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ph-1027

Angiotensin II Receptor Antagonists (ARBs), Renin Inhibitors, and Combinations Step Therapy Program Summary

Policy Number: PH-1027

This program applies to Blue Partner, Commercial, GenPlus, NetResults A series, SourceRx, and Health Insurance Marketplace formularies.

PRIOR AUTHORIZATION CRITERIA FOR APPROVAL

Target Agent(s) will be approved when ONE of the following is met:

Information has been provided that indicates the patient is currently being treated with the requested agent within the past 90 days.

The prescriber states the patient is currently being treated with the requested agent within the past 90 days AND is at risk if therapy is changed

The patient’s medication history includes use of a generic ACEI, generic ACEI combination, generic ARB, generic ARB combination, or generic renin inhibitor product within the past 90 days

The patient has an intolerance or hypersensitivity to a generic ACEI, generic ACEI combination, generic ARB, generic ARB combination, or generic renin inhibitor product

The patient has an FDA labeled contraindication to ALL generic ACEIs, generic ACEI combinations, generic ARBs, generic ARB combinations, or generic renin inhibitor products

Length of Approval: 12 months

FDA APPROVED INDICATIONS AND DOSAGE

ARBs and ARB Combinations ^{1-22, 27}

Agent(s)	Indication(s)	Dosage
ARBs and ARB Combinations
Atacand^® (candesartan)^a Tablet	Treatment of hypertension in adults and children 1 to < 17 years of age Treatment of heart failure (NYHA class II-IV)	Hypertension (HTN): 2-32 mg, usual starting recommended starting dose is 16 mg once daily. 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. Pediatric HTN: See package insert Heart Failure (HF): Recommended initial dose is 4 mg daily. Target dose is 32 mg daily as tolerated by the patient
Atacand HCT^® (candesartan/HCTZ)^a Tablet	Treatment of hypertension	HTN: Usual recommended starting dose is 16-12.5 mg once daily. Dose ranges from 8 mg to 32 mg of candesartan and 12.5 to 50 mg of HCTZ once to twice daily. Doses larger than 32 mg do not appear to have a greater BP lowering effect.
Avalide^® (irbesartan/HCTZ)^a Tablet	Treatment of hypertension: In patients not adequately controlled with monotherapy As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals	HTN: The usual starting dose is 150/12.5 mg once daily. The dosage can be increased to a maximum of 300/25 mg once daily.
Avapro^® (irbesartan)^a Tablet	Treatment of hypertension Treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes, an elevated serum creatinine and proteinuria	HTN: Initially, 150 mg once daily; 75 mg in volume- or salt-depleted patients. Patients requiring further BP reduction may be titrated to a maximum dose of 300 mg once daily. Diabetic Nephropathy: Target dose is 300 mg/day.
Azor^® (olmesartan/ amlodipine)^a Tablet	Treatment of hypertension, alone or with other antihypertensive agents May also be used as initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals	HTN: The recommended starting dose is 5/20 mg once daily. Titrate as needed up to a maximum of 10/40 mg once daily.
Benicar^® (olmesartan)^a Tablet	Treatment of hypertension in adult and pediatric patients six years of age and older, alone or with other antihypertensive agents	HTN: The usual recommended starting dose is 20 mg once daily. Doses more than 40 mg/day do not appear to have greater benefit; twice daily dosing has no advantage over the same dose given once daily. Pediatric HTN: The usual recommended starting dose is 10 mg once daily for patients who weigh 20 to < 35 kg or 20 mg once daily for patients who weigh ≥ 35 kg. May be increased to a maximum of 20 mg once daily for patients who weigh < 35 kg or 40 mg once daily for patients who weigh ≥ 35 kg
Benicar HCT^® (olmesartan/HCTZ)^a Tablet	Treatment of hypertension	HTN: The recommended starting dose in patients whose blood pressure is not adequately controlled with olmesartan monotherapy is 40/12.5 mg. Recommended starting dose for patients whose BP is not adequately controlled with HCT monotherapy or who experience dose-limiting adverse reactions with hydrochlorothiazide is 20/12.5 mg Dose can be titrated up to 40/25 mg if necessary.
