Document
DailyMed Label: Enalapril Maleate and Hydrochlorothiazide
Title
DailyMed Label: ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE
Date
2009
Document type
DailyMed Prescription
Name
ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE
Generic name
ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE
Manufacturer
Physicians Total Care, Inc.
Product information
NDC: 54868-5503
Product information
NDC: 54868-5503
Product information
NDC: 54868-5100
Product information
NDC: 54868-5100
Description
Enalapril maleate and hydrochlorothiazide
combines an angiotensin converting enzyme inhibitor, enalapril maleate, and a
diuretic, hydrochlorothiazide.
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 ( 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 white to off-white crystalline powder with a molecular
weight of 492.52. 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.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its
empirical formula is C 7 H 8 ClN 3 O 4 S 2 and its
structural formula is:
It is a white, or practically white, crystalline powder with a molecular
weight of 297.74, which is slightly soluble in water, but freely soluble in
sodium hydroxide solution.
Enalapril Maleate and Hydrochlorothiazide is available in two tablet
combinations of enalapril maleate with hydrochlorothiazide: Enalapril Maleate
and Hydrochlorothiazide Tablets 5/12.5, containing 5 mg enalapril maleate and
12.5 mg hydrochlorothiazide and Enalapril Maleate and Hydrochlorothiazide
Tablets 10/25, containing 10 mg enalapril maleate and 25 mg hydrochlorothiazide.
Inactive ingredients are: anhydrous lactose, red ferric oxide, and zinc
stearate.
image of Enalapril Maleate chemical structure
image of Hydrochlorothiazide chemical structure
Indications
Enalapril maleate and hydrochlorothiazide tablets are indicated
for the treatment of hypertension.
These fixed dose combinations are not indicated for initial treatment (see DOSAGE AND ADMINISTRATION ).
In using enalapril maleate and hydrochlorothiazide tablets, 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 does not have a similar risk (see WARNINGS ).
In considering use of enalapril maleate and hydrochlorothiazide tablets, 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:
Angioedema
).
Dosage
Enalapril and hydrochlorothiazide are effective treatments for
hypertension. The usual dosage range of enalapril is 10 to 40 mg per day
administered in a single or two divided doses; hydrochlorothiazide is effective
in doses of 12.5 to 50 mg daily. The side effects (see WARNINGS ) of enalapril are generally rare and apparently
independent of dose; those of hydrochlorothiazide are a mixture of
dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena
(e.g., pancreatitis), the former much more common than the latter. Therapy with
any combination of enalapril and hydrochlorothiazide will be associated with
both sets of dose-independent side effects but the addition of enalapril in
clinical trials blunted the hypokalemia normally seen with diuretics. To
minimize dose-independent side effects, it is usually appropriate to begin
combination therapy only after a patient has failed to achieve the desired
effect with monotherapy.
Dose Titration Guided by Clinical
Effect: A patient whose blood pressure is not adequately controlled with
either enalapril or hydrochlorothiazide monotherapy may be given enalapril
maleate and hydrochlorothiazide tablets 5/12.5 or enalapril maleate and
hydrochlorothiazide tablets 10/25. Further increases of enalapril,
hydrochlorothiazide or both depend on clinical response. The hydrochlorothiazide
dose should generally not be increased until 2-3 weeks have elapsed. In general,
patients do not require doses in excess of 20 mg of enalapril or 50 mg of
hydrochlorothiazide. The daily dosage should not exceed four tablets of
enalapril maleate and hydrochlorothiazide tablets 5/12.5 or two tablets of
enalapril maleate and hydrochlorothiazide tablets 10/25.
Replacement Therapy: The combination
may be substituted for the titrated components.
Use in Renal Impairment: The usual
regimens of therapy with enalapril maleate and hydrochlorothiazide need not be
adjusted as long as the patient's creatinine clearance is >30
mL/min/1.73m 2 (serum creatinine approximately ≤ 3 mg/dL
or 265 mcmol/L). In patients with more severe renal impairment, loop diuretics
are preferred to thiazides, so enalapril maleate-hydrochlorothiazide is not
recommended (see WARNINGS:
Anaphylactoid reactions during
membrane exposure
).
