Select therapeutic use:

CHF and arrhythmias:

Indications for: ATACAND

Heart failure (NYHA Class II-IV and ejection fraction ≤40%), to reduce risk of death and hospitalization; alone or with an ACE inhibitor.

Clinical Trials:

Candesartan was evaluated in 2 heart failure outcome studies: (1) The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity trial in patients intolerant of ACE inhibitors (CHARM–Alternative); and (2) CHARM– Added in patients already receiving ACE inhibitors.

Both international, double-blind, placebo-controlled trials evaluated candesartan in patients with NYHA class II–IV heart failure and LVEF ≤40%. Patients were randomly assigned to receive either placebo or Atacand (initially 4–8mg once daily, titrated as tolerated to 32 mg once daily) and followed for up to 4 years. The primary endpoint for both trials was time to either cardiovascular (CV) death or hospitalization for heart failure.

Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity trial in patients intolerant of ACE inhibitors (CHARM–Alternative)

  • The study included 2028 patients who were not receiving an ACE inhibitor due to intolerance. The mean daily dose of Atacand was approximately 23mg; 59% of patients received 32mg once daily.

  • After a median follow-up of 34 months, treatment with Atacand achieved a 23% risk reduction in CV death or heart failure hospitalization (hazard ratio, 0.77 [95% CI, 0.67-0.89]; P <.001).

CHARM– Added in patients already receiving ACE inhibitors

  • The study included 2548 patients receiving an ACE inhibitor. The mean daily dose of Atacand was approximately 24mg; 61% of patients received 32mg once daily.

  • After a median follow-up of 41 months, treatment with Atacand achieved a 15% risk reduction in CV death or heart failure hospitalization (hazard ratio, 0.85 [95% CI, 0.75-0.96]; P =.011).

In both studies, Atacand demonstrated an 18% risk reduction for CV death or heart failure hospitalization in major subgroups and in patients on other combinations of CV and heart failure treatments, including ACE inhibitors and beta-blockers.

 

Adult Dosage:

≥18yrs: Initially 4mg once daily; double daily dose at 2-week intervals as tolerated to target 32mg once daily. Salt/volume depleted or moderate hepatic impairment: consider lower initial dose.

Children Dosage:

<18yrs: not recommended.

ATACAND Contraindications:

Concomitant aliskiren in patients with diabetes.

Boxed Warning:

Fetal toxicity.

ATACAND Warnings/Precautions:

Fetal toxicity may develop; discontinue if pregnancy is detected. Correct hypovolemia before starting or monitor closely. Monitor BP, renal function, serum K+ periodically. Hepatic or renal impairment. Severe CHF. Renal artery stenosis. Surgery. Elderly. Neonates. Pregnancy: monitor. Nursing mothers: not recommended.

ATACAND Classification:

Angiotensin II receptor blocker (ARB).

ATACAND Interactions:

See Contraindications. Dual inhibition of the renin-angiotensin system with ARBs, ACEIs, or aliskiren may increase risk of hypotension, hyperkalemia, renal function changes. Avoid aliskiren in renal impairment (CrCl <60mL/min). Hyperkalemia with K+ supplements, K+ sparing diuretics, K+ containing salt substitutes. May be antagonized by, and renal toxicity potentiated by NSAIDs, including selective COX-2 inhibitors. Monitor lithium levels.

Adverse Reactions:

Headache, dizziness, hypotension, renal dysfunction, hyperkalemia, back pain, upper respiratory tract infection, pharyngitis, rhinitis, rhabdomyolysis (rare).

Metabolism:

Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.

Drug Elimination:

Total plasma clearance – 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of 14C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Biliary excretion contributes to the elimination of candesartan.

How Supplied:

Tabs 4mg, 8mg—30; 16mg, 32mg—30, 90

Hypertension:

Indications for: ATACAND

Hypertension.

Clinical Trials:

Adult - 14 placebo-controlled trials

  • These trials were 4- to 12-week in duration, primarily at daily doses of 2–32 mg per day in patients with baseline diastolic blood pressures of 95–114 mmHg.

  • A total of 2350 patients were randomly assigned to receive one of several doses of candesartan cilexetil and 1027 to placebo.

  • All studies, except for a study in diabetic patients, showed that treatment with candesartan cilexetil 2–32 mg had significant effects on trough (24hr) systolic and diastolic pressures compared with placebo, In particular, candesartan cilexetil 8–32 mg had effects on trough systolic and diastolic pressure of about 8–12/ 4–8 mmg Hg.

