Product Name:  Enacard (Enalapril) 1 mg, 30 Tablets

Description: 

Active Ingredient(s): Each ENACARD® tablet contains either:
Enalapril maleate 1.0 mg (green)
Enalapril maleate 2.5 mg (blue)
Enalapril maleate 5.0 mg (pink)
Enalapril maleate 10.0 mg (yellow)
Enalapril maleate 20.0 mg (white)

Indications: ENACARD® indicated for the treatment of mild, moderate, or severe (modified NYHA Class IIa, IIIb, IVc) heart failure in dogs. (See Case Management section for etiologies and appropriate conjunctive therapies.)

a A dog with modified New York Heart Association Class II heart failure develops fatigue, shortness of breath, coughing, etc., which becomes evident when ordinary exercise is exceeded.

b A dog with modified New York Heart Association Class III heart failure is comfortable at rest, but exercise capacity is minimal.

c A dog with modified New York Heart Association Class IV heart failure has no capacity for exercise and disabling clinical signs are present at rest.

ENACARD® is indicated for the treatment of dogs in heart failure due to mitral regurgitation (chronic valvular disease) and/or reduced ventricular contractility (dilated cardiomyopathy). Conjunctive therapy which should be used with ENACARD® consists of furosemide and digoxin in the treatment of dilated cardiomyopathy, and furosemide with or without digoxin in the treatment of chronic valvular disease. ENACARD® acts to ameliorate the clinical signs associated with heart failure rather than to reverse the degeneration of the atrioventricular valves or to resolve the underlying myocardial disease in dilated cardiomyopathy. Efficacy against heart failure caused by etiologies other than mitral regurgitation or dilated cardiomyopathy has not been demonstrated.

Pharmacology: ENACARD® contains the maleate salt of enalapril, a derivative of two amino acids, L-alanine and L-proline. Following oral administration, enalapril (a prodrug) is rapidly absorbed and then hydrolyzed to enalaprilat, which is a highly specific, long-acting, non-sulfhydryl angiotensin converting enzyme (ACE) inhibitor. ACE is a dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor which stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II levels, which leads to decreased vasopressor activity and to decreased aldosterone secretion. ACE inhibitors are neurohormonal antagonists that are balanced (both arterial and venous) vasodilators resulting in decreased preload and after load. The overall effect of enalapril treatment is a decrease in the workload of the heart resulting from both arterial and venous dilation and decreased fluid retention.

Dosage and Administration: The recommended starting dose of ENACARD® in dogs is 0.5 mg/kg administered orally s.i.d. (once a day) with or without food. In the absence of an adequate clinical response within two (2) weeks, the dosing frequency may be increased to b.i.d. (twice a day) for a total daily dose of 1 mg/kg. The clinical response should be evaluated based upon criteria that include a physical exam, degree of pulmonary congestion/edema demonstrated on chest radiographs, the level of activity displayed by the dog, and exercise tolerance. The dose increase may be initiated earlier if indicated by worsening signs of heart failure such as increased pulmonary congestion/edema, decreased level of activity or decreased exercise tolerance. Dogs should be observed closely for 48 hours following the initial dosing or after increasing the dosing frequency for clinical signs consistent with hypotension such as weakness or depression. In addition, renal function should be monitored closely both before and two (2) to seven (7) days after starting treatment with enalapril. Dogs should be receiving standard heart failure therapy including stable doses of furosemide, with or without digoxin. Dogs should be receiving a stable dose of furosemide for at least two (2) days before treatment with ENACARD® and, if included in the treatment regimen, a stable dose of digoxin should be administered for four (4) days prior to the initiation of therapy with ENACARD®. Case Management: Because of the complexity of the treatment of dogs with heart failure, it may be necessary to consult with a veterinary cardiologist or internist. Diagnosis and Monitoring: As the heart failure disease syndrome is complex and usually requires multiple therapies, it is important to establish an accurate diagnosis. Diagnosis is based on procedures such as a complete physical examination, auscultation, electrocardiography, radiography, echocardiography, and pertinent laboratory tests, including hematology, clinical chemistry and urinalysis. In clinical studies, dogs were evaluated by assessing the class of heart failure, severity of pulmonary edema, appetite, level of activity, mobility, and cough prior to initiating treatment and again two (2) (14 days) and four (4) (28 days) weeks after starting treatment (see Efficacy section). Client observations are important in the successful monitoring of treatment. During long-term therapy, dogs were evaluated approximately every three (3) months unless conditions required that individual dogs be monitored more frequently. For dogs receiving digoxin therapy serum digoxin concentrations were also measured at these times or if indicated by inappetence, vomiting or diarrhea. In addition, pertinent laboratory tests including hematology and clinical chemistry were performed with attention to monitoring BUN and CRT concentrations. In the event that clinical signs of hypotension or reduced kidney function occur or that a significant increase in the concentration of blood urea nitrogen (BUN) and/or serum creatinine (CRT) over pretreatment levels is detected, refer to the Cautions section for the appropriate response.

Compatibilities: Concomitant Therapy: As established during clinical studies, ENACARD® may be used concomitantly with other therapy, which may include furosemide, digoxin, antiarrhythmics, beta-blockers, bronchodilators and cough suppressants for the treatment of heart failure in dogs. ENACARD® may be used in combination with sodium restricted diets. The safety of ENACARD® when used concomitantly with other cardiovascular drugs (e.g. vasodilators) has not been established.

Precaution(s): ENACARD® tablets have been shown to be stable for 24 months at room temperature. Protect from moisture. Store below 86°F (30°C) and avoid transient temperatures above 122°F (50°C). When not in use keep the container tightly closed. Do not remove desiccant from the container. Subdivision of the product package is not recommended, as the product should be stored in an airtight container.

