Bentuk Sediaan
Liquid/Solution
Rute Pemberian
ORAL
About This Medication
11 DESCRIPTION Enalapril maleate oral solution is the maleate salt of enalapril, the ethyl ester prodrug of a long-acting angiotensin-converting enzyme inhibitor, enalaprilat. Enalapril maleate is chemically described as (S)-1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its empirical formula is C 20 H 28 N 2 O 5 •C 4 H 4 O 4 , and its structural formula is: Enalapril maleate is a off-white, crystalline powder with a molecular weight of 492.52. It is practically insoluble in n-Heptane (nonpolar organic solvent), slightly soluble in acetone (semi polar organic solvent), sparingly soluble in water, soluble in alcohol, and freely soluble in methanol and dimethyl formamide. Enalapril maleate oral solution is a ready-to-use oral solution. Each 1 mL contains 1 mg of enalapril maleate, USP equivalent to 0.764 mg of enalapril. Inactive ingredients include citric acid, mixed berry flavor, purified water, sodium citrate, methylparaben, propyl paraben, xylitol and sucralose. It may also contain hydrochloric acid or sodium hydroxide for pH adjustment. Enalapril maleate oral solution is clear and colorless. enalapril-st
Bahan Aktif
| Bahan |
Kekuatan |
| Enalapril Maleate |
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Indikasi & Penggunaan
1 INDICATIONS & USAGE Enalapril maleate is an angiotensin-converting enzyme inhibitor indicated for: treatment of hypertension in adults and children older than one month, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. ( 1.1 ) treatment of symptomatic heart failure. ( 1.2 ) treatment of asymptomatic left ventricular dysfunction, to decrease the rate of development of overt heart failure and reduce hospitalization for heart failure. ( 1.3 ) 1.1 Hypertension Enalapril maleate is indicated for the treatment of hypertension, to lower blood pressure in adults and children older than one month [see Pediatric Use ( 8.4) and Clinical Studies ( 14 )]. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in Black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. Enalapril maleate is effective alone or in combination with other antihypertensive agents, especially thiazide-type diuretics. The blood pressure lowering effects of enalapril maleate and thiazides are approximately additive. 1.2 Heart Failure Enalapril maleate is indicated for the treatment of symptomatic heart failure, usually in combination with diuretics and digitalis. In these patients, enalapril maleate increases survival and decreases the frequency of hospitalization. 1.3 Asymptomatic Left Ventricular Dysfunction In clinically stable asymptomatic patients with left ventricular dysfunction (ejection fraction ≤35 percent), enalapril maleate decreases the rate of development of overt heart failure and decreases the incidence of hospitalization for heart failure.
Cara kerja
12.1 Mechanism of Action Enalapril, after hydrolysis to enalaprilat, inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of enalapril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalapril maleate tablets alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril maleate tablets plus a thiazide diuretic, there was essentially no change in serum potassium [see Warnings and Precautions ( 5.6 )] . Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of enalapril maleate remains to be elucidated. While the mechanism through which enalapril maleate lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension. Although enalapril maleate tablets were antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril monotherapy than non-Black patients.
Dosis & Cara Pemberian
2 DOSAGE & ADMINISTRATION Hypertension Adult: recommended initial dose is 5 mg once daily. Maximum dose is 40 mg daily. ( 2.1 ) Pediatrics: recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. ( 2.1 ) Heart Failure: Initiate at 2.5 mg twice daily. Titrate up to 20 mg twice daily as tolerated. ( 2.2 ) Asymptomatic Left Ventricular Dysfunction: Initiate at 2.5 mg twice daily. Titrate up to 10 mg twice daily. ( 2.3 ) Enalapril maleate oral solution is a ready-to-use solution intended for oral use only. 2.1 Hypertension Adults : The recommended initial dose in adults is 5 mg taken orally once a day. Titrate upward to maximum of 40 mg daily as needed to help achieve blood pressure goals. The dose may be divided and administered twice daily if the antihypertensive effect diminishes at the end of the dosing interval. Use with diuretics: If additional blood pressure reduction is needed, enalapril maleate may be administered with a low dose of diuretic. The recommended initial dose in patients taking diuretics is 2.5 mg daily. Dosage Adjustment for Renal Impairment: See table below. The dosage may be titrated upward as needed to a maximum of 40 mg daily. Renal Status Creatinine-Clearance mL/min Initial Dose mg/day Normal or Mild Impairment of Renal Function greater than 30 mL/min 5 mg Moderate to Severe Impairment ≤30 mL/min 2.5 mg Dialysis Patients*† – 2.5 mg * = [See Warnings and Precautions (5.2)]. † = Should be taken after hemodialysis on dialysis days [see Clinical Pharmacology 12.3)] . Calculated using ideal body weight. Children greater than 1 month of age: The usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily. Adjust dose based on blood pressure response. Doses above 0.58 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients [see Clinical Pharmacology ( 12.3 )] . Enalapril maleate is not recommended in neonates (i.e., infants 1 month of age or less), preterm infants who have not reached a corrected post-conceptual age of 44 weeks, and in pediatric patients with glomerular filtration rate less than 30 mL/min/1.73 m 2 . 2.2 Heart Failure The recommended initial dose is 2.5 mg twice a day titrated up to a maximum of 20 mg twice a day, as tolerated. Doses are usually given in combination with diuretics and digitalis. In patients with hyponatremia (serum sodium less than 130 mEq/L) or serum creatinine greater than 1.6 mg/dL, the recommended initial dose is 2.5 mg once daily. Diuretic dose may need to be adjusted to minimize hypovolemia and hypotension. The appearance of hypotension after the initial dose of enalapril maleate does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. 2.3 Asymptomatic Left Ventricular Dysfunction The recommended initial dose is 2.5 mg twice a day titrated up to a maximum of 10 mg twice a day, as tolerated. Diuretic dose may need to be adjusted [see Dosage and Administration ( 2.1 )] .
