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Candesartan Cilexetil

Pronunciation

Class: Angiotensin II Receptor Antagonists
VA Class: CV805
Chemical Name: (±)-1-[[Cyclohexyloxy)carbonyl]oxy]ethyl ester - 2 - ethoxy - 1 - [[2′ - (1H - tetrazol - 5 - yl)[1,1′ - biphenyl] - 4 - yl]methyl] - 1H - benzimidazole - 7 - carboxylic acid
Molecular Formula: C33H34…N6O6
CAS Number: 145040-37-5
Brands: Atacand, Atacand HCT

Warning(s)

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy.1 2 55 56 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • If pregnancy is detected, discontinue as soon as possible.1 2 56

Introduction

Angiotensin II receptor (AT1) antagonist.1 2 9

Uses for Candesartan Cilexetil

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).1 2 3 16 17 18 19 20 21 500

Angiotensin II receptor antagonists are recommended as one of several preferred agents for the initial management of hypertension; other options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics.501 502 503 504 While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501 502 503 504 Individualize choice of therapy; consider patient characteristics (e.g., age, ethnicity/race, comorbidities, cardiovascular risk) as well as drug-related factors (e.g., ease of administration, availability, adverse effects, cost).500 501 502 503 504 515

Angiotensin II receptor antagonists or ACE inhibitors may be preferred in hypertensive patients with diabetes mellitus or chronic kidney disease; angiotensin II receptor antagonists also may be preferred, as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or post-MI.500 501 502 504 520 523 524 527 534 535 536 543

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Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to angiotensin II receptor antagonists.500 501 504 However, diminished response to an angiotensin II receptor antagonist is largely eliminated when administered concomitantly with a calcium-channel blocker or thiazide diuretic.500 504

The optimum BP threshold for initiating antihypertensive drug therapy is controversial.501 504 505 506 507 508 515 523 530 Further study needed to determine optimum BP thresholds/goals; individualize treatment decisions.501 503 507 515 526 530

JNC 7 recommends initiation of drug therapy in all patients with uncomplicated hypertension and BP ≥140/90 mm Hg;500 JNC 8 panel recommends SBP threshold of 150 mm Hg for patients ≥60 years of age.501 Although many experts agree that SBP goal of <150 mm Hg may be appropriate for patients ≥80 years of age,502 504 505 530 application of this goal to those ≥60 years of age is controversial, especially for those at higher cardiovascular risk.501 502 505 506 508 511 515

In the past, initial antihypertensive drug therapy was recommended for patients with diabetes mellitus or chronic kidney disease who had BP ≥130/80 mm Hg;500 503 current hypertension management guidelines generally recommend a BP threshold of 140/90 mm Hg for these individuals (same as for the general population of patients without these conditions), although a goal of <130/80 mm Hg may still be considered.501 502 503 504 520 530 535 536 541

Heart Failure

Used in the management of heart failure.1 6 35 52 53

Because of their established benefits, ACE inhibitors are the preferred drugs for inhibition of the renin-angiotensin system in patients with heart failure and reduced left ventricular ejection fraction (LVEF); angiotensin II receptor antagonists may be used as an alternative in those intolerant of ACE inhibitors.524 528

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria who have modestly elevated (30–300 mg/24 hours) or higher (>300 mg/24 hours) levels of urinary albumin excretion; slows rate of progression of renal disease in such patients.25 26 27 28 29 30 31 32 36 37 39 40 41 520 535 536

Candesartan Cilexetil Dosage and Administration

General

BP Monitoring and Treatment Goals

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

  • When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

  • If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

  • Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

  • Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

Administration

Oral Administration

Administer orally once or twice daily without regard to meals.1 24

Dosage

Available as candesartan cilexetil; dosage expressed in terms of the salt.1

Adults

Hypertension
Candesartan Therapy
Oral

JNC 8 expert panel recommends initial dosage of 4 mg once daily and target dosage of 12–32 mg once daily based on dosages used in randomized controlled studies.501

Manufacturer recommends initial dosage of 16 mg once daily as monotherapy in adults without intravascular volume depletion.1 2 3

Manufacturer states usual dosage is 8–32 mg daily, given in 1 dose or 2 divided doses;1 2 5 no additional therapeutic benefit with higher dosages.1 2

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

Candesartan/Hydrochlorothiazide Fixed-combination Therapy
Oral

Manufacturer states fixed-combination preparation should not be used for initial antihypertensive therapy.2 5 11

If BP is not adequately controlled by monotherapy with candesartan 32 mg daily, can switch to fixed-combination tablets (candesartan 32 mg and hydrochlorothiazide 12.5 mg; then candesartan 32 mg and hydrochlorothiazide 25 mg).2 24

If BP is not adequately controlled by monotherapy with 25 mg of hydrochlorothiazide or if BP is controlled but hypokalemia is problematic at this dosage, can use fixed-combination tablets containing candesartan 16 mg and hydrochlorothiazide 12.5 mg.2 24

