Anapril/Anapril-S

Enalapril maleate.

Anapril 5/Anapril-S: Each tablet contains enalapril maleate 5 mg.
Anapril 20: Each tablet contains enalapril maleate 20 mg.

Pharmacodynamics: Mechanism of Action: Enalapril maleate inhibits angiotensin-converting enzyme (ACE) after hydrolysis to enalaprilat. The primary mechanism through which enalapril lowers blood pressure is believed to be suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE blocks the conversion of angiotensin I to angiotensin II resulting in decreased vasopressor activity, decreased aldosterone secretion and increased plasma renin activity.
Cardiovascular Effects: In hypertensive patients, enalapril reduces blood pressure by decreasing total peripheral resistance. The drug causes arterial and possibly venous dilation and generally decreases systolic and diastolic blood pressure by approximately 10-15%.
Blood pressure decreases within 1 hour, with peak antihypertensive effect at 4-8 hours. At recommended doses, antihypertensive and hemodynamic effects have been shown to be maintained for 12-24 hours.
In reducing blood pressure, angiotensin converting enzyme (ACE) inhibitors have been documented to cause a significant regression of pathologic left ventricular hypertrophy in patients with hypertension.
In patients with congestive heart failure, beneficial effects of enalapril lead to both improved symptoms and prolonged survival.
Endothelial Functioning: Microvascular endothelial dysfunction associated with atherosclerosis may be improved by the administration of angiotensin converting-enzyme (ACE) inhibitor therapy.
Renal Effects: With angiotensin converting enzyme (ACE) inhibitor therapy, kidney perfusion is increased and renal vascular resistance is decreased as ACE inhibitors induce vasodilation. Glomerular filtration rate (GFR) will generally increase.
BUN and serum creatinine concentrations have occasionally increased during long-term enalapril therapy.
Pharmacokinetics: Absorption: Enalapril maleate is well absorbed following oral administration. About 60% of dose is absorbed from Gl tract. Food does not affect the absorption of enalapril maleate.
Distribution: Approximately 50-60% of enalapril is bound to plasma proteins. Enalapril and enalaprilat are distributed into milk in trace amounts.
Metabolism: Enalapril is metabolized extensively in the liver to active metabolite enalaprilat, a more potent ACE inhibitor than enalapril but poorly absorbed orally. Peak serum concentrations of enalaprilat occur about 3-4.5 hours after an oral dose.
Excretion: Renal excretion is 61% (enalaprilat 43%, enalapril 18%) and feces excretion is 33% (enalaprilat 27%, enalapril 6%).
The half-life of enalapril is less than 2 hours in healthy individuals and in patients with normal hepatic and renal functions, but may be increased in patients with congestive heart failure or impaired hepatic function.
The effective half-life of enalaprilat following multiple oral doses is 11 hours in subjects with normal renal function.

Hypertension: treatment of all grades of essential hypertension and renovascular hypertension.
Congestive heart failure: Symptomatic congestive heart failure; Asymptomatic left ventricular dysfunction: treatment and prevention of progression to symptomatic heart failure in clinically stable asymptomatic patients with left ventricular dysfunction.

