Angiotensin II Receptor Antagonists (ARBs), Renin Inhibitors, and ...

Angiotensin II Receptor Antagonists
(ARBs),
Renin Inhibitors, and Combinations
Step Therapy Program Summary
For FlexRX Closed Formulary, this step therapy edit will be implemented with a 1-step option
and will target the preferred agents Diovan, and Diovan HCT.
For FlexRX Open Formulary, this step therapy edit will be implemented with a 1-step option
and will target the preferred agents Diovan, and Diovan HCT and also all of the nonpreferred
agents, which include all brand ARB, and Renin Inhibitor products, including all combinations
(with diuretics, calcium channel blockers, or /ARBS/Renin).
For GenRX Closed Formulary, this step therapy edit does not apply as there are no preferred
target agents.
For GenRX Open Formulary, this step therapy edit will be implemented with a 1-step option
and will target all of the nonpreferred agents, which include all brand ARB, and Renin Inhibitor
products, including all combinations (with diuretics, calcium channel blockers, or ARBS/renin
inhibitors).
FDA APPROVED INDICATIONS AND DOSAGE
ARBs and ARB Combinations 1-18,80-82
Agents
Atacand
(candesartan)
Atacand HCT
(candesartan/HCTZ)
Avalide*
(irbesartan/HCTZ)
Avapro*
(irbesartan)
Azor
(olmesartan/
amlodipine)
HTN
CV Risk ↓
HTN/
LVH
Post-MI
HF
b
d, e
DMN
c
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Dosing and Administration (adults)
HTN: Initially, 16 mg once daily, lower dose if on diuretic.
May be given once or twice daily with total daily doses from
8-32 mg. Larger doses do not appear to have greater
effects; limited experience with such doses.
HF: Initial, 4 mg once daily. Target dose, 32 mg once daily.
HTN**: Candesartan/HCTZ doses ranging from 8-32 mg of
candesartan with 12.5-25 mg of HCTZ were used in trials;
Maximum dosage is two candesartan/HCTZ 16/12.5 mg
tablets per day (32 mg/day candesartan and 25 mg/day
HCTZ) given once daily.
HTN: Initiate 150/12.5 mg once daily; titrate to 300/12.5
mg, then to a maximum of 300/25 mg once daily if needed.
HTN: Initially, 150 mg once daily; 75 mg in volume- or saltdepleted
patients. Patients requiring further BP reduction
may be titrated to 300 mg once daily. Patients not
adequately treated by the maximum dose of 300 mg once
daily are unlikely to derive benefit from a higher dose or
twice daily dosing.
DMN: Initially 75 mg/day. Target dose is 300 mg/day.
There are no data on clinical effects of lower doses in DMN.
HTN: Initiate amlodipine/olmesartan 5/20 mg once daily
(1 to 2 weeks), titrate to maximum of 10/40 mg once daily.

Agents
Benicar
(olmesartan)
Benicar HCT
(olmesartan/HCTZ)
Cozaar
(losartan)*
Diovan
(valsartan)
Diovan HCT
(valsartan/HCTZ)
Edarbi
(azilsartan)
Edarbyclor
(azilsartan/
chorthalidone
Exforge
(valsartan/
amlodipine)
Exforge HCT
(valsartan/
amlodipine/ HCTZ)
Hyzaar
(losartan/HCTZ)*
Micardis
(telmisartan)
HTN
CV Risk ↓
HTN/
LVH
a
a
Post-MI
HF
b
d
DMN
c
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Dosing and Administration (adults)
HTN: Initially, 20 mg once daily; if volume-depleted, begin
therapy with 5-10 mg once daily. Range 20-40 mg/day,
given once daily. Doses >40 mg/day do not appear to have
greater benefit; twice daily dosing has no advantage over
the same dose given once daily.
HTN**: Initial dose one tablet daily. Adjust based on
clinical response. Olmesartan and HCTZ have been used
together in clinical trials in doses from 10 to 40 mg of
olmesartan with 12.5 to 25 mg of HCTZ. Maximum dosage is
one tablet of olmesartan/HCTZ 40 mg/25 mg per day.
