Atacand

— THERAPEUTIC CATEGORIES —
  • CHF and arrhythmias
  • Hypertension
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Atacand Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Candesartan cilexetil 4mg, 8mg, 16mg, 32mg; scored tabs.

    Pharmacological Class

    Angiotensin II receptor blocker (ARB).

    How Supplied

    Tabs 4mg, 8mg—30; 16mg, 32mg—30, 90

    How Supplied

    • Atacand Tablets, 4 mg, are white to off-white, circular/biconvex-shaped, non-film-coated scored tablets, coded ACF on one side and 004 on the other. They are supplied in bottles of 30 tablets. 

    • Atacand Tablets, 8 mg, are light pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACG on one side and 008 on the other. They are supplied in bottles of 30 tablets. 

    • Atacand Tablets, 16 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACH on one side and 016 on the other. They are supplied in bottles of 30 tablets and bottles of 90 tablets. 

    • Atacand Tablets, 32 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACL on one side and 032 on the other. They are supplied in bottles of 30 tablets and bottles of 90 tablets. 

    Storage

    Store at 20° to 25°C (68° to 77°F); excursions permitted at 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. 

    Manufacturer

    ANI Pharmaceuticals, Inc.

    Atacand Indications

    Indications

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

    Atacand Dosage and Administration

    Adult

    ≥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

    <18yrs: not recommended.

    Atacand Contraindications

    Contraindications

    Concomitant aliskiren in patients with diabetes.

    Atacand Boxed Warnings

    Boxed Warning

    Fetal toxicity.

    Atacand Warnings/Precautions

    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.

    Warnings/Precautions

    Fetal Toxicity

    • 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.

    • Discontinue Atacand as soon as possible when pregnancy is detected.

    Morbidity in Infants

    • Children <1 year of age must not receive Atacand for hypertension. 

    Hypotension

    • Can cause symptomatic hypotension, particularly in patients who have been volume and/or salt depleted resulting from prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

    • Patients with symptomatic hypotension may require temporarily reducing the dose of Atacand, diuretic or both, and volume repletion.

    • Correct volume and/or salt depletion prior to initiating Atacand.

    • Monitoring blood pressure is recommended during dose escalation and periodically thereafter.

    • Hypotension may occur during major surgery and anesthesia. Very rarely, hypotension may be severe and warrant the use of IV fluids and/or vasopressors.

    Impaired Renal Function

    • Monitor renal function periodically.

    • Patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with renal artery stenosis, chronic kidney disease, severe heart failure or volume depletion) may be at risk of developing oliguria and/or progressive azotemia and (rarely) with acute renal failure. Consider withholding or discontinuing therapy if clinically significant decrease in renal function occurs while treatment with Atacand.

    Hyperkalemia

    • Monitor serum potassium periodically

    Pregnancy Considerations

    Risk Summary

    • May cause fetal harm.

    • 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.

    • Discontinue Atacand as soon as possible when pregnancy is detected.

    Clinical Considerations

    • Disease-associated maternal and/or embryo/fetal risk: 

      • Pregnant women with hypertension should be carefully monitored due to increased fetal risk for intrauterine growth restriction and intrauterine death.

      • Pregnant women with chronic heart failure are at increased risk for preterm birth. Closely monitor for destabilization of HF.

    • Fetal/Neonatal Adverse Reactions:

      • Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the 2nd and 3rd trimesters of pregnancy can result in fetal lung hypoplasia and skeletal deformations.

      • Perform serial ultrasound examinations to assess intra-amniotic environment. If oligohydramnios is observed, consider alternative drug treatment.

      • Observe closely infants with histories of in utero exposure to Atacand. If oligouria or hypotension occurs in neonates with a history of in utero exposure to Atacand, support blood pressure and renal perfusion.

    Atacand Pharmacokinetics

    Distribution

    The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells.

    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.

    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.

    Atacand Interactions

    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.

    Atacand Adverse Reactions

    Adverse Reactions

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

    Atacand Clinical Trials

    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.

     

    Atacand Note

    Not Applicable

    Atacand Patient Counseling

    Patient Counseling

    Pregnancy

    • Advise females of childbearing age about the consequences of exposure to Atacand during pregnancy. 
    • Discuss treatment options with women planning to become pregnant. 
    • Tell patients to report pregnancies to their physicians as soon as possible.

