Sylvester O. Agbahiwe PharmD, BCACP

Entresto (sacubitril/valsartan; Novartis Pharmaceuticals), previously known as LCZ696, is a combination of a first-in-class neprilysin inhibitor and an angiotensin receptor blocker (ARB) indicated for the treatment of heart failure (HF) with reduced ejection fraction. It has been proven to reduce the risk of cardiovascular death and hospitalizations from HF and should be administered in conjunction with other therapies for HF in place of an angiotensin-converting enzyme (ACE) inhibitor or ARB.

HF, a common condition affecting roughly 5.1 million individuals in the United States, is the primary diagnosis in more than 1 million hospitalizations annually. Approximately 50% of patients with this condition die within 5 years of receiving the diagnosis, and the total cost of expenditures from HF exceeds $30 billion annually in the United States.

Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and andrenomedullin.

 Inhibition of neprilysin by sacubitril increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling, which increases vasodilation, natriuresis, and diuresis.

 Valsartan inhibits the effects of angiotensin II by selectively blocking the angiotensin II type-1 receptor and inhibiting angiotensin II—dependent aldosterone release, resulting in vasodilation.

In small trials involving patients who had hypertension or HF with preserved ejection fraction, LCZ696 had hemodynamic and neurohormonal effects that were greater than those of an ARB alone.

 Entresto gained FDA approval through the PARADIGM-HF trial in which the coadministration of sacubitril and valsartan was studied in 8442 patients with New York Heart Association class II-IV HF and an ejection fraction of no more than 40%.

 The patients were randomized to receive either Entresto 200 mg (sacubitril 97 mg/valsartan 103 mg) twice daily or enalapril 10 mg twice daily, with the primary outcome being a composite of death from cardiovascular causes or hospitalization for HF.

The trial was terminated early after a median follow-up of 27 months, as Entresto proved superior to enalapril in most of the major outcomes. Entresto reduced the risk of death from cardiovascular causes and HF hospitalizations by 20% and 21%, respectively, and reduced the risk of all-cause mortality by 16%.

 It was not accompanied by important safety concerns, as fewer patients than in the enalapril group discontinued their study medication because of an adverse event (AE) or renal impairment.

Entresto is currently available in 3 dosage strengths: sacubitril/valsartan 24/26 mg, 49/51 mg, and 97/103 mg. The recommended starting dose is 49/51 mg twice daily with or without food. The dose can be doubled after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily as tolerated by the patient. A starting dose of 24/26 mg twice daily is recommended for patients not currently taking an ACE inhibitor or ARB or patients previously taking low doses of these agents, for patients with severe renal impairment (estimated glomerular filtration rate <30 mL/ min/1.73 m

), or for patients with moderate hepatic impairment (Child-Pugh B classification). The oral absolute bioavailability of sacubitril is estimated to be 60% or more, while the valsartan in Entresto is more bioavailable than the valsartan in other marketed formulations. Following oral administration, 52% to 68% of sacubitril and roughly 13% of valsartan and its metabolites are excreted in the urine while 37% to 48% of sacubitril and 86% of valsartan (and its metabolites) are excreted in feces.

Contraindications, Warnings, and Precautions

Common AEs (≥5%) reported with Entresto include hypotension, hyperkalemia, cough, dizziness, and renal failure. Entresto is contraindicated in patients with a history of serious hypersensitivity reactions to any of the components of these products, in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy, concomitant use of ACE inhibitors (do not administer within 36 hours of switching from or to an ACE inhibitor), or concomitant use of aliskiren in patients with diabetes.

Entresto can cause fetal harm when administered to a pregnant woman by reducing fetal renal function, which increases fetal and neonatal morbidity and death. Therefore, alternative treatment should be considered when pregnancy is detected.

 In addition, because Entresto was shown to be present in rat milk, it is not recommended in nursing women who are breast-feeding due to the potential for serious AEs.

Dr. Agbahiwe is clinical pharmacist specialist at Harris Health System, Settegast Health Center, in Houston, Texas, as well as adjunct faculty, Department of Pharmacy Practice, at Texas Southern University College of Pharmacy & Health Sciences. Ms. Emelogu is a PharmD candidate at Texas Southern University College of Pharmacy & Health Sciences.

		Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. 

. 2013;128(16):e240-e327. doi: 10.1161/CIR.0b013e31829e8776.

		Entresto (sacubitril and valsartan) [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2015. www.pharma.us.novartis.com/product/pi/pdf/entresto.pdf. Accessed July 10, 2015.

		von Lueder TG, Atar D, Krum H. Current role of neprilysin inhibitors in hypertension and heart failure. 

. 2014;144(1):41-49. doi: 10.1016/j.pharmthera.2014.05.002.

		Vardeny O, Miller R, Solomon SD. Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure. 

. 2014;2(6):663-670. doi: 10.1016/j.jchf.2014.09.001.

		Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. 

2010;375(9722):1255-1266. doi: 10.1016/S0140-6736(09)61966-8.