HTN: Initial dose 50 mg once daily; 25 mg if volume
depletion or hepatic impairment. May dose once or twice
daily; total daily dose range is 25-100 mg.
HTN/LVH: Usual initial dose is 50 mg once daily, may be
increased to 100 mg once daily, followed by an increase in
HCTZ to 25 mg once daily, based on BP response.
DMN: Usual initial dose is 50 mg once daily. Dose should be
increased to 100 mg once daily based on BP response.
HTN: Initially, 80 or 160 mg once daily in patients not
volume depleted. Patients requiring greater reduction can
start at the higher dose. Range 80-320 mg once daily.
Post-MI: Initiate 20 mg twice daily as early as 12 hours
after MI, titrate over 7 days up to 40 mg twice daily. Titrate
to maintenance dose of 160 mg twice daily, as tolerated.
HF: Initially, 40 mg twice daily. Titrate to highest dose
tolerated, range of 80-160 mg twice daily (maximum dose).
HTN: Initiate with valsartan/HCTZ 160/12.5 mg once daily.
Titrate to maximum of 320/25 mg once daily.
HTN: The recommended dose is 80 mg once daily. Consider
starting dose of 40 mg in patients on high dose diuretics.
HTN: The recommended dose is 40/12.5 mg once daily.
Maximum dose is 40/25 mg once daily.
HTN: When used as initial therapy, start with amlodipine/
valsartan 5/160 mg once daily; then titrate upwards as
necessary to maximum of 10/320 mg once daily.
HTN**: Individualize the dosage by titration of amlodipine,
HCTZ, and valsartan. The dosage of one or all components
may be increased after 2 weeks. Maximum daily dose is
10 mg amlodipine, 25 mg HCTZ, and 320 mg valsartan.
HTN**: Initial dose losartan/HCTZ 50/12.5 mg once daily.
May increase to 2 tablets of 50/12.5 once daily or 1 tablet of
100/25 once daily. Max daily dose is losartan/HCTZ 100/25.
HTN/LVH: Initially, 50 mg losartan once daily. May add
HCTZ 12.5 mg once daily, may increase losartan to 100 mg,
or use losartan/HCTZ 100/12.5 once daily. Maximum daily
dosage is losartan/HCTZ 100/25.
HTN: Usual initial dose is 40 mg once daily; 20 mg once
daily if volume-depleted; range 20-80 mg once daily.
CV risk ↓: Recommended dose is 80 mg once daily;
unknown whether doses

Agents
Micardis HCT
(telmisartan/HCTZ)
Teveten
(eprosartan)
Teveten HCT
(eprosartan/HCTZ)
Tribenzor
(olmesartan/
amlodipine/HCTZ)
Twynsta
(telmisartan/
amlodipine)
HTN
CV Risk ↓
HTN/
LVH
Post-MI
HF
DMN
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Dosing and Administration (adults)
HTN**: Telmisartan/ HCTZ studied in clinical trials in doses
20-160 mg of telmisartan with HCTZ 6.25-25 mg. Maximum
dose is two telmisartan/ HCTZ 80/12.5 mg tablets per day
(160 mg/day telmisartan and 25 mg/day HCTZ).
HTN: Initially, 600 mg once daily in patients not volume
depleted. Give once or twice daily, total daily doses range
400-800 mg. Limited experience with doses >800 mg/day.
HTN**: Initial dose is one tablet of eprosartan/ HCTZ
600/12.5 mg once daily, which may be increased to one
tablet of eprosartan/HCTZ 600/25 mg once daily. If needed,
an additional 200-300 mg eprosartan may be given.
Eprosartan and HCTZ have studied together in clinical trials
in doses of 600-800 mg/day eprosartan (as single or divided
doses) combined with 12.5-25 mg/day HCTZ. Maximum
dosage- 900 mg/day eprosartan and 25 mg/day HCTZ.
HTN: Dose once daily. Dosage may be increased after 2
weeks. The maximum recommended doser is 40/10/25 mg.
