National Geographic : 1995 Jan
Lotensin® benazepril hydrochloride Tablets BRIEFSUMMARY (FOR COMPLETEPRESCRIBINGINFORMATION,SEE PACKAGEINSERT) Use in Pregnancy When used in pregnancy during the second and thirdtrimesters, ACEinhibitorscan cause Injuryand even death to the developing fetus. Whenpregnancy is detected, Lotensin should be discontinued as soon as possible. See WARNINGS,Fetal/Neonatal Morbidity and Mortality. INDICATIONSANDUSAGE Lotensin is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. In using Lotensin, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Availabledata are insufficient to show that Lotensin does not have a similar risk (see WARNINGS). CONTRAINDICATIONS Lotensin is contraindicated in patients who are hypersensitive to this product or to any other ACE inhibitor. WARNINGS Anaphylactold d Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, includingendogenous bradykinin, patients receiving ACEinhibitors (including Lotensin) may besubject to a variety of adverse reactions, some of them serious. Angloedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynxhas been reported in patients treated with angiotensin-converting enzyme inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received Lotensin. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Lotensin should be discontinued and appropriate therapy instituted immediately. Where there Is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3 mL to 0.5 mL) should be promptlyadministered (see ADVERSEREACTIONS). Anaphylactoid Reactions DuringDesensitization:Two patients undergoing desensitizingtreatment with hymenoptera venom while receiving ACEinhibitors sustained life-threateninganaphylactoid reactions. In the same patients, these reactions were avoided when ACEinhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. AnaphylactoidReactions DuringMembrane Exposure: Anaphylactoidreactions have been reported in patients dialyzed withhigh-flux membranes and treated concomitantly with an ACEinhibitor. Anaphylactoidreactions have also been reported in patients undergoinglow-density lipoprotein apheresis withdextran sulfate absorption (a procedure dependent upon devices not approved in the United States). Hypotension Lotensin can cause symptomatic hypotension. Likeother ACEinhibitors, benazeprilhas been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume- and/or salt-depletion should be corrected before initiating therapy with Lotensin. In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and, rarely, with acute renal failure and death. In such patients, Lotensin therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of benazeprilor diuretic is increased. If hypotension occurs, the patient should be placed in a supine position, and, if necessary, treated with intravenous infusion of physiological saline. Lotensin treatment usually can be continued following restoration of blood pressure and volume. Neutropenia/Agranulocytosis Another angiotensin-converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients, but more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinicaltrials of benazeprilare insufficientto show that benazeprildoes not cause agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function. Fetal/Neonatal Morbidityand Mortality ACEinhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACEinhibitors should be discontinued as soon as possible. The use of ACEinhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACEinhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACEinhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACEinhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should makeevery effort to discontinue the use of benazeprilas soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, benazepril should be discontinued unless it is considered life saving for the mother. Contraction stress testing (CST), a nonstress test (NST),or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infantswith histories of in utero exposure to ACEinhibitors should beclosely observed for hypotension, oliguria,and hyperkalemia.If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers with another ACEinhibitor, but experience is limited. Noteratogenic effects of Lotensin were seen in studies of pregnant rats, mice, and rabbits. On a mg/m' basis, the doses used in these studies were 60 times (in rats), 9 times (in mice), and more than 0.8 times (in rabbits) the maximum recommended human dose (assuming a 50 kg woman). On a mg/kg basis these multiples are 300 times (in rats), 90 times (in mice) and more than 3 times (in rabbits) tSe maximumrecommendedhuman dose. HepaticFailure Rarely, ACEinhibitors have been associated witha syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACEinhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACEinhibitor and receive appropriate medicalfollow-up. PRECAUTIONS General Impaired Renal Function:As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin angiotensin-aldosterone system, treatment with angiotensin-converting enzyme inhibitors, including Lotensin, may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. In a small study of hypertensive patients with renal artery stenosis in a solitary kidney or bilateral renal artery stenosis, treatment with Lotensin was associated withincreases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of Lotensin or diuretic therapy, or both. When such patients are treated with ACEinhibitors, renal function should be monitored during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine,usually minor and transient, especiallywhen Lotensin has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of Lotensin and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see DOSAGEANDADMINISTRATION). Hyperkalemia: In clinical trials, hyperkalemia (serum potassium at least 0.5 mEq/Lgreater than the upper limit of normal) occurred in approximately 1% of hypertensive patients receiving Lotensin. In most cases, these were isolated values which resolved despite continued therapy. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Lotensin (see Drug Interactions). Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductivecough has been reported withallACEinhibitors,always resolving after discontinuation of therapy. ACEinhibitor-induced cough should be considered in the differential diagnosis of cough. Impaired Liver Funcion: In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially unaltered (see WARNINGS,Hepatic Failure). Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, benazepril willblock the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. Informationfor Patients Pregnancy: Femalepatients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACEinhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACEinhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician. Symptomatic Hypotension: Patients should be cautioned that lightheadedness can occur, especially during the first days of therapy, and it should be reported to the prescribing physician. Patients should be told that if syncope occurs, Lotensin should be discontinued until the prescribing physician has been consulted. All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope. Hyperkalemia: Patients should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician. Neutropenia: Patients should be told to promptly report any indication of infection (e.g ., sore throat, fever), which could be a sign of neutropenia. DrugInteractions Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Lotensin. The possibility of hypotensive effects with Lotensin can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Lotensin. Ifthis is not possible, the starting dose should be reduced (see DOSAGEAND ADMINISTRATION). Potassium Supplements and Potassium-Sparing Diuretics: Lotensin can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution, and the patient's serum potassium should be monitored frequently. Oral Anticoagulants: Interaction studies with warfarin and acenocoumarol failed to identify any clinically important effects on the serum concentrations or clinical effects of these anticoagulants. Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACEinhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Other: No clinically important pharmacokinetic interactions occurred when Lotensin was administered concomitantly with hydrochlorothiazide, chlorthalidone, furosemide, digoxin, propranolol, atenolol, naproxen, or cimetidine. Lotensin has been used concomitantlywith beta-adrenergic-blockingagents, calcium-channel blocking agents, diuretics, digoxin, and hydralazine, without evidenceof clinically important adverse interactions. Benazepril, like other ACEinhibitors, has had less than additive effects with beta adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renln-angiotensin system. Carcinogenesis, Mutagenesis, Impairmentof Fertility No evidence of carcinogenicity was found when benazepril was administered to rats and mice for up to two years at doses of up to150 mg/ kg/day. When compared on the basis of body weights, this dose is 110 times the maximum recommended human dose. When compared on the basis of body surface areas, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg). No mutagenic activity was detected in the Ames test in bacteria (with or without metabolic activation), in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. In doses of 50-500 mg/kg/day (6-60 times the maximum recommended human dose based on mg/m 2 comparison and 37-375 times the maximum recommended human dose based on a mg/kg comparison), Lotensin had no adverse effect on the reproductive performance of male and female rats. PregnancyCategories C (first trimester) and D (second and thirdtrimesters) See WARNINGS,Fetal/Neonatal Morbidity and Mortality. NursingMothers Minimalamounts of unchanged benazepril and of benazeprilat are excretedinto the breast milk of lactating women treated with benazepril.A newborn child ingesting entirely breast milk would receive less than 0.1% of the mg/kg maternal dose of benazepril and benazeprilat. GeriatricUse Of the total number of patients who received benazepril in U.S . clinical studies of Lotensin, 18% were 65 or older while 2% were 75 or older. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identifieddifferences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Pediatric Use Safety and effectiveness in children have not been established. ADVERSEREACTIONS Lotensin has been evaluated for safety in over 6000 patients with hypertension; over 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was comparable in Lotensin and placebo patients.