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Criteria for Outpatient Use Guidelines

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Angiotensin II Receptor Blockers

[Developed, August 1996; Revised, December 1996; July 1997; June 1998; July 1999; September 2000; July 2001; September 2001; July 2002; July 2003; April 2008; March 2011 ]

MEDICAID DRUG USE REVIEW CRITERIA FOR OUTPATIENT USE

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Adults
Angiotensin II receptor blockers (ARBs) as monotherapy are FDA-approved for use in hypertension (all available ARBs), diabetic nephropathy (irbesartan, losartan), heart failure (candesartan, valsartan), stroke prophylaxis (losartan), cardiovascular risk reduction in patients unable to take angiotensin-converting enzyme (ACE) inhibitors (telmisartan), and post-myocardial infarction (valsartan). ARB combination therapy is FDA-approved for use in hypertension (all available ARB combinations) and stroke risk reduction (Hyzaar®).  The maximum recommended daily doses assigned to ARBs as monotherapy and combination therapy for adult patients are summarized in Tables 1 and 2.  Patient profiles containing ARB dosage regimens exceeding these recommendations will be reviewed.

TABLE 1: Maximum Daily Adult Doses for Angiotensin II Receptor Blockers
DRUG RECOMMENDED MAXIMUM DOSE
azilsartan (Edarbi™) [40 mg, 80 mg tablets] 80 mg/day
candesartan (Atacand®) [4 mg, 8 mg, 16 mg, 32 mg tablets] 32 mg/day
eprosartan (Teveten®) [400 mg, 600 mg tablets] 800 mg/day
irbesartan (Avapro®) [75 mg, 150 mg, 300 mg tablets] 300 mg/day
losartan (Cozaar®) [25 mg, 50 mg, 100 mg tablets] 100 mg/day
olmesartan (Benicar®) [5 mg, 20 mg, 40 mg tablets] 40 mg/day
telmisartan (Micardis®) [20 mg, 40 mg, 80 mg tablets] 80 mg/day
valsartan (Diovan®) [40 mg, 80 mg, 160 mg, 320 mg tablets] 320 mg/day
TABLE 2
Maximum Daily Adult Doses for Angiotensin II Receptor Blockers - Combination Therapy
DRUG RECOMMENDED MAXIMUM DOSE
candesartan/hydrochlorothiazide (Atacand HCT®)
[16 mg/12.5 mg, 32 mg/12.5 mg, 32 mg/25 mg tablets]		 32 mg/25 mg/day
eprosartan/hydrochlorothiazide (Teveten HCT®)
[600 mg/12.5 mg, 600 mg/25 mg tablets]		 600 mg/25 mg/day
irbesartan/hydrochlorothiazide (Avalide®)
[150 mg/12.5 mg, 300 mg/12.5 mg, 300 mg/25 mg tablets]		 300 mg/25 mg/day
losartan/hydrochlorothiazide (Hyzaar®)
[50 mg/12.5 mg, 100 mg/12.5 mg, 100 mg/25 mg tablets]		 100 mg/25 mg/day
olmesartan/amlodipine/hydrochlorothiazide (Tribenzor®)
[20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg,  40 mg/10 mg/25 mg tablets]		 40 mg/10 mg/25 mg/day
olmesartan/hydrochlorothiazide (Benicar HCT®)
[20 mg/12.5 mg, 40 mg/12.5 mg, 40 mg/25 mg tablets]		 40 mg/25 mg/day
amlodipine/olmesartan (Azor®)
[5 mg/20 mg, 10 mg/20 mg, 5 mg/40 mg 10 mg/40 mg tablets] 		10 mg/40 mg/day
telmisartan/hydrochlorothiazide (Micardis HCT®)
[40 mg/12.5 mg, 80 mg/12.5 mg, 80 mg/25 mg tablets]		 160 mg/25 mg/day
telmisartan/amlodipine (Twynsta®)
[40 mg/5 mg, 40 mg/10 mg, 80 mg/5mg, 80 mg/10 mg tablets]		 80 mg/10 mg/day
aliskiren/valsartan (Valturna®)
150 mg/160 mg, 300 mg/320 mg tablets		 300 mg/320 mg/day
valsartan/hydrochlorothiazide (Diovan HCT®)
[80 mg/12.5 mg, 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg, 320 mg/ 25 mg tablets]		 320 mg/25 mg/day
amlodipine/valsartan (Exforge®)
5 mg/160 mg, 5 mg/320 mg, 10 mg/160 mg, 10 mg/320 mg tablets]		 10 mg/320 mg/day
amlodipine/valsartan/hydrochlorothiazide (Exforge® HCT)
[5 mg/160 mg/12.5 mg, 10 mg/160 mg/12.5 mg, 5 mg/160 mg/25 mg,
10 mg/160 mg/25 mg, 10 mg/320 mg/25 mg tablets]		 10 mg/320 mg/25 mg/day

Pediatrics
Candesartan has recently been FDA-approved to manage hypertension in children 1 to < 17 years of age.  Irbesartan, losartan, olmesartan, and valsartan are FDA-approved to manage hypertension in pediatric patients 6 years of age and older.  Recommended dosages are summarized in Table 3.  Dosages exceeding these recommendations will be reviewed.

