Vericiguat

1 INDICATIONS AND USAGE VERQUVO ® is indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic HF and ejection fraction less than 45% [see Clinical Studies (14) ] . VERQUVO is a soluble guanylate cyclase (sGC) stimulator, indicated to reduce the risk of cardiovascular death and heart failure (HF) hospitalization following a hospitalization for heart failure or need for outpatient IV diuretics, in adults with symptomatic chronic HF and ejection fraction less than 45%. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended starting dose of VERQUVO is 5 mg orally once daily with food. ( 2.1 ) For patients at risk of symptomatic hypotension, the recommended starting dose is 2.5 mg orally once daily with food. ( 2.1 ) Double the dose after approximately every 2 weeks to reach the target maintenance dose of 10 mg once daily, as tolerated by the patient. ( 2.1 ) Tablets may be crushed and mixed with water for patients unable to swallow whole tablets. ( 2.1 ) 2.1 Recommended Dosage The recommended starting dose of VERQUVO is 5 mg orally once daily with food. For patients at risk of symptomatic hypotension, the recommended starting dose is 2.5 mg orally once daily with food [see Clinical Trials Experience (6.1) ]. Double the dose approximately every 2 weeks to reach the target maintenance dose of 10 mg once daily, as tolerated by the patient. For patients who are unable to swallow whole tablets, VERQUVO may be crushed and mixed with water immediately before administration [see Clinical Pharmacology (12.3) ] . 2.2 Pregnancy Testing in Females of Reproductive Potential Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with VERQUVO [see Warnings and Precautions (5.1) and Use in Specific Populations (8.3) ].

6 ADVERSE REACTIONS Most common adverse reactions reported in ≥5% are hypotension and anemia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Merck Sharp & Dohme LLC at 1-877-888-4231 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. VERQUVO was evaluated in VICTORIA, which included 2,519 patients treated with VERQUVO (up to 10 mg once daily). The mean duration of VERQUVO exposure was 1 year, and the maximum duration was 2.6 years [see Clinical Studies (14) ] . Table 1 lists adverse drug reactions occurring more commonly with VERQUVO than placebo and in ≥5% of patients treated with VERQUVO in VICTORIA. Table 1: Adverse Drug Reactions Occurring with VERQUVO in VICTORIA Adverse Drug Reaction VERQUVO % N = 2,519 Placebo % N = 2,515 Hypotension 16 15 Anemia 10 7 VELOCITY The safety and tolerability of VERQUVO 5 mg once daily as a starting dose was evaluated in VELOCITY, a single-arm, open-label, 2-week study in 106 patients with symptomatic chronic heart failure (NYHA class II–IV) and left ventricular ejection fraction < 45%. Patients were excluded from the study if they experienced symptomatic hypotension within 4 weeks before screening. Treatment initiation with VERQUVO 5 mg once daily in VELOCITY was similarly tolerated as treatment initiation of 2.5 mg once daily in the VICTORIA study.