Recommended Doses & Mode of Administration: This drug can be given before, during, or after meals since food does not affect its absorption.
Adult Dosage: Hypertension: Initial dose is 5 mg orally once daily (no concurrent diuretic), 2.5 mg (if on existing diuretic). The dose should be titrated to give optimal blood pressure control. The usual maintenance dose is 10 to 40 daily as a single dose or two divided doses; maximum daily dose is 40 mg.
In some patients receiving once daily therapy, antihypertensive effects may diminish toward the end of a dosing interval. An increase in dosage or twice daily dosing should be considered.
Congestive Heart failure: Symptomatic Heart Failure: Initial dose is 2.5 once or twice daily. The usual maintenance dose is 2.5 to 20 mg twice daily; maximum dose is 40 mg daily in divided doses.
Asymptomatic Left Ventricular Dysfunction: Initial dose is 2.5 mg twice daily; maintenance dose is 2.5 to 10 mg twice daily; maximum dose is 20 mg daily in divided doses.
Because of the risk of severe hypotension, enalapril maleate therapy for heart failure should be initiated at low dose under close medical supervision. Carefully monitor hypotensive response to initial dose for the first 2 hours and until blood pressure stabilizes for at least 1 hour. To minimize the likelihood of hypotension, the existing diuretic doses should be reduced prior to adding angiotensin converting enzyme (ACE) inhibitor therapy if possible. Upward dose titration over a few days to weeks is recommended.
Uses in Special Population: Patients with Myocardial Infarction: Initial dose is 2.5 mg twice daily; maintenance dose is 2.5 - 10 mg twice daily; maximum dose is 20 mg daily.
Patients with Kidney Disease (Diabetic and Non-diabetic): Initial dose is 5 mg daily; maintenance dose is 5-20 mg daily; maximum dose is 20 mg daily.
Patients with Impaired Renal Function: Initial dose of 2.5 mg daily recommended for creatinine clearance 30 ml/min or less (serum creatinine 3 mg percent or greater). The dose should be titrated upward until blood pressure is controlled or a maximum of 40 mg daily is administered. (See Table 1.)

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Based on oral doses of 5-10 mg every 12 hours, the following dose adjustments are recommended. (See Table 2.)

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Patients with Hepatic Insufficiency: Since hepatic biotransformation is required for activation of enalapril, the presence of hepatic disease or hepatic congestion secondary to heart failure may impact this process and possibly result in reduced efficacy of the drug. However, dosing adjustment has not been suggested. It is possible that higher doses may have to be given in patients with impaired hepatic function.
Geriatric Patients with Hypertension: The dosage must be modified in response to the degree of renal impairment. (See Patients with Impaired Renal Function as previously mentioned.)
Pediatric Patients with Hypertension (6 months - 16 years old): Initial dose is 0.08 mg/kg (maximum 5 mg) once daily; maintenance dose is 0.08-0.58 mg/kg daily and maximum dose is 0.58 mg/kg (40 mg) daily.

Overdose: Hypotension is the most common overdose effect. Onset of hypotension is generally within 6 hours of ingestion.
Other effects: e.g., bradycardia, bronchospasm, cough, renal insufficiency, nephrotic syndrome, hyperkalemia, and neutropenia.
Treatment: Decontamination: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
Hypotensive episode: IV 0.9% NaCI 10-20 ml/kg, dopamine, norepinephrine.
Naloxone is effective in animal models and several case reports.
Angiotensin Amide - IV infusion 8.5 to 18 mcg/min is effective in several case reports.
Monitoring of patient: Monitor blood pressure, continuous cardiac monitoring, electrolytes, renal function, ECG and urinalysis in symptomatic patients.

Angioedema;
Angioedema related to prior therapy with an ACE inhibitor;
Hypersensitivity to the product (enalapril or enalaprilat or any of its components);
Pregnancy.

1. Use in pregnancy is contraindicated.
2. This drug may induce coughing.
3. Consult physician should patients develop symptoms of drowsiness or nausea/vomiting.
4. If patients develop symptoms of angioneurotic edema of the face, tongue, larynx or dyspnea after using this drug, discontinue drug and consult physician immediately.
5. This drug may cause renal failure. Therefore, it should be used with caution.
6. This drug may increase potassium blood level, so it should not be used in those patients receiving potassium supplement or potassium-sparing diuretics.

