Hypertension Step Therapy Criteria FDA APPROVED INDICATIONS AND DOSAGE





Accuretic (quinapril/HCTZ)*



Aceon (perindopril)*



Altace (ramipril)*



Capozide (captopril/HCTZ)*



CV Risk ↓

LVSHF

Accupril (quinapril)*

DMN

HTN

Agents

Post-MI

ACEIs and ACEI Combinations1-22 Dosing and Administration (adults)

HTN: Initial dose 5 mg (on diuretic) or 10-20 mg (not on diuretic) once daily. Most patients require 20, 40, or 80 mg/day (in 1-2 equally divided doses). HF: Adjunctive therapy with digitalis and diuretics. Initial dose is 5 mg twice daily; titrate to effective dose (usually 20-40 mg/day divided equally into 2 doses). HTN**: Initial dose one tablet of quinapril/HCTZ 10/12.5 or 20/12.5 mg once daily. Dosage titration based on clinical response. Patients with BP controlled on HCTZ 25 mg/day, but with significant potassium loss, may switch to quinapril/HCTZ 10/12.5 or 20/12.5 mg/day. Maximum dosage is two tablets of 20/12.5 mg per day (40 mg/day quinapril and 25 mg/day HCTZ). c

b

d

Stable CAD to ↓Risk: Initial dose 4 mg once daily for 2 weeks; maintenance dose 8 mg once daily. HTN: Initial dose 2-4 mg in 1-2 divided doses (on diuretic) or 4 mg once daily (not on diuretic); maintenance dose 4-8 mg/day, as one or two divided doses; maximum of 16 mg/day. If volume depletion or renal artery stenosis are present, initial ramipril dose is 1.25 mg once daily. HTN: Initial dose 1.25 mg/day (on diuretic) or 2.5 mg once daily (not on diuretic). Maintenance range 2.5-20 mg/day in 1-2 equally divided doses. Post MI (signs of HF): Initial dose is 2.5 mg twice daily (may reduce to 1.25 mg twice daily if hypotension occurs). After 1 week at initial dose, titrate to target of 5 mg twice daily. CV Risk ↓: Initially, 2.5 mg once daily for 1 week, then 5 mg once daily for next 3 weeks; maintenance dose 10 mg once daily. May also be given as divided dose. HTN**: Initially, captopril/HCTZ 25/15 mg once daily. Usual maintenance dose range captopril in HTN is 25-50 mg 2-3 times daily; HCTZ 12.5-50 mg once daily. Maximum dosage limitscaptopril 150 mg/day; HCTZ 50 mg/day. If coexisting hypovolemia, hyponatremia, HF or LVD, may need to start lower and titrate the captopril dosage separately.

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Lexxel (enalapril/ felodipine ER)

Post-MI

DMN





a





Lotensin (benazepril)*



Lotensin HCT (benazepril/HCTZ)*



Lotrel (benazepril/ amlodipine)*

CV Risk ↓

LVSHF

Capoten (captopril)*

HTN

Agents

Dosing and Administration (adults)

HTN: Initially, 12.5-25 mg 2-3 times daily. Increase to 50 mg 3 times daily after 1-2 weeks if needed. If on a diuretic, use lower doses. Maintenance dose range 25-150 mg 2-3 times daily. HF: Initially, 25 mg twice daily; increase up to 50 mg 3 times daily if needed. If on a diuretic, use 6.25-12.5 mg 3 times daily. Maintenance dose 25-50 mg given 2-3 times daily. Maximum daily dose For HTN & HF is 450 mg/day (2-3 doses). Post-MI: 6.25-12.5 mg 3 times daily within 3-16 days in patients with LVD after acute MI. Titrate to 25 mg 3 times daily over several days; then target of 50 mg 3 times daily. DMN: 25 mg 3 times daily; range of 25-150 mg/day. Maximum dose: 450 mg/day. HTN **: Initial dose one tablet of 5/5 mg once daily. If needed, dosage may be increased to two tablets of 5/5 mg once daily. Maximum dosage is four tablets of enalapril/felodipine 5/2.5 mg once daily (20 mg/day enalapril and 10 mg/day felodipine). HTN: Initially, 10 mg once daily. If receiving diuretics, reduce initial dose to 5 mg/day. Usual dosage is 20-40 mg/day in 1-2 divided doses. Maximum dosage is 80 mg/day. HTN**: Patients not adequately controlled on benazepril alone may be switched to benazepril/HCTZ 10/12.5 or 20/12.5 once daily. Increases of either or both components depend on clinical response. Maximum dose limits - benazepril 40 mg/day, HCTZ 50 mg/day. HTN**: The approved dosage range is 2.5 to 10 mg for amlodipine combined with 10 to 40 mg for benazepril given once daily (e.g., one capsule once daily of either 2.5/10, 5/10, 5/20, 10/20, 5/40, or 10/40 mg). Maximum dose is 10 mg/day amlodipine and 40 mg/day benazepril.