Contraindications
Enalapril maleate and hydrochlorothiazide tablets are contraindicated in
patients who are hypersensitive to any component of this product and in patients
with a history of angioedema related to previous treatment with an angiotensin
converting enzyme inhibitor and in patients with hereditary or idiopathic
angioedema. Because of the hydrochlorothiazide component, this product is
contraindicated in patients with anuria or hypersensitivity to other
sulfonamide-derived drugs.
Precautions
General
Enalapril Maleate
Aortic Stenosis/Hypertrophic
Cardiomyopathy: As with all vasodilators, enalapril should be given with
caution to patients with obstruction in the outflow tract of the left
ventricle.
Impaired Renal Function: As a
consequence of inhibiting the renin-angiotensin-aldosterone system, changes in
renal function may be anticipated in susceptible individuals. In patients with
severe congestive heart failure whose renal function may depend on the activity
of the renin-angiotensin-aldosterone system, treatment with angiotensin
converting enzyme inhibitors, including enalapril, may be associated with
oliguria and/or progressive azotemia and rarely with acute renal failure and/or
death.
In clinical studies in hypertensive patients with unilateral or bilateral
renal artery stenosis, increases in blood urea nitrogen and serum creatinine
were observed in 20 percent of patients. These increases were almost always
reversible upon discontinuation of enalapril and/or diuretic therapy. In such
patients renal function should be monitored during the first few weeks of
therapy.
Some patients with hypertension or heart failure with no apparent
pre-existing renal vascular disease have developed increases in blood urea and
serum creatinine, usually minor and transient, especially when enalapril has
been given concomitantly with a diuretic. This is more likely to occur in
patients with pre-existing renal impairment. Dosage reduction of enalapril
and/or discontinuation of the diuretic may be required.
Evaluation of the hypertensive patient should always include
assessment of renal function.
Hyperkalemia: Elevated serum potassium
(greater than 5.7 mEq/L) was observed in approximately one percent of
hypertensive patients in clinical trials treated with enalapril alone. In most
cases these were isolated values which resolved despite continued therapy,
although hyperkalemia was a cause of discontinuation of therapy in 0.28 percent
of hypertensive patients. Hyperkalemia was less frequent (approximately 0.1
percent) in patients treated with enalapril plus hydrochlorothiazide. 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, which should
be used cautiously, if at all, with enalapril (see
Drug Interactions
).
Cough: Presumably due to the
inhibition of the degradation of endogenous bradykinin, persistent nonproductive
cough has been reported with all ACE inhibitors, always resolving after
discontinuation of therapy. ACE inhibitor-induced cough should be considered in
the differential diagnosis of cough.
Surgery/Anesthesia: In patients
undergoing major surgery or during anesthesia with agents that produce
hypotension, enalapril may block angiotensin II formation secondary to
compensatory renin release. If hypotension occurs and is considered to be due to
this mechanism, it can be corrected by volume expansion.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect possible
electrolyte imbalance should be performed at appropriate intervals. All patients
receiving thiazide therapy should be observed for clinical signs of fluid or
electrolyte imbalance: hyponatremia, hypochloremic alkalosis, and hypokalemia.
Serum and urine electrolyte determinations are particularly important when the
patient is vomiting excessively or receiving parenteral fluids. Warning signs or
symptoms of fluid and electrolyte imbalance, irrespective of cause, include
dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness,
confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension,
oliguria, tachycardia, and gastrointestinal disturbances such as nausea and
vomiting.
Hypokalemia may develop, especially with brisk diuresis, when severe
cirrhosis is present, or after prolonged therapy. Interference with adequate
oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may
cause cardiac arrhythmia and may also sensitize or exaggerate the response of
the heart to the toxic effects of digitalis (e.g., increased ventricular
irritability). Because enalapril reduces the production of aldosterone,
concomitant therapy with enalapril attenuates the diuretic-induced potassium
loss (see
Drug Interactions,
Agents Increasing Serum Potassium
).