Renal function should be evaluated prior to initiation of enalapril therapy, and the drug should be used with caution in patients with renal impairment, sodium depletion or hypovolemia, receiving diuretics, and those undergoing dialysis since severe hypotension may occur. Risk for excessive hypotension sometimes associated with oliguria and/or progressive azotemia.
Enalapril should be used with caution and renal function monitored closely for the first few weeks of therapy in patients with renal-artery stenosis.
Enalapril should be administered with caution in patients with obstruction in the outflow tract of the left ventricle (e.g., aortic stenosis, hypertrophic cardiomyopathy).
Congestive heart failure, history of; risk for excessive hypotension sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure.
Hyperkalemia has been reported; increased risk with renal disease, diabetes, and concomitant use of potassium supplements, potassium containing salt substitutes, and potassium-sparing diuretics.

Pregnancy: Use in pregnancy is contraindicated. (See Contraindications and Warnings.)
Lactation: Because enalapril is distributed into human milk and potentially may cause serious adverse reactions, use in nursing infants is not recommended.

Adverse reactions to enalapril usually are mild and transient. Enalapril usually is well tolerated.
Nervous System Effects: Headache and dizziness occur in about 5% of patients receiving enalapril alone for hypertension.
Gl Effects: Diarrhea and nausea occur in about 1-2% of patients with hypertension receiving enalapril. Abdominal pain, vomiting, stomatitis, and dyspepsia occur in 0.5-2% of patients receiving enalapril.
Cardiovascular Effects: The most frequent adverse effect is hypotension which occurs in about 1-2% of patients with hypertension and in about 5-7% of those with congestive heart failure.
Renal Effects: Deterioration in renal function, manifested as transient increases in BUN and serum creatinine concentrations, has occurred in about 20% of patients with renovascular hypertension, especially those with renal-artery stenosis. This effect was usually reversible following discontinuance of enalapril and/or diuretic therapy.
Dermatologic and Sensitivity Reactions: The most frequent adverse effect is rash, (1.5%) and is usually maculopapular.
Pruritus, (0.5-2%) and alopecia (0.5-1%).
Angioedema of the face, lips, tongue, larynx, glottis, or extremities has occurred in patients receiving ACE inhibitor therapy, including enalapril. (See Contraindications.)
Effects on Potassium: Although small increases (i.e., by an average of 0.2 mEq/L) in serum potassium concentrations frequently occur in patients receiving enalapril without a thiazide diuretic, hyperkalemia (i.e., increases to greater than 5.7 mEq/L) occurs in approximately 1 or 4% of patients with hypertension or congestive heart failure, respectively, receiving the drug.
Respiratory Effects: Cough has been reported in 1.3% and 2 % of patients receiving enalapril for hypertension and CHF respectively, and is reversible following discontinuance of the drug.
Other Adverse Effects: such as muscle cramps, pancreatitis, hepatitis or cholestatic jaundice, hepatic failure and impotence.

Hypotensive Agents and Diuretics: When enalapril is administered with diuretics or other hypotensive drugs, the hypotensive effect of enalapril is increased.
Drugs Increasing Serum Potassium Concentration: Potassium-sparing diuretics (e.g., amiloride, spironolactone, triamterene), potassium supplements, or potassium-containing salt substitutes should be used with caution and serum potassium should be determined frequently in patients receiving enalapril, since hyperkalemia may occur.
Nonsteroidal Anti-inflammatory Agents (i.e., aspirin, ibuprofen): May reduce the blood pressure response to ACE inhibitors, including enalapril.
Lithium: Lithium toxicity has occurred following concomitant administration of enalapril and lithium carbonate and was reversible following discontinuance of both drugs. Serum lithium should be monitored frequently when enalapril and lithium are administered concomitantly.
Other drugs: Enalapril may reduce fasting blood glucose concentrations in nondiabetic individuals and may produce hypoglycemia in diabetic patients whose diabetes has been controlled with insulin or oral antidiabetic agents.
Concomitant use of enalapril and some vasodilating agents (e.g., nitrates) or anesthetic agents may cause an exaggerated hypotensive response.

Store below 30 °C. Preserve in well closed container.

ACE Inhibitors/Direct Renin Inhibitors

C09AA02 - enalapril ; Belongs to the class of ACE inhibitors. Used in the treatment of cardiovascular disease.

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