Cozaar^® (losartan)^a Tablet	Treatment of hypertension in adults and pediatric patients 6 years of age and older To reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy Treatment of diabetic nephropathy with an elevated serum creatine and proteinuria in patients with type 2 diabetes and a history of hypertension	HTN: The usual starting dose is 50 mg once daily; can be increased to a maximum of 100 mg once daily as needed to control blood pressure. A starting dose of 25 mg is recommended for patients with possible intravascular depletion. Pediatric HTN: The usual recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total). Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg/kg (or in excess of 100 mg) daily have not been studied in pediatric patients. Hypertensive patients with left ventricular hypertrophy (LVH): The usual starting dose is 50 mg once daily. Hydrochlorothiazide (HCTZ) 12.5 mg daily should be added and/or the dose of Cozaar should be increased to 100 mg once daily followed by an increase in HCTZ to 25 mg once daily, based on blood pressure response. Nephropathy in type 2 diabetic patients: The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response.
Diovan^®^a, Valsartan oral solution Tablet, solution	Treatment of hypertension in adults and pediatric patients one year of age and older Treatment of heart failure (NYHA class II-IV) Post-myocardial infarction in clinically stable patients with left ventricular failure or left ventricular dysfunction	HTN: The recommended starting dose is 80 or 160 mg once daily when used as monotherapy in patients who are not volume depleted. Patients requiring greater reduction may be started at the higher dose. The dose range is 80-320 mg once daily. Pediatric HTN: The usual recommended starting dose is 1 mg/kg once daily (up to 40 mg total). Maximum dose is 4 mg/kg once daily (160 mg). HF: The recommended starting dose is 40 mg twice daily. Up-titrate to 80 mg and 160 mg twice daily or to the highest dose tolerated by the patient. The maximum daily dose administered in clinical trials is 320 mg in divided doses. Post-myocardial infarction: The recommended starting dose is 20 mg twice daily. Patients may be up-titrated to a target maintenance dose of 160 mg twice daily, as tolerated by the patient.
Diovan HCT^® (valsartan/HCTZ)^a Tablet	Treatment of hypertension in patients not adequately controlled with monotherapy, or as initial therapy in patients likely to need multiple drugs to achieve their BP goals.	HTN: The usual starting dose is valsartan/HCTZ 160/12.5 mg once daily. Titrate to maximum of 320/25 mg once daily.
Edarbi^® (azilsartan) Tablet	Treatment of hypertension	HTN: The recommended dose is 80 mg once daily. Consider starting dose of 40 mg for patients who are treated with high doses of diuretics.

Agent(s)

Indication(s)

Dosage

ARBs and ARB Combinations

Atacand^®

(candesartan)^a

Tablet

Treatment of hypertension in adults and children 1 to < 17 years of age
Treatment of heart failure (NYHA class II-IV)

Hypertension (HTN): 2-32 mg, usual starting recommended starting dose is 16 mg once daily. 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.

Pediatric HTN: See package insert

Heart Failure (HF): Recommended initial dose is 4 mg daily. Target dose is 32 mg daily as tolerated by the patient

Atacand HCT^®

(candesartan/HCTZ)^a

Tablet

Treatment of hypertension

HTN: Usual recommended starting dose is 16-12.5 mg once daily. Dose ranges from 8 mg to 32 mg of candesartan and 12.5 to 50 mg of HCTZ once to twice daily. Doses larger than 32 mg do not appear to have a greater BP lowering effect.

Avalide^®

(irbesartan/HCTZ)^a

Tablet

Treatment of hypertension:
- In patients not adequately controlled with monotherapy
- As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals

HTN: The usual starting dose is 150/12.5 mg once daily. The dosage can be increased to a maximum of 300/25 mg once daily.