Table 3
Maximum Recommended Dosages for Select Angiotensin II Receptor Blockers in Pediatric Patients
DRUG MAXIMUM RECOMMENDED DOSE
candesartan

1 to < 6 years of age: 0.4 mg/kg/day
6 to < 17 years of age: < 50 kg:  16 mg/day; > 50 kg:  32 mg/day
irbesartan

6 to 12 years of age:  150 mg/day
13 to 16 years of age: 300 mg/day
losartan

6 years and older: 1.4 mg/kg/day to a maximum of 100 mg/day
olmesartan

6 to 16 years of age: < 35 kg:  20 mg/day; > 35 kg:  40 mg/day
valsartan

6 to 16 years of age:  2.7 mg/kg/day to a maximum of 160 mg/day

The safety and efficacy of azilsartan, eprosartan, and telmisartan in pediatric patients have not been established.  The safety and efficacy of ARBs in combination with hydrochlorothiazide, aliskiren, or amlodipine in pediatric patients have not been established.

2. Duration of Therapy

There is no basis for limiting therapy duration for ARBs as reduction of cardiovascular mortality post-myocardial infarction, stroke risk reduction, managing hypertension, treating diabetic nephropathy, and  managing heart failure require chronic treatment.

3.* Duplicative Therapy

Administration of two or more ARBs concurrently is not justified.  Additional therapeutic benefit is not appreciated when multiple ARBs are utilized concomitantly.  Patient profiles containing regimens comprised of two or more ARBs administered concurrently will be reviewed.

Recent studies have documented concurrent administration of ARBs and ACE inhibitors may result in an increased incidence of adverse effects (e.g., hypotension, hyperkalemia, syncope, renal failure) in patients with heart failure due to myocardial infarction or left ventricular dysfunction, as well as other patients at high risk for vascular events (e.g., diabetic patients) without added benefit.  Additional studies have not documented significant benefit with ACE inhibitor-ARB combination therapy in managing hypertension or diabetic nephropathy.  The American College of Cardiology/American Heart Association guidelines state that ARB-ACE inhibitor combination therapy may be considered in heart failure patients, not recently post myocardial infarction, who have not responded to target doses of an ACE inhibitor and beta blocker.  Adjunctive administration of ARBs and ACE inhibitors should be considered cautiously, if at all, in these patient populations.

4.* Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.
The following drug-drug interactions are considered clinically relevant for ARBs.  Only those drug-drug interactions classified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

a. Potassium-Sparing Diuretics [e.g., amiloride, spironolactone, triamterene] [clinical significance level- moderate (DrugReax); 2-major (CP); 1 (DIF)]

The use of ARBs in conjunction with potassium-sparing diuretics may result in hyperkalemia. ARBs reduce circulating aldosterone concentrations resulting in potassium retention.  When administered concomitantly with potassium-sparing diuretics, an additive pharmacologic interaction is likely to occur, resulting in elevated serum potassium concentrations.  Elderly patients as well as patients with impaired renal function, diabetes, high potassium diets or concurrent use of potassium supplements may be at increased risk for hyperkalemia.  Measure serum potassium concentrations and monitor for signs and symptoms of hyperkalemia when ARBs and potassium-sparing diuretics are administered concurrently, especially in patients with predisposing factors.

b. Lithium - [clinical significance level – major (DrugReax); 3-moderate (CP); 2 (DIF)]

Combined administration of ARBs and lithium may result in enhanced pharmacologic and toxic effects of lithium. It is proposed that ARBs augment lithium reabsorption by decreasing lithium renal excretion.  Patients receiving adjuvant therapy with ARBs and lithium should be monitored for signs and symptoms of lithium toxicity.  Lithium dosages should be adjusted as necessary, or alternative cardiovascular therapies that do not interact with lithium should be considered.