    Atacand Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Candesartan cilexetil 4mg, 8mg, 16mg, 32mg; scored tabs.

    Pharmacological Class

    Angiotensin II receptor blocker (ARB).

    How Supplied

    Tabs 4mg, 8mg—30; 16mg, 32mg—30, 90

    How Supplied

    • Atacand Tablets, 4 mg, are white to off-white, circular/biconvex-shaped, non-film-coated scored tablets, coded ACF on one side and 004 on the other. They are supplied in bottles of 30 tablets. 

    • Atacand Tablets, 8 mg, are light pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACG on one side and 008 on the other. They are supplied in bottles of 30 tablets. 

    • Atacand Tablets, 16 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACH on one side and 016 on the other. They are supplied in bottles of 30 tablets and bottles of 90 tablets. 

    • Atacand Tablets, 32 mg, are pink, circular/biconvex-shaped, non-film-coated scored tablets, coded ACL on one side and 032 on the other. They are supplied in bottles of 30 tablets and bottles of 90 tablets. 

    Storage

    Store at 20° to 25°C (68° to 77°F); excursions permitted at 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed. 

    Manufacturer

    ANI Pharmaceuticals, Inc.

    Atacand Indications

    Indications

    Hypertension.

    Atacand Dosage and Administration

    Adult

    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

    <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

    Contraindications

    Concomitant aliskiren in patients with diabetes.

    Atacand Boxed Warnings

    Boxed Warning

    Fetal toxicity.

    Atacand Warnings/Precautions

    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.

    Warnings/Precautions

    Fetal Toxicity

    • 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.

    • Discontinue Atacand as soon as possible when pregnancy is detected.

    Morbidity in Infants

    • Children <1 year of age must not receive Atacand for hypertension. 

    Hypotension

    • Can cause symptomatic hypotension, particularly in patients who have been volume and/or salt depleted resulting from prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

    • Patients with symptomatic hypotension may require temporarily reducing the dose of Atacand, diuretic or both, and volume repletion.

    • Correct volume and/or salt depletion prior to initiating Atacand.

    • Monitoring blood pressure is recommended during dose escalation and periodically thereafter.

    • Hypotension may occur during major surgery and anesthesia. Very rarely, hypotension may be severe and warrant the use of IV fluids and/or vasopressors.

    Impaired Renal Function

    • Monitor renal function periodically.

    • Patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (eg, patients with renal artery stenosis, chronic kidney disease, severe heart failure or volume depletion) may be at risk of developing oliguria and/or progressive azotemia and (rarely) with acute renal failure. Consider withholding or discontinuing therapy if clinically significant decrease in renal function occurs while treatment with Atacand.

    Hyperkalemia

    • Monitor serum potassium periodically

    Pregnancy Considerations

    Risk Summary

    • May cause fetal harm.

    • 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.

    • Discontinue Atacand as soon as possible when pregnancy is detected.

    Clinical Considerations

    • Disease-associated maternal and/or embryo/fetal risk: 

      • Pregnant women with hypertension should be carefully monitored due to increased fetal risk for intrauterine growth restriction and intrauterine death.

      • Pregnant women with chronic heart failure are at increased risk for preterm birth. Closely monitor for destabilization of HF.

    • Fetal/Neonatal Adverse Reactions:

      • Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the 2nd and 3rd trimesters of pregnancy can result in fetal lung hypoplasia and skeletal deformations.

      • Perform serial ultrasound examinations to assess intra-amniotic environment. If oligohydramnios is observed, consider alternative drug treatment.

      • Observe closely infants with histories of in utero exposure to Atacand. If oligouria or hypotension occurs in neonates with a history of in utero exposure to Atacand, support blood pressure and renal perfusion.

    Atacand Pharmacokinetics

    Distribution

    The volume of distribution of candesartan is 0.13 L/kg. Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells.

    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.

    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.

    Atacand Interactions

    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.

    Atacand Adverse Reactions

    Adverse Reactions

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

    Atacand Clinical Trials

    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.

    Atacand Note

    Not Applicable

    Atacand Patient Counseling

    Patient Counseling

    Pregnancy

    • Advise females of childbearing age about the consequences of exposure to Atacand during pregnancy. 
    • Discuss treatment options with women planning to become pregnant. 
    • Tell patients to report pregnancies to their physicians as soon as possible.

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