BP lowering in a single pill

When an ARB or CCB is not enough

Results in stage 2 moderate to severe hypertension

EXFORGE

In an EXFORGE trial in patients with stage 2 HTN (SBP 160-199 mm Hg), EXFORGE 10/160 mg reduced SBP by 30 mm Hg at week 4; in a subset of patients with severe HTN (SBP 180-199 mm Hg), EXFORGE 10/160 mg reduced SBP by 40 mm Hg; at week 8, SBP reductions in patients with SBP 180-199 mm Hg were 42 mm Hg with EXFORGE 10/160 mg ± HCTZ 12.5 mg and 37 mm Hg with amlodipine 10 mg ± HCTZ 12.5 mg.4

In a separate double-blind, 12-week study, black patients with stage 2 HTN (SBP ≥160 mm Hg and <200 mm Hg) were randomized to amlodipine 5 mg QD or EXFORGE 5/160 mg QD. At week 2, patients were force-titrated to amlodipine 10 mg QD or EXFORGE 10/160 mg QD. At week 4, patients on EXFORGE 10/160 mg QD with SBP ≥130 mm Hg were titrated to EXFORGE 10/320 mg QD, and patients on amlodipine 10 mg QD continued the current dose. At week 8, patients with SBP ≥130 mm Hg had open-label HCTZ 12.5 mg QD added to their treatments.3

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When olmesartan is not enough

Patients not at BP goal on ARB monotherapy switched to EXFORGE

Subgroup of patients treated and not controlled on either 20 mg or 40 mg
olmesartan5,6

EXFORGE

Primary end point was change in msSBP from baseline to week 4 in patients uncontrolled on non-valsartan ARB monotherapy who were switched to EXFORGE 5/320 mg and were titrated to 10/320 mg at week 2 (n=366) versus those switched to and maintained on EXFORGE 5/160 mg (n=357), which was –23 versus –19 mm Hg, respectively (P<0.01).5,6

In the EXTRA study (AUS02), prespecified analysis of the patient subgroup that failed on olmesartan and was switched to EXFORGE 5/160 mg (the lower-dose treatment arm) resulted in mean additional SBP reduction of –22 mm Hg at week 4 (n=62) from mean baseline SBP of 162 mm Hg.5,6 In the EXFORGE Prescribing Information, changes from baseline SBP in patients taking EXFORGE 10/160 mg were –14 mm Hg when switched from valsartan.7

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When a DHP-CCB is not enough

Patients not at goal on a DHP-CCB monotherapy switched to EXFORGE

Patients treated and not controlled on a CCB7,8

EXFORGE

In another clinical study, patients with mild to moderate HTN not controlled on amlodipine 10 mg received EXFORGE 10/160 mg or amlodipine alone (10 mg). At week 8, the EXFORGE treatment was statistically significantly superior to amlodipine alone (10 mg) in the reduction of DBP and SBP. The msDBP was 11.8 mm Hg vs 10.0 mm Hg for a difference in the msDBP of –1.8 mm Hg. The msSBP was 12.7 mm Hg vs 10.8 mm Hg for a difference in msSBP of –1.9 mm Hg.3

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SWITCH appropriate patients to EXFORGE HCT

Results in stage 2/severe hypertension9-11

EXFORGE

DBP primary end points: –25 mm Hg EXFORGE HCT 10/320/25 mg, –20 mm Hg valsartan/HCTZ 320/25 mg, –22 mm Hg amlodipine/valsartan 10/320 mg, and –20 mm Hg amlodipine/HCTZ 10/25 mg.10

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When Iosartan + HCTZ is not enough

Achieve BP-lowering power with
EXFORGE + HCTZ

EXFORGE + HCTZ compared to Iosartan + HCTZ in stage 2 systolic HTN12

EXFORGE

Patients uncontrolled on dual-combination therapy may experience additional lowering of BP by switching to triple-combination therapy.12

EXFORGE HCT may be used for patients not adequately controlled on any 2 of the following antihypertensive classes: CCBs, ARBs, and diuretics.9

Prespecified primary end point: change from baseline in msSBP at week 6.12

  • Reduction in msSBP from baseline to week 6 was significantly greater in the valsartan/amlodipine/HCTZ group than in the losartan/HCTZ group (–32 mm Hg vs
    –26 mm Hg, respectively; P<0.001)12

When Iosartan + HCTZ is not enough

Additional BP lowering achieved at week 6

BP reductions were achieved with EXFORGE + HCTZ by week 912

EXFORGE

Prespecified primary end point: change from baseline in msSBP at week 6.12
Prespecified secondary end point: change from baseline in msDBP and change from baseline in msSBP at weeks 3, 9, and 12.12

Patients in the losartan group were switched to valsartan/amlodipine/
HCTZ 160/5/25 mg at week 6.12
The reductions in msDBP in the valsartan/amlodipine and losartan groups,
respectively, were as follows:
week 3 (–9.8 mm Hg vs –4.8 mm Hg), week 6 (–13.7 mm Hg vs –9.6 mm Hg),
week 9 (–16.2 mm Hg vs –13.7 mm Hg) and week 12 (–16.3 mm Hg vs
–15.7 mm Hg).12

