WARNINGS
Fetal/Neonatal Morbidity and Mortality
Drugs that act directly on the renin-angiotensin system
can cause fetal and neonatal morbidity and death when
administered to pregnant women. Several dozen cases have
been reported in the world literature in patients who
were taking angiotensin converting enzyme inhibitors.
When pregnancy is detected, AVALIDE (irbesartan-hydrochlorothiazide)
Tablets should be discontinued as soon as possible.
The use of drugs that act directly on the renin-angiotensin
system 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
defor-mation, 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 exposure to the drug.
These adverse effects do not appear to have resulted
from intrauterine drug exposure that has been limited
to the first trimester.
Mothers whose embryos and fetuses are exposed to an angiotensin
II receptor antagonist only during the first trimester
should be so informed. Nonetheless, when patients become
pregnant, physicians should have the patient discontinue
the use of AVALIDE as soon as possible.
Rarely (probably less often than once in every thousand
pregnancies),no alternative to a drug acting on the renin-angiotensin
system will be found. In these rare cases, the mothers
should be apprised of the potential hazards to their fetuses,
and serial ultrasound examinations should be performed
to assess the intraamniotic environment.
If oligohydramnios is observed, AVALIDE (irbesartan-hydrochlorothiazide)
Tablets should be discontinued unless it is considered
life-saving for the mother. Contraction stress testing
(CST),a non-stress test (NST), or biophysical profiling
(BPP) may be appropriate depending upon the week of pregnancy.
Patients and physicians should be aware, however, that
oligohydramnios may not appear until after the fetus has
sustained irreversible injury.
Infants with histories of in utero exposure to an angiotensin
II receptor antagonist 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 a means of reversing hypotension and/or
substituting for disordered renal function.
When pregnant rats were treated with irbesartan from
day 0 to day 20 of gestation (oral doses of 50, 180, and
650 mg/kg/day), increased incidences of renal pelvic cavitation,
hydroureter and/or absence of renal papilla were observed
in fetuses at doses >50 mg/kg/day [approximately equivalent
to the maximum recommended human dose (MRHD), 300 mg/day,
on a body surface area basis]. Subcutaneous edema was
observed in fetuses at doses >180 mg/kg/day (about
4 times the MRHD on a body surface area basis). As these
anomalies were not observed in rats in which irbesartan
exposure (oral doses of 50, 150 and 450 mg/kg/day) was
limited to gestation days 6–15, they appear to reflect
late gestational effects of the drug. In pregnant rabbits,
oral doses of 30 mg irbe-sartan /kg/day were associated
with maternal mortality and abortion. Surviving females
receiving this dose (about 1.5 times the MRHD on a body
surface area basis) had a slight increase in early resorptions
and a corresponding decrease in live fetuses. Irbesartan
was found to cross the placental barrier in rats and rabbits.
Radioactivity was present in the rat and rabbit fetus
during late gestation and in rat milk following oral doses
of radiolabeled irbesartan.
Studies in which hydrochlorothiazide was 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.
A development toxicity study was performed in rats with
doses of 50/50 and 150/150 mg/kg/day irbesartan-hydrochlorothiazide.
Although the high dose combination appeared to be more
toxic to the dams than either drug alone, there did not
appear to be an increase in toxicity to the developing
embryos.
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.
Hypotension in Volume- or Salt-depleted Patients
Excessive reduction of blood pressure was rarely seen
in patients with uncomplicated hypertension treated with
irbesartan alone (<0.1%) or with irbesartan-hydrochlorothiazide
(approximately 1%). Initiation of antihypertensive therapy
may cause symptomatic hypotension in patients with intravascular
volume- or sodium-depletion, e.g., in patients treated
vigorously with diuretics or in patients on dialysis.
Such volume depletion should be corrected prior to administration
of antihypertensive therapy.
If hypotension occurs, the patient should be placed in
the supine position and, if necessary, given an intravenous
infusion of normal saline. A transient hypotensive response
is not a contraindication to further treatment, which
usually can be continued without difficulty once the blood
pressure has stabilized.
Hydrochlorothiazide
Hepatic Impairment
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.
Hypersensitivity Reaction
Hypersensitivity reactions to hydrochlorothiazide may
occur in patients with or without a history of allergy
or bronchial asthma, but are more likely in patients with
such a history.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation
or activation of systemic lupus erythematosus.
Lithium Interaction
Lithium generally should not be given with thiazides
(see
PRECAUTIONS
: Drug Interactions;
Hydrochlorothiazide, Lithium).
PRECAUTIONS
General
Irbesartan-Hydrochlorothiazide
In double-blind clinical trials of various doses of irbesartan
and hydrochlorothiazide, the incidence of hypertensive
patients who developed hypokalemia (serum potassium <3.5
mEq/L) was 7.5% versus 6.0% for placebo; the incidence
of hyperkalemia (serum potassium >5.7 mEq/L) was <1.0%
versus 1.7% for placebo. No patient discontinued due to
increases or decreases in serum potassium. Overall, the
combination of irbesartan and hydrochlorothiazide had
no effect on serum potassium. Higher doses of irbesartan
ameliorated the hypokalemic response to hydrochlorothiazide.
Hydrochlorothiazide
Periodic determination of serum electrolytes to detect
possible electrolyte imbalance should be performed at
appropriate intervals. All patients receiving thiazide
therapy should be observed for clinical signs of fluid
or electrolyte imbalance: hyponatremia, hypochloremic
alkalosis, and hypokalemia. Serum and urine electrolyte
determinations are particularly important when the patient
is vomiting excessively or receiving parenteral fluids.
Warning signs or symptoms of fluid and electrolyte imbal-ance,
irrespective of cause,include dryness of mouth, thirst,
weakness, lethargy, drowsiness, restless-ness, confusion,
seizures, muscle pains or cramps, muscular fatigue, hypotension,
oliguria, tachycar-dia, 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).
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 hyponatrem-ia 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 post sympathectomy 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.
Impaired Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in
susceptible individuals. In patients whose renal function
may depend on the activity of the renin-angiotensin-aldosterone
system (e.g., patients with severe congestive heart failure),treatment
with angiotensin converting enzyme inhibitors has been
associated with oliguria and/or progressive azotemia and
(rarely) with acute renal failure and/or death. Irbesartan
would be expected to behave similarly. In studies of ACE
inhibitors in patients with unilateral or bilateral renal
artery stenosis, increases in serum creatinine or BUN
have been reported. There has been no known use of irbesartan
in patients with unilateral or bilateral renal artery
stenosis, but a similar effect should be anticipated.
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.
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