Although any chloride deficit is generally mild and usually does not require
specific treatment except under extraordinary circumstances (as in liver disease
or renal disease), chloride replacement may be required in the treatment of
metabolic alkalosis.
Dilutional hyponatremia may occur in edematous patients in hot weather;
appropriate therapy is water restriction, rather than administration of salt
except in rare instances when the hyponatremia is life-threatening. In actual
salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients
receiving thiazide therapy.
In diabetic patients dosage adjustments of insulin or oral hypoglycemic
agents may be required. Hyperglycemia may occur with thiazide diuretics. Thus
latent diabetes mellitus may become manifest during thiazide therapy.
The antihypertensive effects of the drug may be enhanced in the
postsympathectomy patient.
If progressive renal impairment becomes evident consider withholding or
discontinuing diuretic therapy.
Thiazides have been shown to increase the urinary excretion of magnesium;
this may result in hypomagnesemia.
Thiazides may decrease urinary calcium excretion. Thiazides may cause
intermittent and slight elevation of serum calcium in the absence of known
disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden
hyperparathyroidism. Thiazides should be discontinued before carrying out tests
for parathyroid function.
Increases in cholesterol and triglyceride levels may be associated with
thiazide diuretic therapy.
Information for Patients
Angioedema: Angioedema, including
laryngeal edema, may occur at any time during treatment with angiotensin
converting enzyme inhibitors, including enalapril. Patients should be so advised
and told to report immediately any signs or symptoms suggesting angioedema
(swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or
breathing) and to take no more drug until they have consulted with the
prescribing physician.
Hypotension: Patients should be
cautioned to report lightheadedness especially during the first few days of
therapy. If actual syncope occurs, the patients should be told to discontinue
the drug until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration
may lead to an excessive fall in blood pressure because of reduction in fluid
volume. Other causes of volume depletion such as vomiting or diarrhea may also
lead to a fall in blood pressure; patients should be advised to consult with the
physician.
Hyperkalemia: Patients should be told
not to use salt substitutes containing potassium without consulting their
physician.
Neutropenia: Patients should be told
to report promptly any indication of infection (e.g., sore throat, fever) which
may be a sign of neutropenia.
Pregnancy: Female patients of
childbearing age should be told about the consequences of second- and
third-trimester exposure to ACE inhibitors, and they should also be told that
these consequences do not appear to have resulted from intrauterine
ACE-inhibitor exposure that has been limited to the first trimester. These
patients should be asked to report pregnancies to their physicians as soon as
possible.
NOTE: As with many other drugs, certain advice to patients being treated with
enalapril maleate and hydrochlorothiazide is warranted. This information is
intended to aid in the safe and effective use of this medication. It is not a
disclosure of all possible adverse or intended effects.
Drug Interactions
Enalapril Maleate
Hypotension – Patients on Diuretic
Therapy: Patients on diuretics and especially those in whom diuretic
therapy was recently instituted, may occasionally experience an excessive
reduction of blood pressure after initiation of therapy with enalapril. The
possibility of hypotensive effects with enalapril can be minimized by either
discontinuing the diuretic or increasing the salt intake prior to initiation of
treatment with enalapril. If it is necessary to continue the diuretic, provide
medical supervision for at least two hours and until blood pressure has
stabilized for at least an additional hour (see WARNINGS and DOSAGE AND
ADMINISTRATION ).
Agents Causing Renin Release: The
antihypertensive effect of enalapril is augmented by antihypertensive agents
that cause renin release (e.g., diuretics).
Non-steroidal Anti-inflammatory
Agents: In some patients with compromised renal function who are being
treated with non-steroidal anti-inflammatory drugs, the coadministration of
enalapril may result in a further deterioration of renal function. These effects
are usually reversible.
In a clinical pharmacology study, indomethacin or sulindac was administered
to hypertensive patients receiving enalapril maleate. In this study there was no
evidence of a blunting of the antihypertensive action of enalapril maleate.
