ENTRESTO™ (sacubitril and valsartan) tablets, for oral use Initial U.S. Approval: 2015 BRIEF SUMMARY: Please see package insert for full prescribing information. WARNING: FETAL TOXICITY • When pregnancy is detected, discontinue ENTRESTO 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) 1 INDICATIONS AND USAGE 1.1 Heart Failure ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced ejection fraction. ENTRESTO is usually administered in conjunction with other heart failure therapies, in place of an ACE inhibitor or other ARB. 4 CONTRAINDICATIONS ENTRESTO is contraindicated: • in patients with hypersensitivity to any component • in patients with a history of angioedema related to previous ACE inhibitor or ARB therapy [see Warn-ings and Precautions (5.2)] • with concomitant use of ACE inhibitors. Do not administer within 36 hours of switching from or to an ACE inhibitor [see Drug Interactions (7.1)] • with concomitant use of aliskiren in patients with diabetes [see Drug Interactions (7.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Fetal Toxicity ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal func-tion and increases fetal and neonatal morbidity and death. When pregnancy is detected, consider alterna-tive drug treatment and discontinue ENTRESTO. However, if there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a pregnant woman of the potential risk to the fetus [see Use in Specific Populations (8.1)]. 5.2 Angioedema ENTRESTO may cause angioedema. In the double-blind period of PARADIGM-HF, 0.5% of patients treated with ENTRESTO and 0.2% of patients treated with enalapril had angioedema [see Adverse Reac-tions (6.1)]. If angioedema occurs, discontinue ENTRESTO immediately, provide appropriate therapy, and monitor for airway compromise. ENTRESTO must not be re-administered. In cases of confirmed angioedema where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, administer appropriate therapy, e.g., subcutaneous epinephrine/adrenaline solution 1:1000 (0.3 mL to 0.5 mL) and take measures necessary to ensure maintenance of a patent airway. ENTRESTO has been associated with a higher rate of angioedema in Black than in non-Black patients. Patients with a prior history of angioedema may be at increased risk of angioedema with ENTRESTO [see Adverse Reactions (6.1)]. ENTRESTO should not be used in patients with a known history of angioedema related to previous ACE inhibitor or ARB therapy [see Contraindications (4)]. 5.3 Hypotension ENTRESTO lowers blood pressure and may cause symptomatic hypotension. Patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), are at greater risk. In the double-blind period of PARADIGM-HF, 18% of patients treated with ENTRESTO and 12% of patients treated with enalapril reported hypotension as an adverse event [see Adverse Reactions (6.1)], with hypotension reported as a serious adverse event in approxi-mately 1.5% of patients in both treatment arms. Correct volume or salt depletion prior to administration of ENTRESTO or start at a lower dose. If hypotension occurs, consider dose adjustment of diuretics, concomitant antihypertensive drugs, and treatment of other causes of hypotension (e.g., hypovolemia). If hypotension persists despite such measures, reduce the dosage or temporarily discontinue ENTRESTO. Permanent discontinuation of therapy is usually not required. 5.4 Impaired Renal Function As a consequence of inhibiting the renin-angiotensin-aldosterone system (RAAS), decreases in renal function may be anticipated in susceptible individuals treated with ENTRESTO. In the double-blind period of PARADIGM-HF, 5% of patients in both the ENTRESTO and enalapril groups reported renal failure as an adverse event [see Adverse Reactions (6.1)]. In patients whose renal function depends upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treat-ment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria, pro-gressive azotemia and, rarely, acute renal failure and death. Closely monitor serum creatinine, and down-titrate or interrupt ENTRESTO in patients who develop a clinically significant decrease in renal function [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) in the full prescribing information]. As with all drugs that affect the RAAS, ENTRESTO may increase blood urea and serum creatinine levels in patients with bilateral or unilateral renal artery stenosis. In patients with renal artery stenosis, monitor renal function. 5.5 Hyperkalemia Through its actions on the RAAS, hyperkalemia may occur with ENTRESTO. In the double-blind period of PARADIGM-HF, 12% of patients treated with ENTRESTO and 14% of patients treated with enalapril reported hyperkalemia as an adverse event [see Adverse Reactions (6.1)]. Monitor serum potassium peri-odically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet. Dosage reduction or interruption of ENTRESTO may be required [see Dosage and Administration (2.1) in the full prescribing information]. 