the effects 01 captoprlilablet on renal function

were graaterthanwould be expected from the group differences In blood pressure reduction alone. Captopril tablets were well tolerated

in this palienl population.

In two multicenter, double-blind, placebo controlled studies, a total of 235 normotensive patienls with inSUlin-dependent diabetes

mellitus, reUnopathy and m~roalbumlnuria (20-200 meg/min) were randomized to placebo or Captopnl tablets (SO mg b.l.d.) and

followad tor upto 2years. Captopril tabtats dalayed Ihe progression 10 overt nephropathy(protelriurla;,soD mg/day) In both sludles (risk

reduction 67% to 76%; P<O.05). Captopriltablets also reduced the albumin excretion ·rale. However, the long term clInical benefit 01

reducing 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.
INDICATIONS AND USAGE

Hypertension: Captopril tablets US?are indicated for the Teatment of hypertension.

tn using captopril, conslderallon should be gtven to the risk of neutropenia!agranutocytosls (seeWARNINGS).

Captoprll maybe used as Initial therapy for patientswilh normal renal function, In whomthe rlskls relatively low. In patients with impaired

renal function, particularly those wfth collagen vascular olSeas6, captopril should be reseNed for,hypertenslves who have either

develoPed 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 pressure

lowering effecls of captoprif and thlazldes are approximalaly a<!dlltva.Heart Failure:Captopril tabletsare indicated in the treatmentof congestive heart failure usually in cornblnatlpn with

diuretics and

di9italls_ The beneficial effect 01 captopril in~eart failure does notrequl.re the presence 01 digllaUs, however, most controlled cliniCal trial

experience 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 myocardial

fnfarclion In clinically stable patients with left ventriCUlardysfUnction manlfesled as an ejection fraction ::;40% and 10 reduce the Incidence

01 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 paUents

with type Ilnsulin-dependenl diabetes mellitus and retinopathy. Caplopriltablets decreases the rate of progression of renallns·uffJcienCy

and 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 is

less in black patients than In nonblacks. In addition, ACE Inhibitors (for which adequate data are available) cause a higher rate of

angioedema in black than In non-black palients {seeWARNINGS: Head and NeckAngloedema and Intestinal AngIQedema}.
CONTRAINDICATIONS

Captopril tablets are contraindicatedin patients who are hypersensitive to this product or any other anglolensln. converting enzyme inhibitor

(e.g., a patient who has experienced angloedema during therapy with any other ACE inhibitor).
WARNINGS

Anaphylaclold and Possibly Related Reactions

Presumably because angiotensln·converting enzyme inhibitors affect the metabolism of elcosanoids and polypeptides, inclUding

endogenous bradykinin, patients receiving ACE}nhibitors (including caplopril) may be subject to avariety 01 adverse reactions, some of

them serious.

Headand Neck Angioedema: AngioedemaInvolving the extremities, face, Ij~, mucous membranes, longue, glottis or larynx has been

seen In patients Irealed with ACE inhibitors, Including captopril. If angioedema Involves the tongue, glottis or larynx, airway obstruction

may occur and be falal. Emergencytherapy, including but not necessarily limited 10, sUbculaneous administration of a1:1000 solution of

epinephrine should be prompUyinsUtuted.

Swelling confined to ~_e face, mucous membranes of the mouth, lips and extremities has usually resolved with discontinuatJon of

captopril; 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 presenled

with abdominal pain (with or without naUSeaorvomiting); in somecasesIherewas noprior history of facial angioedemaandC·l esterase

levels were normal. Thf! angioedema Vias diagnosed by procedures Including abdominal CT scan or ultrasound, or at surgery, and

symploms resolved after slopping the ACE inhibitor.lnlestinal angioedema shouldbe Included In the dillerential diagnosis of patlents on

ACEInhibitorspresenting with abdominal pain.

Anaphylactoid reactions during desensitization: Two patienls undergoing desensitizing lreatment wilh hymenoplera venom while

receiving ACE Inhibitors suslained liIe-threatenlng anaphylactoid reactions. In the same patients, these reacUonswere avoided When

ACE inhibilors were temporarity wHhheld, butthey reappeared uponinadvertentrechallenge.

Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in pauenls dIalyzed with highflux

membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patienls

undergoing low-densitylipoproleln apheresls with dextran sulfate absorption.

Neutropenia/Agranulocytosis

Neutropenia «1OOO!mm~ with myeloid hypoplasia has resulted from use of caplopril. About hal( of the neutropenic patients developed

syslemic 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 ml}'dL and no collagen

vascular 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 of

neutropenia in cl!nicallrials was about 1per 500, afrequency over 15 times that for uncomplicated hYpertension. Dally doses of

caplopril were relatively highin these patients, p~rticulartyln view of Ihelrdiminished renal function. In foreign markeling experience

In patients wilh renal fallure, use of allopUrinol concomitantly with caplopril has been assoclaled with neutropenIa but this

association 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 the

subsequent clinical experience. About half of the reported cases had &erurn creatinine ~1.6 mgldL and more than 75 percent were In

patlenls 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 with

neutropenia consistently showed myeloId hypoplasia, frequently accompanied by erythroid hypoplasia and decreased numbers of

megakaryocytes (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 to

clinically complex patients. About 13 percent oIlhe cases of neutropenia have eooed fatally, but afmostall falalitles were In patients with

serious illness, having collagen vascular disease, renalfaHure, heart failure or immunosuppressant therapy, or acombination of these

complicalingfactors.

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 evalualedpn"orto starting

treatment 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 with

caution.

All patients Ireated wilh capt~'" shouldbe told to report any signs of Infection (e.g., sore Ihroat, fever). 'infection Is susPected, white cell

counts 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 of

neutropenia(neutrophil count<1OOOImm~ Ihe physlcien should wilhdraw captopol and closely follow the patienrs course.

Proteinuria

Total urinary proteins greater than 1gperday were seen in about 0.7 percentaf patients receiving captopril. Aboul90 petcentofaffected

patlents had evidence of prior renal disease or received relatively high doses of captopril (in excess 01150 rng/day), or both. The

nephrotic syndrome occurred In aboul one·fifth of protelnuric patients. In most cases, proteinuria subsided or cleared within six months

whether or not captopril was continued. Parameters of renal function, such as BUN and creatinIne, were s~ldom altered In the patients

with proteinuria.

Hypotension

Excessive hypotension was rarely seen in hypertensive paUenls but is apossible consequence of captopril use in salVvolume depleted

persons (such as those treated vigorously with diurelics), patients with heart faflure or those paUenls undergoing renal dialysis (see

PRECAUTIONS: Drug Interactions.)

In heart failure, where the blood pressure was elther nonnal or low, lranslentdecreases In mean blood pressure greater than 20 percent

were recorded in about half of the patients. This transient hypotension is more likely 10 occur after any of the first several doses and Is

usually welliolerated, producing

either 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 UNDER

VERY CLOSE MEDlCA~ SUPERVISION.

Astarting dosa of 6.25 or 12.5mg t.i.d. may minimize the hypotensive effect

Pellents should

be followed closely for the first two weeks of treatment and whenever the dose of captopril and/or diurelic Is increased. In patients with

hearffailure, reducing the dose of diuretic, if feasible, mayminimize the fall in blood pressure.

Hypotension is not per se a reason to disconlinue captoprll. Some decrease of systemic blood pressure is acommon and desirable

observation upon initiation of caploprillablets, USP treatment in heart failure. The magnItude of the decrease Is greatesl earty in the

course of treatment; this effect stabHizes within a week or two, and generally relums to prelreatmentlevels, without a decrease in

therapeutic efficacy, wilhlntwomonlhs.

FetallNeonatal MorbiditY and Mortality

ACE inhibitors can cause fetal and neonalal morbidity and death when admlnlslered to pregnant women. Several dozen cases have

been 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 also

been reported, presumably resulling from decreased fetal renal function; oligohydramnios

in this selling has been assoclated with fetal

limb cootraclures, craniofacial defonnalfon, and hypoplastic lung developmenl. Premalunty, Intrauterine growth retardation, and patent

ductus. arteriosus havEl alsobeen reported, althougbJt Is notdear'Yheth.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 to

assess the Intraamnlotlcenvironment.

If oligohydramnios is obselVed, caploprilshould be discon~nued unless it is considered life.saving for lhe mother. Contraction stress

lesting{CST}, a 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 Irreversible

InJury.

