WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS · Avoid fetal (in utero) and neonatal exposure (5.1).

· Children < 1 year of age must not receive ATACAND for hypertension (5.2).

· Observe for signs and symptoms of hypotension (5.3).

· Use with caution in patients with impaired hepatic (5.4) or renal (5.5) function.

· Hyperkalemia may occur in heart failure patients treated with ATACAND (5.6).

5.1 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.

Post-marketing experience has identified reports of fetal and neonatal toxicity in babies born to women treated with ATACAND during pregnancy.

When pregnancy is detected, ATACAND 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 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 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 ATACAND 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 intra-amniotic environment.

If oligohydramnios is observed, ATACAND should be discontinued unless it is considered life saving for the mother.

Contraction stress testing (CST), a nonstress 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 means of reversing hypotension and/or substituting for disordered renal function.

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.

5.2 Morbidity in Infants Children < 1 year of age must not receive ATACAND for hypertension.

The consequences of administering drugs that act directly on the renin-angiotensin system (RAS) can have effects on the development of immature kidneys.

5.3 Hypotension 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 (2.1)].

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.

Major Surgery/Anesthesia 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.

5.4 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 (12.3)].

5.5 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 (12.3)].

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.

5.6 Hyperkalemia 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.