(i) ROUTE OF ADMINISTRATION
Oral
DOSAGE AND ADMINISTRATION

Hypertension: In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of enalapril. The diuretic should, if possible, be discontinued for two to three days before beginning therapy with enalapril to reduce the likelihood of hypotension. If the patient's blood pressure is not controlled with enalapril alone, diuretic therapy may be resumed.
If the diuretic cannot be discontinued an initial dose of 2.5 mg should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. The recommended initial dose in patients not on diuretics is 5 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 10 to 40 mg per day administered in 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 patient an increase in dosage or twice daily administration should be considered. If blood pressure is not controlled with enalapril alone, a diuretic may be added.
Concomitant administration of enalapril with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium.
Dosage Adjustment in Hypertensive Patients with Renal Impairment: The usual dose of enalapril is recommended for patients with a creatinine clearance >30 ml/min (serum creatinine of up to approximately 3 mg/dl). For patients with creatinine clearance ?30 ml/min (serum creatinine ?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 Creatine- 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 patients * ----- 2.5 mg on dialysis days†
* see Precautions, Hemodialysis patients
†Dosage on non-dialysis days should be adjusted depending on the blood pressure response
Heart Failure: Enalapril is 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 starting 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, 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.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 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, 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. 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 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.The dose may be increased to 2.5 mg twice daily, then 5 mg twice daily. 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.

(ii) THERAPEUTIC / DIAGNOSTIC CLAIMS

Hypertension: Enalapril is indicated for the treatment of hypertension.
Enalapril is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of enalapril and thiazides are approximately additive.
Heart Failure: Enalapril is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis. In these patients enalapril improves symptoms, increases survival, and decreases the frequency of hospitalization.
Asymptomatic Left Ventricular Dysfunction: In clinically stable asymptomatic patients with left ventricular dysfunction,enalapril decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure.
In using enalapril 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 does not have a similar risk.

(iii) DESCRIPTION OF DOSAGE FORM

Enalapril maleate is a prodrug that is not highly active & must be hydrolysed by esterases in the liver to produce the active parent dicarboxylic acid .

(iv) CONTRAINDICATIONS

Enalapril is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor.

WARNING AND PRECAUTIONS

Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including enalapril) may be subject to a variety of adverse reactions, some of them serious.
Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril. In such cases enalapril or enalapril IV should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred. In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. 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. Patients with a history of angioedema unrelated to ACE inhibitor therapy may not be at increased risk of angioedema while receiving an ACE inhibitor.
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 (a procedure dependent upon devices not approved in the United States).
Hypotension: Excessive hypotension is rare in uncomplicated hypertensive patients treated with enalapril alone. Patients with heart failure given enalapril 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. 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 or enalapril IV in patients at risk for excessive hypotension who are able to tolerate such adjustments.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, which usually can be given without difficulty once the blood pressure has stabilized and/or has increased after volume expansion. If symptomatic hypotension develops, a dose reduction or discontinuation of enalapril 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 several 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/Neonatal Morbidity and Mortality: ACE inhibitors 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, ACE inhibitors should be discontinued as soon as possible.
The use of ACE inhibitors 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 ACE-inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of enalapril as 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, enalapril or enalapril IV should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a non-stress 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.
Infants with histories of in utero exposure to ACE inhibitors should be closely 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. Enalapril, which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.
No teratogenic effects of enalapril were seen in studies of pregnant rats, and rabbits. On a mg/kg basis, the doses used were up to 333 times (in rats), and 50 times (in rabbits) the maximum recommended human dose.

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 heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including enalapril or enalaprilat, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In clinical studies in hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine were observed in 20 percent of patients. These increases were almost always reversible upon discontinuation of enalapril and/or diuretic therapy. In such patients renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when enalapril or enalapril IV has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or enalapril or enalapril IV may be required.
Evaluation of patients with hypertension or heart failure should always include assessment of renal function.
Hyperkalemia: Elevated serum potassium (greater than 5.7 mEq/L) was observed in approximately one percent of hypertensive patients in clinical trials. In most cases these were isolated values which resolved despite continued therapy. Hyperkalemia was a cause of discontinuation of therapy in 0.28 percent of hypertensive patients. In clinical trials in heart failure, hyperkalemia was observed in 3.8 percent of patients but was not a cause for discontinuation.
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 enalapril or enalapril IV.
Cough: Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is nonproductive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, enalapril may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Information for the Patient
Angioedema: Angioedema, including laryngeal edema, may occur especially following the first dose of enalapril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician.
Hypotension: Patients should be cautioned to report light-headedness, especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with the physician.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.
Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.
Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.
NOTE: As with many other drugs, certain advice to patients being treated with enalapril is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
Enalapril is commonly used in combination with diuretics, especially furosemide. In this situation, monitoring kidney parameters is especially important as both these medications serve to decrease blood supply to the kidney as they support the heart. Should a heart failure crisis occur while a patient is on these two medications, it will become necessary to rely on the diuretic to resovle the crisis. High doses of diuretic are typically needed. This can easily lead to kidney failure though there is no alternative when the heart is failing.
Blood potassium levels can become dangerously high when enalapril is used with other medications that elevate blood potassium level. Such drugs might include: potassium supplements (Polycitra, or Urocit-K) or spironolactone (a potassium sparing diuretic.)
Enalapril is less effective in the presence of aspirin or other NSAIDS.

(v) SIDE EFFECTS

Nausea, appetite loss, or diarrhea are sometimes observed with this medication. In some patients, these effects are severe enough to preclude the use of enalapril.
In some patients, blood pressure can drop too low as the peripheral blood vessels are dilated. This manifests as listlessness and lethargy. Often the dose of enalapril can be modified should this side effect occur.
Enalapril may lead to elevations in potassium blood levels.

(vi) TOXIC EFFECTS

CARCINOGENECITY

Studies in rats for 106 weeks and in mice for 94 weeks at doses up to 150 and 300 times the maximum daily human dose (based on a patient weight of 50 kg), respectively, found no evidence of tumorigenicity or carcinogenicity

MUTAGENECITY

No evidence of mutagenicity was found in tests including the Ames bacterial assay with or without metabolic activation, rec-assay, reverse mutation assay with E. coli , sister chromatid exchange with cultured mammalian cells, the micronucleus test with mice, and in an in vivo cytogenic study using mouse bone marrow.

TERATOGENECITY

No adverse effects on reproductive performance were found in male and female rats given 10 to 90 mg/kg of enalapril per day .

Enalapril maleate