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Help reduce dose-related peripheral edema

Switch patients from Amlodipine 10 mg to
EXFORGE 5/160 mg

Amlodipine can cause dose-dependent peripheral edema13

EXFORGE

Lower incidence of peripheral edema

Lower incidence of peripheral edema with EXFORGE 5/160 versus amlodipine 10 mg14

EXFORGE

The co-primary end points were change in msSBP from baseline (day of randomization) up to week 8 (LOCF) and the presence of peripheral edema as an adverse event up to and including week 8.2

A patient who experiences dose-limiting adverse reactions on amlodipine may be switched to EXFORGE containing a lower dose of amlodipine to achieve similar BP reductions.7
Incidence of peripheral edema seen with EXFORGE versus placebo was 5% versus 3%, respectively.7

*P<0.001 versus amlodipine 10 mg week 1 through week 8.2
In this double-blind 12-week study, hypertensive patients not adequately controlled (msSBP ≥130 mm Hg and ≤160 mm Hg) on amlodipine 5 mg were randomized to EXFORGE 5/160 mg QD (n=592) or amlodipine 10 mg QD (n=591) for 8 weeks. At week 8, patients on EXFORGE 5/160 mg QD continued the current dose, and patients on amlodipine 10 mg QD were switched to EXFORGE 5/160 mg QD and treated for an additional 4 weeks. The primary efficacy end point was LSM change from baseline to week 8 in msSBP (EXFORGE 5/160 mg: -8 mm Hg, amlodipine 10 mg: -6 mm Hg, tested for noninferiority [P<0.001] and superiority [P<0.002]). The primary safety end point was incidence of peripheral edema reported up to and including week 8.2

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INDICATIONS

EXFORGE and EXFORGE HCT are indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

EXFORGE may be used for patients not adequately controlled on monotherapy with an angiotensin receptor blocker (ARB) or a dihydropyridine calcium channel blocker (DHP-CCB).

EXFORGE may also be used as initial therapy in patients who are likely to need multiple drugs to achieve their blood pressure goals. The choice of EXFORGE as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the lowest dose of EXFORGE, the baseline blood pressure, the target goal, and the incremental likelihood of achieving goal with a combination product compared to monotherapy.

EXFORGE HCT is not indicated for the initial therapy of hypertension.
EXFORGE HCT may be used for patients not adequately controlled on any two of the following antihypertensive classes: CCBs, ARBs, and diuretics.

IMPORTANT SAFETY INFORMATION

WARNING: FETAL TOXICITY

  • When pregnancy is detected, discontinue EXFORGE or EXFORGE HCT as soon as possible. (5.1)
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)

Contraindications: Do not use in patients with known hypersensitivity to any component of either product. In addition, EXFORGE HCT is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
Do not coadminister aliskiren with EXFORGE or EXFORGE HCT in patients with diabetes.

Hypotension: Excessive hypotension was seen in 0.4% of patients treated with EXFORGE and, including orthostatic hypotension, in 1.7% of patients treated with EXFORGE HCT 10/320/25 mg in controlled trials. In patients with an activated renin-angiotensin system (RAS), such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur in patients receiving angiotensin receptor blockers. Correct this condition before administering EXFORGE or EXFORGE HCT. Caution should be observed when initiating therapy with EXFORGE in patients with heart failure or recent myocardial infarction and in patients undergoing surgery or dialysis. Do not initiate treatment with EXFORGE HCT in patients with aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Risk of MI or Increased Angina: Worsening angina and acute myocardial infarction (MI) can develop after starting or increasing the dose of amlodipine, particularly in patients with severe obstructive coronary artery disease.

Renal Considerations: Changes in renal function, including acute renal failure, can be caused by drugs that inhibit the RAS and by diuretics. Patients whose renal function may depend in part on the activity of the RAS (eg, patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on EXFORGE HCT. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on EXFORGE or EXFORGE HCT.

Monitor renal function periodically in patients receiving valsartan and non-steroidal anti-inflammatory drugs (NSAIDs) who are also elderly, volume-depleted (including those on diuretics), or who have compromised renal function due to potential reversible deterioration of renal function, including acute renal failure. The antihypertensive effect of ARBs, including valsartan, may be attenuated by NSAIDs.

Avoid use of aliskiren with EXFORGE or EXFORGE HCT in patients with renal impairment (GFR <60 mL/min).

Potassium Abnormalities: In the controlled trial of EXFORGE HCT in moderate to severe hypertensive patients, the incidence of hypokalemia (serum potassium <3.5 mEq/L) at any time post-baseline with the maximum dose of EXFORGE HCT (10/320/25 mg) was 10% compared to 25% with HCTZ/amlodipine (25/10 mg), 7% with valsartan/HCTZ (320/25 mg), and 3% with amlodipine/valsartan (10/320 mg). One patient (0.2%) discontinued therapy due to an adverse event of hypokalemia in each of the EXFORGE HCT and HCTZ/amlodipine groups. The incidence of hyperkalemia (serum potassium >5.7 mEq/L) was 0.4% with EXFORGE HCT compared to 0.2-0.7% with the dual therapies.

