Enalapril Maleate (Page 5 of 8)

Non-Steroidal 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, co-administration 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. In this study there was no evidence of a blunting of the antihypertensive action of enalapril. However, reports suggest that NSAIDs may diminish the antihypertensive effect of ACE inhibitors.

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, 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.

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.

Gold

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.

mTOR (Mammalian Target of Rapamycin) Inhibitors

Patients receiving co-administration of ACE inhibitor and mTOR inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema. (See WARNINGS.)

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).

Pregnancy

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 made whether to discontinue nursing or to discontinue enalapril, taking into account the importance of the drug to the mother.

Pediatric Use

Neonates with a History of In Utero Exposure to Enalapril

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 have been established in hypertensive pediatric patients age 1 month to 16 years. Use of enalapril in these age groups is supported by evidence from adequate and well-controlled studies of enalapril 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 is not recommended in neonates and in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m 2 , as no data are available.

ADVERSE REACTIONS

Enalapril has been evaluated for safety in more than 10,000 patients, including over 1,000 patients treated for 1 year or more. Enalapril has been found to be generally well tolerated in controlled clinical trials involving 2,987 patients. For the most part, adverse experiences were mild and transient in nature. In clinical trials, discontinuation of therapy due to clinical adverse experiences was required in 3.3% of patients with hypertension and in 5.7% of patients with heart failure. The frequency of adverse experiences was not related to total daily dosage within the usual dosage ranges. In patients with hypertension the overall percentage of patients treated with enalapril reporting adverse experiences was comparable to placebo.

Hypertension

Adverse experiences occurring in greater than 1% of patients with hypertension treated with enalapril in controlled clinical trials are shown below. In patients treated with enalapril, the maximum duration of therapy was 3 years; in placebo treated patients the maximum duration of therapy was 12 weeks.

Enalapril Maleate (n = 2,314) Incidence (discontinuation)

Placebo (n = 230) Incidence

Body as a Whole

Fatigue

3 (< 0.1)

2.6

Orthostatic Effects

1.2 (< 0.1)

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

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