However, reports suggest that NSAIDs may diminish the antihypertensive effect of
ACE inhibitors. This interaction should be given consideration in patients
taking NSAIDs concomitantly with ACE inhibitors.
Other Cardiovascular Agents: Enalapril
has been used concomitantly with beta adrenergic-blocking agents, methyldopa,
nitrates, calcium-blocking agents, hydralazine and prazosin without evidence of
clinically significant adverse interactions.
Agents Increasing Serum Potassium:
Enalapril attenuates diuretic-induced potassium loss. 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.
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.
Hydrochlorothiazide
When administered concurrently the following drugs may interact
with thiazide diuretics:
Alcohol, barbiturates, or narcotics – potentiation
of orthostatic hypotension may occur.
Antidiabetic drugs (oral agents and insulin) –
dosage adjustment of the antidiabetic drug may be required.
Other antihypertensive drugs – additive effect or
potentiation.
Cholestyramine and colestipol resins – Absorption
of hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Single doses of either cholestyramine or colestipol resins bind the
hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by
up to 85 and 43 percent, respectively.
Corticosteroids, ACTH – intensified electrolyte
depletion, particularly hypokalemia.
Pressor amines (e.g., norepinephrine) – possible
decreased response to pressor amines but not sufficient to preclude their
use.
Skeletal muscle relaxants, nondepolarizing (e.g.,
tubocurarine) – possible increased responsiveness to the muscle
relaxant.
Lithium – should not generally be given with
diuretics. Diuretic agents reduce the renal clearance of lithium and add a high
risk of lithium toxicity. Refer to the package insert for lithium preparations
before use of such preparations with enalapril maleate and
hydrochlorothiazide.
Non-steroidal Anti-inflammatory Drugs – In some
patients, the administration of a non-steroidal anti-inflammatory agent can
reduce the diuretic, natriuretic, and antihypertensive effects of loop,
potassium-sparing and thiazide diuretics. Therefore, when enalapril maleate and
hydrochlorothiazide and non-steroidal anti-inflammatory agents are used
concomitantly, the patient should be observed closely to determine if the
desired effect of the diuretic is obtained.
Carcinogenesis, Mutagenesis, Impairment of
Fertility
Enalapril in combination with hydrochlorothiazide was not mutagenic in the
Ames microbial mutagen test with or without metabolic activation.
Enalapril-hydrochlorothiazide did not produce DNA single strand breaks in an
in vitro alkaline elution assay in rat hepatocytes or
chromosomal aberrations in an in vivo mouse bone
marrow assay.
Enalapril Maleate : 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).
Hydrochlorothiazide:
Two year feeding studies in mice and rats conducted under the
auspices of the National Toxicology Program (NTP) uncovered no evidence of a
carcinogenic potential of hydrochlorothiazide in female mice at doses up to
approximately 600 mg/kg/day (53 times the MRHDD when compared on a body surface
area basis) or in male and female rats at doses up to approximately 100
mg/kg/day (18 times the MRHDD when compared on a body surface area basis). The
NTP, however, found equivocal evidence for hepatocarcinogenicity in male
mice.
Hydrochlorothiazide was not genotoxic in vitro in
the Ames mutagenicity assay of Salmonella typhimurium
strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 and in the Chinese Hamster
Ovary (CHO) test for chromosomal aberrations, or in
vivo in assays using mouse germinal cell chromosomes, Chinese hamster
bone marrow chromosomes, and the Drosophila
sex-linked recessive lethal trait gene. Positive test results were obtained only
in the in vitro CHO Sister Chromatid Exchange
(clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using
concentrations of hydrochlorothiazide from 43 to 1300 mcg/mL, and in the Aspergillus nidulans non-disjunction assay at an
unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats
of either sex in studies wherein these species were exposed, via their diet, to
doses of up to 100 and 4 mg/kg, respectively, prior to mating and throughout
gestation. In mice and rats these doses are 9 times and 0.7 times, respectively,
the MRHDD when compared on a body surface area basis.
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters): See WARNINGS:
Pregnancy, Enalapril Maleate, Fetal/Neonatal
Morbidity and Mortality
.
