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ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE
Overview
What is ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
Enalapril maleate and 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 ()-1-[-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline,
()-2-butenedioate salt (1:1). Its empirical formula
is CHNO•CHO, 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-2-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its
empirical formula is CHClNOS 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.
What does ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE look like?
What are the available doses of ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
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How should I use ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
Enalapril maleate and hydrochlorothiazide tablets are indicated
for the treatment of hypertension.
These fixed dose combinations are not indicated for initial treatment (see ).
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 ).
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
).
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 ) 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:
Replacement Therapy:
Use in Renal Impairment:
What interacts with ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
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.
What are the warnings of ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
Reports in the published literature have raised a question regarding the possible association between the use of methylxanthines and development of necrotizing enterocolitis, although a causal relationship between methylxanthine use and necrotizing enterocolitis has not been established. Therefore, as with all preterm infants, patients being treated with caffeine citrate should be carefully monitored for the development of necrotizing enterocolitis.
General
Hypotension:
Syncope has been reported in 1.3 percent of patients receiving enalapril
maleate and hydrochlorothiazide. In patients receiving enalapril alone, the
incidence of syncope is 0.5 percent. The overall incidence of syncope may be
reduced by proper titration of the individual components (see
and ).
In patients with severe congestive heart failure, with or without associated
renal insufficiency, excessive hypotension has been observed and may be
associated with oliguria and/or progressive azotemia, and rarely with acute
renal failure and/or death. Because of the potential fall in blood pressure in
these patients, therapy should be started under very close medical supervision.
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 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, which usually
can be given without difficulty once the blood pressure has increased after
volume expansion.
Presumably because angiotensin-converting enzyme inhibitors
affect the metabolism of eicosanoids and polypeptides, including endogenous
bradykinin, patients receiving ACE inhibitors (including enalapril maleate and
hydrochlorothiazide) may be subject to a variety of adverse reactions, some of
them serious.
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 and ).
Anaphylactoid reactions during
desensitization:
Anaphylactoid reactions during membrane
exposure:
Neutropenia/Agranulocytosis:
Hepatic Failure:
Thiazides should be used with caution in severe renal disease. In
patients with renal disease, thiazides may precipitate azotemia. Cumulative
effects of the drug may develop in patients with impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic
function or progressive liver disease, since minor alterations of fluid and
electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with or without a history of
allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus
has been reported.
Lithium generally should not be given with thiazides (see
).
Enalapril-Hydrochlorothiazide
There was no teratogenicity in mice given up to 30 mg/kg/day or in rats given
up to 90 mg/kg/day of enalapril in combination with 10 mg/kg/day of
hydrochlorothiazide. These doses of enalapril are 4.3 and 26 times (mice and
rats, respectively) the maximum recommended human daily dose (MRHDD) when
compared on a body surface area basis (mg/m); the dose
of hydrochlorothiazide is 0.8 times (in mice) and 1.6 times (in rats) the MRHDD.
At these doses, fetotoxicity expressed as a decrease in average fetal weight
occurred in both species. No fetotoxicity occurred at lower doses; 30/10
mg/kg/day of enalapril-hydrochlorothiazide in rats and 10/10 mg/kg/day of
enalapril-hydrochlorothiazide in mice.
When used in pregnancy during the second and third trimesters, ACE inhibitors
can cause injury and even death to the developing fetus. When pregnancy is
detected, enalapril maleate and hydrochlorothiazide should be discontinued as
soon as possible (see ).
Enalapril Maleate
Fetal/Neonatal Morbidity and
Mortality:
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
and hydrochlorothiazide 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 intra-amniotic
environment.
If oligohydramnios is observed, enalapril maleate and hydrochlorothiazide
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 exposure to ACE
inhibitors should be closely observed for hypotension, oliguria, and
hyperkalemia. If oliguria occurs, attention should be directed toward 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 were 57 times and 12 times,
respectively, the MRHDD.
Studies in which hydrochlorothiazide was orally administered to
pregnant mice and rats during their respective periods of major organogenesis at
doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm
to the fetus. These doses are more than 150 times the MRHDD on a body surface
area basis. Thiazides cross the placental barrier and appear in cord blood.