References

  1. Azilsartan tablets (Edarbi™) Package Insert.  Takeda Pharmaceuticals America, Inc., February 2011.
  2. Candesartan tablets (Atacand®) Package Insert.  AstraZeneca, October 2009.
  3. Eprosartan tablets (Teveten®) Package Insert.  Abbott Laboratories, June 2010.
  4. Eprosartan/hydrochlorothiazide tablets (Teveten® HCT) Package Insert.  Abbott Laboratories, March 2011.
  5. Irbesartan tablets (Avapro®) Package Insert.  Bristol-Myers Squibb, April 2007.
  6. Losartan/hydrochlorothiazide tablets (Hyzaar®) Package Insert.  Merck & Co., Inc., February 2011.
  7. Losartan tablets (Cozaar®) Package Insert.  Merck & Co., June 2010.
  8. Olmesartan tablets (Benicar®) Package Insert.  Daiichi Sankyo, Inc., February 2010.
  9. Olmesartan/amlodipine/hydrochlorothiazide tablets (Tribenzor®) Package Insert.  Daiichi Sankyo, Inc., July 2010.
  10. Telmisartan tablets (Micardis®) Package Insert.  Boehringer Ingelheim Pharmaceuticals, Inc., January 2011.
  11. Telmisartan/hydrochlorothiazide tablets (Micardis® HCT) Package Insert.  Boehringer Ingelheim Pharmaceuticals, Inc., January 2011.
  12. Telmisartan/amlodipine tablets (Twynsta®) Package Insert.  Boehringer Ingelheim Pharmaceuticals, Inc., February 2011.
  13. Valsartan tablets (Diovan®) Package Insert.  Novartis, June 2010.
  14. Aliskiren/valsartan tablets (Valturna®) Package Insert.  Novartis, February 2011.
  15. Amlodipine/valsartan (Exforge®) Package Insert.  Novartis, February 2009.
  16. Amlodipine/valsartan/hydrochlorothiazide (Exforge® HCT) Package Insert.  Novartis, February 2011.
  17. DRUGDEX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.   Accessed March 22nd, 2011.
  18. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc; 2011. Available at: http://www.clinicalpharmacology.com. Accessed March 22nd, 2011.
  19. Drug Facts and Comparisons.  Clin-eguide [database online].  St. Louis, MO:  Wolters Kluwer Health, Inc; 2011.  Available at:  http://clineguide.com.  Accessed March 22nd, 2011.
  20. Litwin M, Grenda R, Sladowska J, Antoniewicz J. Add-on therapy with angiotensin II receptor 1 blocker in children with chronic kidney disease already treated with angiotensin-converting enzyme inhibitors.  Pediatr Nephrol. 2006;21:1716-22.
  21. Majani G, Giardini A, Opasich C, et al.  Effect of valsartan on quality of life when added to usual therapy for heart failure: results from the Valsartan Heart Failure Trial.  J Cardiac Fail.
    2005;11:253-9.
  22. Fujisawa T, Ikegami H, Ono M, et al. Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy. Am J Hypertens. 2005;18:13-7.
  23. Cocco G, Kohn S, Jerie P. Effects of combined treatment with enalapril and losartan on myocardial function in heart failure. Heart. 2002;88:185-6.
  24. Bohm M. Angiotensin receptor blockers versus angiotensin-converting enzyme inhibitors: where do we stand now?  Am J Cardiol. 2007;100(suppl):38J-44J.
  25. Matchar DB, McCrory DC, Orlando LA, et al.  Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers for treating essential hypertension.  Ann Intern Med. 2008;148:16-29.
  26. McCall KL, Craddock D, Edwards K. Effect of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers on the rate of new-onset diabetes mellitus: a review and pooled analysis.  Pharmacotherapy. 2006;26:1297-306.
  27. Finnegan PM, Gleason BL. Combination ACE inhibitors and angiotensin II receptor blockers for hypertension.  Ann Pharmacother. 2003;37:886-9.
  28. The ONTARGET Investigators.  Telmisartan, ramipril, or both in patients at high risk for vascular events.  N Engl J Med. 2008;358:1547-59.
  29. Phillips CO, Kashani A, Ko DK, et al.  Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction. A quantitative review of data from randomized clinical trials.  Arch Intern Med. 2007;167:1930-6.
  30. Baker WL, Coleman CI, Kluger J, et al.  Systematic review: comparative effectiveness of angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers for ischemic heart disease.  Ann Intern Med. 2009;151(12):861-71.
  31. Catanzaro DF, Frishman WH. Angiotensin receptor blockers for management of hypertension.  South Med J. 2010;103(7):669-73.
  32. Holdiness A, Monahan K, Minor D, de Shazo RD. Renin angiotensin aldosterone system blockade: little to no rationale for ACE inhibitor and ARB combinations. Am J Med. 2011;124(1):15-9. 
  33. Drug interaction facts.  Clin-eguide [database online].  St. Louis, MO:  Wolters Kluwer Health, Inc; 2011.  Available at:  http://clineguide.com.  Accessed March 22nd, 2011.
  34. DRUG-REAX® System (electronic version). Thomson Reuters (Healthcare) Inc., Greenwood Village, Colorado, USA. Available at: http://www.thomsonhc.com.libproxy.uthscsa.edu.  Accessed March 22nd, 2011.

Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.