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Indications:

Hypertension, Heart failure, Asymptomatic Left Ventricular Dysfunction.

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 5mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 10 to 40mg 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 patients, 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 >30mL/min (serum creatinine of up to approximately 3mg/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.

* Normal Renal Function: >80mL/min (Creatinine Clearance ml/min) 5mg of initial dose (mg/day)

* Mild impairment: </=80 & >30mL/min (Creatinine Clearance ml/min) 5mg of initial dose (mg/day)

* Moderate to severe impairment: </=30 mL/min (Creatinine Clearance ml/min) 2.5mg of initial dose (mg/day)

* Dialysis patients: 2.5mg of initial dose on dialysis days (Dosage on nondialysis days should be adjusted 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 40mg, administered in two divided doses.

The recommended initial dose is 2.5mg. The recommended dosing range is 2.5 to 20mg 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 diminished 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 2.5mg twice daily and were titrated as tolerated to the targeted daily dose of 20mg (in divided doses). After the initiated dose of Enalapril, the patients 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 creatine greater that 1.6mg/dL, therapy should be initiated at 2.5mg daily under close medical supervision. 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 40mg.

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

More Frequent: Cough, headache

Less Frequent Diarrhea, dizziness, Fainting, Fatigue, Fever, Hypotension, Joint pain, loss of taste, nausea, skin rash.

Hypotension-Patients on Diuretic Therapy: Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with enalapril. The possibility of hypotensive effects with enalapril can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with enalapril. If it is necessary to continue the diuretic, provide close medical supervision after the initial dose for at least two hours and until blood pressure has stabilized for at least an additional hour.

Agents Causing Renin Releasing: The antihypertensive effect of Enalapril is augmented by antihypertensive agents that cause renin release (e.g., diuretics).

Non-steroidal Anti-inflammatory agents: In some patients with compromised renal function who are being treated with non-steroidal anti-inflammatory drugs, the co-administration of enalapril may result in a further deterioration of renal function. These effects are usually reversible.

Other Cardiovascular Agents: Enalapril has been used concomitantly with beta adrenergic-blocking agents, methyldopa, nitrates, calcium-blocking agents, hydralazine, prazosin and digoxin without evidence of clinically significant adverse interactions.

Agents Increasing Serum Potassium: Enalapril attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterence, amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium sparing agents should generally not be used in patients with heart failure receiving Enalapril.

Lithium: lithium toxicity has been reported in patients receiving lithium concomitantly with drugs which cause elimination of sodium, including ACE inhibitors. A few cases of lithium toxicity have been reported in patients receiving concomitant Enalapril and lithium and were reversible upon discontinuation of both drugs. It is recommended that serum lithium levels be monitored frequently if enalapril is administered concomitantly with lithium.

Pregnant women

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.

Nursing mothers

Enalapril and enalaprilat have been detected in human breast milk. Because of the potential for serious adverse reactions in nursing infants from enalapril, a decision should be make whether to discontinue nursing or to discontinue Enalapril, taking into account the importance of the drug to the mother.

Aortic Stenosis/Hypertrophic Cardiomyopathy: As with all vasodilators, enalapril be given with caution to patients with obstruction in the outflow tract of the left ventricle. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individual. 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, may be associated with oligouria 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 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 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.

Cough: Presumable due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in 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.