Heart Failure
Oral

Initially, 4 mg once daily.1 Increase dosage (by doubling the dosage at approximately 2-week intervals) as tolerated to a target dosage of 32 mg once daily.1

Special Populations

Hepatic Impairment

No initial dosage adjustments necessary in patients with mild hepatic impairment.1

Manufacturer recommends considering initial dosage reduction in patients with moderate hepatic impairment.1

If a lower initial candesartan cilexetil dosage (<8 mg once daily) is selected in patients with moderate hepatic impairment, do not use the commercially available preparation containing candesartan cilexetil in fixed combination with hydrochlorothiazide for initial titration, because the appropriate starting dose of candesartan cilexetil is not available as a fixed-combination preparation.2 Individualize and adjust dosage carefully when using the fixed combination preparation in patients with hepatic impairment .2 Some clinicians recommend initial candesartan cilexetil dosage of 4 or 8 mg daily in patients with severe hepatic impairment.3 10 22 23 24

Renal Impairment

Manufacturer states that no initial candesartan cilexetil dosage adjustments are necessary in patients with renal impairment.1 2 However, some clinicians recommend initial dosage of 4 or 8 mg daily in those with severe impairment.3 10 22 23 24

Volume- and/or Salt-Depleted Patients

Correct volume and/or salt depletion prior to initiation of therapy or initiate therapy under close medical supervision using lower initial dosage.1 2

Cautions for Candesartan Cilexetil

Contraindications

  • Known hypersensitivity to candesartan or any ingredient in the formulation.1 2 7 24

Warnings/Precautions

Warnings

Hypotension

Possible symptomatic hypotension, particularly in patients with intravascular volume depletion (e.g., those treated with diuretics).1 2 (See Volume- and/or Salt-Depleted Patients under Dosage and Administration.)

May need temporarily to reduce dosage of candesartan cilexitil and/or of a diuretic in patients with heart failure; monitor BP during dosage escalation and periodically thereafter.1 Initiate candesartan with caution in patients with heart failure.1

Transient hypotension is not a contraindication to additional doses; may reinstate therapy cautiously after BP is stabilized.1 2 24

Fetal/Neonatal Morbidity and Mortality

Possible fetal and neonatal morbidity and mortality when used during pregnancy.1 2 56 (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.56

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy.55 56

Discontinue as soon as possible when pregnancy is detected, unless continued use is considered lifesaving.55 56 Nearly all women can be transferred successfully to alternative therapy for the remainder of their pregnancy.12

Malignancies

In July 2010, FDA initiated a safety review of angiotensin II receptor antagonists after a published meta-analysis found a modest but statistically significant increase in risk of new cancer occurrence in patients receiving an angiotensin II receptor antagonist compared with control.120 121 123 126 However, subsequent studies, including a larger meta-analysis conducted by FDA, have not shown such risk.126 127 128 129 Based on currently available data, FDA has concluded that angiotensin II receptor antagonists do not increase the risk of cancer.126

Sensitivity Reactions

Anaphylactoid reactions and/or angioedema possible;1 2 7 13 not recommended in patients with a history of angioedema associated with or unrelated to ACE inhibitor or angiotensin II receptor antagonist therapy.14 21

General Precautions

Renal Effects

Possible oliguria, progressive azotemia and, rarely, acute renal failure and/or death in patients with severe heart failure.1 2

Increases in BUN and SCr possible in patients with unilateral or bilateral renal artery stenosis.1 2

Hyperkalemia

Possible hyperkalemia in patients with heart failure, especially those receiving concomitant therapy with an ACE inhibitor and/or a potassium-sparing diuretic.1 Monitor serum potassium during dosage escalation and periodically thereafter.1

Use of Fixed Combinations

When candesartan is used in fixed combination with hydrochlorothiazide, consider the cautions, precautions, and contraindications associated with hydrochlorothiazide.2

Specific Populations

Pregnancy

Category C (1st trimester); Category D (2nd and 3rd trimesters).1 2 (See Boxed Warning and Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 2 Discontinue nursing or the drug.1 2

Pediatric Use

Safety and efficacy not established in children <18 years of age.1 24

Geriatric Use

No substantial differences in safety or efficacy for the treatment of hypertension relative to younger adults, but increased sensitivity cannot be ruled out.1 2 3

Increased incidence of adverse effects (e.g., abnormal renal function, hypotension, hyperkalemia) and consequent discontinuance of candesartan in patients with heart failure who were ≥75 years of age when compared with younger patients.1

Hepatic Impairment

Systemic exposure to candesartan may be increased.1 (See Absorption: Special Populations, under Pharmacokinetics.) Dosage adjustments may be necessary based on degree of hepatic impairment.1 3 10 22 23 24 (See Hepatic Impairment under Dosage and Administration.)

Renal Impairment

Systemic exposure to candesartan may be increased.1 (See Absorption: Special Populations, under Pharmacokinetics.) Some clinicians recommend initial dosage adjustment in patients with severe renal impairment.3 10 22 23 24 (See Renal Impairment under Dosage and Administration.)