There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly
other adverse reactions that have occurred in adults.
What are the precautions of ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
General
Enalapril Maleate
Aortic Stenosis/Hypertrophic
Cardiomyopathy:
Impaired Renal Function:
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:
Cough:
Surgery/Anesthesia:
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 ).
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:
Hypotension:
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:
Neutropenia:
Pregnancy:
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
Hypotension – Patients on Diuretic
Therapy:
Agents Causing Renin Release:
Non-steroidal Anti-inflammatory
Agents:
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:
Agents Increasing Serum Potassium:
Lithium:
When administered concurrently the following drugs may interact
with thiazide diuretics:
Alcohol, barbiturates, or narcotics
Antidiabetic drugs
Other antihypertensive drugs
Cholestyramine and colestipol resins
Corticosteroids, ACTH
Pressor amines (e.g., norepinephrine)
Skeletal muscle relaxants, nondepolarizing (e.g.,
tubocurarine)
Lithium
Non-steroidal Anti-inflammatory Drugs
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
alkaline elution assay in rat hepatocytes or
chromosomal aberrations in an mouse bone
marrow assay.
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 , sister chromatid exchange with
cultured mammalian cells, and the micronucleus test with mice, as well as in an
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).
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
the Ames mutagenicity assay of
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 assays using mouse germinal cell chromosomes, Chinese hamster
bone marrow chromosomes, and the
sex-linked recessive lethal trait gene. Positive test results were obtained only
in the 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 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
D
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 ).
What are the side effects of ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
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.
The most frequent clinical adverse experiences in controlled trials were:
dizziness (8.6 percent), headache (5.5 percent), fatigue (3.9 percent) and cough
(3.5 percent). Generally, adverse experiences were mild and transient in nature.
Adverse experiences occurring in greater than two percent of patients treated
with enalapril maleate and hydrochlorothiazide in controlled clinical trials are
shown below.
Clinical adverse experiences occurring in 0.5 to 2.0 percent of patients in
controlled trials included: Syncope,
chest pain, abdominal pain;
Orthostatic hypotension, palpitation, tachycardia; Vomiting, dyspepsia, constipation, flatulence,
dry mouth; Insomnia,
nervousness, paresthesia, somnolence, vertigo;
Pruritus, rash; Dyspnea, gout, back pain,
arthralgia, diaphoresis, decreased libido, tinnitus, urinary tract
infection.
Angioedema:
Hypotension:
Cough:
Clinical Laboratory Test Findings
Serum Electrolytes:
Creatinine, Blood Urea Nitrogen:
Serum Uric Acid, Glucose, Magnesium, and
Calcium:
Hemoglobin and Hematocrit:
Liver Function Tests:
Other adverse reactions that have been reported with the individual
components are listed below and, within each category, are in order of
decreasing severity.
Enalapril Maleate
Body As A
Whole:
Cardiovascular:
Digestive:
Hematologic:
Nervous System/Psychiatric:
Urogenital:
Respiratory:
Skin:
Special
Senses:
Miscellaneous:
Fetal/Neonatal Morbidity and Mortality:
Hydrochlorothiazide
Body as a Whole:
Digestive:
Hematologic:
Hypersensitivity:
Musculoskeletal:
Nervous
System/Psychiatric:
Renal:
Skin:
Special Senses:
| Percent of Patientsin Controlled Studies | ||
|---|---|---|
| Enalapril maleate and hydrochlorothiazide(n=1580)Incidence(discontinuation) | Placebo(n=230)Incidence | |
| Dizziness | 8.6 (0.7) | 4.3 |
| Headache | 5.5 (0.4) | 9.1 |
| Fatigue | 3.9 (0.8) | 2.6 |
| Cough | 3.5 (0.4) | 0.9 |
| Muscle Cramps | 2.7 (0.2) | 0.9 |
| Nausea | 2.5 (0.4) | 1.7 |
| Asthenia | 2.4 (0.3) | 0.9 |
| Orthostatic Effects | 2.3 (less than 0.1) | 0.0 |
| Impotence | 2.2 (0.5) | 0.5 |
| Diarrhea | 2.1 (less than 0.1) | 1.7 |
What should I look out for while using ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
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.
