Sacubitril and Valsartan 97 mg; 103 mg Tablet, Film Coated, 60-count — NDC 72205-282-60 (Billing 72205-0282-60)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Sacubitril and valsartan contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. Sacubitril and valsartan inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT 1 ) receptor via valsartan. The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan.

Valsartan inhibits the effects of angiotensin II by selectively blocking the AT 1 receptor, and also inhibits angiotensin II-dependent aldosterone release.

12.2Pharmacodynamics The pharmacodynamic effects of sacubitril and valsartan 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. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril and valsartan resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan.

In a 21-day study in HFrEF patients, sacubitril and valsartan significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. Sacubitril and valsartan also blocked the AT 1 -receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, sacubitril and valsartan decreased plasma NT- proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril.

In PANORAMA-HF, a reduction in NT-proBNP was observed at Weeks 4 and 12 for sacubitril and valsartan (40% and 50%) compared to baseline. The NT-proBNP levels continued to decrease over the duration of the study with a reduction of 65% for sacubitril and valsartan at Week 52 compared to baseline. QT Prolongation: In a thorough QTc clinical study in healthy male subjects, single doses of sacubitril and valsartan 194 mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarization.

Amyloid-β: Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF). Administration of sacubitril and valsartan 194 mg sacubitril/206 mg valsartan once-daily for 2 weeks to healthy subjects was associated with an increase in CSF Aβ 1-38 compared to placebo; there were no changes in concentrations of CSF Aβ 1-40 or CSF Aβ 1-42 . The clinical relevance of this finding is unknown [see Nonclinical Toxicology (13) ].

Blood Pressure: Addition of a 50 mg single dose of sildenafil to sacubitril and valsartan at steady state (194 mg sacubitril/206 mg valsartan once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP) reduction (approximately 5/4 mmHg, systolic/diastolic BP) compared to administration of sacubitril and valsartan alone. Co-administration of sacubitril and valsartan did not significantly alter the BP effect of intravenous nitroglycerin.

12.3Pharmacokinetics Absorption Following oral administration, sacubitril and valsartan 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.

The oral absolute bioavailability of sacubitril is estimated to be greater than or equal to 60%. The valsartan in sacubitril and valsartan is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril and val… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Sacubitril and valsartan contains a neprilysin inhibitor, sacubitril, and an angiotensin receptor blocker, valsartan. Sacubitril and valsartan inhibits neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT 1 ) receptor via valsartan. The cardiovascular and renal effects of sacubitril and valsartan in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan.

Valsartan inhibits the effects of angiotensin II by selectively blocking the AT 1 receptor, and also inhibits angiotensin II-dependent aldosterone release.

12.3Pharmacokinetics Absorption Following oral administration, sacubitril and valsartan 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.

The oral absolute bioavailability of sacubitril is estimated to be greater than or equal to 60%. The valsartan in sacubitril and valsartan is more bioavailable than the valsartan in other marketed tablet formulations; 26 mg, 51 mg, and 103 mg of valsartan in sacubitril and valsartan is equivalent to 40 mg, 80 mg, and 160 mg of valsartan in other marketed tablet formulations, respectively. Following twice-daily dosing of sacubitril and valsartan, steady-state levels of sacubitril, LBQ657, and valsartan are reached in 3 days.

At steady- state, sacubitril and valsartan do not accumulate significantly, whereas LBQ657 accumulates by 1.6-fold. Sacubitril and valsartan administration with food has no clinically significant effect on the systemic exposures of sacubitril, LBQ657, or valsartan. Although there is a decrease in exposure to valsartan when sacubitril and valsartan is administered with food, this decrease is not accompanied by a clinically significant reduction in the therapeutic effect.

Sacubitril and valsartan can therefore be administered with or without food. 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. Valsartan is minimally metabolized; only about 20% of the dose is recovered as metabolites.

A hydroxyl metabolite has been identified in plasma at low concentrations (less than 10%). Elimination Following oral administration, 52% to 68% of sacubitril (primarily as LBQ657) and approximately 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. Sacubitril, LBQ657, and valsartan are eliminated from plasma with a mean elimination half-life (T 1/2 ) of approximately 1.4 hours, 11.5 hours, and 9.9 hours, respectively.

