Brand name: Atacand
Drug 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: C₃₃H_34…N₆O₆
CAS number: 145040-37-5

Medically reviewed by Drugs.com on Oct 28, 2024. Written by ASHP.

Introduction

Angiotensin II receptor (AT₁) antagonist (i.e., angiotensin II receptor blocker, ARB).

Uses for Candesartan

Hypertension

Management of hypertension (alone or in combination with other classes of antihypertensive agents).

Angiotensin II receptor antagonists are recommended as one of several preferred agents for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include ACE inhibitors, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.

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).

A 2017 ACC/AHA multidisciplinary hypertension guideline classifies BP in adults into 4 categories: normal, elevated, stage 1 hypertension, and stage 2 hypertension. (See Table 1.)

Source: Whelton PK, Carey RM, Aronow WS et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13-115.

Individuals with SBP and DBP in 2 different categories (e.g., elevated SBP and normal DBP) should be designated as being in the higher BP category (i.e., elevated BP).

The goal of hypertension management and prevention is to achieve and maintain optimal control of BP. However, the BP thresholds used to define hypertension, the optimum BP threshold at which to initiate antihypertensive drug therapy, and the ideal target BP values remain controversial.

The 2017 ACC/AHA hypertension guideline generally recommends a target BP goal (i.e., BP to achieve with drug therapy and/or nonpharmacologic intervention) of <130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk. In addition, an SBP goal of <130 mm Hg is recommended for noninstitutionalized ambulatory patients ≥65 years of age with an average SBP of ≥130 mm Hg. These BP goals are based upon clinical studies demonstrating continuing reduction of cardiovascular risk at progressively lower levels of SBP.

Previous hypertension guidelines generally have based target BP goals on age and comorbidities. Guidelines such as those issued by the JNC 8 expert panel generally have targeted a BP goal of <140/90 mm Hg regardless of cardiovascular risk and have used higher BP thresholds and target BPs in elderly patients compared with those recommended by the 2017 ACC/AHA hypertension guideline.

Some clinicians continue to support previous target BPs recommended by JNC 8 due to concerns about the lack of generalizability of data from some clinical trials (e.g., SPRINT study) used to support the current ACC/AHA hypertension guideline and potential harms (e.g., adverse drug effects, costs of therapy) versus benefits of BP lowering in patients at lower risk of cardiovascular disease.

Consider potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs when deciding a patient’s BP treatment goal.

For decisions regarding when to initiate drug therapy (BP threshold), the 2017 ACC/AHA hypertension guideline incorporates underlying cardiovascular risk factors. ASCVD risk assessment recommended by ACC/AHA for all adults with hypertension.

ACC/AHA currently recommend initiation of antihypertensive drug therapy in addition to lifestyle/behavioral modifications at an SBP ≥140 mm Hg or DBP ≥90 mm Hg in adults who have no history of cardiovascular disease (i.e., primary prevention) and a low ASCVD risk (10-year risk <10%).

For secondary prevention in adults with known cardiovascular disease or for primary prevention in those at higher risk for ASCVD (10-year risk ≥10%), ACC/AHA recommend initiation of antihypertensive drug therapy at an average SBP ≥130 mm Hg or an average DBP ≥80 mm Hg.

Adults with hypertension and diabetes mellitus, chronic kidney disease (CKD), or age ≥65 years are assumed to be at high risk for cardiovascular disease; ACC/AHA state that such patients should have antihypertensive drug therapy initiated at a BP ≥130/80 mm Hg.

In stage 1 hypertension, experts state that it is reasonable to initiate drug therapy using the stepped-care approach in which one drug is initiated and titrated and other drugs are added sequentially to achieve the target BP. Initiation of antihypertensive therapy with 2 first-line agents from different pharmacologic classes recommended in adults with stage 2 hypertension and average BP >20/10 mm Hg above BP goal.

Black hypertensive patients generally tend to respond better to monotherapy with calcium-channel blockers or thiazide diuretics than to angiotensin II receptor antagonists. However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar BP lowering in black patients as in other racial groups.