General
Hypotension:
Syncope has been reported in 1.3 percent of patients receiving enalapril
maleate and hydrochlorothiazide. In patients receiving enalapril alone, the
incidence of syncope is 0.5 percent. The overall incidence of syncope may be
reduced by proper titration of the individual components (see
and ).
In patients with severe congestive heart failure, with or without associated
renal insufficiency, excessive hypotension has been observed and may be
associated with oliguria and/or progressive azotemia, and rarely with acute
renal failure and/or death. Because of the potential fall in blood pressure in
these patients, therapy should be started under very close medical supervision.
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 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, which usually
can be given without difficulty once the blood pressure has increased after
volume expansion.
Presumably because angiotensin-converting enzyme inhibitors
affect the metabolism of eicosanoids and polypeptides, including endogenous
bradykinin, patients receiving ACE inhibitors (including enalapril maleate and
hydrochlorothiazide) may be subject to a variety of adverse reactions, some of
them serious.
Angioedema:
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
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 and ).
Anaphylactoid reactions during
desensitization:
Anaphylactoid reactions during membrane
exposure:
Neutropenia/Agranulocytosis:
Hepatic Failure:
Thiazides should be used with caution in severe renal disease. In
patients with renal disease, thiazides may precipitate azotemia. Cumulative
effects of the drug may develop in patients with impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic
function or progressive liver disease, since minor alterations of fluid and
electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with or without a history of
allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus
has been reported.
Lithium generally should not be given with thiazides (see
).
Enalapril-Hydrochlorothiazide
There was no teratogenicity in mice given up to 30 mg/kg/day or in rats given
up to 90 mg/kg/day of enalapril in combination with 10 mg/kg/day of
hydrochlorothiazide. These doses of enalapril are 4.3 and 26 times (mice and
rats, respectively) the maximum recommended human daily dose (MRHDD) when
compared on a body surface area basis (mg/m); the dose
of hydrochlorothiazide is 0.8 times (in mice) and 1.6 times (in rats) the MRHDD.
At these doses, fetotoxicity expressed as a decrease in average fetal weight
occurred in both species. No fetotoxicity occurred at lower doses; 30/10
mg/kg/day of enalapril-hydrochlorothiazide in rats and 10/10 mg/kg/day of
enalapril-hydrochlorothiazide in mice.
When used in pregnancy during the second and third trimesters, ACE inhibitors
can cause injury and even death to the developing fetus. When pregnancy is
detected, enalapril maleate and hydrochlorothiazide should be discontinued as
soon as possible (see ).
Enalapril Maleate
Fetal/Neonatal Morbidity and
Mortality:
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
and hydrochlorothiazide 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 intra-amniotic
environment.
If oligohydramnios is observed, enalapril maleate and hydrochlorothiazide
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 exposure to ACE
inhibitors should be closely observed for hypotension, oliguria, and
hyperkalemia. If oliguria occurs, attention should be directed toward 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 were 57 times and 12 times,
respectively, the MRHDD.
Studies in which hydrochlorothiazide was orally administered to
pregnant mice and rats during their respective periods of major organogenesis at
doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm
to the fetus. These doses are more than 150 times the MRHDD on a body surface
area basis. Thiazides cross the placental barrier and appear in cord blood.
There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly
other adverse reactions that have occurred in adults.
What might happen if I take too much ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
No specific information is available on the treatment of
overdosage with enalapril maleate and hydrochlorothiazide. Treatment is
symptomatic and supportive. Therapy with enalapril maleate and
hydrochlorothiazide should be discontinued and the patient observed closely.
Suggested measures include induction of emesis and/or gastric lavage, and
correction of dehydration, electrolyte imbalance and hypotension by established
procedures.
Enalapril Maleate
Hydrochlorothiazide
How should I store and handle ENALAPRIL MALEATE AND HYDROCHLOROTHIAZIDE?
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP] .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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3Enalapril 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 USP5/12.5 mg and 10/25 mgManufactured for:Apotex Corp.Weston, Florida USA 33326Revised: November 2006Rev. 3
Clinical Information
Chemical Structure
No Image foundClinical 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:
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:
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 C enalapril maleate. Radioactivity was found to cross the
placenta following administration of labeled drug to pregnant hamsters.