Concomitant use of EXFORGE or EXFORGE HCT with other agents that block the RAS, potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium. Monitor serum electrolytes periodically.

Important Considerations Due to the HCTZ Component of EXFORGE HCT: Hypersensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Thiazides have been reported to cause exacerbation or activation of systemic lupus erythematosus.

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction resulting in transient myopia and angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Discontinue hydrochlorothiazide as rapidly as possible in these patients. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Dual Blockade of the RAAS: Dual blockade of the RAS with angiotensin receptor blockers, angiotensin-converting enzyme inhibitors (ACEIs), or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function, and electrolytes in patients on EXFORGE or EXFORGE HCT and other agents that affect the RAS.

Lithium: Monitor lithium levels in patients receiving EXFORGE or EXFORGE HCT and lithium, as increases in serum lithium concentrations and lithium toxicity have been reported.

Common Adverse Events: The most common adverse events that occurred more frequently with EXFORGE than placebo were peripheral edema (5% vs 3%), nasopharyngitis (4% vs 2%), upper respiratory tract infection (3% vs 2%), and dizziness (2% vs 1%).
The most frequent adverse events that occurred in ≥2% of patients treated with EXFORGE HCT were dizziness (8.2%), edema (6.5%), headache (5.2%), dyspepsia (2.2%), fatigue (2.2%), muscle spasms (2.2%), back pain (2.1%), nausea (2.1%) and nasopharyngitis (2.1%).

Please see accompanying full Prescribing Information, including Boxed WARNING, for EXFORGE and EXFORGE HCT.

References: 1. Data on file. Fingertip Formulary. October 2014. Novartis Pharmaceuticals Corp. 2.  Schrader J, Salvetti A, Calvo C, et al. The combination of amlodipine/valsartan 5/160 mg produces less peripheral oedema than amlodipine 10 mg in hypertensive patients not adequately controlled with amlodipine 5 mg. Int J Clin Pract. 2009;63(2):217-225. 3. Flack JM, Calhoun DA, Satlin L, Barbier M, Hilkert R, Brunel P. Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study. J Hum Hypertens. 2009;23(7):479-489. 4. Destro M, Luckow A, Samson M, Kandra A, Brunel P. Efficacy and safety of amlodipine/valsartan compared with amlodipine monotherapy in patients with stage 2 hypertension: a randomized, double-blind, multicenter study: the EX-EFFeCTS Study. J Am Soc Hypertens. 2008;2(4):294-302. 5. Oparil S, Giles T, Ofili EO, et al. Intensive treatment with combination amlodipine/valsartan provides greater antihypertensive efficacy vs moderate treatment for hypertensive patients uncontrolled on ARB monotherapy: the EXTRA study. J Clin Hypertens. 2010;12(Suppl 1):A42. 6. Data on file. Study CVAA489AUSO2. Novartis Pharmaceuticals Corp. 7. EXFORGE [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp. 2014. 8. Allemann Y, Fraile B, Lambert M, Barbier M, Ferber P, Izzo JL Jr. Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure After Single Therapy (EX-FAST) study. J Clin Hypertens (Greenwich). 2008;10(3):185-194. 9. EXFORGE HCT [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2014. 10. Calhoun DA, Lacourcière Y, Chang YT, Glazer RD. Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: a randomized clinical trial. Hypertension. 2009;54(1):32-39. 11. Calhoun DA, Crikelair NA, Yen J, Glazer RD. Amlodipine/valsartan/hydrochlorothiazide triple combination therapy in moderate/severe hypertension: secondary analyses evaluating efficacy and safety. Adv Ther. 2009;26(11):1012-1023. 12. Wright RF, Duprez D, Purkayastha D, Samuel R, Ferdinand KC. Combination angiotensin-receptor blocker (ARB)/calcium channel blocker with HCTZ vs the maximal recommended dose of an ARB with HCTZ in patients with stage 2 hypertension: the Exforge as Compared to Losartan Treatment in Stage 2 Systolic Hypertension (EXALT) study. J Clin Hypertens (Greenwich). 2011;13(8):588-597. 13. Norvasc [package insert]. New York, NY: Pfizer Inc; 2014. 14. Sica DA. Calcium channel blocker-related peripheral edema: can it be resolved? J Clin Hypertens (Greenwich). 2003;5(4):291-297.

* Source: National formulary data are provided by Fingertip Formulary and are accurate as of October 2014. Data from the Department of Veterans Affairs, Department of Defense, Indian Health Service, Kaiser Permanente, and HealthTrans are not included. Please note that formularies are subject to change and many health plans offer more than one formulary. Please check with the health plan directly to confirm coverage for individual patients. Tier status may include step edits and/or prior authorizations. Inclusion on formulary or formulary status does not imply superior clinical efficacy or safety. Includes plans listing products in any cost-sharing tier and certain plans may have quantity limits, prior authorizations, or step edits in place. Patient costs may vary significantly among plans.

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