Angiotensin II receptor antagonists or ACE inhibitors may be particularly useful in hypertensive patients with diabetes mellitus or CKD; 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.

Heart Failure

Used in the management of heart failure.

Because of their established benefits, ACE inhibitors have been the preferred drugs for inhibition of the renin-angiotensin-aldosterone (RAA) system in patients with heart failure and reduced left ventricular ejection fraction (LVEF); however, some evidence indicates that therapy with an ACE inhibitor (enalapril) may be less effective than angiotensin receptor-neprilysin inhibitor (ARNI) therapy (e.g., sacubitril/valsartan) in reducing cardiovascular death and heart failure-related hospitalization.

Angiotensin II receptor antagonists may be used as an alternative for those patients in whom use of an ACE inhibitor or ARNI is inappropriate.

ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend that patients with chronic symptomatic heart failure and reduced LVEF (NYHA class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality.

Diabetic Nephropathy

A recommended agent in the management of patients with diabetes mellitus and persistent albuminuria^{† [off-label]} 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.

Candesartan Dosage and Administration

General

BP Monitoring and Treatment Goals

• Monitor BP regularly (i.e., monthly) during therapy and adjust dosage of the antihypertensive drug until BP controlled.

• If unacceptable adverse effects occur, discontinue drug and initiate another antihypertensive agent from a different pharmacologic class.

• If adequate BP response not achieved with a single antihypertensive agent, either increase dosage of single drug or add a second drug with demonstrated benefit and preferably a complementary mechanism of action (e.g., calcium-channel blocker, thiazide diuretic). Many patients will require at least 2 drugs from different pharmacologic classes to achieve BP goal; if goal BP still not achieved with 2 antihypertensive agents, add a third drug.

Administration

Oral Administration

Administer orally once or twice daily without regard to meals.

May substitute oral suspension in children who cannot swallow tablets.

Reconstitution

Prepare extemporaneous candesartan cilexetil oral suspension in concentration range of 0.1–2 mg/mL (1 mg/mL generally suitable for administering most dosages). May use any strength of candesartan tablets.

To prepare 160 mL of a 1-mg/mL suspension, use equal volumes (80 mL each) of Ora-Plus and Ora-Sweet SF or use 160 mL of Ora-Blend SF. Add a small amount of the vehicle to the required number of candesartan cilexetil tablets (i.e., five 32-mg tablets), and grind into a smooth paste using a mortar and pestle. Add the paste to a preparation container of suitable size.

Rinse the mortar and pestle clean using the vehicle and add the resulting vehicle mixture to the container; repeat as necessary. Add the remaining vehicle to the container and mix thoroughly. Dispense in suitably sized amber polyethylene terephthalate (PET) bottles.

Label with an expiration date of 100 days and the following instructions: Store at room temperature (below 30°C/86°F), use within 30 days after first opening, do not use after the expiration date stated on the bottle, do not freeze, and shake well before each use.

Dosage

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

Pediatric Patients

Hypertension

Oral

Some experts state drug should be initiated at the low end of the dosage range; dosage may be increased every 2–4 weeks until BP controlled, maximum dosage reached, or adverse effects occur.

Children <1 year of age: Do not use candesartan. (See Infant Morbidity under Cautions.)

Patients 1 to <6 years of age: Initially, 0.2 mg/kg daily (range: 0.05–0.4 mg/kg daily) as oral suspension. Safety and efficacy of dosages >0.4 mg/kg daily not established.

Patients 6 to <17 years of age who weigh <50 kg: Initially, 4–8 mg daily (range: 2–16 mg daily). Safety and efficacy of dosages >32 mg daily not established.

Patients 6 to <17 years of age who weigh >50 kg: Initially, 8–16 mg daily (range: 4–32 mg daily). Safety and efficacy of dosages >32 mg daily not established.

Adjust dosage according to BP response. Antihypertensive effect usually present within 2 weeks; full effect generally obtained within 4 weeks.