Avapro^®

(irbesartan)^a

Tablet

Treatment of hypertension
Treatment of diabetic nephropathy in hypertensive patients with type 2 diabetes, an elevated serum creatinine and proteinuria

HTN: Initially, 150 mg once daily; 75 mg in volume- or salt-depleted patients. Patients requiring further BP reduction may be titrated to a maximum dose of 300 mg once daily.

Diabetic Nephropathy: Target dose is 300 mg/day.

Azor^®

(olmesartan/

amlodipine)^a

Tablet

Treatment of hypertension, alone or with other antihypertensive agents
May also be used as initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals

HTN: The recommended starting dose is 5/20 mg once daily. Titrate as needed up to a maximum of 10/40 mg once daily.

Benicar^®

(olmesartan)^a

Tablet

Treatment of hypertension in adult and pediatric patients six years of age and older, alone or with other antihypertensive agents

HTN: The usual recommended starting dose is 20 mg once daily. Doses more than 40 mg/day do not appear to have greater benefit; twice daily dosing has no advantage over the same dose given once daily.

Pediatric HTN: The usual recommended starting dose is 10 mg once daily for patients who weigh 20 to < 35 kg or 20 mg once daily for patients who weigh ≥ 35 kg. May be increased to a maximum of 20 mg once daily for patients who weigh < 35 kg or 40 mg once daily for patients who weigh ≥ 35 kg

Benicar HCT^®

(olmesartan/HCTZ)^a

Tablet

Treatment of hypertension

HTN: The recommended starting dose in patients whose blood pressure is not adequately controlled with olmesartan monotherapy is 40/12.5 mg. Recommended starting dose for patients whose BP is not adequately controlled with HCT monotherapy or who experience dose-limiting adverse reactions with hydrochlorothiazide is 20/12.5 mg Dose can be titrated up to 40/25 mg if necessary.

Cozaar^®

(losartan)^a

Tablet

Treatment of hypertension in adults and pediatric patients 6 years of age and older
To reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy
Treatment of diabetic nephropathy with an elevated serum creatine and proteinuria in patients with type 2 diabetes and a history of hypertension

HTN: The usual starting dose is 50 mg once daily; can be increased to a maximum of 100 mg once daily as needed to control blood pressure. A starting dose of 25 mg is recommended for patients with possible intravascular depletion.

Pediatric HTN: The usual recommended starting dose is 0.7 mg/kg once daily (up to 50 mg total). Dosage should be adjusted according to blood pressure response. Doses above 1.4 mg/kg (or in excess of 100 mg) daily have not been studied in pediatric patients.

Hypertensive patients with left ventricular hypertrophy (LVH): The usual starting dose is 50 mg once daily. Hydrochlorothiazide (HCTZ) 12.5 mg daily should be added and/or the dose of Cozaar should be increased to 100 mg once daily followed by an increase in HCTZ to 25 mg once daily, based on blood pressure response.

Nephropathy in type 2 diabetic patients: The usual starting dose is 50 mg once daily. The dose should be increased to 100 mg once daily based on blood pressure response.

Diovan^®^a,

Valsartan oral solution

Tablet, solution

Treatment of hypertension in adults and pediatric patients one year of age and older
Treatment of heart failure (NYHA class II-IV)
Post-myocardial infarction in clinically stable patients with left ventricular failure or left ventricular dysfunction

HTN: The recommended starting dose is 80 or 160 mg once daily when used as monotherapy in patients who are not volume depleted. Patients requiring greater reduction may be started at the higher dose. The dose range is 80-320 mg once daily.

Pediatric HTN: The usual recommended starting dose is 1 mg/kg once daily (up to 40 mg total). Maximum dose is 4 mg/kg once daily (160 mg).