Nursing Mothers
Enalapril, enalaprilat, and hydrochlorothiazide have been detected in human
breast milk. Because of the potential for serious reactions in nursing infants
from either drug, a decision should be made whether to discontinue nursing or to
discontinue enalapril maleate and hydrochlorothiazide, taking into account the
importance of the drug to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been
established.
Geriatric Use
Clinical studies of enalapril maleate and hydrochlorothiazide tablets did not
include sufficient numbers of subjects aged 65 and over to determine whether
they respond differently from younger subjects. Other reported clinical
experience has not identified differences in responses between the elderly and
younger patients. In general, dose selection for an elderly patient should be
cautious, usually starting at the low end of the dosing range, reflecting the
greater frequency of decreased hepatic, renal, or cardiac function, and of
concomitant disease or other drug therapy.
This drug is known to be substantially excreted by the kidney, and the risk
of toxic reactions to this drug may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selection. Evaluation of the hypertensive
patient should always include assessment of renal function (see DOSAGE AND ADMINISTRATION ).
Adverse reactions
Enalapril maleate and hydrochlorothiazide has been evaluated for
safety in more than 1500 patients, including over 300 patients treated for one
year or more. In clinical trials with enalapril maleate and hydrochlorothiazide
no adverse experiences peculiar to this combination drug have been observed.
Adverse experiences that have occurred, have been limited to those that have
been previously reported with enalapril or hydrochlorothiazide.
How supplied
Enalapril Maleate and Hydrochlorothiazide Tablets USP 5/12.5 mg are available
for oral administration as reddish-brown, round, unscored tablets, imprinted
"APO" on one side and "5" over "12.5" on the other side. They are supplied as
follows:
Bottles of 30 (NDC 54868-5100-1)
Bottles of 90 (NDC 54868-5100-2)
Bottles of 100 (NDC 54868-5100-0)
Enalapril Maleate and Hydrochlorothiazide Tablets USP 10/25 mg are available
for oral administration as reddish-brown, round, unscored tablets, imprinted
"APO" on one side and "10" over "25" on the other side. They are supplied as
follows:
Bottles of 30 (NDC 54868-5503-0)
Bottles of 90 (NDC 54868-5503-1)
Store at 20° to 25°C (68° to 77°F); excursions permitted to 15°-30°C
(59°-86°F) [see USP Controlled Room Temperature].
Protect from moisture.
Dispense in a tight, light-resistant container [see USP].
APOTEX INC.
ENALAPRIL MALEATE AND
HYDROCHLOROTHIAZIDE TABLETS USP
5/12.5 mg and 10/25 mg
Manufactured for:
Apotex Corp.
Weston, Florida
USA 33326
Revised: November 2006
Rev. 3
Clinical pharmacology
As a result of its diuretic effects, hydrochlorothiazide
increases plasma renin activity, increases aldosterone secretion, and decreases
serum potassium. Administration of enalapril maleate blocks the
renin-angiotensin-aldosterone axis and tends to reverse the potassium loss
associated with the diuretic.
In clinical studies, the extent of blood pressure reduction seen with the
combination of enalapril maleate and hydrochlorothiazide was approximately
additive. The antihypertensive effect of enalapril maleate and
hydrochlorothiazide was usually sustained for at least 24 hours.
Concomitant administration of enalapril maleate and hydrochlorothiazide has
little, or no effect on the bioavailability of either drug. The combination
tablet is bioequivalent to concomitant administration of the separate
entities.
Enalapril Maleate
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.
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 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 plus a thiazide diuretic,
there was essentially no change in serum potassium (see PRECAUTIONS ). 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 remains to be elucidated.
While the mechanism through which enalapril 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 was antihypertensive in all races studied, black hypertensive
patients (usually a low-renin hypertensive population) had a smaller average
response to enalapril maleate monotherapy than non-black patients. In contrast,
hydrochlorothiazide was more effective in black patients than enalapril.
Concomitant administration of enalapril maleate and hydrochlorothiazide was
equally effective in black and non-black patients.