Linearity/Nonlinearity The pharmacokinetics of sacubitril, LBQ657, and valsartan were linear over an sacubitril and valsartan dose range of 24 mg sacubitril/26 mg valsartan to 194 mg sacubitril/206 mg valsartan. Drug Interactions: Effect of Co-administered Drugs on Sacubitril and Valsartan: 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 sacubitril and valsartan. 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.

Effect of Sacubitril and Valsartan on Co-administered Drugs: In vitro data indicate that sacubitril inhibits OATP1B1 and OATP1B3 transporters. The effects of sacubitril and valsartan on the pharmacokinetics of coadministered drugs are summarized in Figure 1. Figure 1: Effect of Sacubitril and Valsartan on Pharmacokinetics of Coadministered Drugs Specific Populations Effect of specific populations on the pharmacokinetics of LBQ657 and valsartan are shown in Figure 2.

Figure 2: Pharmacokinetics of Sacubitril and Valsartan in Specific Populations Note: Child-Pugh Classification was used for hepatic impairment. Pediatric Patients: The pharmacokinetics of sacubitril and valsartan were… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics The pharmacodynamic effects of sacubitril and valsartan 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. In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril and valsartan resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan.

In a 21-day study in HFrEF patients, sacubitril and valsartan significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1. Sacubitril and valsartan also blocked the AT 1 -receptor as evidenced by increased plasma renin activity and plasma renin concentrations. In PARADIGM-HF, sacubitril and valsartan decreased plasma NT- proBNP (not a neprilysin substrate) and increased plasma BNP (a neprilysin substrate) and urine cGMP compared with enalapril.

In PANORAMA-HF, a reduction in NT-proBNP was observed at Weeks 4 and 12 for sacubitril and valsartan (40% and 50%) compared to baseline. The NT-proBNP levels continued to decrease over the duration of the study with a reduction of 65% for sacubitril and valsartan at Week 52 compared to baseline. QT Prolongation: In a thorough QTc clinical study in healthy male subjects, single doses of sacubitril and valsartan 194 mg sacubitril/206 mg valsartan and 583 mg sacubitril/617 mg valsartan had no effect on cardiac repolarization.

Amyloid-β: Neprilysin is one of multiple enzymes involved in the clearance of amyloid-β (Aβ) from the brain and cerebrospinal fluid (CSF). Administration of sacubitril and valsartan 194 mg sacubitril/206 mg valsartan once-daily for 2 weeks to healthy subjects was associated with an increase in CSF Aβ 1-38 compared to placebo; there were no changes in concentrations of CSF Aβ 1-40 or CSF Aβ 1-42 . The clinical relevance of this finding is unknown [see Nonclinical Toxicology (13) ].

Blood Pressure: Addition of a 50 mg single dose of sildenafil to sacubitril and valsartan at steady state (194 mg sacubitril/206 mg valsartan once daily for 5 days) in patients with hypertension was associated with additional blood pressure (BP) reduction (approximately 5/4 mmHg, systolic/diastolic BP) compared to administration of sacubitril and valsartan alone. Co-administration of sacubitril and valsartan did not significantly alter the BP effect of intravenous nitroglycerin.

14 CLINICAL STUDIES Dosing in clinical trials was based on the total amount of both components of sacubitril and valsartan, i.e., 24/26 mg, 49/51 mg, and 97/103 mg were referred to as 50 mg, 100 mg, and 200 mg, respectively.

14.1Adult Heart Failure PARADIGM-HF PARADIGM-HF was a multinational, randomized, double-blind trial comparing sacubitril and valsartan and enalapril in 8,442 adult patients with symptomatic chronic heart failure (NYHA class II–IV) and systolic dysfunction (left ventricular ejection fraction ≤ 40%). Patients had to have been on an ACE inhibitor or ARB for at least four weeks and on maximally tolerated doses of beta-blockers. Patients with a systolic blood pressure of less than 100 mmHg at screening were excluded.

The primary objective of PARADIGM-HF was to determine whether sacubitril and valsartan, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to an RAS inhibitor (enalapril) alone in reducing the risk of the combined endpoint of cardiovascular (CV) death or hospitalization for heart failure (HF). After discontinuing their existing ACE inhibitor or ARB therapy, patients entered sequential single-blind run-in periods during which they received enalapril 10 mg twice-daily, followed by sacubitril and valsartan 100 mg twice-daily, increasing to 200 mg twice daily.