HF: The recommended starting dose is 40 mg twice daily. Up-titrate to 80 mg and 160 mg twice daily or to the highest dose tolerated by the patient. The maximum daily dose administered in clinical trials is 320 mg in divided doses.

Post-myocardial infarction: The recommended starting dose is 20 mg twice daily. Patients may be up-titrated to a target maintenance dose of 160 mg twice daily, as tolerated by the patient.

Diovan HCT^®

(valsartan/HCTZ)^a

Tablet

Treatment of hypertension in patients not adequately controlled with monotherapy, or as initial therapy in patients likely to need multiple drugs to achieve their BP goals.

HTN: The usual starting dose is valsartan/HCTZ 160/12.5 mg once daily. Titrate to maximum of 320/25 mg once daily.

Edarbi^®

(azilsartan)

Tablet

Treatment of hypertension

HTN: The recommended dose is 80 mg once daily. Consider starting dose of 40 mg for patients who are treated with high doses of diuretics.

Edarbyclor^®

(azilsartan/

chorthalidone)

Tablet

Treatment of hypertension in patients not adequately controlled with monotherapy or as initial therapy in patients likely to need multiple drugs to help achieve blood pressure goals

HTN: The recommended starting dose is 40/12.5 mg once daily. The dosage may be increased to 40/25 mg after 2 to 4 weeks as need to achieve blood pressure goals. Doses above 40/25 mg are probably not useful.

Eprosartan

Tablet

Treatment of hypertension

HTN: The usual recommended dose is 600 mg once daily when used in patients not volume depleted. Give once or twice daily with total daily doses range 400-800 mg. There is limited experience with doses beyond 800 mg/day.

Exforge^®

(valsartan/

amlodipine)^a

Tablet

Treatment of hypertension in patients not adequately controlled with monotherapy or as initial therapy in patients likely to need multiple drugs to achieve blood pressure goals

HTN: Dose once daily. Increase as needed to a maximum dose of 10/320 mg once daily.

Exforge HCT^®

(valsartan/

amlodipine/HCTZ)^a

Tablet

Treatment of hypertension

Limitation of use: Exforge HCT is not indicated for initial treatment of hypertension

HTN: Initial dose 5/160 mg once daily. The maximum recommended dose is 10/320/25 mg.

Hyzaar^®

(losartan/HCTZ)^a

Tablet

Treatment of hypertension
Reduction in the risk of stroke in patients with hypertension and left ventricular hypertrophy.

HTN: The usual starting dose is losartan/HCTZ 50/12.5 mg once daily. May increase to a maximum of losartan/HCTZ 100/25 once daily.

HTN/LVH: In patients whose blood pressure is not adequately controlled on 50 mg losartan once daily, initiate treatment with Hyzaar 50/12.5 mg. If additional blood pressure reduction is needed, increase to 100/12.5 mg, followed by 100/25 mg once daily.

Micardis^®

(telmisartan)^a

Tablet

Treatment of hypertension
Cardiovascular risk reduction in patients unable to take ACE inhibitors

HTN: The usual starting dose is 40 mg once daily. Blood pressure response is dose-related over the range of 20 to 80 mg.

Cardiovascular risk reduction: The recommended dose is 80 mg once daily.

Micardis HCT^®

(telmisartan/HCTZ)^a

Tablet

Treatment of hypertension

Limitation of use: Micardis HCT is not indicated for initial therapy

HTN: Initiate a patient whose blood pressure is not adequately controlled with telmisartan monotherapy 80 mg or HCTZ 25 mg on 80/12.5 mg. Dose can be titrated up to 160/25 mg if necessary.

Tribenzor^®

(olmesartan/

amlodipine/HCTZ)^a

Tablet

Treatment of hypertension

Limitation of use: Tribenzor is not indicated for initial therapy

HTN: Dose once daily. Dosage may be increased after 2 weeks. The maximum recommended dose is 40/10/25 mg.