Infants with histories of in utero expOsure to ACE inhibitors should be closely observed for hypolension, oliguria, and hyperkalemia. If

oliguria occurs. atlention.should be directed toward support of blood pressure and renal perfusion. Exchangetransfusion or dialysis may

be required as ameans of reversing hypotension and/or sUbsli!utingIor disordered renal fuoction. While captopril maybe removed from

the adult circulation by hemodialysis, there is inadequate data concerning the effectiveness of hemodialysis for removing it from the

clrculalion ofneonates orchildren. Peritoneal dialysis is not effective for removing captopril; there is no Informationconcerning exchange

transfusion 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, low

incidences of craniofacial malformations were seen. No teratogenic effects of captopril were seen In studies of pregnant rats and

hamsters. On amg!k:g basts, the doses used were up to 150 times (in hamsters) and 625 times ~n rats} the maximum recommended

humandose.

Hepatic Failure

Rarely, ACE inhibitors have been associated with asyndrome that starts with cholestaUc Jaundice and progresses to fulminant h!3psllc

necrosis and {sometimes} death. The mechanism of this syndrome Is not understood. Patienls receMng ACE inhibitors who develop

Jaundice or marked elevations of hepaticenzymesshould discontinue theACEinhlbllorand receive appropriate medical follOW-Up.
PRECAUTIONS

General

ImpairedRena/Function

Hypertension -Some patients with renal disease, particularly those with severe renal artery stenosis. have developed increases InnUN

and serum creatinIne after reduct10n of blood pressure with captopril..Captopril dosage reduction and/or discontlnuation of diurelic may

be 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 above

normal or baseline uponlong-term treatment with captopril. Less than 5percent 01 patients, generally those with severe preexisting renal

disease, reqUired discontinuation of treatment due 10 progressively increasing creatinine; subsequent improvement probably depends

upon 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; diabetes

mellitus; 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 withdrawal

of 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 been

Presumably due to the inhibition of the degradation of endogenous bradykinin, persislent nonproductive cough has been

reported with all ACE

inhibitors, always resotving after disconlivuation of therapy. ACE Inhibitor-induced cough should be considered in the. differential

diagnosis of cough.

Valvular Stenosis: There 15 concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreased

There 15 concern, on theoretical grounds, that patients with aortic stenosis might be at particular risk of decreased

coronal)" 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 block

In patients undergoIng major surgery or during anesthesia with agents that produce hypotension, captopril will block

angiotensin II fannalion secondary to compensatOlY renin release. If hypotension occurs and is considered 10 be due to this mechanism, it

can be corrected by volu'me expansion.

Hemodialysis

Recent 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 a

different type 01 dialysis membrane or a different class medkation. (See WARNINGS: Anaphylactoid Reactions DUring Membrane

Exposure.)

Information for Patients

Patients 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 of

progressive edemawhich might be related 10proteinuriaandnephrotic syndrome. '

All patients should be cautioned that excessive perspiration and dehydration may lead !o an excessive lallin blood pressure because 01

reduction in fluid volume. Other causes 01 volume depletion such as vomltlng or diarrhea may also lead to afall in blood pressure; patients

should be advised 10consul! with the physician.

PaUenls shOUld be advised not to use potassium·sparing diuretics, potassium supplements or polassium-containing salt subsUMes

wilhouiconsulllng 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 ACE

lnhlbilors, and they should also be told that these consequences do not appear to have resulted from inlrauterine ACE·lnhibilor exposure

that 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, as

Patienls on Diurelic Therapy:Palienfs on diuretics and especially lhose iowhom diuretic therapy was recently Instituted, as

well as lhose 00 severe dietary salt restriction or dialysis, may occasionally experience aprecipitous reduction of blood pressure usually

within 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 Intake

approximately 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 a

supine posi1lon and, II necessal)", receive an Inlravenous Infusion of normal saline. This transient hypotensive response Is nol a

contraindication 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 heart

Dala on Ute effect of concomllant use of other vasodilators In patienls receiving captopril for heart

failure are nol available; therelore, nitroglycerin or other nitrates (as used for management of angina) or other drugs having vasodilator

activily should, If possible. be discontinued before slarllng caplopnl. II resumed dunng caplopnllsblellherapy, such agenls should ba

admlnlslered 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 in

The sympathetic nelVous system may be especially Important I.n supporting blood pressure in

paUenlS receMng captopnl alone or with dluretfcs_ Therefore, aganls affecUng sympathetic activity (e.g.; gangUonlc blocking agents or

adrenergic n.euron blocking agents) should be used with caution. Beta·adrenergic blocking drugs addsome further antihyp~rtensive effect