HTN: Initial: 1 tablet amlodipine/telmisartan 5/40 mg once
daily. Initiate with amlodipine/ telmisartan 5/80 mg once
daily in patients requiring larger BP reductions. Maximum
dose: 10 mg/day amlodipine/80 mg/day telmisartan
HTN= hypertension; LVH = left ventricular hypertrophy; MI = myocardial infarction; DMN = diabetic nephropathy;
HCTZ = hydrochlorothiazide, HF=heart failure; CV risk ↓= cardiovascular risk reduction (MI, stroke, death) in high risk
patients unable to take ACE inhibitors
All ACEI and ARB single entity agents may be used as monotherapy or in combination for the treatment of hypertension.
*agents available as generics
** To minimize dose independent side effects, it is usual to begin combination therapy only after patients fail to achieve
desired effects with monotherapy; combination products may be substituted for previously titrated components.
a - Reduction in the risk of stroke in patients with hypertension and LVH
b - Treatment of heart failure [New York Heart Association (NYHA) class II-IV] in patients unable to tolerate an ACEI
c - Treatment of DMN with an elevated serum creatinine and in patients with type 2 diabetes and HTN
d - In patients intolerant of ACEIs e - In combination with ACEI
Renin Inhibitors, Renin Inhibitor Combinations 19-21,66,67
Agents
Amturnide
(aliskiren/
amlodipine/HCTZ)
Tekamlo
(aliskiren/
amlodipine)
Tekturna
(aliskiren)
Tekturna HCT
(aliskiren/HCTZ)
HTN
CV Risk ↓
HTN/LV
H
Post-MI
HF
DMN
Dosing and Administration (adults)
HTN: Initial dosing will depend on prior therapy. Dose
once-daily. Maximum dose- 300 mg/10 mg/25 mg once
daily.
HTN: Initially, aliskiren/amlodipine 150 mg/5 mg once
daily. Titrate as needed up to maximum dose of
300 mg/10 mg daily.
HTN: Initially, aliskiren 150 mg once daily. If BP
remains uncontrolled, titrate up to 300 mg daily.
Maximum dose- 300 mg/day.
HTN: Usual recommended starting dose is
aliskiren/HCTZ 150/12.5 mg once daily. If BP remains
uncontrolled after 2-4 weeks of therapy, may be titrated
to a maximum of 300 mg aliskiren, 25 mg HCTZ.

Valturna
(aliskiren/valsartan)
HTN: Initially, aliskiren/valsartan 150/160 mg once
daily. Titrate up to a maximum of 300/320 mg if
hypertension remains uncontrolled after 2-4 weeks.
HTN= hypertension; LVH = left ventricular hypertrophy; MI = myocardial infarction; DMN = diabetic nephropathy;
HCTZ = hydrochlorothiazide, HF=heart failure
CLINICAL RATIONALE
Hypertension
All of the currently available ACEIs are indicated for the treatment of hypertension and there are
minimal data to suggest that one ACEI is superior to another. 22.22, Multiple outcome trials with
ACEIs in the treatment of hypertension have been conducted. Two outcome trials, ALLHAT 24 and
ANBP2, 25 are particularly important in establishing ACEIs as first or second line treatment
options for hypertension.
ACEIs are recommended as a first-line option for patients with hypertension, hypertension
complicated by comorbidities, such as cerebrovascular disease, chronic kidney disease (of
diabetic or nondiabetic origin), diabetes, HF, left ventricular dysfunction and MI by nine sets of
clinical guidelines ( JNC 7 32 , European Society of Cardiology/European Society of Hypertension 70 ,
American Heart Association / American College of Cardiology(AHA/ACC 49) , British Hypertension
Society 71 National Kidney Foundation 72 American Diabetes Association 73 , Agency for Healthcare
Research and Quality[AHRQ] 71 , AHA Council for High Blood Pressure Research and the Councils
on Clinical Cardiology and Epidemiology, and Prevention 75 , and the Heart Failure Society of
America 65 ) and all of these agencies do not establish a preference for one ACEI over another.
