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Generic Name: Candesartan Cilexetil
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

Warning(s)

  • May cause fetal and neonatal morbidity and mortality if used during pregnancy.1 2 4 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 Atacand

Hypertension

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

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One of several preferred initial therapies in hypertensive patients with chronic kidney disease, diabetes mellitus, or heart failure.46

Can be used as monotherapy for initial management of uncomplicated hypertension; however, thiazide diuretics are preferred by JNC 7.46

CHF

A second-line agent in the treatment of CHF; should be used only in those intolerant of ACE inhibitors.1 6 35 52 53

Diabetic Nephropathy

A first-line agent in the treatment of diabetic nephropathy.33 34

Atacand Dosage and Administration

General

Hypertension

  • Fixed-combination candesartan/hydrochlorothiazide tablets should not be used for initial treatment of hypertension.2 5 11

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
Monotherapy
Oral

Initially, 16 mg once daily in adults without intravascular volume depletion.1 2 3 Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients) to achieve BP control.4 46

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

Combination Therapy
Oral

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

CHF
Monotherapy
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 Atacand

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 CHF; monitor BP during dosage escalation and periodically thereafter.1 Initiate candesartan with caution in patients with CHF.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 CHF.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 CHF, 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 CHF 75 years of age or older 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.)

Blacks

BP reduction may be smaller in black patients compared with nonblack patients;1 46 use in combination with a diuretic.46

Common Adverse Effects

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

Interactions for Atacand

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

Atacand 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.4 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 02/2014. 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 December 23, 2011. 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.

1. AstraZeneca. Atacand (candesartan cilexetil) tablets prescribing information. Wilmington, DE; 2005 May.

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

3. McClellan KJ, Goa KL. Candesartan cilexetil: a review of its use in essential hypertension. Drugs. 1998; 56:847-69. [PubMed 9829158]

4. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

5. Anon. Drugs for hypertension. Med Lett Drugs Ther. 2001; 43:17-22. [PubMed 11242494]

6. Anon. Consensus recommendations for the management of chronic heart failure. On behalf of the membership of the advisory council to improve outcomes nationwide in heart failure. Part II. Management of heart failure. Am J Cardiol. 1999; 83:9-38A.

7. Warner KK, Visconti JA, Tschampel MM. Angiotensin II receptor blockers in patients with ACE inhibitor-induced angioedema. Ann Pharmacother. 2000; 34:526-8. [IDIS 443518] [PubMed 10772441]

8. Zuschke CA, Keys I, Munger MA et al. (Candesartan Cilexetil Study Investigators.) Candesartan cilexetil: comparison of once-daily versus twice-daily administration for systemic hypertension. Candesartan Cilexetil Study Investigators. Clin Ther. 1999; 21:464-74. [IDIS 427445] [PubMed 10321416]

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10. Martineau P, Goulet J. New competition in the realm of renin-angiotensin axis inhibition; the angiotensin II receptor antagonists in congestive heart failure. Ann Pharmacother. 2001; 35:71-84. [IDIS 457649] [PubMed 11197588]

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12. US Food and Drug Administration. Dangers of ACE inhibitors during second and third trimesters of pregnancy. FDA Med Bull. 1992; 22:2.

13. Mazzolai L, Burnier M. Comparative safety and tolerability of angiotensin II receptor antagonists. Drug Safety. 1999; 21:23-33. [PubMed 10433351]

14. Kirk JK. Therapy with angiotensin II receptor antagonists. Clin Geriatrics. From the MultiMedia Health Care website: ().

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22. Buter H, Navis GY, Woittiez AJJ et al. Pharmacokinetics and pharmacodynamics of candesartan cilexetil in patients with normal to severely impaired renal function. Eur J Clin Pharmacol. 1999; 54:953-8. [IDIS 424653] [PubMed 10192757]

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24. AstraZeneca, Wayne, PA: Personal communication.

25. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2002; 25:134-47. [IDIS 479088] [PubMed 11772914]

26. Brenner BM, Cooper ME, de Zeeuw D et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001; 345:861-9. [IDIS 469607] [PubMed 11565518]

27. Lewis EJ, Hunsicker LG, Claarke WR et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345:851-60. [IDIS 469606] [PubMed 11565517]

28. Sica DA, Bakris GL. Type 2 diabetes: RENAAL and IDNT—the emergence of new treatment options. J Clin Hypertens (Greenwich). 2002; 4:52-7. [PubMed 11821641]

29. Parving HH, Brenner BM, Cooper ME et al. [Effect of losartan on renal and cardiovascular complications of patients with type 2 diabetes and nephropathy.] (Danish; with English abstract.) Ugeskr Laeger. 2001; 163:5514-9.

30. Weekers L, Krzesinski JM. [Clinical study of the month. Nephroprotective role of angiotensin II receptor antagonists in typre 2 diabetes: results of IDNT and RENAAL trials.] (French; with English abstract.) Rev Med Liege. 2001; 56:723-6.

31. Parving HH, Lehnert H, Brochner-Mortensen J et al and the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001; 345:870-8. [IDIS 469608] [PubMed 11565519]

32. Walser M. Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N Engl J Med. 2002; 346:706.

33. American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care. 2002; 25(Suppl 1):S33-43.

34. American Diabetes Association. Clinical Practice Recommendations 2002. Position Statement. Diabetic nephropathy. Diabetes Care. 2002; 25(Suppl 1): S85-9.

35. Hunt SA, Baker DW, Chin MH et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure). 2001. Available from website. Accessed July 25, 2002.

36. Fournier A. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1994; 330:937. [PubMed 8114873]

37. Viberti G, Mogensen CE, Groop LC et al. Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA. 1994; 271:275-9. [IDIS 324307] [PubMed 8295285]

38. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health; 1997 Nov. (NIH publication No. 98-4080.)

39. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med. 1993; 329:1456-62. [IDIS 321612] [PubMed 8413456]

40. Remuzzi G. Slowing the progression of diabetic nephropathy. N Engl J Med. 1993; 329:1496-7. [PubMed 8413463]

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48. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. [PubMed 10818055]

49. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000; 36:646-61. [IDIS 452007] [PubMed 10977801]

50. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003; 26(Suppl 1):S80-2.

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52. Granger CB, McMurray JJ, Yusuf S et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003; 362:772-6. [IDIS 504620] [PubMed 13678870]

53. McMurray JJ, Ostergren J, Swedberg K et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003; 362:767-71. [IDIS 504619] [PubMed 13678869]

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55. Cooper WO, Hernandez-Diaz S, Arbogast PG et al. Major congenital malformations after first-trimester exposure to ACE inhibitors. N Engl J Med. 2006; 354:2443-51. [PubMed 16760444]

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