10caplopril, 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 lor

documented hypokalemia, and then with caution, since they may lead 10 a significant increase of serum polassium. Salt sUbstitutes

cont~.Inlng potassium sllould also be used with caulion.

Inhibitors Of Endogenous Prostaglandin Synthesis: It has been reported that indomethacin may reduge the anlihypertensive effect of

It has been reported that indomethacin may reduge the anlihypertensive effect of

captopril, especially in cases of low renIn hypertension. Other nonsteroidal anli-inflammatory agElnls'{e.g., aspirin) may·also have this

effect

Ulhium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomUa.nt lithium and

Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving concomUa.nt lithium and

ACE Inhibitor therapy. These drugs shook:! be coadmlnistered with caution and frequent monitoring of serum lithium levels Is

recommended. 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 could

In asludy 01 young heallhy maJe subjects no evidence 01adlrecl phannacoklnetic captopril-digoxln interaction could

befound.

Loop Diuretics: Furosemide administered concurrently with caplopril does not aller the pharmacokinetiQS of caploprilln renally impaired

Furosemide administered concurrently with caplopril does not aller the pharmacokinetiQS of caploprilln renally impaired

hypertensive patients.

Allopurinol: In astudy of h¢.althy male volunteers no significant pharmacokinetic InteractiOn oIXured when captopril and allopurinol were

In astudy of h¢.althy male volunteers no significant pharmacokinetic InteractiOn oIXured when captopril and allopurinol were

admlnlslered concom~anlly for6days.

Gold: Nitritoid reactions (symptoms Include facialllushing, nausea, vomiting and hypotension) have been reported rarely in patients on

Nitritoid reactions (symptoms Include facialllushing, nausea, vomiting and hypotension) have been reported rarely in patients on

therapywith injectable gold (sodium aurothiomaJate) and concomitantACEinhibitor therapy including captoprn.

Drug and!or LaboratoryTest Interaction

CaptoprUmaycauseafalse-positive urine test foracetone.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis, MutagenasIs"andImpaIrmental Fertl Illy

Two-year studies with doses of SOto 1350mglkgfdayln miceand rats failed to show any evidence of carcinogenic potential. The high dose

In these studies Is 150 limes the maximum recommended human dose of 450 mg, assuming a5O-kg subject. On a body-surface-area

basis, the high doses formlce and rats are 13 and26times the maximum recommendedhumandose, respectively.

Studies In rats have revealed noImpairmentoffertility.

AnlmalToxlcology

Chronic oralloXlclty sludies were conducted in rals (2 years), dogs (47 weeks; 1year), mlco (2 years), and monkeys (1 year). Signiflcanl

drug related toxicity included effects On hematopoiesis, renal toxicity, erosion/ulceration of the stomach and variation of retinal blood

vessels.

Reductions in hemoglof?in and/or hematocril values were seen in mice, rats and monkeys" at doses 50 to 150 limes the maximum

recommended human dose (MRHD) 01450 mg, assuming a 50-kg subject. On abody-surface-area basis, these doses are 5to 25 times

maximum recommended human dose (MRHD). Anemia, leUkopenia, thrombocytopenia, and bone marrow suppression occurred In dogs

atdoses8to30timesMRHDon 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 continued

dosingby 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 at15

and 30 times MRHD and thrombocytopenia at 30 times MAHD. The anemia GOuld be reversed upon discontinuation of dosing. Bone

marrow suppression occurred to avarying degree, being associated only with dogs that died or were sacrifICed in amoribund condition In

the 1year study. However,ln the 47-weekstudy at adose 30 limes MRHD, bone marrow suppression was found to be reversible upon

continued drug administration.

