FDA label 37a87b27-8dc3-4651-aa26-19280ff715e8

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.

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.

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.