Side Effects Overview
6 ADVERSE REACTIONS The following adverse reactions are described elsewhere: Angioedema [see Warnings and Precautions ( 5.2 )] Hypotension [see Warnings and Precautions ( 5.3 )] Hepatic failure [see Warnings and Precautions ( 5.4 )] Renal impairment [see Warnings and Precautions ( 5.5 )] Hyperkalemia [see Warnings and Precautions ( 5.6 )] The most common adverse reaction for patients treated for hypertension (≥3%) was fatigue. ( 6.1 ) The most common adverse reactions for patients treated for heart failure (greater than 6%) were hypotension and dizziness. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Ascend Laboratories, LLC at 1-877-ASC-RX01 (877-272-7901) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Enalapril has been evaluated for safety in more than 10,000 patients, including over 1,000 patients treated for one year or more. In clinical trials, discontinuation of therapy for clinical adverse experiences was required in 3.3% of patients with hypertension and in 5.7% of patients with heart failure. Hypertension Adverse reactions (where rate on enalapril exceeds the rate on placebo by at least 0.2%) 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 three years; in placebo treated patients, the maximum duration of therapy was 12 weeks. Adverse Reactions Occurring in Greater Than 1% of Patients With Hypertension Enalapril Maleate Tablets (n=2314) Incidence (discontinuation) Placebo (n = 230) Incidence Body As A Whole Fatigue 3.0 (less than 0.1) 2.6 Orthostatic Effects 1.2 (less than 0.1) 0.0 Asthenia 1.1 (0.1) 0.9 Respiratory Cough 1.3 (0.1) 0.9 Skin Rash 1.4 (0.4) 0.4 Heart Failure Adverse reactions seen in clinical trials of heart failure were similar to those seen in clinical trials for hypertension. In patients treated for heart failure, there was an increased incidence of hypotension 6.7 percent versus 0.6 percent in placebo and dizziness 7.9 percent versus 0.6 percent in placebo. 6.2 Other Adverse Reactions from Clinical Studies or Postmarketing Experience The following adverse reactions have been reported in clinical studies or postmarketing experience with enalapril. Because some of these reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Other serious clinical adverse experiences occurring since the drug was marketed or adverse experiences occurring in 0.5 to 1.0% of patients with hypertension or heart failure in clinical trials are listed below and, within each category, are in order of decreasing severity. Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident, possibly secondary to excessive hypotension in high risk patients [see Warnings and Precautions ( 5.3 )] ; pulmonary embolism and infarction; pulmonary edema; rhythm disturbances, including atrial tachycardia and bradycardia; atrial fibrillation; palpitation; Raynaud's phenomenon. Digestive: Ileus, pancreatitis, melena, anorexia, dyspepsia, constipation, glossitis, stomatitis, dry mouth. Hematologic: Rare cases of neutropenia, thrombocytopenia, and bone marrow depression. Musculoskeletal: Muscle cramps. Nervous/Psychiatric: Depression, confusion, ataxia, somnolence, insomnia, nervousness, peripheral neuropathy (e.g., paresthesia, dysesthesia), dream abnormality. Respiratory: Bronchospasm, rhinorrhea, sore throat and hoarseness, asthma, upper respiratory infection, pulmonary infiltrates, eosinophilic pneumonitis. Skin: Exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, pemphigus, herpes zoster, erythema multiforme, urticaria, pruritus, alopecia, flushing, diaphoresis, photosensitivity. Special Senses: Blurred vision, taste alteration, anosmia, tinnitus, conjunctivitis, dry eyes, tearing. Urogenital: Flank pain, gynecomastia, impotence. Miscellaneous: A symptom complex has been reported which may include some or all of the following: a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia/myositis, fever, serositis, vasculitis, leukocytosis, eosinophilia, photosensitivity, dermatologic manifestations.
