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 ATACAND as soon as possible [see
USE IN SPECIFIC POPULATIONS
Oral doses ≥10 mg of candesartan cilexetil/kg/day administered to pregnant rats during late gestation and continued through lactation were associated with reduced survival and an increased incidence of hydronephrosis in the offspring. The 10-mg/kg/day dose in rats is approximately 2.8 times the maximum recommended daily human dose (MRHD) of 32 mg on a mg/m2 basis (comparison assumes human body weight of 50 kg). Candesartan cilexetil given to pregnant rabbits at an oral dose of 3 mg/kg/day (approximately 1.7 times the MRHD on a mg/m2 basis) caused maternal toxicity (decreased body weight and death) but, in surviving dams, had no adverse effects on fetal survival, fetal weight, or external, visceral, or skeletal development. No maternal toxicity or adverse effects on fetal development were observed when oral doses up to 1000 mg of candesartan cilexetil/kg/day (approximately 138 times the MRHD on a mg/m2 basis) were administered to pregnant mice.
Morbidity in Infants
Children < 1 year of age must not receive ATACAND for hypertension. Drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys.
In adult or children patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with diuretics), symptomatic hypotension may occur. These conditions should be corrected prior to administration of ATACAND, or the treatment should start under close medical supervision [see DOSAGE AND ADMINISTRATION].
If hypotension occurs, the patients 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.
Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given ATACAND commonly have some reduction in blood pressure. In patients with symptomatic hypotension this may require temporarily reducing the dose of ATACAND, or diuretic, or both, and volume repletion. In the CHARM program, hypotension was reported in 18.8% of patients on ATACAND versus 9.8% of patients on placebo. The incidence of hypotension leading to drug discontinuation in ATACAND-treated patients was 4.1% compared with 2.0% in placebo-treated patients.
Monitoring of blood pressure is recommended during dose escalation and periodically thereafter.
Hypotension may occur during major surgery and anesthesia in patients treated with angiotensin II receptor antagonists, including ATACAND, due to blockade of the renin-angiotensin system. Very rarely, hypotension may be severe such that it may warrant the use of intravenous fluids and/or vasopressors.
Impaired Hepatic Function
Based on pharmacokinetic data which demonstrate significant increases in candesartan AUC and Cmax in patients with moderate hepatic impairment, a lower initiating dose should be considered for patients with moderate hepatic impairment [see CLINICAL PHARMACOLOGY].
Renal Function Deterioration
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in some individuals treated with ATACAND. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (eg, patients with severe heart failure), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with ATACAND [see CLINICAL PHARMACOLOGY].
In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of ATACAND in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
In heart failure patients treated with ATACAND, increases in serum creatinine may occur. Dosage reduction or discontinuation of the diuretic or ATACAND, and volume repletion may be required. In the CHARM program, the incidence of abnormal renal function (e.g., creatinine increase) was 12.5% in patients treated with ATACAND versus 6.3% in patients treated with placebo. The incidence of abnormal renal function (eg, creatinine increase) leading to drug discontinuation in ATACAND-treated patients was 6.3% compared with 2.9% in placebo-treated patients. Evaluation of patients with heart failure should always include assessment of renal function and volume status. Monitoring of serum creatinine is recommended during dose escalation and periodically thereafter.
Pediatrics - ATACAND has not been studied in children with estimated glomerular filtration rate < 30 mL/min/1.73m2.
In heart failure patients treated with ATACAND, hyperkalemia may occur, especially when taken concomitantly with ACE inhibitors and potassium-sparing diuretics such as spironolactone. In the CHARM program, the incidence of hyperkalemia was 6.3% in patients treated with ATACAND versus 2.1% in patients treated with placebo. The incidence of hyperkalemia leading to drug discontinuation in ATACAND-treated patients was 2.4% compared with 0.6% in placebo-treated patients. During treatment with ATACAND in patients with heart failure, monitoring of serum potassium is recommended during dose escalation and periodically thereafter.
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 ATACAND 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 ATACAND, 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 ATACAND for hypotension, oliguria, and hyperkalemia. [see USE IN SPECIFIC POPULATIONS (8. 4)
Labor and Delivery
The effect of ATACAND on labor and delivery in humans is unknown [see WARNINGS AND PRECAUTIONS].
It is not known whether candesartan is excreted in human milk, but candesartan has been shown to be present in rat milk. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue ATACAND, taking into account the importance of the drug to the mother.
Neonates with a history of in utero exposure to ATACAND:
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.
The antihypertensive effects of ATACAND were evaluated in hypertensive children 1 to < 17 years of age in randomized, double-blind clinical studies [see CLINICAL STUDIES]. The pharmacokinetics of ATACAND have been evaluated in pediatric patients 1 to < 17 years of age [see Pharmacokinetics].
Children < 1 year of age must not receive ATACAND for hypertension [see WARNINGS AND PRECAUTIONS].
Of the total number of subjects in clinical studies of ATACAND, 21% (683/3260) were 65 and over, while 3% (87/3260) were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In a placebo-controlled trial of about 200 elderly hypertensive patients (ages 65 to 87 years), administration of candesartan cilexetil was well tolerated and lowered blood pressure by about 12/6 mm Hg more than placebo.
Of the 7599 patients with heart failure in the CHARM program, 4343 (57%) were age 65 years or older and 1736 (23%) were 75 years or older. In patients ≥ 75 years of age, the incidence of drug discontinuations due to adverse events was higher for those treated with ATACAND or placebo compared with patients <75 years of age. In these patients, the most common adverse events leading to drug discontinuation at an incidence of at least 3%, and more frequent with ATACAND than placebo, were abnormal renal function (7.9% vs. 4.0%), hypotension (5.2% vs. 3.2%) and hyperkalemia (4.2% vs. 0.9%). In addition to monitoring of serum creatinine, potassium, and blood pressure during dose escalation and periodically thereafter, greater sensitivity of some older individuals with heart failure must be considered.