Adults

Hypertension

Candesartan Therapy

Oral

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

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

Candesartan/Hydrochlorothiazide Fixed-combination Therapy

Oral

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

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).

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.

Heart Failure

Oral

Initially, 4 mg once daily recommended by manufacturer; some experts recommend initial dosage of 4–8 mg once daily. Increase dosage (by doubling the dosage at approximately 2-week intervals) as tolerated to target dosage of 32 mg once daily; ACCF/AHA recommend maximum dosage of 32 mg once daily.

Special Populations

Hepatic Impairment

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

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

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. Individualize and adjust dosage carefully when using the fixed combination preparation in patients with hepatic impairment . Some clinicians recommend initial candesartan cilexetil dosage of 4 or 8 mg daily in patients with severe hepatic impairment.

Renal Impairment

Manufacturer states that no initial candesartan cilexetil dosage adjustments are necessary in adults with renal impairment. However, some clinicians recommend initial dosage of 4 or 8 mg daily in those with severe impairment.

Do not administer to pediatric patients with GFR <30 mL/minute per 1.73 m²; safety and efficacy not established in this patient population.

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.

Cautions for Candesartan

Contraindications

• Known hypersensitivity to candesartan or any ingredient in the formulation.

• Concomitant use of aliskiren and candesartan in patients with diabetes mellitus. (See Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Fetal/Neonatal Morbidity and Mortality

Possible reduction in fetal renal function and increase in fetal and neonatal morbidity and mortality when used during pregnancy. (See Boxed Warning.) Such potential risks occur throughout pregnancy, especially during the second and third trimesters.

Also may increase the risk of major congenital malformations when administered during the first trimester of pregnancy. Potential neonatal effects include skull hypoplasia, anuria, hypotension, renal failure, and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

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

Sensitivity Reactions

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

Other Warnings and Precautions

Effects on Potassium

Potential hyperkalemia, especially in patients receiving drugs that can increase serum potassium concentration (e.g., potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes). Monitor serum potassium levels periodically.

Hypotension

Possible symptomatic hypotension, particularly in patients with intravascular volume depletion (e.g., those treated with diuretics). (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. Initiate candesartan with caution in patients with heart failure.

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

Infant Morbidity

Patients <1 year of age must not receive candesartan; drugs that act directly on the renin-angiotensin system can affect development of immature kidneys.

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. However, subsequent studies, including a larger meta-analysis conducted by FDA, have not shown such risk. Based on currently available data, FDA has concluded that angiotensin II receptor antagonists do not increase the risk of cancer.

Renal Effects

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

Increases in BUN and S_Cr possible in patients with unilateral or bilateral renal artery stenosis.

Use of Fixed Combinations

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

Specific Populations

Pregnancy

Category D.

Can cause fetal and neonatal morbidity and mortality when administered to a pregnant woman. Discontinue drug as soon as possible when pregnancy is detected. (See Boxed Warning.) Effects on labor and delivery in humans not established.

Lactation

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

Pediatric Use

If oliguria or hypotension occurs in neonates with a history of in utero exposure to candesartan, support BP and renal function; exchange transfusions or dialysis may be required. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

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.

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.

Hepatic Impairment

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

Renal Impairment

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

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

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

Black Patients

BP reduction may be smaller in black patients than in patients of other races. (See Hypertension under Uses.)

Common Adverse Effects

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

Drug Interactions

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

Specific Drugs

Candesartan Pharmacokinetics

Absorption

Bioavailability

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

Absolute bioavailability of candesartan is about 15%.

Onset

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

Food

Food with high-fat content does not affect bioavailability.

Special Populations

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

In patients with severe renal impairment (Cl_cr <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.

Distribution

Extent

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

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

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

Plasma Protein Binding

>99%.

Elimination

Metabolism

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

Elimination Route

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

Half-life

Approximately 9 hours.

Special Populations

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

Stability

Storage

Oral

Tablets

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

Actions

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

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

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

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

Advice to Patients

• Risks of use during pregnancy.

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

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

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

Preparations

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

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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