Caution(s): Federal (U.S.A.) law restricts this drug to use by or on the order of a licensed veterinarian. Renal Function: The use of diuretics is considered an important part of therapy for heart failure. The result is that some dogs are kept in a volume-depleted (slightly dehydrated) state to control their heart failure. If cardiac function is impaired, the relative volume of blood reaching the kidneys is decreased, leading to prerenal azotemia. If the renal flow, already impaired by heart failure, is further compromised by volume depletion, prerenal azotemia is exacerbated. In normal dogs, prerenal azotemia is confirmed by examination of urine specific gravity; however, administration of diuretics renders this diagnostic test invalid. In clinical trials, the pretreatment serum chemistry profiles showed that the mean BUN was 28.7 mg/dL and the mean serum CRT was 1.27 mg/dL, indicating that dogs in heart failure receiving furosemide therapy may have elevations in BUN and CRT. Clinical manifestations of the heart failure syndrome may include prerenal azotemia, which is defined as an elevation in BUN and/or CRT with a normal urinalysis. This usually results from decreased renal blood flow induced by impaired cardiovascular performance. Compounds that cause volume depletion, such as diuretics or angiotensin converting enzyme inhibitors, may lower systemic blood pressure, which may further decrease renal perfusion and lead to the development of azotemia. Dogs with no detectable renal disease may develop minor and transient increases in blood urea nitrogen or serum creatinine when ENACARD® is administered concomitantly with furosemide.

1. If clinical signs of hypotension or signs of azotemia develop, the dose of furosemide should be reduced first.

2. If signs of azotemia continue it may be necessary to further reduce the daily dose of furosemide or discontinue administration.

3. If there is still not an improvement in clinical signs, dosing with ENACARD® should be decreased in frequency to once a day if being given twice a day, or discontinued.

4. Renal function (BUN and CRT) should be monitored periodically until it returns to pretreatment levels.

5. Appropriate fluid therapy, carefully monitored, should be considered if the above steps do not reverse azotemia. Use in Breeding Animals: The safety of enalapril in breeding dogs has not been established. Use of enalapril in pregnant bitches is not recommended.

Keep this and all drugs out of the reach of children.

In case of ingestion by humans, clients should be advised to contact a physician immediately.

Toxicology: Safety: Healthy Dogs: Healthy dogs that received enalapril maleate at a dose rate of 15 mg/kg/day (15X) for up to one year did not show any adverse changes. Dogs in acute and subacute toxicity studies also received enalapril maleate at doses including 10, 30, 90, 100 and 200 mg/kg/day for shorter periods. In an acute oral toxicity study, death was observed at 200 mg/kg, but effect was not noted at 100 mg/kg/day. In studies lasting one to three months, death was observed in dogs administered very high doses of 30 and 90 mg/kg/day. Signs observed in these dogs consisted of emesis, anorexia, weight loss, decreased activity, dehydration and tremors. At the highest dose of 90 mg/kg/day, nephrosis, characterized by tubular cell necrosis, tubular casts, crystals and mineralization, tubular cell cytoplasmic vacuolation and diffusely distributed lipids in the tubular cells, was observed. Secondary changes consisted of increased BUN and serum potassium with decreased serum chloride. Drug-induced changes were not seen on electrocardiograms. Dogs in Heart Failure: The safety of ENACARD® was demonstrated in clinical trials when administered at the recommended dose level to dogs in heart failure. In these studies, clinical observations/adverse reactions were reported with similar frequency in both treatment groups (enalapril treated and placebo controls). (See Other Clinical Observations/Adverse Reactions section.)

Side Effects: ENACARD® has been demonstrated to be generally well-tolerated in controlled, open-label field and clinical laboratory studies that involved 414 dogs with mild, moderate, or severe heart failure. In clinical studies, the overall prevalence of adverse effects was not greater in dogs treated with standard therapy (furosemide with or without digoxin) and ENACARD® than in those treated with standard therapy and placebo. Since three therapies (enalapril, furosemide, and digoxin) were used in conjunctive therapy, adverse reactions were difficult to associate with a particular drug. If adverse effects associated with azotemia are observed, refer to the Cautions section for recommended action. Azotemia: In clinical studies, azotemia was based on the clinical investigator's medical opinion (clinical signs or laboratory values) or defined as a BUN value of ≥50 mg/dL and/or a CRT value of ≥2.5 mg/dL, since dogs in heart failure and dogs receiving furosemide have higher values than normal dogs. There was no significant difference in the prevalence of azotemia in dogs receiving standard therapy and placebo compared with those receiving standard therapy and ENACARD®. Of 381 dogs in clinical field studies, azotemia as defined above was reported in 25.9% of 116 dogs receiving standard therapy and placebo, and in 28.7% of 265 dogs receiving standard therapy and enalapril. Azotemia was the cause of discontinuation of therapy in 4.3% of the dogs receiving standard therapy and placebo and of 3.0% of dogs receiving standard therapy and ENACARD® in these clinical studies. Other Clinical Observations/Adverse Reactions: Some clinical observations are attributable to treatment with furosemide and digoxin, and to the disease process itself. These include polyuria and polydipsia, depression, lethargy, anorexia, and decreased activity. Vomiting and other signs associated with the gastro-intestinal tract may be seen as a result of cardiac glycoside toxicity when digoxin is administered in conjunction with furosemide or furosemide and ENACARD®. No statistically significant differences in the prevalence of clinical signs were reported between dogs given standard therapy and placebo and those given standard therapy and ENACARD®. Clinical observations/adverse reactions reported in field clinical studies are tabulated as follows. Prevalence of clinical observations/adverse reactions reported in controlled and open-label field clinical studies involving 381 dogs that were treated for up to 15.5 months.

*Removed from study

Product Information Provided by Merial. © Merial