Methyldopa should be used with caution in patients with a history of previous
liver disease or dysfunction (see WARNINGS).
Some patients taking methyldopa
experience clinical edema or weight gain which may be controlled by use of a
diuretic. Methyldopa should not be continued if edema
progresses or signs of heart failure appear.
Hypertension has recurred
occasionally after dialysis in patients given methyldopa because the drug is
removed by this procedure.
choreoathetotic movements have been observed during therapy with methyldopa in
patients with severe bilateral cerebrovascular disease. Should
these movements occur, stop therapy.
All patients receiving diuretic
therapy should be observed for evidence of fluid or electrolyte imbalance:
namely; 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
Hypokalemia may develop, especially after prolonged therapy or when severe
cirrhosis is present (see CONTRAINDICATIONS and
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). Hypokalemia may be avoided or
treated by use of potassium sparing diuretics or potassium supplements such as
foods with a high potassium content.
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
Hyperuricemia may occur or acute
gout may be precipitated in certain patients receiving thiazides.
In diabetic patients dosage
adjustment 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.
Blood count, Coombs test and liver function test, are recommended before initiating
therapy and at periodic intervals (see WARNINGS).
Periodic determination of serum
electrolytes to detect possible electrolyte imbalance should be done at
Impairment of Fertility
Long-term studies in animals have
not been performed to evaluate the effects upon fertility, mutagenic or
carcinogenic potential of the combination.
No evidence of a tumorigenic
effect was seen when methyldopa was given for two years to mice at doses up to
1800 mg/kg/day or to rats at doses up to 240
mg/kg/day (30 and 4 times the maximum recommended human dose in mice and rats,
respectively, when compared on the basis of body
weight; 2.5 and 0.6 times the maximum recommended human dose in mice and rats,
respectively, when compared on the basis of body
surface area; calculations assume a patient weight of 50 kg).
Methyldopa was not mutagenic in
the Ames Test and did not increase chromosomal aberration or sister chromatid
exchanges in Chinese hamster ovary cells.
These in vitro studies were carried out both with and without exogenous
Fertility was unaffected when
methyldopa was given to male and female rats at 100 mg/kg/day (1.7 times the
maximum daily human dose when compared on the basis
of body weight; 0.2 times the maximum daily human dose when compared on the
basis of body surface area). Methyldopa
decreased sperm count, sperm motility, the number of late spermatids and the
male fertility index when given to male rats at 200 and 400
mg/kg/day (3.3 and 6.7 times the maximum daily human dose when compared on the
basis of body weight; 0.5 and 1 times the
maximum daily human dose when compared on the basis of body surface area).
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 of up to
approximately 600 mg/kg/day) or in male and female rats (at
doses of up to approximately 100 mg/kg/day). The NTP, however, found equivocal
evidence for hepatocarcinogenicity in male
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 μg/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 conception and throughout
Use of diuretics during normal
pregnancy is inappropriate and exposes mother and fetus to unnecessary hazard.
Diuretics do not prevent development of toxemia of
pregnancy and there is no satisfactory evidence that they are useful in the
treatment of toxemia.
Pregnancy Category C: Animal
reproduction studies have not been conducted with ALDORIL (methyldopa-hydrochlorothiazide) . It is also not known
whether ALDORIL (methyldopa-hydrochlorothiazide) can affect reproduction
capacity or can cause fetal harm when given to a pregnant woman. ALDORIL (methyldopa-hydrochlorothiazide) should
be given to a pregnant woman only if clearly
Hydrochlorothiazide: 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 hydrochlorothiazide/kg,
respectively, provided no evidence of harm to the fetus. There are, however,
no adequate and well-controlled studies in pregnant women.
Methyldopa: Reproduction studies performed with methyldopa at
oral doses up to 1000 mg/kg in mice, 200 mg/kg in rabbits and 100 mg/kg in rats
revealed no evidence of harm to the fetus. These doses are 16.6 times, 3.3 times
and 1.7 times, respectively, the maximum daily human dose when compared on the
basis of body weight; 1.4 times, 1.1 times and 0.2 times, respectively, when
compared on the basis of body surface area; calculations assume a patient weight
of 50 kg. There are, however, no adequate and well-controlled studies in pregnant
women in the first trimester of pregnancy. Because animal reproduction studies
are not always predictive of human response, methyldopa should be used during
pregnancy only if clearly needed.
Published reports of the use of
methyldopa during all trimesters indicate that if this drug is used during
pregnancy the possibility of fetal harm appears remote. In
five studies, three of which were controlled, involving 332 pregnant
hypertensive women, treatment with methyldopa was associated
with an improved fetal outcome. The majority of these women were in the third
trimester when methyldopa therapy was begun.
In one study, women who had begun
methyldopa treatment between weeks 16 and 20 of pregnancy gave birth to infants
whose average head circumference was
reduced by a small amount (34.2 Â± 1.7 cm vs. 34.6 Â± 1.3 cm [mean Â± 1 S.D.]).
Long term followup of 195 (97.5%) of the children
born to methyldopa-treated pregnant women (including those who began treatment
between weeks 16 and 20) failed to uncover
any significant adverse effect on the children. At four years of age, the
developmental delay commonly seen in children born to
hypertensive mothers was less evident in those whose mothers were treated with
methyldopa during pregnancy than those whose
mothers were untreated. The children of the treated group scored consistently
higher than the children of the untreated group
on five major indices of intellectual and motor development. At age 7 and
one-half developmental scores and intelligence indices showed
no significant differences in children of treated or untreated hypertensive
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.
Methyldopa and thiazides appear
in breast milk. Therefore, because of the potential for serious adverse
reactions in nursing infants from hydrochlorothiazide, a
decision should be made whether to discontinue nursing or to discontinue the
drug, taking into account the importance of the drug to the
Clinical studies of ALDORIL (methyldopa-hydrochlorothiazide) 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, and it may be useful
to monitor renal function.
Safety and effectiveness of
ALDORIL (methyldopa-hydrochlorothiazide) in pediatric patients have not been established.