12.3 Pharmacokinetics Vericiguat steady-state mean (coefficient of variation %) C max is 350 mcg/L (29%) and AUC is 6,680 mcg•h/L (33.9%) following administration of VERQUVO 10 mg in patients with heart failure. Vericiguat pharmacokinetics increases in a slightly less than dose-proportional manner. Vericiguat accumulates in plasma up to 155-171% and reaches steady-state after approximately 6 days. Absorption The absolute bioavailability of vericiguat is 93% when taken with food. Results were comparable when VERQUVO was administered orally as a whole tablet or as a crushed tablet in water. Effect of Food Administration of VERQUVO 10 mg with a high-fat, high-calorie meal increases T max from about 1 hour (fasted) to about 4 hours (fed), reduces PK variability, and increases vericiguat AUC by 44% and C max by 41% compared with administration in the fasted state. Similar results were obtained when VERQUVO was administered with a low-fat, low-calorie meal when compared to administration with a high-fat, high-calorie meal. Distribution The mean steady-state volume of distribution of vericiguat is approximately 44 L in healthy subjects. Protein binding (primarily to serum albumin) of vericiguat is about 98%. Elimination The half-life of vericiguat is 30 hours in patients with heart failure. Clearance in healthy subjects is 1.6 L/h. Metabolism Vericiguat primarily undergoes glucuronidation by UGT1A9 and to a lesser extent, by UGT1A1 to form an inactive N-glucuronide metabolite. CYP-mediated metabolism is a minor clearance pathway (<5%). Excretion Following oral administration of radiolabeled vericiguat to healthy subjects, approximately 53% of the dose was excreted in urine (primarily as inactive metabolite) and 45% in feces (primarily as unchanged drug). Specific Populations Renal Impairment In patients with heart failure with mild, moderate, and severe renal impairment not requiring dialysis, the mean exposure (AUC) of vericiguat was increased by 5%, 13%, and 20% respectively, compared to patients with normal renal function. These differences in exposure are not considered clinically relevant. The pharmacokinetics of vericiguat have not been studied in patients with eGFR <15 mL/min/1.73m 2 at treatment initiation or on dialysis [see Use in Specific Populations (8.6) ] . In a dedicated clinical pharmacology study, otherwise healthy participants with mild, moderate, and severe renal impairment, had 8%, 73%, and 143% respectively, higher mean vericiguat exposure (unbound AUC normalized for body weight) after a single dose compared to healthy controls. The apparent discrepancy of the effect of renal impairment on vericiguat exposure between the dedicated clinical pharmacology study and the analysis in patients with heart failure may be attributed to differences in study design and size. Hepatic Impairment No clinically relevant increases in exposure (unbound AUC normalized for body weight) were observed for individuals with mild and moderate hepatic impairment (Child Pugh A-B). Mean vericiguat exposures were 21% and 47% higher, respectively, compared to individuals with normal hepatic function. The pharmacokinetics of vericiguat have not been studied in patients with severe hepatic impairment (e.g., Child-Pugh C) [see Use in Specific Populations (8.7) ] . No clinically significant differences in the pharmacokinetics of vericiguat were observed based on age, sex, race/ethnicity (Black, White, Asian, Hispanic, Latino), body weight, or baseline NT-proBNP. Effects of specific populations on the pharmacokinetics of vericiguat are shown in Figure 1 . Figure 1: Pharmacokinetics of Vericiguat in Specific Populations Drug Interaction Studies Clinical Studies Effects of Other Drugs on the Pharmacokinetics of Vericiguat Vericiguat is less soluble at neutral than at acidic pH. Pre- and co-treatment with drugs that increase gastric pH, such as proton pump inhibitors or antacids, decrease vericiguat exposure (AUC) by about 30% following fasted administration. However, co-treatment with drugs that increase gastric pH did not affect vericiguat exposure in patients with heart failure when vericiguat was taken as directed with food. No clinically significant differences on vericiguat pharmacokinetics were observed with co-administration of mefenamic acid (UGT1A9 inhibitor), ketoconazole (multi-pathway CYP and transporter inhibitor), rifampin (inducer), digoxin (P-gp substrate), warfarin, aspirin, sildenafil, or the combination of sacubitril/valsartan in healthy subjects. No clinically significant differences on vericiguat pharmacokinetics were predicted with co-administration of atazanavir (UGT1A1 inhibitor). Effects of Vericiguat on the Pharmacokinetics of Other Drugs No clinically significant differences on the pharmacokinetics of midazolam (CYP3A substrate), digoxin (P-gp substrate), warfarin, sildenafil, or the combination of sacubitril (including metabolite LBQ657)/valsartan were observed when coadministered with VERQUVO in healthy subjects. In Vitro Studies Cytochrome P450 (CYP) enzymes: vericiguat is not an inhibitor of CYP1A2, 2B6, 2C8, 2C9, 2C19, or 2D6, 3A4 and is not an inducer of CYP1A2, 2B6, or 3A4. Uridine diphosphate (UDP)-glucuronosyl transferase (UGT) enzymes: vericiguat is not an inhibitor of UGT1A1, 1A4, 1A6, 1A9, 2B4, or 2B7. Transporter systems: vericiguat is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) but is not a substrate of organic cation transporter (OCT1) or organic anion transporting polypeptides (OATP1B1 and OATP1B3). Vericiguat is not an inhibitor of P-gp, BCRP, BSEP, OATP1B1/1B3, OAT1, OAT3, OCT1, OCT2, MATE1, or MATE2K. Figure 1