WARNINGS AND PRECAUTIONS
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue AVALIDE as soon as possible [see
Use in Specific Populations
Thiazides cross the placenta, and use of thiazides during pregnancy is associated with 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.
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.
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
Systemic Lupus Erythematosus
diuretics have been reported to cause exacerbation or activation of systemic
generally should not be given with thiazides. [See
Drug Interactions (7)
Electrolyte and Metabolic Imbalances
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. On average, the combination of irbesartan and hydrochlorothiazide had no effect on serum potassium. Higher doses of irbesartan ameliorated the hypokalemic response to hydrochlorothiazide.
Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. Concurrent therapy with hydrochlorothiazide may reduce the frequency of this effect.
Hydrochlorothiazide can cause hypokalemia and hyponatremia. Hypomagnesemia can result in hypokalemia which appears difficult to treat despite potassium repletion. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Monitor serum electrolytes periodically.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving
Hydrochlorothiazide may alter glucose tolerance and raise serum levels of cholesterol and triglycerides.
The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.
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.
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.
Impaired Renal Function
As a consequence of inhibiting the renin-angiotensin-aldosterone
system, changes in renal function may be anticipated in susceptible individuals [see
Drug Interactions (7)
]. 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 ACE
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
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
Acute Myopia and Secondary Angle-Closure Glaucoma
Sulfonamide or sulfonamide derivative drugs, such as hydrochlorothiazide, can cause an idiosyncratic reaction, resulting in transient myopia and acute angle-closure glaucoma. Cases of acute angle-closure glaucoma have been reported with hydrochlorothiazide. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
USE IN SPECIFIC POPULATIONS
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue AVALIDE as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue AVALIDE, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to AVALIDE for hypotension, oliguria, and hyperkalemia [see
Use in Specific Populations
Irbesartan crosses the placenta in rats and rabbits. In pregnant rats given irbesartan at doses greater than the maximum recommended human dose (MRHD), fetuses showed increased incidences of renal pelvic cavitation, hydroureter and/or absence of renal papilla. Subcutaneous edema also occurred in fetuses at doses about 4 times the MRHD (based on body surface area). These anomalies occurred when pregnant rats received irbesartan through Day 20 of gestation but not when
drug was stopped on gestation Day 15. The observed effects are believed to be late gestational effects of the drug. Pregnant rabbits given oral doses of irbesartan equivalent to 1.5 times the MRHD experienced a high rate of maternal mortality and abortion. Surviving females had a slight increase in early resorptions and a corresponding decrease in live fetuses [see
Radioactivity was present in the rat and rabbit fetus during late gestation and in rat milk following oral doses of radiolabeled irbesartan.
When pregnant mice and rats were given hydrochlorothiazide at doses up to 3000 and 1000 mg/kg/day, respectively (about 600 and 400 times the MRHD) during their respective periods of major organogenesis, there was no evidence of fetal harm.
A development toxicity study was performed in rats with doses of 50/50 mg/kg/day 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.
It is not known whether irbesartan is
excreted in human milk, but irbesartan or some metabolite of irbesartan is
secreted at low concentration in the milk of lactating rats.
appear in human milk. Because of the potential for adverse effects on the
nursing infant, a decision should be made whether to discontinue nursing or
discontinue the drug, taking into account the importance of the drug to the
Neonates with a history of in utero exposure to AVALIDE:
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Safety and effectiveness in pediatric patients have not been established.
Of 1694 patients receiving AVALIDE in
controlled clinical studies of hypertension, 264 (15.6%) were 65 years and
over, while 45 (2.7%) were 75 years and over. No overall differences in safety
or effectiveness were observed between these patients and younger patients,
but greater sensitivity of some older individuals cannot be ruled out. [See