Enalapril Maleate (Page 3 of 6)
Aortic Stenosis/Hypertrophic Cardiomyopathy
As with all vasodilators, enalapril should 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 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 Maleate Tablets, may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death (see PRECAUTIONS, Drug Interactions).
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 Maleate Tablets 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 Maleate Tablets may be required.
Evaluation of patients with hypertension or heart failure should always include assessment of renal function ( see DOSAGE AND ADMINISTRATION).
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 Maleate Tablets (see Drug Interactions).
Presumably 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.
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 Patients
Angioedema, including laryngeal edema, may occur at any time during treatment with angiotensin- converting enzyme inhibitors, including 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.
Patients should be cautioned to report lightheadedness, 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.
Patients should be told not to use salt substitutes containing potassium without consulting their physician.
Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.
Female patients of childbearing age should be told about the consequences of exposure to Enalapril Maleate Tablets during pregnancy. Discuss treatment options with women planning to become pregnant. 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.
Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema (see WARNINGS).
Dual Blockade of the Renin-Angiotensin System (RAS)
Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on Enalapril Maleate Tablets and other agents that affect the RAS.
Do not coadminister aliskiren with Enalapril Maleate Tablets in patients with diabetes. Avoid use of aliskiren with Enalapril Maleate Tablets in patients with renal impairment (GFR <60 mL/min).
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 (see WARNINGS, Hypotension and DOSAGE AND ADMINISTRATION).
Agents Causing Renin Release
The antihypertensive effect of Enalapril Maleate Tablets is augmented by antihypertensive agents that cause renin release (e.g., diuretics).
Nonsteroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including enalapril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving enalapril and NSAID therapy.
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. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors.
Other Cardiovascular Agents
Enalapril Maleate Tablets have 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 Maleate Tablets attenuate potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or 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 Maleate Tablets.
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 Maleate Tablets 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.
Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including Enalapril Maleate Tablets.
mTOR (Mammalian Target of Rapamycin) Inhibitors
Patients receiving coadministration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema (see WARNINGS, Head and Neck Angioedema).
Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect when enalapril was administered for 106 weeks to male and female rats at doses up to 90 mg/kg/day or for 94 weeks to male and female mice at doses up to 90 and 180 mg/kg/day, respectively. These doses are 26 times (in rats and female mice) and 13 times (in male mice) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis.
Neither enalapril maleate nor the active diacid was mutagenic in the Ames microbial mutagen test with or without metabolic activation. Enalapril was also negative in the following genotoxicity studies: rec-assay, reverse mutation assay with E. coli , sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an in vivo cytogenic study using mouse bone marrow.
There were no adverse effects on reproductive performance of male and female rats treated with up to 90 mg/kg/day of enalapril (26 times the MRHDD when compared on a body surface area basis).
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 made whether to discontinue nursing or to discontinue Enalapril Maleate Tablets, taking into account the importance of the drug to the mother.
Neonates with a History of In Utero Exposure to Enalapril Maleate Tablets
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a 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.
Antihypertensive effects of Enalapril Maleate Tablets have been established in hypertensive pediatric patients age 1 month to 16 years. Use of Enalapril Maleate Tablets in these age groups is supported by evidence from adequate and well-controlled studies of Enalapril Maleate Tablets in pediatric and adult patients as well as by published literature in pediatric patients (see CLINICAL PHARMACOLOGY, Clinical Pharmacology in Pediatric Patients and DOSAGE AND ADMINISTRATION).
Enalapril Maleate Tablets are not recommended in neonates and in pediatric patients with glomerular filtration rate <30 mL/min/1.73 m2 , as no data are available.
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