Pharmacodynamics:
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
).
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.
Non-Clinical Toxicology
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.General
Hypotension:
Syncope has been reported in 1.3 percent of patients receiving enalapril maleate and hydrochlorothiazide. In patients receiving enalapril alone, the incidence of syncope is 0.5 percent. The overall incidence of syncope may be reduced by proper titration of the individual components (see and ).
In patients with severe congestive heart failure, with or without associated renal insufficiency, excessive hypotension has been observed and may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death. Because of the potential fall in blood pressure in these patients, therapy should be started under very close medical supervision. 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 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, which usually can be given without difficulty once the blood pressure has increased after volume expansion.
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including enalapril maleate and hydrochlorothiazide) may be subject to a variety of adverse reactions, some of them serious.
Angioedema:
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
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 and ).
Anaphylactoid reactions during desensitization:
Anaphylactoid reactions during membrane exposure:
Neutropenia/Agranulocytosis:
Hepatic Failure:
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
Lithium generally should not be given with thiazides (see ).
Enalapril-Hydrochlorothiazide
There was no teratogenicity in mice given up to 30 mg/kg/day or in rats given up to 90 mg/kg/day of enalapril in combination with 10 mg/kg/day of hydrochlorothiazide. These doses of enalapril are 4.3 and 26 times (mice and rats, respectively) the maximum recommended human daily dose (MRHDD) when compared on a body surface area basis (mg/m); the dose of hydrochlorothiazide is 0.8 times (in mice) and 1.6 times (in rats) the MRHDD. At these doses, fetotoxicity expressed as a decrease in average fetal weight occurred in both species. No fetotoxicity occurred at lower doses; 30/10 mg/kg/day of enalapril-hydrochlorothiazide in rats and 10/10 mg/kg/day of enalapril-hydrochlorothiazide in mice.
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, enalapril maleate and hydrochlorothiazide should be discontinued as soon as possible (see ).
Enalapril Maleate
Fetal/Neonatal Morbidity and Mortality:
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 and hydrochlorothiazide 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 intra-amniotic environment.
If oligohydramnios is observed, enalapril maleate and hydrochlorothiazide 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 exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward 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 were 57 times and 12 times, respectively, the MRHDD.
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus. These doses are more than 150 times the MRHDD on a body surface area basis. Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.
Drug Interactions:
It has been reported that ZYLOPRIM prolongs the half-life of the anticoagulant, dicumarol. The clinical basis of this drug interaction has not been established but should be noted when ZYLOPRIM is given to patients already on dicumarol therapy.
Since the excretion of oxipurinol is similar to that of urate, uricosuric agents, which increase the excretion of urate, are also likely to increase the excretion of oxipurinol and thus lower the degree of inhibition of xanthine oxidase. The concomitant administration of uricosuric agents and ZYLOPRIM has been associated with a decrease in the excretion of oxypurines (hypoxanthine and xanthine) and an increase in urinary uric acid excretion compared with that observed with ZYLOPRIM alone. Although clinical evidence to date has not demonstrated renal precipitation of oxypurines in patients either on ZYLOPRIM alone or in combination with uricosuric agents, the possibility should be kept in mind.
The reports that the concomitant use of ZYLOPRIM and thiazide diuretics may contribute to the enhancement of allopurinol toxicity in some patients have been reviewed in an attempt to establish a cause-and-effect relationship and a mechanism of causation. Review of these case reports indicates that the patients were mainly receiving thiazide diuretics for hypertension and that tests to rule out decreased renal function secondary to hypertensive nephropathy were not often performed. In those patients in whom renal insufficiency was documented, however, the recommendation to lower the dose of ZYLOPRIM was not followed. Although a causal mechanism and a cause-and-effect relationship have not been established, current evidence suggests that renal function should be monitored in patients on thiazide diuretics and ZYLOPRIM even in the absence of renal failure, and dosage levels should be even more conservatively adjusted in those patients on such combined therapy if diminished renal function is detected.
