decreases the incidence of hospitalization for heart failure (see clinical pharmacology , heart failure , mortality trials for details and limitations of survival trials). in using enalapril maleate tablets 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, and that available data are insufficient to show that enalapril maleate tablets do not have a similar risk (see warnings , neutropenia/agranulocytosis ). in considering use of enalapril maleate tablets, it should be noted that in controlled clinical trials ace inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. in addition, it should be noted that black patients receiving ace inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks (see warnings , head and neck angioedema ).

ms. angioedema associated with laryngeal edema may be fatal. where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures necessary to ensure a patent airway, should be promptly provided (see adverse reactions ). patients receiving coadministration of ace inhibitor and mtor (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema (see precautions ). intestinal angioedema : intestinal angioedema has been reported in patients treated with ace inhibitors. these patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and c1 esterase levels were normal. the angioedema was diagnosed by procedures including abdominal ct scan or ultrasound, or at surgery, and symptoms resolved after stopping the ace inhibitor. intestinal angioedema should be included in the differential diagnosis of patients on ace inhibitors presenting with abdominal pain. patients with a history of angioedema unrelated to ace inhibitor therapy may be at increased risk of angioedema while receiving an ace inhibitor (see indications and usage and contraindications ). anaphylactoid reactions during desensitization two patients undergoing desensitizing treatment with hymenoptera venom while receiving ace inhibitors sustained life-threatening anaphylactoid reactions. in the same patients, these reactions were avoided when ace inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge. anaphylactoid reactions during membrane exposure anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ace inhibitor. anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. hypotension excessive hypotension is rare in uncomplicated hypertensive patients treated with enalapril maleate tablets alone. patients with heart failure given enalapril maleate tablets commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy (see dosage and administration ). patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high-dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. it may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with enalapril maleate tablets in patients at risk for excessive hypotension who are able to tolerate such adjustments (see precautions , drug interactions and adverse reactions ). in patients at risk for excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril and/or diuretic is increased. similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident. if excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. a transient hypotensive response is not a contraindication to further doses of enalapril maleate tablets, which usually can be given without difficulty once the blood pressure has stabilized. if symptomatic hypotension develops, a dose reduction or discontinuation of enalapril maleate tablets or concomitant diuretic may be necessary. 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. available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates. marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded. periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered. hepatic failure rarely, ace inhibitors have been associated with a 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 ace inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ace inhibitor and receive appropriate medical follow-up. fetal toxicity use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. when pregnancy is detected, discontinue enalapril maleate tablets as soon as possible. these adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. in the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. perform serial ultrasound examinations to assess the intra-amniotic environment. if oligohydramnios is observed, discontinue enalapril maleate tablets, unless it is considered lifesaving for the mother. fetal testing may be appropriate, based on the week of pregnancy. patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. closely observe infants with histories of in utero exposure to enalapril maleate tablets for hypotension, oliguria, and hyperkalemia (see precautions , pediatric use ). no teratogenic effects of enalapril were seen in studies of pregnant rats and rabbits. on a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (mrhdd).