Peringatan & Tindakan Pencegahan
5 WARNINGS AND PRECAUTIONS Angioedema and Anaphylactoid Reactions. (5.2) Impaired Renal Function: Assess renal function. (5.5) Hyperkalemia. (5.6) 5.1 Fetal Toxicity Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Enalapril maleate as soon as possible [see Use in Specific Populations ( 8.1 )] . 5.2 Angioedema and Anaphylactoid Reactions Angioedema Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis and/or larynx, including some fatal reactions, have occurred in patients treated with angiotensin converting enzyme inhibitors, including enalapril maleate, at any time during treatment. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. Enalapril maleate should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor [see Contraindications ( 4 )] . ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema [see Drug Interactions ( 7.6 , 7.7 )]. Intestinal Angioedema Intestinal angioedema has occurred in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. In some cases, the angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Anaphylactoid Reactions Anaphylactoid Reactions during Desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. Anaphylactoid Reactions during Dialysis Sudden and potentially life-threatening anaphylactoid reactions have occurred in some patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. 5.3 Hypotension Enalapril maleate can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure or death. Patients at risk of excessive hypotension include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal dialysis, or severe volume and/or salt depletion of any etiology. In these patients, Enalapril maleate should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of enalapril maleate and/or diuretic is increased. Symptomatic hypotension is also possible in patients with severe aortic stenosis or hypertrophic cardiomyopathy. Surgery/Anesthesia In patients undergoing major surgery or during anesthesia with agents that produce hypotension, Enalapril maleate may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be through this mechanism, it can be corrected by volume expansion. 5.4 Hepatic Failure Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis, and (sometimes) death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. 5.5 Impaired Renal Function Monitor renal function in patients treated with enalapril maleate. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system(e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post-myocardial infarction or volume depletion) may be at particular risk of developing acute renal failure on enalapril maleate. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on enalapril maleate [see Adverse Reactions ( 6.2 ), Drug Interactions ( 7.2 , 7.3 )] . 5.6 Hyperkalemia Serum potassium should be monitored in patients receiving enalapril maleate. Drugs that inhibit the renin angiotensin system can cause hyperkalemia. 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 [see Drug Interactions ( 7.3 )].
Kontraindikasi
4 CONTRAINDICATIONS Enalapril maleate is contraindicated in patients with: a history of angioedema or hypersensitivity related to previous treatment with an angiotensin converting enzyme (ACE) inhibitor. [see Warnings and Precautions (5.2)] hereditary or idiopathic angioedema. [see Warnings and Precautions ( 5.2 )] Do not co-administer aliskiren with enalapril maleate in patients with diabetes [see Drug Interactions ( 7.2 )] Enalapril maleate is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer enalapril maleate within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see Warnings and Precautions (5.2)] . Hypersensitivity related to previous treatment with an ACEI. (4) Hereditary or idiopathic angioedema. (4) Do not co-administer aliskiren in patients with diabetes. (4) In combination with a neprilysin inhibitor. (4)
Farmakokinetik
12.3 Pharmacokinetics The pharmacokinetics of ready-to-use enalapril maleate oral solution was shown to be bioequivalent to that of reconstituted enalapril maleate powder for oral solution under fasted conditions. Reconstituted enalapril maleate Powder for oral solution was shown to be bioequivalent to Vasotec ® tablets. Reconstituted enalapril maleate Powder for oral solution was also evaluated under fed and fasted conditions. A high-fat meal reduced the Cmax of enalapril and enalaprilat by 46% and 36%, respectively. The exposure, as measured by AUC, to enalaprilat was reduced by 23%. The time to peak concentrations (Cmax) was delayed by 20 minutes for enalapril and 62 minutes for enalaprilat. The trough plasma concentrations of enalapril (from 6 to 12 hours) and enalaprilat (from 16 to 36 hours) are similar between fasted and fed administrations. Adults Following oral administration of enalapril maleate tablets, peak serum concentrations of enalapril occur within about one hour. Based on urinary recovery, the extent of absorption of enalapril is approximately 60%. Enalapril absorption is not influenced by the presence of food in the gastrointestinal tract. Following absorption, enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin-converting enzyme inhibitor than enalapril; enalaprilat is poorly absorbed when administered orally. Peak serum concentrations of enalaprilat occur three to four hours after an oral dose of enalapril maleate. Excretion of enalapril is primarily renal. Approximately 94% of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours. The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With glomerular filtration rate ≤30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases, and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency [see Dosage and Administration (2.1)] . Enalaprilat is dialyzable at the rate of 62 mL/min. Administering enalapril 1 h after hemodialysis led to a reduction of approximately 50% in the enalaprilat AUC 0 to 6h compared to off dialysis days. Pediatric Patients A multiple dose pharmacokinetics study was conducted in 40 hypertensive male and female pediatric patients aged 2 months to ≤16 years following daily oral administration of 0.07 to 0.14 mg/kg enalapril maleate. At steady state, the mean effective half-life for accumulation of enalaprilat was 14 hours and the mean urinary recovery of total enalapril and enalaprilat in 24 hours was 68% of the administered dose. Conversion of enalapril to enalaprilat was in the range of 63 to76%. The overall results of this study indicate that the pharmacokinetics of enalapril in hypertensive children aged 6 to ≤16 years are consistent across the studied age groups and consistent with pharmacokinetic historical data in healthy adults. Hypertensive children aged 2 months to 6 years required higher weight-based doses (0.13 mg/kg and 0.11 mg/kg) compared to the older age groups (0.11 mg/kg and 0.07 mg/kg), to achieve similar steady-state AUC. In the above pediatric study, enalapril maleate was given as tablets and for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form, enalapril was administered in a suspension formulation.