Patients who successfully completed the sequential run-in periods were randomized to receive either sacubitril and valsartan 200 mg (N = 4,209) twice-daily or enalapril 10 mg (N = 4,233) twice-daily. The primary endpoint was the first event in the composite of CV death or hospitalization for HF. The median follow-up duration was 27 months and patients were treated for up to 4.3 years.

The population was 66% Caucasian, 18% Asian, and 5% Black; the mean age was 64 years and 78% were male. At randomization, 70% of patients were NYHA Class II, 24% were NYHA Class III, and 0.7% were NYHA Class IV. The mean left ventricular ejection fraction was 29%.

The underlying cause of heart failure was coronary artery disease in 60% of patients; 71% had a history of hypertension, 43% had a history of myocardial infarction, 37% had an eGFR less than 60 mL/min/1.73m 2 , and 35% had diabetes mellitus. Most patients were taking beta-blockers (94%), mineralocorticoid antagonists (58%), and diuretics (82%). Few patients had an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) (15%).

PARADIGM-HF demonstrated that sacubitril and valsartan, a combination of sacubitril and an RAS inhibitor (valsartan), was superior to and RAS inhibitor (enalapril), in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, based on a time-to-event analysis (hazard ratio [HR] 0.80; 95% confidence interval [CI], 0.73, 0.87, p <0.0001). The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization; see Table 4 and Figure 3. Sudden death accounted for 45% of cardiovascular deaths, followed by pump failure, which accounted for 26%.

Sacubitril and valsartan also improved overall survival (HR 0.84; 95% CI [0.76, 0.93], p = 0.0009) (Table 4). This finding was driven entirely by a lower incidence of cardiovascular mortality on sacubitril and valsartan. Table 4: Treatment Effect for the Primary Composite Endpoint, Its Components, and All-cause Mortality in PARADIGM-HF Sacubitril and Valsartan N =4,187 n (%) Enalapril N =4,212 n (%) Hazard Ratio (95% CI) p -value Primary composite endpoint of cardiovascular death or heart failure hospitalization Cardiovascular death as first event Heart failure hospitalization as first event 914 (21.8) 377 (9.0) 537 (12.8) 1,117 (26.5) 459 (10.9) 658 (15.6) 0.80 (0.73, 0.87) <0.0001 Number of patients with events: * Cardiovascular death** Heart failure hospitalizations 558 (13.3) 537 (12.8) 693 (16.5) 658 (15.6) 0.80 (0.71, 0.89) 0.79 (0.71, 0.89) All-cause mortality 711 (17.0) 835 (19.8) 0.84 (0.7… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis and Mutagenesis Carcinogenicity studies conducted in mice and rats with sacubitril and valsartan did not identify any carcinogenic potential for sacubitril and valsartan. The LBQ657 C max at the high dose (HD) of 1200 mg/kg/day in male and female mice was, respectively, 14 and 16 times that in humans at the MRHD. The LBQ657 C max in male and female rats at the HD of 400 mg/kg/day was, respectively, 1.7 and 3.5 times that at the MRHD.

The doses of valsartan studied (high dose of 160 and 200 mg/kg/day in mice and rats, respectively) were about 4 and 10 times, respectively, the MRHD on a mg/m 2 basis. Mutagenicity and clastogenicity studies conducted with sacubitril and valsartan, sacubitril, and valsartan did not reveal any effects at either the gene or chromosome level. Impairment of Fertility Sacubitril and valsartan did not show any effects on fertility in rats up to a dose of 73 mg sacubitril/77 mg valsartan/kg/day (≤1.0­-fold and ≤0.18-fold the MRHD on the basis of the AUCs of valsartan and LBQ657, respectively).

13.2Animal Toxicology and/or Pharmacology The effects of sacubitril and valsartan on amyloid-β concentrations in CSF and brain tissue were assessed in young (2 to 4 years old) cynomolgus monkeys treated with sacubitril and valsartan (24 mg sacubitril/26 mg valsartan/kg/day) for 2 weeks. In this study, sacubitril and valsartan affected CSF Aβ clearance, increasing CSF Aβ 1-40, 1-42, and 1-38 levels in CSF; there was no corresponding increase in Aβ levels in the brain. In addition, in a toxicology study in cynomolgus monkeys treated with sacubitril and valsartan at 146 mg sacubitril/154 mg valsartan/kg/day for 39-weeks, there was no amyloid-β accumulation in the brain.