a single dose or two divided doses. in some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. in such patients, an increase in dosage or twice daily administration should be considered. if blood pressure is not controlled with enalapril maleate tablets alone, a diuretic may be added. concomitant administration of enalapril maleate tablets with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see precautions ). dosage adjustment in hypertensive patients with renal impairment the usual dose of enalapril is recommended for patients with a creatinine clearance more than 30 ml/min (serum creatinine of up to approximately 3 mg/dl). for patients with creatinine clearance less than or equal to 30 ml/min (serum creatinine more than or equal to 3 mg/dl), the first dose is 2.5 mg once daily. the dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily. renal status creatinine clearance (ml/min) initial dose (mg/day) normal renal function >80 ml/min 5 mg mild impairment ≤80 >30 ml/min 5 mg moderate to severe impairment ≤30 ml/min 2.5 mg dialysis patients¹ 2.5 mg on dialysis days ² * see warnings , anaphylactoid reactions during membrane exposure . ² dosage on nondialysis days should be adjusted depending on the blood pressure response. heart failure enalapril maleate tablets are indicated for the treatment of symptomatic heart failure, usually in combination with diuretics and digitalis. in the placebo-controlled studies that demonstrated improved survival, patients were titrated as tolerated up to 40 mg, administered in two divided doses. the recommended initial dose is 2.5 mg. the recommended dosing range is 2.5 to 20 mg given twice a day. doses should be titrated upward, as tolerated, over a period of a few days or weeks. the maximum daily dose administered in clinical trials was 40 mg in divided doses. after the initial dose of enalapril maleate tablets, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see warnings and precautions , drug interactions ). if possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. the appearance of hypotension after the initial dose of enalapril maleate tablets does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. asymptomatic left ventricular dysfunction in the trial that demonstrated efficacy, patients were started on 2.5 mg twice daily and were titrated as tolerated to the targeted daily dose of 20 mg (in divided doses). after the initial dose of enalapril maleate tablets, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour (see warnings and precautions , drug interactions ). if possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension. the appearance of hypotension after the initial dose of enalapril maleate tablets does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. dosage adjustment in patients with heart failure and renal impairment or hyponatremia in patients with heart failure who have hyponatremia (serum sodium less than 130 meq/l) or with serum creatinine greater than 1.6 mg/dl, therapy should be initiated at 2.5 mg daily under close medical supervision (see dosage and administration , heart failure , warnings and precautions , drug interactions ). the dose may be increased to 2.5 mg b.i.d., then 5 mg b.i.d. and higher as needed, usually at intervals of four days or more if at the time of dosage adjustment there is not excessive hypotension or significant deterioration of renal function. the maximum daily dose is 40 mg. pediatric hypertensive patients the usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. dosage should be adjusted according to blood pressure response. doses above 0.58 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients (see clinical pharmacology , clinical pharmacology in pediatric patients). enalapril maleate tablets are not recommended in neonates and in pediatric patients with glomerular filtration rate less than 30 ml/min/1.73 m 2 , as no data are available. preparation of suspension (for 200 ml of a 1.0 mg/ml suspension) add 50 ml of sodium citrate and citric acid oral solution, usp to a polyethylene terephthalate (pet) bottle containing ten 20 mg tablets of enalapril maleate tablets and shake for at least 2 minutes. let concentrate stand for 60 minutes. following the 60-minute hold time, shake the concentrate for an additional minute. add 150 ml of ora-sweet sf to the concentrate in the pet bottle and shake the suspension to disperse the ingredients. the suspension should be refrigerated at 2° to 8°c (36° to 46°f) and can be stored for up to 30 days. shake the suspension before each use.

shown below. in patients treated with enalapril maleate tablets, the maximum duration of therapy was three years; in placebo-treated patients the maximum duration of therapy was 12 weeks. enalapril maleate tablets (n=2314) incidence (discontinuation) placebo (n=230) incidence body as a whole fatigue 3.0 (<0.1) 2.6 orthostatic effects 1.2 (<0.1) 0.0 asthenia 1.1 (0.1) 0.9 digestive diarrhea 1.4 (<0.1) 1.7 nausea 1.4 (0.2) 1.7 nervous/psychiatric headache 5.2 (0.3) 9.1 dizziness 4.3 (0.4) 4.3 respiratory cough 1.3 (0.1) 0.9 skin rash 1.4 (0.4) 0.4 heart failure adverse experiences occurring in greater than one percent of patients with heart failure treated with enalapril maleate tablets are shown below. the incidences represent the experiences from both controlled and uncontrolled clinical trials (maximum duration of therapy was approximately one year). in the placebo-treated