Enalapril Maleate 2.5 MG Oral Tablet

WARNINGS

Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including enalapril maleate) may be subject to a variety of adverse reactions, some of them serious.

Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with angiotensin converting enzyme inhibitors, including enalapril maleate.

This may occur at any time during treatment.

In such cases enalapril maleate should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms has occurred.

In instances where swelling has been confined to the face and lips the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms.

Angioedema associated with laryngeal edema may be fatal.

Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, e.g., Subcutaneous epinephrine solution 1:1000 (0.3 mL to 0.5 mL) and/or measures necessary to ensure a patent airway, should be promptly provided.

(See ADVERSE REACTIONS.) Intestinal Angioedema: Intestinal angioedema has been reported 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.

The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor.

Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also INDICATIONS AND USAGE and CONTRAINDICATIONS).

Anaphylactoid reactions during desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions.

In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid reactions during membrane exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor.

Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

Hypotension Excessive hypotension is rare in uncomplicated hypertensive patients treated with enalapril maleate alone.

Patients with heart failure given enalapril maleate commonly have some reduction in blood pressure, especially with the first dose, but discontinuation of therapy for continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy.

(See DOSAGE AND ADMINISTRATION.) Patients at risk for excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology.

It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with enalapril maleate in patients at risk for excessive hypotension who are able to tolerate such adjustments.

(See PRECAUTIONS, Drug Interactions and ADVERSE REACTIONS.) In patients at risk for excessive hypotension, therapy 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 and/or diuretic is increased.

Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.

If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline.

A transient hypotensive response is not a contraindication to further doses of enalapril maleate, which usually can be given without difficulty once the blood pressure has stabilized.

If symptomatic hypotension develops, a dose reduction or discontinuation of enalapril maleate or concomitant diuretic may be necessary.

Neutropenia/Agranulocytosis Another angiotensin converting enzyme inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment especially if they also have a collagen vascular disease.

Available data from clinical trials of enalapril are insufficient to show that enalapril does not cause agranulocytosis at similar rates.

Marketing experience has revealed cases of neutropenia or agranulocytosis in which a causal relationship to enalapril cannot be excluded.

Periodic monitoring of white blood cell counts in patients with collagen vascular disease and renal disease should be considered.

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.

Fetal/Neonatal Morbidity and Mortality ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women.

Several dozen cases have been reported in the world literature.

When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.

In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first timester exposure to ACE inhibitor drugs.

The number of cases of birth defects is small and the findings of this study are not yet been repeated.

The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death.

Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.

Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed.

Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of enalapril maleate as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found.

In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.

If oligohydramnios is observed, enalapril maleate should be discontinued unless it is considered lifesaving for the mother.

Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia.

If oliguria occurs, attention should be directed towards support of blood pressure and renal perfusion.

Exchange transfusion or dialysis may be required as 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.

No teratogenic effects of enalapril were seen in studies of pregnant rats, and rabbits.

On a body surface area basis, the doses used were 57 times and 12 times, respectively, the maximum recommended human daily dose (MRHDD)

OVERDOSAGE

Limited data are available in regard to overdosage in humans.

Single oral doses of enalapril above 1,000 mg/kg and ≥1,775 mg/kg were associated with lethality in mice and rats, respectively.

The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution.

Enalaprilat may be removed from general circulation by hemodialysis and has been removed from neonatal circulation by peritoneal dialysis.

(See WARNINGS, Anaphylactoid reactions during membrane exposure.

)

DESCRIPTION

Enalapril maleate is the maleate salt of enalapril, the ethyl ester of a long-acting angiotensin converting enzyme inhibitor, enalaprilat.

Enalapril maleate is chemically described as L-Proline,1-[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]- , (S)-, (Z)-2-butenedioate (1:1).

Its molecular 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 white to off-white, crystalline powder with a molecular weight of 492.53.

It is sparingly soluble in water, soluble in ethanol, and freely soluble in methanol.

Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme inhibitor.

Enalapril maleate is supplied as 2.5 mg, 5 mg,10 mg and 20 mg tablets for oral administration.

In addition, each tablet contains the following inactive ingredients: hypromellose, anhydrous lactose, corn starch, stearic acid and talc.

The 10 mg and 20 mg tablets also contain iron oxides.

Enalapril Structure Label

HOW SUPPLIED

Enalapril Maleate Tablets, USP NDC number Strength Description Quantity NDC 0615-4589-39 2.5 mg White, round flat-faced beveled edged, compressed tablets with W on one side and breakline on the other side.

923 Blisterpacks of 30’s.

NDC 0615-4590-39 NDC 0615-4590-31 5 mg White, round flat-faced beveled edged, compressed tablets with W on one side and breakline on the other side.

924 Blisterpacks of 30’s and 31’s.

NDC 0615-4591-39 NDC 0615-4591-31 10 mg Light Salmon, round flat-faced beveled edged, compressed tablets with W on one side plain on the other side.

925 Blisterpacks of 30’s and 31’s.

NDC 0615-4593-39 20 mg Light Beige, round flat-faced beveled edged, compressed tablets with W on one side plain on the other side.

926 Blisterpacks of 30’s.

S to rage Store below 30°C (86°F) and avoid transient temperatures above 50°C (122°F).

Keep container tightly closed.

Protect from moisture.

Dispense in a tight container as per USP, if product package is subdivided.

___________________________________________________________________________________________________________________________________ ** Registered trademark of Alza Corporation.