ARBs
Large outcome trials 26-29 as well as nine sets of guidelines (National Institute for Health and
Human Excellence [NICE] 77 , Agency of Healthcare Research and Quality [AHRQ], 74 Heart Failure
Society of America [HFSA], 65 American College of Cardiology Foundation/American Heart
Association [ACCF/AHA Hypertension in the Elderly 50 , American Society of HTN [ASH] 79 ,
International Society of Nephrology 100 , ACCF/AHA Guideline for the Diagnosis and Treatment of
Hypertrophic Cardiomyopathy [HCM] 25 , The American Diabetes Association [ADA] 73 , and the
Medical Letter 23 ) document that ARBs provide significant benefits and are recommended as first
line agents in the treatment of HTN, HTN with left ventricular hypertrophy, diabetic
nephropathy, chronic HF and HF following MI., ARBs are as effective as ACEIs , and appear
equally reno and cardioprotective, with fewer adverse effects in some patients.
In patients with essential hypertension, high cardiac risk factors, recent MI, HF, or nephropathy
there are no data to suggest that one ARB is superior to another for safety or efficacy. 10,77,50,73
Direct Renin Inhibitors
Aliskiren was evaluated by the FDA for treatment of hypertension in a large clinical development
program including five primary randomized, double-blind, placebo-controlled studies (these are
all published); several other supportive studies (posters/abstracts and/or unpublished) were
reviewed by the FDA as well. The five pivotal studies were randomized, double-blind, placebocontrolled,
8 week trials, with a primary endpoint of change from baseline in seated trough cuff
diastolic blood pressure (DBP). Some trials evaluated active control arms, and/or combinations
with another antihypertensive. The FDA felt that these studies provided evidence that aliskiren
reduces blood pressure (BP). Blood pressure reduction was typically seen after two weeks of
therapy, and effects were maximal by four weeks. Antihypertensive effects were sustained for at
least 11 months in a randomized, double-blind, placebo controlled withdrawal at the end of a
long-term safety study. 20
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In December 2010 the FDA approved the triple combination product Amturnide (aliskerin/
amlodipine/ HCTZ) for the treatment of hypertension. This fixed dose combination is not
indicated for the initial treatment of hypertension. Amturnide is indicated for patients not
adequately controlled with any tow ot the following: aliskerin, dihydropyridine calcium channel
blockers, and thiazide diuretics. Amturnide was approved pursuant to section 505(b)(2) of the
Federal Food, Drug and Cosmetic act 67 . A 505(b)(2) application is one for which one or more of
the investigations relied upon by the applicant for approval "were not conducted by or for the
applicant and for which the applicant has not obtained a right of reference or use from the
person by or for whom the investigations were conducted" 68
In 2010 the FDA also approved the combination product Tekamlo (aliskerin/amlodipine) for
treatment of hypertension. 66 It is indicated as initial therapy in patients likely to need multiple
drugs to achieve their blood pressure goals; in patients not adequately controlled with
monotherapy; and as a substitute for Tekamlo’s titrated components. Similar to Amtunide,
Tekamlo was FDA approved pursuant to section 505 (b)(2) of the Federal Food, Drug, and
Cosmetic act. 68
In January 2012, Novartis Pharmaceuticals sent out a safety letter informing healthcare
professionals of the results of the Aliskiren Trial in Type 2 Diabetics Using Cardio-Renal
Endpoints (ALTITUDE) trial. 76 The ALTITUDE study was conducted in type 2 diabetic patients,
known to be at risk of fatal and non-fatal cardiovascular and renal events. In this study,
aliskiren 300 mg (or placebo) was given in addition to standard of care, including an angiotensin
ACEI or an ARB. The independent Data Monitoring Committee overseeing the trial concluded
that patients were unlikely to benefit from treatment added to standard antihypertensives. The
committee also noted a higher adverse event rate in these high-risk patients receiving aliskiren
combined with standard care. Specifically, the committee highlighted an increased incidence of
nonfatal stroke, renal complications, hyperkalemia and hypotension among those who had
received 18 to 24 months of treatment with aliskiren as well as standard therapy. Novartis
advised healthcare professionals, pending further analyses, a contra-indication in patients with
diabetes taking an ACEI or an ARB is now advised. The treatment of diabetic patients taking
aliskiren-containing products should therefore be reviewed as early as possible, taking the
following advice into consideration and stopped.