captopril caused hyperplasia of the juxtaglomerular apparatus of the kidneys In mice and rals at doses 7to 2QO times MRHD on abodyweight

basis (O.6 to 35 limes MAHD on asurface-area basis); in monkeys at 20 10 60 times MRHDon abody·weight basis (7 to 20 limes

MRHDonasUrface-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 limes

MRHD on asurface-area basis); In dogs at 30 limes MAHD on abody·weight basls(15llmes on MRHD on a surface-area basis); and in

monkeys at 65 times MRHD on a body-weigl"ll basis (20 times MRHD on asurt.ce-area bas~). Rabbits developed gaslric and Inlestinal

ulcerswhen given oral doses approximately 30 timesMRHDon abody-weight basIs (10 timesMRHD on asudaee-area basis) for only 510

7days.

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·relaled

fashion. The effect wC!sfirst observed In Ihe ~th week of dosing, with aprogressivelyIncreased Incidence therea'e"r, even after cessation

of dosing.

Pregnancy

PregnMcy C.tegories C(lirsl trimester) and 0 (second and third trimesters)

SeeWARNINGS: Felell Neonetal Morbldityand Mortality.

Nursing Mothers

Concenlra!ions of captoprilln human milk are apprOXimately one percent of those In maternal blood. Because of the polential for serious

adverse 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 use

of caplopril in the pediatric population; dosage, on aweight basis, was generally rsported to be comparabfe 10 or less than that used in

adults.

Infants, especially newborns, may be more susceptible to tpe adverse hemodynamic etfects of eaptopril. Ex~essive. prolonged and

unpredictable 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.
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 1 102 of 1000 patients and are of uncertain relationship 10 drug use: renal

Insufficiency. r~nal faHure, nephrotic syndrome, polyuria, oliguria, andurinary frequency. . . .

Hematoldgic: Neutropenia/agranulocytosis has occurred (see WARNINGS). Cases of anemia, thrombocytopenia, and pancytopenia

Neutropenia/agranulocytosis has occurred (see WARNINGS). Cases of anemia, thrombocytopenia, and pancytopenia

havebeenreportedt

Detmaf9foglc :R~h, otten Vvilh pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 410 7 (depending on

:R~h, otten Vvilh pruritus, and sometimes with fever, arthralgia, and eosinophilia, occurred in about 410 7 (depending on

renal status and-dose) 01100 patients, usually dUring the first four weeks of therapy. It is usually maCUlopapular, and rarely urUcarial. The

rash is usually mild and disappears within a few days of dosage ~eduction, short-tenn treatmenl with an anUhlstaminic agent, and/or

disconlinuing therapy; remission mayoccur even lfcaptoprills conllnued.Prurilus, without rash, occurs in about2 of 100patients. Between

7and 10 percenl of patients with skin rash haveshown an eosinophilia and/or positive ANA titers. Areversible associated pemphigoid-like

lesion, and photosensitivity, have alsobeen reported. '

Flushing orpallorhasMenreported In 2to5of1000patlenls.

Cardiovascular: Hypotension may occur; see WARNINGS and PRECAUTIONS (Drug Interactions) for discussion of hypotension with

Hypotension may occur; see WARNINGS and PRECAUTIONS (Drug Interactions) for discussion of hypotension with

captoprlilherapy,

Tachycardia, Chest pain, andpalpitations have eachbeenobseNed in approximately1of100 patients.

Angina pectoris, myocardiallnfarclion, Raynaud"s syndrome, and congestive heart failure have each occurred ln2lo 3 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 3 months) even with coolinued drug adminiStration. Weighlless-may be

assoclatedwiththelossottasle.

Angioedema: Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in

Angioedema involving the extremities, face, lips, mucous membranes, tongue, glottis or larynx has been reported in

approxImately one In 1000 patrents. AngIoedema Involving lhe"'upperaiWiays 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 2 percent of patients but did not appear at Increased frequency compared to placebo or

other treatments used In controlled trials: gastric irritation, abdominal pain, nausea, vomiting, diarrhea, anorexia, constipation, aphthous

ulcers, 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 causal

relationship cannot be accurately determined.