Use of candesartan in fixed combination with hydrochlorothiazide is not recommended in patients with Clcr <30 mL/minute.2

Deterioration of renal function may occur in susceptible patients.1 30 (See Renal Effects under Cautions.)

Black Patients

BP reduction may be smaller in black patients compared with nonblack patients.1 (See Hypertension under Uses.)

Common Adverse Effects

Back pain, dizziness, upper respiratory tract infection, pharyngitis, rhinitis.1 3

Interactions for Candesartan Cilexetil

Not substantially metabolized by CYP isoenzymes; has no effect on CYP isoenzymes at therapeutic concentrations.1

Specific Drugs

Drug

Interaction

Comment

Cardiac drugs (e.g., digoxin, enalapril, hydrochlorothiazide, nifedipine)

Pharmacologic interactions unlikely1 2 3

Contraceptives, oral

Pharmacokinetic interaction unlikely1 2 3

Glyburide

Pharmacologic interaction unlikely1 2

Lithium

Increased serum lithium concentrations; possible toxicity1

Closely monitor serum lithium concentrations1

Warfarin

Pharmacologic interaction unlikely1 2 3

Candesartan Cilexetil Pharmacokinetics

Absorption

Bioavailability

Candesartan cilexetil (prodrug) is rapidly and completely hydrolyzed to candesartan during absorption in the GI tract.1 2 3

Absolute bioavailability of candesartan is about 15%.1

Onset

Antihypertensive effect evident within 2 weeks, with maximum BP reduction after 4–6 weeks.1

Food

Food with high-fat content does not affect bioavailability.1

Special Populations

In patients with mild hepatic impairment (Child-Pugh class A), peak plasma concentration and AUC are increased by 56 and 30%, respectively,1 2 while in those with moderate hepatic insufficiency (Child-Pugh class B), peak plasma concentration and AUC are increased by 73 and 145%, respectively.1 2 Pharmacokinetics not studied in patients with severe hepatic impairment.1 2

In patients with severe renal impairment (Clcr <30 mL/min/1.73 m2), AUC and peak plasma concentration after repeated dosing are approximately double the values in patients with normal renal function.1

Distribution

Extent

Crosses the placenta and is distributed in the fetus in animals.

Crosses the blood-brain barrier poorly, if at all, in animals.1

Distributed into milk in rats; not known whether distributed into human milk.1 2

Plasma Protein Binding

>99%.1

Elimination

Metabolism

Undergoes minor hepatic metabolism by O-deethylation to an inactive metabolite.1

Elimination Route

Eliminated mainly as unchanged drug in urine and feces (via bile).1 2

Half-life

Approximately 9 hours.1

Special Populations

Not removed by hemodialysis.1 Pharmacokinetics in hypertensive patients undergoing hemodialysis are similar to those in hypertensive patients with severe renal impairment.1 (See Absorption: Special Populations, under Pharmacokinetics.)

Stability

Storage

Oral

Tablets

Tightly closed container at 25°C (may be exposed to 15–30°C).1 2

Actions

  • Candesartan cilexetil (prodrug) has little pharmacologic activity until hydrolyzed to candesartan during absorption.1 2 3

  • Blocks the physiologic actions of angiotensin II, including vasoconstrictor and aldosterone-secreting effects.1

  • Does not interfere with response to bradykinins and substance P.1

  • Does not share the ACE inhibitor common adverse effect of dry cough.5 13 24

Advice to Patients

  • Risks of use during pregnancy.1 2 55 56

  • Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1 2

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Candesartan Cilexetil

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

4 mg

Atacand

AstraZeneca

8 mg

Atacand

AstraZeneca

16 mg

Atacand

AstraZeneca

32 mg

Atacand

AstraZeneca

Candesartan Cilexetil Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

16 mg with Hydrochlorothiazide 12.5 mg

Atacand HCT

AstraZeneca

32 mg with Hydrochlorothiazide 12.5 mg

Atacand HCT

AstraZeneca

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 12/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Atacand 16MG Tablets (ASTRAZENECA LP): 30/$85.99 or 90/$235.96

Atacand 32MG Tablets (ASTRAZENECA LP): 30/$111.99 or 90/$314.98

Atacand 4MG Tablets (ASTRAZENECA LP): 30/$84.99 or 90/$237.98

Atacand 8MG Tablets (ASTRAZENECA LP): 30/$84.99 or 90/$238.96

Atacand HCT 16-12.5MG Tablets (ASTRAZENECA LP): 30/$110.99 or 90/$315.97

Atacand HCT 32-12.5MG Tablets (ASTRAZENECA LP): 30/$115.99 or 90/$325.97

Atacand HCT 32-25MG Tablets (ASTRAZENECA LP): 30/$121.99 or 90/$340.98

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 12, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

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2. AstraZeneca. Atacand HCT (candesartan cilexetil-hydrochlorothiazide) tablets prescribing information. Wilmington, DE; 2005 Dec.

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