6 ADVERSE REACTIONS Clinically significant adverse reactions that appear in other sections of the labeling include: • Angioedema [see Warnings and Precautions (5.2)] • Hypotension [see Warnings and Precautions (5.3)] • Impaired Renal Function [see Warnings and Precautions (5.4)] • Hyperkalemia [see Warnings and Precautions (5.5)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In the PARADIGM-HF trial, subjects were required to complete sequential enalapril and ENTRESTO run-in periods of (median) 15 and 29 days, respectively, prior to entering the randomized double-blind period comparing ENTRESTO and enalapril. During the enalapril run-in period, 1,102 patients (10.5%) were per-manently discontinued from the study, 5.6% because of an adverse event, most commonly renal dys-function (1.7%), hyperkalemia (1.7%) and hypotension (1.4%). During the ENTRESTO run-in period, an additional 10.4% of patients permanently discontinued treatment, 5.9% because of an adverse event, most commonly renal dysfunction (1.8%), hypotension (1.7%) and hyperkalemia (1.3%). Because of this run-in design, the adverse reaction rates described below are lower than expected in practice. In the double-blind period, safety was evaluated in 4,203 patients treated with ENTRESTO and 4,229 treated with enalapril. In PARADIGM-HF, patients randomized to ENTRESTO received treatment for up to 4.3 years, with a median duration of exposure of 24 months; 3,271 patients were treated for more than one year. Discontinuation of therapy because of an adverse event during the double-blind period occurred in 450 (10.7%) of ENTRESTO treated patients and 516 (12.2%) of patients receiving enalapril. Adverse reactions occurring at an incidence of ≥ 5% in patients who were treated with ENTRESTO in the double-blind period are shown in Table 1. Table 1: Adverse Reactions Reported in ≥ 5% of Patients Treated with ENTRESTO in the Double-Blind Period ENTRESTO Enalapril (n = 4,203) (n = 4,229) %% Hypotension Hyperkalemia Cough Dizziness Renal failure/acute renal failure 18 12 9 6 5 12 14 13 5 5 In the PARADIGM-HF trial, the incidence of angioedema was 0.1% in both the enalapril and ENTRESTO run-in periods. In the double-blind period, the incidence of angioedema was higher in patients treated with ENTRESTO than enalapril (0.5% and 0.2%, respectively). The incidence of angioedema in Black patients was 2.4% with ENTRESTO and 0.5% with enalapril [see Warnings and Precautions (5.2)]. Orthostasis was reported in 2.1% of patients treated with ENTRESTO compared to 1.1% of patients treated with enalapril during the double-blind period of PARADIGM-HF. Falls were reported in 1.9% of patients treated with ENTRESTO compared to 1.3% of patients treated with enalapril. Laboratory Abnormalities Hemoglobin and Hematocrit Decreases in hemoglobin/hematocrit of >20% were observed in approximately 5% of both ENTRESTO-and enalapril-treated patients in the double-blind period in PARADIGM-HF. Serum Creatinine Increases in serum creatinine of >50% were observed in 1.4% of patients in the enalapril run-in period and 2.2% of patients in the ENTRESTO run-in period. During the double-blind period, approximately 16% of both ENTRESTO-and enalapril-treated patients had increases in serum creatinine of >50%. Serum Potassium Potassium concentrations >5.5 mEq/L were observed in approximately 4% of patients in both the enalapril and ENTRESTO run-in periods. During the double-blind period, approximately 16% of both ENTRESTO-and enalapril-treated patients had potassium concentrations >5.5 mEq/L. 7 DRUG INTERACTIONS 7.1 Dual Blockade of the Renin-Angiotensin-Aldosterone System Concomitant use of ENTRESTO with an ACE inhibitor is contraindicated because of the increased risk of angioedema [see Contraindications (4)]. Avoid use of ENTRESTO with an ARB, because ENTRESTO contains the angiotensin II receptor blocker valsartan. The concomitant use of ENTRESTO with aliskiren is contraindicated in patients with diabetes [see Contra -indications (4)]. Avoid use with aliskiren in patients with renal impairment (eGFR <60 mL/min/1.73 m²). 7.2 Potassium-Sparing Diuretics As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuret-ics (e.g., spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium [see Warnings and Precautions (5.5)]. 7.3 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, concomitant use of NSAIDs, including COX-2 inhibitors, with ENTRESTO may result in worsening of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically. 7.4 Lithium Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists. Monitor serum lithium levels during concomitant use with ENTRESTO. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary ENTRESTO can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal func-tion and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. In animal reproduction stud-ies, ENTRESTO treatment during organogenesis resulted in increased embryo-fetal lethality in rats and rabbits and teratogenicity in rabbits. When pregnancy is detected, consider alternative drug treatment and discontinue ENTRESTO. However, if there is no appropriate alternative to therapy with drugs affect-ing the renin-angiotensin system, and if the drug is considered lifesaving for the mother, advise a preg-nant woman of the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and mis-carriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the sec-ond and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypoten-sion, and death. Perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, consider alternative drug treatment. Closely observe neonates with histories of in utero exposure to ENTRESTO for hypotension, oliguria, and hyperkalemia. In neonates with a history of in utero exposure to ENTRESTO, if oliguria or hypotension occurs, support blood pressure and renal per-fusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and replac-ing renal function.