Body as B whole: Anaphylactoid reactions (see WARNINGS: Anaphylactoid and possible related reactions and PRECAUTIONS:

as B 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 Mortality

See WARNINGS: FataUNaonetat Morbldltyand Mortality,

Altered Laboratory Findings

SewfTJ Elecfrolytes: HyperkafemJa: small increases in serum potassium, especially in patients' with renal Impairment (see

small increases in serum potassium, especially in patients' with renal Impairment (see

PRECAUTIONS),

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 with

Transient elevations of BUN or serum creatinine especially in volume or salt depleted patients or those with

renovascular hypertension may occur. Rapid reduction of longstanding or markedly elevated blood pressure can result in decreases in the

glomerular 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.
OVERDOSAGE

Correction of hypotension would beof primary concern. Volume expansion with an intravenous infusIon of normal saline Is the treatment of

choice for restoration of blood pressure.

While captopril may be remOved from the'adult cIrculation by hemodialysis, there is Inadequate data concerning the effectiveness of

hemodialysis for removing it from the circulation of neonates or chfldren. Peritoneal dialysIs is not effeclive for removing captopril; there is

no information concerning exchange transfusion for removing captopril from the general circulation.
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 pressure

elevation, salt restriction, and other clinical circumstances. Ifpossible, discontinue the paUenfs prf?vious antihypertensive drug regimen for

one weekbefore starting captopril.

The initial dose of captopril tablels US?is 25mgb.l.d. orUd.1f satisfactory reduction of blood pressure has not been achieved after one or

two weeks, the dose may be increased 10 50 ffig b.l.d. or t.l.d. Concomitant sodium restrictfon may be beneficial when caploprills used

alone.

The dose of caplopril in hypertension usually does not exceed 50 mg t.i.d. Therefore, if the blood pressure has not been satisfactorily

controlled after one to two weeks at this dose, (and the patrent is nol already receiving adiuretic), a 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 highest

usual antihypertensive dose isreached.. .

If cap!opril is beIng starte~ in a 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 150

mg 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 mg

caplopril should notbe exceeded.

For patients vlith severe hypertension (e.g., accelerated or malignant hypertension), when temporary discontinualion of curren!

antihypertensive 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 patient"s clinical condition, the dallydose of captopril maybeincreased every 24 hours or less undercontinuous

medical 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 two

drugs are less than additive.

Heart Failure -Initiation ollherapv requiles consideration of recent diuretic therapy and the possibility of severe salVvolume depletion. In

patients with either normal or low blood pressure, who have been vigorously lrealed with diuretics and who may be hyponalremic and/or

hypoVolemic, 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 be

delayed, whete possible, for at least two weeks to determine Ha satisfactory response occurs. Most patients studied have had a

sallsfactol)" 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 amyocardial

infarction is atarget maintenance dO!je of 50mgU.d.

Therapy may be Initiated as early as three days following amyocardial infarction. After asingle dose of 6.25l"ng, caploprillablets therapy

should 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 atarget

dose 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 Captopril

lablelsit additiqnal therapyIS reqUired 10 further lowerblood pressure.

Dosage Adjustment In Renal Impairment - Because captopril is excreled primarily by the kidneys, excretion rates are reduced in

patients with Impaired renal function.

These paUenls will take longer. 10 reach steady-state cap!oprtllevels and will reach higher steady·stale levels for agiven daily dose Ihan

patients 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 Incremenls

utilized fortltration, Yihich should be quite"slow (one-Io two-week intelVals). After the desired therapeutic effect has been achIeved, the

dose should be slowlyback titrated to determine the minimal effective dose. When concomitant diurellc-therapy Is required, aloOp diuretic

(e.g., furosemide), ratherlhan athiazidediuretlp, Is preferred"ln palienlswlthsevere renal Impairment. (Sea WARNINGS: Anaphylactoid

reactions during membrane exposure B'nd PRECAUTIONS: Hemodialysis.)
HOW SUPPLIED

Captopril Tablets USP

12.5 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 a bisect bar on one side and W;902 on the other side; the 25mg Captopril tablet is a white, flat vevelled-edge round with a quadrisect bar on one side and W;903 on the other side; the 50mg Captopril tablet is a white, flat vevelled-edge round with a bisect bar on one side and W;904 on the other side.
REFERENCES

All caplopril tablets are while and may exhlblt a slight sulfurous odor.

Dispensein a light container as defined in the USP.

Storage

Do nol store above 30"C (86"F) Keep bottles tIghtly closed (protect from moisture).