Heart Failure, Including Post Myocardial Infarction
ACEI and ARBsACEIs are well established for the treatment of heart failure (HF), and are
strongly recommended in treatment guidelines. 34,42 A retrospective cohort study comparing the
effectiveness of different ACEIs in the treatment of patients with HF found no significant
differences in the combined endpoint of hospital readmission for HF or mortality and suggests a
class effect among the ACEIs for this indication. 46 There are outcomes data for three ARBs
(candesartan, losartan, valsartan) in congestive heart failure (CHF). 32,34,42,44-48 One head-tohead
trial found no difference in mortality between an ACEI and an ARB, but due to the study
design, equivalence could not be concluded. 46 In another head-to-head trial valsartan was found
to be as effective as captopril in patients who were at high risk for cardiovascular events after
myocardial infarction (MI). 48 ARBs may be a reasonable alternative in HF patients unable to
tolerate ACEIs.
• The Heart Failure Society of America (HFSA) 2010 Comprehensive Heart Failure Practice
Guideline states the following: 65 ACEIs are recommended for routine administration to
symptomatic and asymptomatic patients with LVEF ≤ 40%. ARBs are recommended for
routine administration to symptomatic and asymptomatic patients with LVEF≤ 40% who
are intolerant to ACEIs for reasons other than hyperkalemia or renal insufficiency.
Renal Disease Diabetic Nephropathy
ACEIs
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While both ACEIs and ARBs given alone have been found to decrease the progression of
microalbuminuria to overt proteinuria, ACEIs currently have the strongest evidence for delaying
progression of chronic non-diabetic renal disease as well as nephropathy in type 1 diabetes. 23
ARBs
Two ARBs, losartan and irbesartan, have been found to be of benefit in preventing worsening
renal function in type 2 diabetes patients with proteinuria; 8,47 no ACEIs have been proven, in a
single randomized, controlled trial to offer this benefit in this population. However, captopril has
been found to reduce risk of a combined endpoint of death, dialysis and transplantation in type
1 diabetes patients with overt proteinuria, 52 and a meta-analysis of patients with or without
diabetes and with overt proteinuria found that ACEIs reduced risk of a composite of doubling of
serum creatinine or development of end stage renal disease (ESRD). 53 Furthermore, persons
with type 2 diabetes and renal disease are at increased cardiovascular risk. There is evidence
that indicates this risk may be reduced with the use of an ACEI. In the absence of long-term
outcome trials comparing an ACEI to an ARB to determine if these agents provide similar
benefits in patients with type 2 diabetes and microalbuminuria or nephropathy, major clinical
guidelines either are neutral or recommend an ACEI as first line therapy. 33,54,55
Guidelines from the American Diabetes Association (ADA, 2010) state: “Pharmacologic therapy
for patients with diabetes and hypertension should be with a regimen that includes either an
ACEI or an ARB. If one class is not tolerated, the other should be substituted.” 54
Safety
In a drug class review of ACEIs for its practitioner-managed prescription drug plan, the Oregon
Evidence-based Practice Center identified 24 head-to-head trials comparing adverse event rates
of different ACEIs in the treatment of hypertension, prevention of events after MI, and HF. 56
There was little evidence of meaningful differences in tolerability profiles for the agents. 78 As a
class, ARBs are well tolerated, with adverse events profiles for the agents generally similar to
placebo, 56,67 though large placebo-controlled trials have found more discontinuations due to
adverse events with ARBs. 44,58 Some trials comparing ACEIs and ARBs have found differences in
rate of cough, and in discontinuations due to adverse events, favoring the ARBs, primarily due
to differences in rate of cough. 45,46,59,60 Although the rate of angioedema appears to be lower
with ARBs than ACEIs, the rates are low for each class. 60 It is unclear if there are important
differences in effects on potassium between ACEIs and ARBs.
For additional clinical information see the Prime Therapeutics Formulary Chapters 5.6A ACE
Inhibitors & ACE/diuretic combinations; 5.6B Angiotensin II Receptor Blockers and
Combinations; 5.6H ACEI and ARB/Calcium Channel Antagonists Combinations.