Pharmacokinetics and Metabolism:
Following oral administration of enalapril maleate, peak serum concentrations of
enalapril occur within about one hour. Based on urinary recovery, the extent of
absorption of enalapril is approximately 60 percent. 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
enalaprilat and enalapril is primarily renal. Approximately 94 percent 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 percent
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. Enalaprilat is dialyzable at the
rate of 62 mL/min.
Studies in dogs indicate that enalapril crosses the blood-brain barrier
poorly, if at all; enalaprilat does not enter the brain. Multiple doses of
enalapril maleate in rats do not result in accumulation in any tissues. Milk of
lactating rats contains radioactivity following administration of 14 C enalapril maleate. Radioactivity was found to cross the
placenta following administration of labeled drug to pregnant hamsters.
Pharmacodynamics: Administration of
enalapril maleate to patients with hypertension of severity ranging from mild to
severe results in a reduction of both supine and standing blood pressure usually
with no orthostatic component. Symptomatic postural hypotension is infrequent
with enalapril alone but it can be anticipated in volume-depleted patients, such
as patients treated with diuretics. In clinical trials with enalapril and
hydrochlorothiazide administered concurrently, syncope occurred in 1.3 percent
of patients (see WARNINGS and DOSAGE AND ADMINISTRATION ).
In most patients studied, after oral administration of a single dose of
enalapril maleate, onset of antihypertensive activity was seen at one hour with
peak reduction of blood pressure achieved by four to six hours.
At recommended doses, antihypertensive effects of enalapril maleate
monotherapy have been maintained for at least 24 hours. In some patients the
effects may diminish toward the end of the dosing interval; this was less
frequently observed with concomitant administration of enalapril maleate and
hydrochlorothiazide.
Achievement of optimal blood pressure reduction may require several weeks of
enalapril therapy in some patients.
The antihypertensive effects of enalapril have continued during long term
therapy. Abrupt withdrawal of enalapril has not been associated with a rapid
increase in blood pressure.
In hemodynamic studies in patients with essential hypertension, blood
pressure reduction produced by enalapril was accompanied by a reduction in
peripheral arterial resistance with an increase in cardiac output and little or
no change in heart rate. Following administration of enalapril maleate, there is
an increase in renal blood flow; glomerular filtration rate is usually
unchanged. The effects appear to be similar in patients with renovascular
hypertension.
In a clinical pharmacology study, indomethacin or sulindac was administered
to hypertensive patients receiving enalapril maleate. In this study there was no
evidence of a blunting of the antihypertensive action of enalapril maleate (see
PRECAUTIONS:
Drug Interactions, Enalapril Maleate
).
Hydrochlorothiazide
The mechanism of the antihypertensive effect of thiazides is unknown.
Thiazides do not usually affect normal blood pressure. Hydrochlorothiazide is a
diuretic and antihypertensive. It affects the distal renal tubular mechanism of
electrolyte reabsorption. Hydrochlorothiazide increases excretion of sodium and
chloride in approximately equivalent amounts. Natriuresis may be accompanied by
some loss of potassium and bicarbonate. After oral use diuresis begins within
two hours, peaks in about four hours and lasts about 6 to 12 hours.
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney.
When plasma levels have been followed for at least 24 hours, the plasma
half-life has been observed to vary between 5.6 and 14.8 hours. At least 61
percent of the oral dose is eliminated unchanged within 24 hours.
Hydrochlorothiazide crosses the placental but not the blood-brain barrier.
Package label
Enalapril Maleate and Hydrochlorothiazide Tablets USP 5 mg/12.5 mg
Enalapril Maleate and Hydrochlorothiazide Tablets USP 10 mg/25 mg
image of Enalapril Maleate & Hctz package label for 5 mg/12.5 mg
image of Enalapril Maleate & Hctz package label for 10 mg/25 mg
3 organizations
1 product
Organization
Rebel Distributors Corp.Organization
Taro Pharmaceuticals U.S.A., Inc.Organization
Physicians Total Care, Inc.