patients, the incidences reported are from the controlled trials (maximum duration of therapy is 12 weeks). the percentage of patients with severe heart failure (nyha class iv) was 29 percent and 43 percent for patients treated with enalapril maleate tablets and placebo, respectively. enalapril maleate tablets (n=673) incidence (discontinuation) placebo (n=339) incidence body as a whole orthostatic effects 2.2 (0.1) 0.3 syncope 2.2 (0.1) 0.9 chest pain 2.1 (0.0) 2.1 fatigue 1.8 (0.0) 1.8 abdominal pain 1.6 (0.4) 2.1 asthenia 1.6 (0.1) 0.3 cardiovascular hypotension 6.7 (1.9) 0.6 orthostatic hypotension 1.6 (0.1) 0.3 angina pectoris 1.5 (0.1) 1.8 myocardial infarction 1.2 (0.3) 1.8 digestive diarrhea 2.1 (0.1) 1.2 nausea 1.3 (0.1) 0.6 vomiting 1.3 (0.0) 0.9 nervous/psychiatric dizziness 7.9 (0.6) 0.6 headache 1.8 (0.1) 0.9 vertigo 1.6 (0.1) 1.2 respiratory cough 2.2 (0.0) 0.6 bronchitis 1.3 (0.0) 0.9 dyspnea 1.3 (0.1) 0.4 pneumonia 1.0 (0.0) 2.4 skin rash 1.3 (0.0) 2.4 urogenital urinary tract infection 1.3 (0.0) 2.4 other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0 percent of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity. body as a whole: anaphylactoid reactions (see warnings , anaphylactoid and possibly related reactions ). cardiovascular: cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients (see warnings, hypotension) ; pulmonary embolism and infarction; pulmonary edema; rhythm disturbances including atrial tachycardia and bradycardia; atrial fibrillation; palpitation, raynaud’s phenomenon. digestive: ileus, pancreatitis, hepatic failure, hepatitis (hepatocellular [proven on rechallenge] or cholestatic jaundice) (see warnings , hepatic failure ), melena, anorexia, dyspepsia, constipation, glossitis, stomatitis, dry mouth. hematologic: rare cases of neutropenia, thrombocytopenia and bone marrow depression. musculoskeletal: muscle cramps. nervous/psychiatric: depression, confusion, ataxia, somnolence, insomnia, nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality. respiratory: bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis. skin: exfoliative dermatitis, toxic epidermal necrolysis, stevens-johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity. special senses: blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing. urogenital: renal failure, oliguria, renal dysfunction (see precautions and dosage and administration) , flank pain, gynecomastia, impotence. miscellaneous: a symptom complex has been reported which may include some or all of the following: a positive ana, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. angioedema: angioedema has been reported in patients receiving enalapril maleate tablets, with an incidence higher in black than in non-black patients. angioedema associated with laryngeal edema may be fatal. if angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with enalapril maleate tablets should be discontinued and appropriate therapy instituted immediately (see warnings , head and neck angioedema ). hypotension: in the hypertensive patients, hypotension occurred in 0.9 percent and syncope occurred in 0.5 percent of patients following the initial dose or during extended therapy. hypotension or syncope was a cause for discontinuation of therapy in 0.1 percent of hypertensive patients. in heart failure patients, hypotension occurred in 6.7 percent and syncope occurred in 2.2 percent of patients. hypotension or syncope was a cause for discontinuation of therapy in 1.9 percent of patients with heart failure (see warnings , hypotension ). cough: see precautions , cough. pediatric patients the adverse experience profile for pediatric patients appears to be similar to that seen in adult patients. clinical laboratory test findings serum electrolytes hyperkalemia (see precautions , hyperkalemia ), hyponatremia. creatinine, blood urea nitrogen in controlled clinical trials minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 0.2 percent of patients with essential hypertension treated with enalapril maleate tablets alone. increases are more likely to occur in patients receiving concomitant diuretics or in patients with renal artery stenosis (see precautions , impaired renal function ). in patients with heart failure who were also receiving diuretics with or without digitalis, increases in blood urea nitrogen or serum creatinine, usually reversible upon discontinuation of enalapril maleate tablets and/or other concomitant diuretic therapy, were observed in about 11 percent of patients. increases in blood urea nitrogen or creatinine were a cause for discontinuation in 1.2 percent of patients. hematology small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.3 g percent and 1.0 vol percent, respectively) occur frequently in either hypertension or congestive heart failure patients treated with enalapril maleate tablets but are rarely of clinical importance unless another cause of anemia coexists. in clinical trials, less than 0.1 percent of patients discontinued therapy due to anemia. hemolytic anemia, including cases of hemolysis in patients with g6pd deficiency, has been reported; a causal relationship to enalapril cannot be excluded. liver function tests elevations of liver enzymes and/or serum bilirubin have occurred (see warnings , hepatic failure ). to report suspected adverse reactions, contact oceanside pharmaceuticals at 1-800-321-4576 or fda at 1-800-fda-1088 or www.fda.gov/medwatch .