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4. Avalide prescribing information. Bristol-Myers Squibb, Sanofi-Aventis. November 2008.
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6. Benicar HCT prescribing information. Daiichi-Sankyo, Inc. July 2007.
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52. Lewis EJ, Hunsicker LG. The effect of angiotensin-converting-enzyme inhibition on
diabetic nephropathy. N Engl J Med 1993;329:1456-62.
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Angiotensin II Receptor Antagonists (ARBs), Renin Inhibitors, and
Combinations
Step Therapy (1-Step)
OBJECTIVE
The intent of the Angiotensin II Receptor Antagonists (ARBs), Renin Inhibitors and
Combinations Step Therapy (ST) program is to encourage use of cost-effective generic
products - ACEIs, ACEI combinations (ACEI/diuretics or ACEI/calcium channel blockers
[CCBs]), ARBs, or ARB combinations - over the more expensive brand ARBs, brand ARB
combinations, brand renin inhibitors and renin inhibitor combinations (renin inhibitor/diuretic,
renin inhibitor/ARB, or renin inhibitor/CCB). This program will accommodate for use of brand
products when generic or preferred prerequisites cannot be used due to previous trial and
failure, documented intolerance, FDA labeled contraindication, or hypersensitivity. Requests for
brand ARB or renin inhibitor products will be reviewed when patient-specific documentation is
provided.
TARGET DRUGS
Angiotensin II Receptor Antagonists (ARBs),
Combinations
Brand Generic
Atacand ® candesartan c
Atacand HCT ® candesartan/HCTZ bc
Avapro ® irbesartan a
Avalide ® irbesartan/HCTZ ab
Azor ® olmesartan/amlodipine
Benicar ® olmesartan
Benicar HCT ® olmesartan/HCTZ b
Cozaar ® losartan a
Edarbi ® azilsartan
Edarbyclor ® azilsartan/chlorthalidone
Exforge ® valsartan/amlodipine c
Exforge HCT ® valsartan/amlodipine/HCTZ bc
Hyzaar ® losartan/HCTZ ab
Diovan ® valsartan c
Diovan HCT ® valsartan/HCTZ bc
Micardis ® telmisartan
Micardis HCT ® telmisartan/HCTZ b
Teveten ® eprosartan a
Teveten HCT ® eprosartan/HCTZ b
Tribenzor ® olmesartan/amlodipine/HCTZ
Twynsta ® telmisartan/amlodipine
Renin Inhibitors, Combinations
Brand Generic
Amturnide ® aliskiren/amlodipine/HCTZ b
Tekamlo ® aliskiren/amlodipine
Tekturna ® aliskiren
Tekturna HCT ® aliskiren/HCTZ b
Valturna ® aliskiren/valsartan
a – generic available that is a prerequisite agent for step therapy program
b - HCTZ = hydrochlorothiazide
c – generic product anticipated in 2012; will be prerequisite for step therapy progam
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PRIOR AUTHORIZATION CRITERIA FOR APPROVAL
Brand ARBs, ARB Combinations, Renin Inhibitors, or Renin Inhibitor combinations will
be approved when ONE of the following is met:
1. The patient’s medication history includes use of a generic ACEI, generic ACEI
combination, generic ARB or a generic ARB combination OR
2. There is documentation that the patient is currently using the requested brand ARB,
ARB combination, renin inhibitor, or renin inhibitor combination, OR the requested
brand ARB or renin inhibitor in another product (single ingredient or combination) OR
3. The prescribing physician states the patient is using the requested brand ARB, ARB
combination, renin inhibitor, or renin inhibitor combination or the requested brand ARB
or renin inhibitor in another product (single ingredient or combination) AND is at risk if
therapy is changed OR
4. The patient has a documented intolerance, FDA labeled contraindication, or
hypersensitivity to a generic ACEI, genric ACEI combination, generic ARB, or generic
ARB combination product
Length of Approval: 12 months
NOTE: If Quantity Limit program also applies, please refer to Quantity Limit documents.
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