*** Trademark of Paddock Laboratories, Inc.

Manufactured by: Wockhardt Limited , Mumbai, India.

Distributed by: Wockhardt USA LLC.

20 Waterview Blvd.

Parsippany, NJ 07054 USA.

Rev.

080610

INDICATIONS AND USAGE

Hypertension Enalapril maleate is indicated for the treatment of hypertension.

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.

Heart Failure Enalapril maleate is indicated for the treatment of symptomatic congestive heart failure, usually in combination with diuretics and digitalis.

In these patients enalapril maleate improves symptoms, increases survival, and decreases the frequency of hospitalization (see CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials).

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.

(See CLINICAL PHARMACOLOGY, Heart Failure, Mortality Trials for details and limitations of survival trials.) In using enalapril maleate, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that enalapril maleate does not have a similar risk.

(See WARNINGS.) In considering use of enalapril maleate, it should be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks.

In addition, it should be noted that black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.

(See WARNINGS, Head and Neck Angioedema .)

DOSAGE AND ADMINISTRATION

Hypertension In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally may occur following the initial dose of Enalapril Maleate Tablets.

The diuretic should, if possible, be discontinued for two to three days before beginning therapy with Enalapril Maleate Tablets to reduce the likelihood of hypotension.

(See WARNINGS.) If the patient’s blood pressure is not controlled with Enalapril Maleate Tablets alone, diuretic therapy may be resumed.

If the diuretic cannot be discontinued an initial dose of 2.5 mg should be used under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour.

(See WARNINGS and PRECAUTIONS, Drug Interactions .) The recommended initial dose in patients not on diuretics is 5 mg once a day.

Dosage should be adjusted according to blood pressure response.

The usual dosage range is 10 to 40 mg per day administered in a single dose or two divided doses.

In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval.

In such patients, an increase in dosage or twice daily administration should be considered.

If blood pressure is not controlled with Enalapril Maleate Tablets alone, a diuretic may be added.

Concomitant administration of Enalapril Maleate Tablets with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium (see PRECAUTIONS).

Dosage Adjustment in Hypertensive Patients with Renal Impairment The usual dose of enalapril is recommended for patients with a creatinine clearance >30 mL/min (serum creatinine of up to approximately 3 mg/dL).

For patients with creatinine clearance ≤30 mL/min (serum creatinine ≥3 mg/dL), the first dose is 2.5 mg once daily.

The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.

Renal Status Creatinine- Clearance ml/min Initial Dose mg/day Normal Renal Function >80 mL/min 5 mg Mild Impairment ≤80> 30 mL/min 5 mg Moderate to Severe Impairment ≤30 mL/min 2.5 mg Dialysis Patients*** – – 2.5 mg on dialysis days † ***See WARNINGS, Anaphylactoid reactions during membrane exposure.

† Dosage on nondialysis days should be adjusted depending on the blood pressure response.

Heart Failure Enalapril Maleate Tablets are indicated for the treatment of symptomatic heart failure, usually in combination with diuretics and digitalis.

In the placebo-controlled studies that demonstrated improved survival, patients were titrated as tolerated up to 40 mg, administered in two divided doses.

The recommended initial dose is 2.5 mg.

The recommended dosing range is 2.5 to 20 mg given twice a day.

Doses should be titrated upward, as tolerated, over a period of a few days or weeks.

The maximum daily dose administered in clinical trials was 40 mg in divided doses.

After the initial dose of Enalapril Maleate Tablets, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour.

(See WARNINGS and PRECAUTIONS, Drug Interactions .) If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension.

The appearance of hypotension after the initial dose of Enalapril Maleate Tablets does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

Asymptomatic Left Ventricular Dysfunction In the trial that demonstrated efficacy, patients were started on 2.5 mg twice daily and were titrated as tolerated to the targeted daily dose of 20 mg (in divided doses).

After the initial dose of Enalapril Maleate Tablets, the patient should be observed under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour.

(See WARNINGS and PRECAUTIONS, Drug Interactions .) If possible, the dose of any concomitant diuretic should be reduced which may diminish the likelihood of hypotension.

The appearance of hypotension after the initial dose of Enalapril Maleate Tablets does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.

Dosage Adjustment in Patients with Heart Failure and Renal Impairment or Hyponatremia In patients with heart failure who have hyponatremia (serum sodium less than 130 mEq/L) or with serum creatinine greater than 1.6 mg/dL, therapy should be initiated at 2.5 mg daily under close medical supervision.

(See , Heart Failure, WARNINGS and PRECAUTIONS, Drug Interactions .) The dose may be increased to 2.5 mg b.i.d., then 5 mg b.i.d.

and higher as needed, usually at intervals of four days or more if at the time of dosage adjustment there is not excessive hypotension or significant deterioration of renal function.

The maximum daily dose is 40 mg.

Pediatric Hypertensive Patients The usual recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily.

Dosage should be adjusted according to 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, Clinical Pharmacology in Pediatric Patients.

) Enalapril maleate 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.

Preparation of Suspension (for 200 mL of a 1.0 mg/mL suspension) Add 50 mL of Bicitra ®** to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of Enalapril maleate and shake for at least 2 minutes.

Let concentrate stand for 60 minutes.

Following the 60-minute hold time, shake the concentrate for an additional minute.

Add 150 mL of Ora-Sweet SF TM*** to the concentrate in the PET bottle and shake the suspension to disperse the ingredients.

The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 30 days.

Shake the suspension before each use.