  • The antihypertensive effect of candesartan cilexetil was observed within 2 weeks of initial dosing and the full effect in 4 weeks. Blood pressure effect was maintained over 24 hours with once-daily dosing.

Adult - 2 randomized, double-blind trials

  • These trials compared the antihypertensive effects of candesartan cilexetil to losartan potassium at their highest recommended doses administered once-daily in a total of 1268 patients with mild to moderate hypertension who were not receiving other antihypertensive therapy.

  • Candesartan 32 mg lowered systolic and diastolic blood pressure by 2–3 mm Hg on average more than losartan potassium 100 mg, when measured at the time of either peak or trough effect.

  • The antihypertensive effect was somewhat less in blacks. There was no rebound after abrupt withdrawal.

Pediatric

  • In 2 randomized, double-blind, multicenter, 4-week dose ranging studies, the antihypertensive effects of Atacand were evaluated in hypertensive children 1 to <6 years of age (n=93) and 6 to <17 years of age (n=240).

  • Children 1 to <6 years were randomly assigned to receive an oral dose of candesartan cilexetil suspension 0.05, 0.20, or 0.40 mg/kg once daily. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased 6.0/5.2 to 12.0/11.1 mmHg from baseline across the 3 doses.

  • Children 6 to <17 years were randomly assigned 1:2:2:2 to receive either placebo or low, medium, or high doses of Atacand. Children who weighed <50kg were given 2mg, 8mg, or 16mg of Atacand once daily. Children who weighed >50kg were 4mg, 16mg, or 32mg of Atacand once daily. The placebo subtracted effect at trough for sitting systolic blood pressure/sitting diastolic blood pressure for the different doses were from 4.9/3.0 to 7.5/6.2 mmHg.

Adult Dosage:

Individualize. ≥18yrs: Monotherapy and not volume-depleted: initially 16mg once daily; usual range: 8–32mg per day once daily or in 2 divided doses. Moderate hepatic impairment: initially 8mg once daily. Salt/volume depleted: consider lower initial dose. May add diuretic if needed.

Children Dosage:

<1yr or CrCl<30mL/min: not recommended. Give once daily or in 2 divided doses. 1–<6yrs (may give oral susp if unable to swallow tabs): initially 0.2mg/kg/day; usual range: 0.05–0.4mg/kg/day. 6–<17yrs (<50kg): initially 4–8mg/day; usual range: 2–16mg/day; (>50kg): initially 8–16mg/day; usual range: 4–32mg/day. Salt/volume depleted: consider lower initial dose.

ATACAND Contraindications:

Concomitant aliskiren in patients with diabetes.

Boxed Warning:

Fetal toxicity.

ATACAND Warnings/Precautions:

Fetal toxicity may develop; discontinue if pregnancy is detected. Correct hypovolemia before starting or monitor closely. Monitor BP, renal function, serum K+ periodically. Hepatic or renal impairment. Severe CHF. Renal artery stenosis. Surgery. Elderly. Neonates. Pregnancy: monitor. Nursing mothers: not recommended.

ATACAND Classification:

Angiotensin II receptor blocker (ARB).

ATACAND Interactions:

See Contraindications. Dual inhibition of the renin-angiotensin system with ARBs, ACEIs, or aliskiren may increase risk of hypotension, hyperkalemia, renal function changes. Avoid aliskiren in renal impairment (CrCl <60mL/min). Hyperkalemia with K+ supplements, K+ sparing diuretics, K+ containing salt substitutes. May be antagonized by, and renal toxicity potentiated by NSAIDs, including selective COX-2 inhibitors. Monitor lithium levels.

Adverse Reactions:

Headache, dizziness, hypotension, renal dysfunction, hyperkalemia, back pain, upper respiratory tract infection, pharyngitis, rhinitis, rhabdomyolysis (rare).

Metabolism:

Because candesartan is not significantly metabolized by the cytochrome P450 system and at therapeutic concentrations has no effects on P450 enzymes, interactions with drugs that inhibit or are metabolized by those enzymes would not be expected.

Drug Elimination:

Total plasma clearance – 0.37 mL/min/kg, with a renal clearance of 0.19 mL/min/kg. When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Following an oral dose of 14C-labeled candesartan cilexetil, approximately 33% of radioactivity is recovered in urine and approximately 67% in feces. Biliary excretion contributes to the elimination of candesartan.

How Supplied:

Tabs 4mg, 8mg—30; 16mg, 32mg—30, 90