ic, there was essentially no change in serum potassium (see precautions ). removal of angiotensin ii negative feedback on renin secretion leads to increased plasma renin activity. ace is identical to kininase, an enzyme that degrades bradykinin. whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalapril maleate tablets remains to be elucidated. while the mechanism through which enalapril maleate tablets lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril maleate tablets are antihypertensive even in patients with low-renin hypertension. although enalapril maleate tablets were antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril monotherapy than non-black patients. pharmacokinetics and metabolism following oral administration of enalapril maleate tablets, peak serum concentrations of enalapril occur within about one hour. based on urinary recovery, the extent of absorption of enalapril is approximately 60 percent. enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin- converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. excretion of enalapril maleate tablets is primarily renal. approximately 94 percent of the dose is recovered in the urine and feces as enalaprilat or enalapril. the principal components in urine are enalaprilat, accounting for about 40 percent of the dose, and intact enalapril. there is no evidence of metabolites of enalapril, other than enalaprilat. the serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ace. the amount bound does not increase with dose, indicating a saturable site of binding. the effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. the disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 ml/min or less. with glomerular filtration rate ≤30 ml/min, peak and trough enalaprilat levels increase, time to peak concentration increases and time to steady state may be delayed. the effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency (see dosage and administration) . enalaprilat is dialyzable at the rate of 62 ml/min. studies in dogs indicate that enalapril crosses the blood-brain barrier poorly, if at all; enalaprilat does not enter the brain. multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. milk of lactating rats contains radioactivity following administration of 14 c-enalapril maleate. radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters. pharmacodynamics and clinical effects hypertension administration of enalapril maleate tablets to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure usually with no orthostatic component. symptomatic postural hypotension is therefore infrequent, although it might be anticipated in volume-depleted patients (see warnings , hypotension ). in most patients studied, after oral administration of a single dose of enalapril, onset of antihypertensive activity was seen at one hour with peak reduction of blood pressure achieved by four to six hours. at recommended doses, antihypertensive effects have been maintained for at least 24 hours. in some patients the effects may diminish toward the end of the dosing interval (see dosage and administration , hypertension ). in some patients achievement of optimal blood pressure reduction may require several weeks of therapy. the antihypertensive effects of enalapril maleate tablets have continued during long-term therapy. abrupt withdrawal of enalapril maleate tablets has not been associated with a rapid increase in blood pressure. in hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. following administration of enalapril maleate tablets, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. the effects appear to be similar in patients with renovascular hypertension. when given together with thiazide-type diuretics, the blood pressure lowering effects of enalapril maleate tablets are approximately additive. in a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril maleate tablets. in this study there was no evidence of a blunting of the antihypertensive action of enalapril maleate tablets (see precautions , drug interactions ). heart failure in trials in patients treated with digitalis and diuretics, treatment with enalapril resulted in decreased systemic vascular resistance, blood pressure, pulmonary capillary wedge pressure and heart size, and increased cardiac output and exercise tolerance. heart rate was unchanged or slightly reduced, and mean ejection fraction was unchanged or increased. there was a beneficial effect on severity of heart failure as measured by the new york heart association (nyha) classification and on symptoms of dyspnea and fatigue. hemodynamic effects were observed after the first dose and appeared to be maintained in uncontrolled studies lasting as long as four months. effects on exercise tolerance, heart size, and severity and symptoms of heart failure were observed in placebo-controlled studies lasting from eight weeks to over one year. heart failure, mortality trials in a multicenter, placebo-controlled clinical trial, 2,569 patients with all degrees of symptomatic heart failure and ejection fraction ≤35 percent were randomized to placebo or enalapril and followed for up to 55 months (solvd-treatment). use