DRUG INTERACTIONS-

 Dual blockade of the renin-angiotensin system: Do not use with an ACEi, do not use with aliskiren in patients with diabetes, and avoid use with an ARB. (4, 7.1) ? Potassium-sparing diuretics: May lead to increased serum potassium. (7.2) ? NSAIDs: May lead to increased risk of renal impairment. (7.3) ? Lithium: Increased risk of lithium toxicity. (7.4) ------------------

Novel Drug Approvals for 2015

1.Name       -  ENTRESTO

2. Active Ingredient-     Sacubitril/ Valsatran

3. Indication-      To treat heart failure

Date of Approval     July  2015

HIGHLIGHTS OF PRESCRIBING INFORMATION-

These highlights do not include all the information needed to use ENTRESTO safely and effectively. See full prescribing information for ENTRESTO. ENTRESTO™ (sacubitril and valsartan) tablets, for oral use

Initial U.S. Approval: 2015

WARNING: FETAL TOXICITY-

 See full prescribing information for complete boxed warning. ? 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) ---

INDICATIONS AND USAGE-

 ENTRESTO is a combination of sacubitril, a neprilysin inhibitor, and valsartan, an angiotensin II receptor blocker, 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.

.

ADVERSE REACTIONS-

 Adverse reactions occurring =5% are hypotension, hyperkalemia, cough, dizziness, and renal failure

CONTRAINDICATIONS-

 Hypersensitivity to any component. (4) ? History of angioedema related to previous ACE inhibitor or ARB therapy.

 Concomitant use with ACE inhibitors. (4, 7.1) ? Concomitant use with aliskiren in patients with diabetes.

WARNINGS AND PRECAUTIONS--

 Observe for signs and symptoms of angioedema and hypotension. Monitor renal function and potassium in susceptible patients.

DOSAGE AND ADMINISTRATION-

 The recommended starting dose of ENTRESTO is 49/51 mg (sacubitril/valsartan) twice-daily. Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as tolerated by the patient.

 Reduce the starting dose to 24/26 mg (sacubitril/valsartan) twice-daily for: - patients not currently taking an angiotensin-converting enzyme inhibitor (ACEi) 

Double the dose of ENTRESTO every 2 to 4 weeks to the target maintenance dose of 97/103 mg (sacubitril/valsartan) twice-daily, as tolerated by the patient. 

DOSAGE FORMS AND STRENGTHS-

 Film-coated tablets (sacubitril/valsartan): 24/26 mg; 49/51 mg; 97/103 mg

PATIENT COUNSELING INFORMATION

Advise patients to read the FDA-approved patient labeling (Patient Information).

Pregnancy-  ENTRESTO during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their physicians as soon as possible

Angioedema: Advise patients to discontinue use of their previous ACE inhibitor or ARB. Advise patients to allow a 36 hour wash-out period if switching from or to an ACE inhibitor

CLINICAL PHARMACOLOGY

1 Mechanism of Action ENTRESTO contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. ENTRESTO inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT1) receptor via valsartan.

2. Pharmacodynamics -                                                                                                The pharmacodynamic effects of ENTRESTO were evaluated after single and multiple dose administrations in healthy subjects and in patients with heart failure, and are consistent with simultaneous neprilysin inhibition and renin-angiotensin system blockade.

3 Pharmacokinetics-                                                                                           Absorption Following oral administration, ENTRESTO dissociates into sacubitril and valsartan. Sacubitril is further metabolized to LBQ657. The peak plasma concentrations of sacubitril, LBQ657, and valsartan are reached in 0.5 hours, 2 hours, and 1.5 hours, respectively.

Distribution-

Sacubitril, LBQ657 and valsartan are highly bound to plasma proteins (94% to 97%). Based on the comparison of plasma and CSF exposures, LBQ657 crosses the blood brain barrier to a limited extent (0.28%).

The average apparent volumes of distribution of valsartan and sacubitril are 75 and 103 L, respectively

 Metabolism-

Sacubitril is readily converted to LBQ657 by esterases; LBQ657 is not further metabolized to a significant extent.

Elimination-                                                                                                            Following oral administration, 52% to 68% of sacubitril (primarily as LBQ657) and ~13% of valsartan and its metabolites are excreted in urine; 37% to 48% of sacubitril (primarily as LBQ657), and 86% of valsartan and its metabolites are excreted in feces.

Drug Interactions:

Effect of co-administered drugs on ENTRESTO: Because CYP450 enzyme-mediated metabolism of sacubitril and valsartan is minimal, coadministration with drugs that impact CYP450 enzymes is not expected to affect the pharmacokinetics of ENTRESTO.

Dedicated drug interaction studies demonstrated that coadministration of furosemide, warfarin, digoxin, carvedilol, a combination of levonorgestrel/ethinyl estradiol, amlodipine, omeprazole, hydrochlorothiazide (HCTZ), metformin, atorvastatin, and sildenafil, did not alter the systemic exposure to sacubitril, LBQ657 or valsartan.

USE IN SPECIFIC POPULATIONS

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 function and increases fetal and neonatal morbidity and death.

The 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 miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

2 Lactation Risk Summary-                                                                                        There is no information regarding the presence of sacubitril/valsartan in human milk, the effects on the breastfed infant, or the effects on milk production. 

Sacubitril/valsartan is present in rat milk. Because of the potential for serious adverse reactions in breastfed infants from exposure to sacubitril/valsartan, advise a nursing woman that breastfeeding is not recommended during treatment with ENTRESTO.

3. Pediatric Use -                                                                                                                Safety and effectiveness in pediatric patients have not been established

4. Geriatric Use-                                                                                                               No relevant pharmacokinetic differences have been observed in elderly (=65 years) or very elderly (=75 years) patients compared to the overall population 

5.Hepatic impairment-                                                                                                      TRESTO to patients with mild hepatic impairment (Child-Pugh A classification). The recommended starting dose in patients with moderate hepatic impairment (Child-Pugh B classification) is 24/26 mg twice daily.

The use of ENTRESTO in patients with severe hepatic impairment (Child-Pugh C classification) is not recommended, as no studies have been conducted in these patients 

 6. Renal Impairment No dose adjustment is required in patients with mild (eGFR 60 to 90 mL/min/1.73 m2) to moderate (eGFR 30 to 60 mL/min/1.73 m2) renal impairment.

The recommended starting dose in patients with severe renal impairment (eGFR <30 mL/min/1.73 m2) is 24/26 mg twice daily 

10 OVERDOSAGE Limited data are available with regard to overdosage in human subjects with ENTRESTO. In healthy volunteers, a single dose of ENTRESTO 583 mg sacubitril/617 mg valsartan, and multiple doses of 437 mg sacubitril/463 mg valsartan (14 days) have been studied and were well tolerated. Hypotension is the most likely result of overdosage due to the blood pressure lowering effects of ENTRESTO. Symptomatic treatment should be provided. ENTRESTO is unlikely to be removed by hemodialysis because of high protein binding. 11 DESCRIPTION