An increase in the frequency of skin rash has been reported among patients receiving ampicillin or amoxicillin concurrently with ZYLOPRIM compared to patients who are not receiving both drugs. The cause of the reported association has not been established.
Enhanced bone marrow suppression by cyclophosphamide and other cytotoxic agents has been reported among patients with neoplastic disease, except leukemia, in the presence of ZYLOPRIM. However, in a well-controlled study of patients with lymphoma on combination therapy, ZYLOPRIM did not increase the marrow toxicity of patients treated with cyclophosphamide, doxorubicin, bleomycin, procarbazine, and/or mechlorethamine.
Tolbutamide's conversion to inactive metabolites has been shown to be catalyzed by xanthine oxidase from rat liver. The clinical significance, if any, of these observations is unknown.
Chlorpropamide's plasma half-life may be prolonged by ZYLOPRIM, since ZYLOPRIM and chlorpropamide may compete for excretion in the renal tubule. The risk of hypoglycemia secondary to this mechanism may be increased if ZYLOPRIM and chlorpropamide are given concomitantly in the presence of renal insufficiency.
Rare reports indicate that cyclosporine levels may be increased during concomitant treatment with ZYLOPRIM. Monitoring of cyclosporine levels and possible adjustment of cyclosporine dosage should be considered when these drugs are co-administered.
General
Enalapril Maleate
Aortic Stenosis/Hypertrophic Cardiomyopathy:
Impaired Renal Function:
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:
Cough:
Surgery/Anesthesia:
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 ).
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:
Hypotension:
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:
Neutropenia:
Pregnancy:
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
Hypotension – Patients on Diuretic Therapy:
Agents Causing Renin Release:
Non-steroidal Anti-inflammatory Agents:
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:
Agents Increasing Serum Potassium:
Lithium:
When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, barbiturates, or narcotics
Antidiabetic drugs
Other antihypertensive drugs
Cholestyramine and colestipol resins
Corticosteroids, ACTH
Pressor amines (e.g., norepinephrine)
Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine)
Lithium
Non-steroidal Anti-inflammatory Drugs
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 alkaline elution assay in rat hepatocytes or chromosomal aberrations in an mouse bone marrow assay.
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 , sister chromatid exchange with cultured mammalian cells, and the micronucleus test with mice, as well as in an 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).
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 the Ames mutagenicity assay of 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 assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the sex-linked recessive lethal trait gene. Positive test results were obtained only in the 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 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
D
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 ).
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.
The most frequent clinical adverse experiences in controlled trials were: dizziness (8.6 percent), headache (5.5 percent), fatigue (3.9 percent) and cough (3.5 percent). Generally, adverse experiences were mild and transient in nature. Adverse experiences occurring in greater than two percent of patients treated with enalapril maleate and hydrochlorothiazide in controlled clinical trials are shown below.
Clinical adverse experiences occurring in 0.5 to 2.0 percent of patients in controlled trials included: Syncope, chest pain, abdominal pain; Orthostatic hypotension, palpitation, tachycardia; Vomiting, dyspepsia, constipation, flatulence, dry mouth; Insomnia, nervousness, paresthesia, somnolence, vertigo; Pruritus, rash; Dyspnea, gout, back pain, arthralgia, diaphoresis, decreased libido, tinnitus, urinary tract infection.
Angioedema:
Hypotension:
Cough:
Clinical Laboratory Test Findings
Serum Electrolytes:
Creatinine, Blood Urea Nitrogen:
Serum Uric Acid, Glucose, Magnesium, and Calcium:
Hemoglobin and Hematocrit:
Liver Function Tests:
Other adverse reactions that have been reported with the individual components are listed below and, within each category, are in order of decreasing severity.
Enalapril Maleate
Body As A Whole:
Cardiovascular:
Digestive:
Hematologic:
Nervous System/Psychiatric:
Urogenital:
Respiratory:
Skin:
Special Senses:
Miscellaneous:
Fetal/Neonatal Morbidity and Mortality:
Hydrochlorothiazide
Body as a Whole:
Digestive:
Hematologic:
Hypersensitivity:
Musculoskeletal:
Nervous System/Psychiatric:
Renal:
Skin:
Special Senses:
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).