of enalapril was associated with an 11 percent reduction in all-cause mortality and a 30 percent reduction in hospitalization for heart failure. diseases that excluded patients from enrollment in the study included severe stable angina (>2 attacks/day), hemodynamically significant valvular or outflow tract obstruction, renal failure (creatinine >2.5 mg/dl), cerebrovascular disease (e.g., significant carotid artery disease), advanced pulmonary disease, malignancies, active myocarditis and constrictive pericarditis. the mortality benefit associated with enalapril does not appear to depend upon digitalis being present. a second multicenter trial used the solvd protocol for study of asymptomatic or minimally symptomatic patients. solvd-prevention patients, who had left ventricular ejection fraction ≤35% and no history of symptomatic heart failure, were randomized to placebo (n=2117) or enalapril (n=2111) and followed for up to 5 years. the majority of patients in the solvd-prevention trial had a history of ischemic heart disease. a history of myocardial infarction was present in 80 percent of patients, current angina pectoris in 34 percent, and a history of hypertension in 37 percent. no statistically significant mortality effect was demonstrated in this population. enalapril-treated subjects had 32% fewer first hospitalizations for heart failure, and 32% fewer total heart failure hospitalizations. compared to placebo, 32 percent fewer patients receiving enalapril developed symptoms of overt heart failure. hospitalizations for cardiovascular reasons were also reduced. there was an insignificant reduction in hospitalizations for any cause in the enalapril treatment group (for enalapril vs. placebo, respectively, 1166 vs. 1201 first hospitalizations, 2649 vs. 2840 total hospitalizations), although the study was not powered to look for such an effect. the solvd-prevention trial was not designed to determine whether treatment of asymptomatic patients with low ejection fraction would be superior, with respect to preventing hospitalization, to closer follow-up and use of enalapril at the earliest sign of heart failure. however, under the conditions of follow-up in the solvd-prevention trial (every 4 months at the study clinic; personal physician as needed), 68% of patients on placebo who were hospitalized for heart failure had no prior symptoms recorded which would have signaled initiation of treatment. the solvd-prevention trial was also not designed to show whether enalapril modified the progression of underlying heart disease. in another multicenter, placebo-controlled trial (consensus) limited to patients with nyha class iv congestive heart failure and radiographic evidence of cardiomegaly, use of enalapril was associated with improved survival. the results are shown in the following table. survival (%) six months one year enalapril maleate tablets (n=127) 74 64 placebo (n=126) 56 48 in both consensus and solvd-treatment trials, patients were also usually receiving digitalis, diuretics or both. clinical pharmacology in pediatric patients a multiple dose pharmacokinetic study was conducted in 40 hypertensive male and female pediatric patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg enalapril maleate. at steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours, and the mean urinary recovery of total enalapril and enalaprilat in 24 hours was 68% of the administered dose. conversion of enalapril to enalaprilat was in the range of 63-76%. the overall results of this study indicate that the pharmacokinetics of enalapril in hypertensive children aged 2 months to ≤16 years are consistent across the studied age groups and consistent with pharmacokinetic historic data in healthy adults. in a clinical study involving 110 hypertensive pediatric patients 6 to 16 years of age, patients who weighed <50 kg received either 0.625, 2.5 or 20 mg of enalapril daily and patients who weighed ≥50 kg received either 1.25, 5, or 40 mg of enalapril daily. enalapril administered once daily lowered trough blood pressure in a dose-dependent manner. the dose-dependent antihypertensive efficacy of enalapril was consistent across all subgroups (age, tanner stage, gender, race). however, the lowest doses studied, 0.625 mg and 1.25 mg, corresponding to an average of 0.02 mg/kg once daily, did not appear to offer consistent antihypertensive efficacy. in this study, enalapril maleate tablets were generally well tolerated. in the above pediatric studies, enalapril maleate was given as tablets of enalapril maleate tablets and for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form, enalapril was administered in a suspension formulation (see dosage and administration , preparation of suspension ).

°f) [see usp controlled room temperature]. keep container tightly closed. protect from moisture. dispense in a tight container as per usp, if product package is subdivided. distributed by : oceanside pharmaceuticals, a division of bausch health us, llc bridgewater, nj 08807 usa manufactured by : bausch health companies inc. steinbach, mb r5g 1z7, canada © 2020 bausch health companies inc. or its affiliates 9450104_20003098 rev. 12/2020