		Solomon SD, Zile M, Pieske B, et al; Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fracTion (PARAMOUNT) Investigators. The angiotensin receptor neprilysin inhibitor LCQ696 in heart failure with preserved ejection fraction: a phase 2 double blind randomized controlled trial. 

 2012;380(9851):1387-1395. doi: 10.1016/S0140-6736(12)61227-6.

		McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. 

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Articles

Entresto is a combination of a first-in-class neprilysin inhibitor and an angiotensin receptor blocker indicated for the treatment of heart failure with reduced ejection fraction.

Entresto

Kcentra is the first nonactivated 4-factor prothrombin complex concentrate for the urgent reversal of acquired coagulation deficiency induced by vitamin K antagonist therapy. 

Kcentra (human prothrombin complex concentrate) is the first nonactivated 4-factor prothrombin complex concentrate for the urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist (VKA) therapy (eg, warfarin) in adult patients with acute major bleeding. Each year, approximately 3 to 4 million people in the United States are treated with the oral anticoagulant warfarin to prevent blood clots from forming; however, because of the inhibition in blood clotting factors, patients may experience severe bleeding. It has been estimated that emergency departments in the United States see approximately 29,000 cases of warfarin-associated bleeding annually.

Kcentra contains the vitamin K—dependent coagulation factors II, VII, IX, and X—together known as the prothrombin complex&mdash;and the antithrombotic proteins C and S. The coagulation cascade is a series of procoagulant and antithrombotic reactions involving the activation of zymogens. The vascular endothelium provides a protective barrier separating blood cells and plasma factors from subendothelial vessel wall–reactive adhesive proteins and tissue factor. The latter proteins trigger blood coagulation. Thrombin converts fibrinogen to fibrin for clot formation. The administration of Kcentra rapidly increases plasma levels of the vitamin K–dependent coagulation factors (II, VII, IX, and X) as well as the antithrombotic proteins C and S.

The efficacy of Kcentra has been evaluated in a prospective, open-label, active-controlled, noninferiority, randomized, controlled phase-IIIb study. A total of 212 subjects were randomized to receive Kcentra or plasma for acute major bleeding in the setting of an international normalized ratio (INR) ≥2.0 and recent use of a VKA anticoagulant. The doses of Kcentra (25, 35, or 50 IU/kg) were calculated according to the subjects’ baseline INR (2 to <4, 4 to 6, or >6, respectively), and the observation period lasted 90 days after infusion of Kcentra or plasma. Kcentra achieved the end points of hemostatic efficacy with respect to the adequate stopping of a major bleed assessed at 24 hours from the start of infusion (72.4% of patients receiving Kcentra vs 65.4% receiving plasma) and INR reduction (≤1.3) at 30 minutes after treatment (62.2% of patients receiving Kcentra vs 9.6% receiving plasma).

In regards to secondary end points, a single Kcentra infusion produced a rapid and sustained increase in plasma levels of clotting factors II, VII, IX, and X within 30 minutes after treatment (P <.0001), with 87% less volume than plasma.

The dosing of Kcentra is shown in the Table.

Kcentra has a rapid onset of action in which a significant INR reduction is seen (INR reduced to <1.3 in more than 60% of patients); the duration of effect is approximately 6 to 8 hours. Kcentra is given by intravenous administration only. It should be reconstituted at room temperature before infusion should not be mixed with other medicinal productions, and must be administered through a separate infusion line.

Common (≥2.8%) adverse reactions to Kcentra include headache, nausea/vomiting, arthralgia, and hypotension. The most serious adverse reactions have been thromboembolic events, including stroke, deep venous thrombosis, and pulmonary embolism. Use of Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any components of Kcentra, including heparin; factors II, VII, IX, and X; proteins C and S; antithrombin III; and human albumin. Its use is also contraindicated in patients with disseminated intravascular coagulation and patients with known heparin-induced thrombocytopenia. No specific dosage adjustments are necessary for renal or hepatic impairment, although caution should be used in pregnant women, as Kcentra is rated Pregnancy Category C. 

		Zareh M, Davis A, Henderson S. Reversal of warfarin-induced hemorrhage in the emergency department. 

		Pabinger I, Brenner B, Kalina U, et al. Prothrombin complex concentrate (Kcentra) for emergency anticoagulation reversal: a prospective multinational clinical trial.

		Bleeding from acquired coagulation defects and antithrombotic therapy. In: Raife TJ, Rose JS, Lentz SR, eds. 

Rossi’s Principles of Transfusion Medicine

. 4th ed. Hoboken, NJ: Wiley-Blackwell; 2009.

		Wysowski D, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. 

 is a clinical pharmacist specialist at Harris Health System, Settegast Health Center, in Houston, Texas, as well as adjunct faculty, Department of Pharmacy Practice, at Texas Southern University College of Pharmacy & Health Sciences. 

is a PharmD candidate at Texas Southern University College of Pharmacy & Health Sciences. 