Mavik (trandolapril)*





Monopril (fosinopril)*





Monopril HCT (fosinopril/HCTZ)*



HTN: Initial dose 0.5 mg (on diuretic) or 1 mg once daily (not on diuretic, non-black patients) or 2 mg once daily (not on diuretic, black patients). Most patients require 2-4 mg once daily; Patients not adequately treated with once daily 4 mg dose may be treated with twice daily dosing. HF or LVD post MI: Initial dose 1 mg once daily; titrate as tolerated to target of 4 mg once daily. HTN: Initially, 10 mg once daily both (as monotherapy and added to diuretic). Usual range 20-40 mg; some patients have further response at 80 mg. Patients not adequately treated with once daily dose may be treated with twice daily dosing. HF: Most clinical experience is in patients also on digitalis and diuretics. Initial dose is 10 mg once daily. Effective dose range 20-40 mg once daily (maximum dose). HTN**: Initial dose is one tablet of fosinopril/HCTZ 10/12.5 or 20/12.5 mg once daily. Usual dose ranges for fosinopril monotherapy 10 to 80 mg/day (maximum dose); for HCTZ monotherapy 12.5 to 50 mg/day (maximum dose). Trials of fosinopril/HCTZ used dose ranges of 2.5-40 mg fosinopril and 537.5 mg HCTZ.

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Prinzide (lisinopril/HCTZ)* Zestoretic (lisinopril/HCTZ)* Tarka (trandolapril/ verapamil ER)*





CV Risk ↓

Post-MI



DMN

LVSHF

Prinivil, Zestril (lisinopril)*

HTN

Agents

HTN**: Clinical trials have used a range of verapamil ER 120-240 mg once daily and trandolapril 0.5-8 mg once daily. Maximum dosage for combination therapy is 8 mg/day trandolapril and 240 mg/day verapamil ER. Patients on diuretics need lower doses.





Uniretic (moexipril/HCTZ)*



Vaseretic (enalapril/HCTZ)*



Vasotec (enalapril)*



HTN: Initial dose 10 mg once daily (not on diuretic) or 5 mg once daily (on diuretic). Usual dose range 20-40 mg once daily. Doses up to 80 mg do not appear to give greater effects. HF: Usually adjunctive with digitalis and diuretics. Initial dose is 5 mg once daily; usual effective dose range 5-40 mg once daily. Post-MI: In hemodynamically stable patients within 24 hours of onset of symptoms of acute MI, initial dose is 5 mg, followed by 5 mg after 24 hours, 10 mg after 48 hours, and then 10 mg once daily. Continue dosing for 6 weeks. Patients with low SBP (55 years at high risk of developing a major CV event due to history of CAD, stroke, peripheral vascular disease, DM HCSC_CS_S_Hypertension_ST_AR1210_r0111.doc © Copyright Prime Therapeutics LLC. 01/2011 All Rights Reserved

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Atacand (candesartan)



Atacand HCT (candesartan/HCTZ)



Avalide (irbesartan/HCTZ)



Avapro (irbesartan)



Azor (olmesartan/ amlodipine)

DMN

Dosing and Administration (adults) HF

Post-MI

HTN/ LVH

HTN

Agents

CV Risk ↓

ARBs and ARB Combinations23-39,41

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.

b

d, e

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. c



Benicar (olmesartan)



Benicar HCT (olmesartan/HCTZ)



Cozaar (losartan)*



Diovan (valsartan)



Diovan HCT (valsartan/HCTZ)



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. 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.

a

c



b d

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.