Manufaclured by:

Wockhardt Limited

Mumbal, India.

Distributed by:

Wockhardt USA LLC.

20 Walervlew Blvd.

Parsippany, NJ 07054

USA.

Rev.220709
PRINCIPAL DISPLAY PANEL

Captopril Tablets,

USP 12.5 mg
PRINCIPAL DISPLAY PANEL

Captopril Tablets,

USP 25mg
PRINCIPAL DISPLAY PANEL

Captopril Tablets,

USP 50mg

CAPTOPRIL
captopril tablet

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0615-4519(NDC:64679-902)
Route of Administration	ORAL

Ingredient Name	Basis of Strength	Strength
Active Ingredient/Active Moiety
CAPTOPRIL (UNII: 9G64RSX1XD) (CAPTOPRIL - UNII:9G64RSX1XD)	CAPTOPRIL	12.5 mg

Ingredient Name	Strength
Inactive Ingredients
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
STARCH, CORN (UNII: O8232NY3SJ)
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
COLLOIDAL SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
TALC (UNII: 7SEV7J4R1U)
PALMITIC ACID (UNII: 2V16EO95H1)

Product Characteristics
Color	WHITE	Score	2 pieces
Shape	ROUND	Size	5mm
Flavor		Imprint Code	W;902
Contains

#	Item Code	Package Description	Marketing Start Date	Marketing End Date
Packaging
1	NDC: 0615-4519-39	30 in 1 BLISTER PACK

Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Marketing Information
ANDA	ANDA074532	03/28/1997

CAPTOPRIL
captopril tablet

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0615-4520(NDC:64679-903)
Route of Administration	ORAL

Ingredient Name	Basis of Strength	Strength
Active Ingredient/Active Moiety
CAPTOPRIL (UNII: 9G64RSX1XD) (CAPTOPRIL - UNII:9G64RSX1XD)	CAPTOPRIL	25 mg

Ingredient Name	Strength
Inactive Ingredients
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
STARCH, CORN (UNII: O8232NY3SJ)
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
COLLOIDAL SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
TALC (UNII: 7SEV7J4R1U)
PALMITIC ACID (UNII: 2V16EO95H1)

Product Characteristics
Color	WHITE	Score	2 pieces
Shape	ROUND	Size	6mm
Flavor		Imprint Code	W;903
Contains

#	Item Code	Package Description	Marketing Start Date	Marketing End Date
Packaging
1	NDC: 0615-4520-39	30 in 1 BLISTER PACK

Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Marketing Information
ANDA	ANDA074532	03/28/1997

CAPTOPRIL
captopril tablet

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0615-4521(NDC:64679-904)
Route of Administration	ORAL

Ingredient Name	Basis of Strength	Strength
Active Ingredient/Active Moiety
CAPTOPRIL (UNII: 9G64RSX1XD) (CAPTOPRIL - UNII:9G64RSX1XD)	CAPTOPRIL	50 mg

Ingredient Name	Strength
Inactive Ingredients
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
STARCH, CORN (UNII: O8232NY3SJ)
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
COLLOIDAL SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
TALC (UNII: 7SEV7J4R1U)
PALMITIC ACID (UNII: 2V16EO95H1)

Product Characteristics
Color	WHITE	Score	2 pieces
Shape	ROUND	Size	8mm
Flavor		Imprint Code	W;904
Contains

#	Item Code	Package Description	Marketing Start Date	Marketing End Date
Packaging
1	NDC: 0615-4521-39	30 in 1 BLISTER PACK

Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Marketing Information
ANDA	ANDA074532	03/28/1997

Labeler - NCS HealthCare of KY, Inc dba Vangard Labs (050052943)

Name	Address	ID/FEI	Business Operations
Establishment
NCS HealthCare of KY, Inc dba Vangard Labs		050052943	RELABEL, REPACK

Captopril by NCS HealthCare of KY, Inc dba Vangard Labs CAPTOPRIL tablet

Captopril by

Drug Labeling and Warnings

Drug Details [pdf]

BOXED WARNING

Pharmacodynamics

Pharmacokinetics

General

Drug Interactions

Carcinogenesis, Mutagenesis, Impairment of Fertility

Pregnancy

Nursing Mothers

Pediatric Use