Twynsta^®

(telmisartan/

amlodipine)^a

Tablet

Treatment of hypertension
Initial therapy in patients likely to need multiple antihypertensive agents to achieve their blood pressure goals

HTN: The usual starting dose is 40/5 mg once daily. Patients requiring larger blood pressure reductions may be started on 80/5 mg once daily. The maximum recommended dose is 80/10 mg once daily.

HCTZ = hydrochlorothiazide

HTN = hypertension

a –generic available

Agent(s)	Indication(s)	Dosage
Renin Inhibitors, Renin Inhibitor Combinations
Tekturna^® (aliskiren)^a Tablet	Treatment of hypertension in adults and in pediatric patients weighing 50 kg or greater who are at least 6 years of age	HTN: Recommended starting dose is 150 mg once daily. In patients whose blood pressure is not adequately controlled, dose may be increased to 300 mg daily. Doses above 300 mg did not give an increased BP response.
Tekturna HCT^® (aliskiren/HCTZ) Tablet	Treatment of hypertension As initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals	HTN: The usual recommended starting dose is 150/12.5 mg once daily. The dose may be titrated to a maximum of 300/25 mg.

HCTZ = hydrochlorothiazide

HTN= hypertension

a - generic available

CLINICAL RATIONALE

ACEIs & ARBs

Angiotensin Converting Enzyme Inhibitors (ACEIs) and Angiotensin II Receptor Blockers (ARBs) are recommended as a first-line pharmacotherapy options for adults with hypertension (HTN), for adults with hypertension and comorbid stable ischemic heart disease (SIHD), and heart failure with reduced ejection fraction (HFrEF). In adults with hypertension and heart failure with preserved ejection fraction (HFpEF), ACEI and ARBs are to be added once diuretics have managed volume overload. ACEIs are first-line options for adults with hypertension and chronic kidney disease (CKD). ARBs are a reasonable alternative if the patient is intolerant of ACEIs. For adults who experience a stroke or transient ischemic attack (TIA) and are hypertensive, once stabilized, thiazide diuretics, ACEIs, ACEi and thiazide combinations, and ARBs are useful. In adults with hypertension and diabetes mellitus, ACEIs and ARBs are among first-line options. If albuminuria is present, ACEis or ARBs may be considered due to their best efficacy among the drug classes on urinary albumin excretion. Treatment of adults with hypertension with an ARB can be useful for prevention of recurrence of atrial fibrillation. The American College of Cariology/American Heart Association Task Force on Clinical Practice Guidelines did not differentiate ACEIs or ARBs within their pharmacological classes.²³

Pediatric guidelines state that pharmacologic treatment of hypertension in children and adolescents should be initiated with an ACEI, ARB, long-acting calcium channel blocker, or a thiazide diuretic. In children with hypertension and CKD, proteinuria, or diabetes mellitus, an ACEI or ARB is recommended as the initial antihypertensive agent unless there is an absolute contraindication.²⁴

Direct Renin Inhibitors

Aliskiren decreases plasma renin activity, a different mechanism than ACEIs and ARBS. Studies have shown aliskiren to be as effective as other antihypertensive drugs. It is unclear whether the PRA decrease provided by aliskiren has an impact on clinical outcomes and cardiovascular endpoints.²⁵

Safety

In patients with hypertension undergoing major surgery, discontinuation of ACEIs or ARBs perioperatively may be considered.²³

The FDA added a contraindication against the use of aliskiren with ARBs or ACEIs in patients with diabetes because of the risk of renal impairment, hypotension, and hyperkalemia. A warning was added to avoid use of aliskiren with ARBs or ACEIs in patients with moderate to severe renal impairment (i.e., where glomerular filtration rate [GFR] < 60 mL/min). The FDA stated that Valturna (a combination containing aliskiren and valsartan) should not be used in patients with diabetes and Valturna was removed from the market in July 2012.²⁶