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Exforge (valsartan/ amlodipine)



Exforge HCT (valsartan/ amlodipine/ HCTZ)



Hyzaar (losartan/HCTZ)*



Micardis (telmisartan)



Micardis HCT (telmisartan/HCTZ)



Teveten (eprosartan)



Teveten HCT (eprosartan/HCTZ)



Tribenzor (olmesartan/ amlodipine/HCTZ)



Twynsta (telmisartan/ amlodipine)



DMN

Dosing and Administration (adults) HF

Post-MI

HTN/ LVH

CV Risk ↓

HTN

Agents

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.

a

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 is losartan/HCTZ 50/12.5 mg once daily. May increase to two tablets of 50/12.5 once daily or one tablet of 100/25 once daily. Maximum 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 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 angiotensin converting enzyme inhibitor (ACEI) and angiotensin II receptor antagonist (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 e - In combination with ACEI d - In patients intolerant of ACEIs HCSC_CS_S_Hypertension_ST_AR1210_r0111.doc © Copyright Prime Therapeutics LLC. 01/2011 All Rights Reserved

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DMN

Dosing and Administration (adults) HF

Post-MI

HTN/LV H

HTN

Agents

CV Risk ↓

Renin Inhibitors, Renin Inhibitor Combinations40,42,43,89,90

Amturnide (aliskiren/ amlodipine/HCTZ)



HTN: Initial dosing will depend on prior therapy. If switching patients previously on any component, use lower dose in combination product to start; if replacing individual tablets of 3 components, substitute same doses of components. Dose once-daily. Maximum dose300 mg/10 mg/25 mg once daily.

Tekamlo (aliskiren/ amlodipine)



HTN: Initially, aliskiren/amlodipine 150 mg/5 mg once daily. Titrate as needed up to 300 mg/10 mg daily. Maximum dose- 300 mg/10 mg once daily.

Tekturna (aliskiren)



HTN: Initially, aliskiren 150 mg once daily. If BP remains uncontrolled, titrate up to 300 mg daily. Maximum dose- 300 mg/day.

Tekturna HCT (aliskiren/HCTZ)



Valturna (aliskiren/valsartan)



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. 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.44,45 Multiple outcome trials with ACEIs in the treatment of hypertension have been conducted. Two outcome trials, ALLHAT46 and ANBP2,47 are particularly important in establishing ACEIs as first or second line treatment options for hypertension. Each of the ARBs is also indicated for the treatment of hypertension. For the ARBs, there are four major outcome trials showing benefit from their use in treatment of hypertension.48-51 A two part meta-analysis evaluating all ARBs but olmesartan showed only minor differences in antihypertensive effects with all ARBs when given at their recommended doses. This metaanalysis concluded that there is little clinically significant difference in efficacy between the six ARBs in hypertension.52 There are no outcome trials in hypertension powered to show differences in clinical endpoints between any two ACEIs or ARBs. Multiple guidelines suggest ACEIs or ARBs be considered as part of first-line treatment for hypertension. In addition to effects on hypertension, other compelling reasons for use of ACEIs or ARBs include renoprotective effects in patients with diabetes and kidney disease, and other benefits in patients with heart failure.53-63 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 HCSC_CS_S_Hypertension_ST_AR1210_r0111.doc © Copyright Prime Therapeutics LLC. 01/2011 All Rights Reserved

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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.42 Heart Failure, Including Post Myocardial Infarction ACEIs are well established for the treatment of heart failure (HF), and are strongly recommended in treatment guidelines.56,64 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.68 There are outcomes data for three ARBs (candesartan, losartan, valsartan) in congestive heart failure (CHF).54,56,64,66-70 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.68 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).70 ARBs may be a reasonable alternative in HF patients unable to tolerate ACEIs.  The American College of Cardiology/American Heart Association (ACC/AHA) guidelines on treatment of chronic HF (updated 2009) suggests that ACEIs should be prescribed for all patients with HF due to left ventricular dysfunction (LVD) with reduced left ventricular ejection fraction (LVEF) unless there is a contraindication. ARBs are considered reasonable to use as alternatives to ACEIs as first line therapy. Preference may be given to the ACEIs shown to reduce morbidity and mortality in clinical trials in HF or post MI (captopril, enalapril, lisinopril, ramipril, perindopril, trandolapril). The ARBs candesartan and valsartan demonstrated benefit by reducing hospitalizations and mortality.64,71  The ACC/AHA guidelines on treatment of ST-elevation MI (2008) state that ACEIs are beneficial in the following situations: within first 24 hours of MI with ST elevation (STEMI) or with HF, or with MI and LVEF