Kcentra by CSL Behring

Kazano (alogliptin/metformin) is a dipeptidyl-peptidase-4 (DPP-4) inhibitor and a biguanide combination in a single tablet indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). As the most common form of the disease, T2DM affects roughly 24 million people and accounts for more than 90% of diabetes cases diagnosed in the United States.

 It is a progressive and chronic condition that can lead to serious complications, including heart disease, blindness, and nerve and kidney damage. According to the International Diabetes Federation, the global health care expenditures for type 1 diabetes mellitus and T2DM were estimated to be $471.6 billion in 2012, and these expenditures are projected to exceed $595 billion by the year 2030.

Alogliptin is a DPP-4 inhibitor that is designed to slow the inactivation of the incretin hormones glucagon- like peptide-1 and glucose-dependent insulinotropic peptide, thereby increasing their bloodstream concentrations. This enables the pancreas to secrete insulin in a glucose-dependent manner, thus reducing fasting and postprandial glucose concentrations. Metformin is a biguanide that decreases hepatic glucose production and intestinal absorption of glucose and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.

The coadministration of alogliptin and metformin has been studied in patients with T2DM inadequately controlled on either diet or exercise alone, metformin alone, or metformin in combination with a thiazolidinedione. The safety and efficacy of Kazano were demonstrated in 4 clinical trials involving more than 2700 patients with T2DM. Results from studies showed that when alogliptin was coadministered with metformin, patients experienced significant improvements in their glycemic control compared with monotherapy. In a 26-week, double- blind, placebo-controlled study involving patients inadequately controlled on diet and exercise alone, Kazano resulted in additional reductions in glycated hemoglobin (A1C) of 1.0% over alogliptin alone and 0.5% over metformin alone. In a 26-week placebo-controlled study of alogliptin administered once daily as add-on to metformin regimen, the number of patients reporting hypoglycemic events was 0% in the Kazano group versus 2.9% in the placebo treatment group.

In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline A1C = 8.2%) on a current regimen of pioglitazone 30 mg and metformin were randomized to receive either the addition of once-daily alogliptin 25 mg or the titration of pioglitazone 30 mg to 45 mg following a 4-week single-blind, placebo run-in period. Patients were maintained on a stable dose of metformin HCl (median daily dose = 1700 mg). In combination with pioglitazone and metformin, alogliptin 25 mg was shown to be statistically superior in lowering A1C and fasting plasma glucose compared with the titration of pioglitazone from 30 to 45 mg at week 26 and at week 52.

Kazano (alogliptin and metformin HCl 12.5 mg/500 mg and 12.5 mg/1000 mg) should be taken twice daily with food. The dose may be adjusted based on effectiveness and tolerability while not exceeding the maximum recommended daily dose of 25 mg of alogliptin and 2000 mg of metformin. Alogliptin is 100% bioavailable (metformin is 50% to 60% bioavailable) with a 21-hour elimination half-life. It does not undergo extensive metabolism; 76% is excreted in the urine.

Contraindications, Warnings, and Precautions 

Common adverse reactions (≥4%) reported with Kazano include upper respiratory tract infection, nasopharyngitis, diarrhea, hypertension, headache, back pain, and urinary tract infections. Kazano is contraindicated in patients with a history of serious hypersensitivity reactions to any of the components of these products, patients with renal impairment (serum creatinine ≥1.5 mg/dL in men, ≥1.4 mg/dL in women, or abnormal creatinine clearance), or patients with acute or chronic metabolic acidosis. Kazano carries a black box warning for lactic acidosis, a buildup of lactic acid in the bloodstream, associated with metformin use. The FDA is requiring 2 postmarketing studies to monitor for liver abnormalities, serious cases of pancreatitis, and severe hypersensitivity reactions, as well as a pediatric safety and efficacy study. Kazano is Pregnancy Category B; however, whether Kazano is distributed in breast milk is unknown.

Dr. Agbahiwe is clinical pharmacist specialist at Harris Health System, Settegast Health Center, in Houston, Texas, as well as adjunct faculty, Department of Pharmacy Practice, at Texas Southern University College of Pharmacy & Health Sciences. Ms. Obi is a PharmD candidate at Texas Southern University College of Pharmacy & Health Sciences.

References (updated since publication of the print edition)

		International Diabetes Federation website. www.idf.org/diabetesatlas. Accessed December 4, 2013.

		Lexicomp website. www.lexi.com. Accessed November 20, 2013.

		McAuley D. KAZANO (alogliptin and metformin HCl) tablet, film coated. Global RPH, 02 Feb 2013. www.globalrph.com/drug_kazano.htm. Accessed December 1, 2013.

		Highlights of prescribing information. Dailymed website. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=83cb7914-a683-47bb-a713-f2bc6a596bd2. Accessed December 1, 2013.

		Nauck MA, Ellis GC, Fleck PR, et al. Efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicentre, randomised, double-blind, placebo-controlled study. 

		Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study. 

		Wu D, Li L, Liu C. Efficacy and safety of dipeptidyl peptidase-4 inhibitors and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes mellitus: a meta-analysis. 