All ARBS and Renin Inhibitors have a black box warning concerning fetal toxicity. When pregnancy is detected, the agent should be discontinued. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.^1-22

Atacand prescribing information. AstraZeneca. June 2020.
Atacand HCT prescribing information. AstraZeneca. May 2020.
Avalide prescribing information. Bristol-Myers Squibb, Sanofi-Aventis. December 2020.
Avapro prescribing information. Bristol-Myers Squibb, Sanofi-Aventis. December 2020.
Azor prescribing information. Daiichi-Sankyo, Inc. October 2020.
Benicar prescribing information. Daiichi-Sankyo, Inc. October 2019.
Benicar HCT prescribing information. Daiichi-Sankyo, Inc. May 2020.
Cozaar prescribing information. Merck & Co., Inc. June 2020.
Diovan prescribing information. Novartis Pharmaceuticals Corporation. April 2021.
Diovan HCT prescribing information. Novartis Pharmaceuticals Corporation. August 2020.
Edarbi prescribing information. Takeda Pharmaceuticals Amerca, Inc. March 2020.
Edarbyclor prescribing information. Takeda Pharmaceuticals America, Inc. March 2020.
Eprosartan prescribing information. Mylan Pharmaceuticals, Inc. November 2014.
Exforge prescribing information. Novartis Pharmaceuticals Corporation. March 2020.
Exforge HCT prescribing information. Novartis Pharmaceuticals Corporation. February 2021.
Hyzaar prescribing information. Merck & Co., Inc. August 2020.
Micardis prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. July 2020.
Micardis HCT prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. August 2020.
Tribenzor prescribing information. Daiichi Sankyo, Inc. October 2020.
Twynsta prescribing information. Boehringer Ingelheim Pharmaceuticals Inc. November 2018.
Tekturna prescribing information. Novartis Pharmaceuticals Corporation. June 2020.
Tekturna HCT prescribing information. Novartis Pharmaceuticals Corporation. November 2016.
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. Journal of the American College of Cardiology. 71(19): e127-e248. May 2018. http://www.onlinejacc.org/content/71/19/e127?_ga=2.237976455.681665904.1587569918-1112583575.1587569918 Accessed 4/8/2021.
Clinical practice guideline for screening and management of high blood pressure in children and adolescents. Pediatrics. 2017;140(3):e20171904 September 2017. https://pediatrics.aappublications.org/content/140/3/e20171904 Accessed 4/8/2021.
Sen S, Ufuktepe B, et al. “Renin inhibitors in diabetes and hypertension: an update”. EXCLI Journal 2014; 13: 1111-1119. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4464353/ Accessed 4/22/2020
FDA. FDA Drug Safety Communication: New Warning and Contraindication for blood pressure medicines containing aliskiren (Tekturna). https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-new-warning-and-contraindication-blood-pressure-medicines-containing Content current as of 1/19/2016. Accessed 4/08/2021.
Valsartan oral solution prescribing information. Lifsa Drugs, LLC. 04/2022

This pharmacy policy is not an authorization, certification, explanation of benefits or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All pharmacy policies are based on (i) information in FDA approved package inserts (and black box warning, alerts, or other information disseminated by the FDA as applicable); (ii) research of current medical and pharmacy literature; and/or (iii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

The purpose of Blue Cross and Blue Shield of Alabama’s pharmacy policies are to provide a guide to coverage. Pharmacy policies are not intended to dictate to physicians how to practice medicine. Physicians should exercise their medical judgment in providing the care they feel is most appropriate for their patients.

Neither this policy, nor the successful adjudication of a pharmacy claim, is guarantee of payment.

Asset Publisher

Angiotensin II Receptor Antagonists (ARBs), Renin Inhibitors, and Combinations Step Therapy Program Summary

Policy Number: PH-1027

ARBs and ARB Combinations 1-22, 27

ARBs and ARB Combinations ^{1-22, 27}