Vericiguat

Lactation: Breastfeeding is not recommended ( 8.2 )

8.1 Pregnancy Pregnancy Surveillance Program There is a Pregnancy Surveillance Program that monitors pregnancy outcomes in women exposed to VERQUVO during pregnancy. Health care providers should report any prenatal exposure to VERQUVO by calling 1-877-888-4231 or at https://pregnancyreporting.verquvo-us.com. Risk Summary Based on data from animal reproduction studies, VERQUVO may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy [see Contraindications (4) ] . There are no available data with VERQUVO use in pregnant women. In animal reproduction studies, oral administration of vericiguat to pregnant rabbits during organogenesis, at ≥4 times the human exposure (total AUC) with the maximum recommended human dose (MRHD) of 10 mg, resulted in malformations of the heart and major vessels, as well as increased number of abortions and resorptions ( see Animal Data ). In a pre/postnatal toxicity study, vericiguat administered orally to rats during gestation through lactation caused maternal toxicity, which resulted in decreased pup body weight gain (≥10 times the MRHD) and increased pup mortality (24 times the MRHD) during the preweaning period (see Animal Data ) . The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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. Data Animal Data In an embryo-fetal development study in rabbits, vericiguat was administered orally to pregnant rabbits during the period of organogenesis from gestation day (GD) 6 to 20 at doses of 0.75, 2.5 or 7.5 mg/kg/day. An increased incidence of cardiac ventricular septal defect along with truncus arteriosus communis was observed at ≥2.5 mg/kg/day, which is ≥4 times the human exposure at the MRHD. Maternal toxicity (decreased food consumption and body weight loss), which may have resulted in late spontaneous abortions and resorptions was noted at ≥2.5 mg/kg/day (≥4 times the human exposure at the MRHD). There were no maternal toxicity or abortions/resorptions and no malformations of the heart and major vessels in rabbits at an exposure approximately equivalent to the human exposure at the MRHD. In a prenatal developmental toxicity study in rats, vericiguat was administered orally to pregnant rats during the period of organogenesis from GD 6 to 17 at doses of 5, 15 or 50 mg/kg/day. No developmental toxicity was observed up to the highest dose (36 times the human exposure [total AUC] at the MRHD). Maternal toxicity (decreased body weight gain and food consumption) was observed at ≥15 mg/kg/day (≥10 times the human exposure at the MRHD). There was no maternal toxicity at 5 mg/kg/day (4 times the human exposure at the MRHD). In a pre-postnatal development study in rats, vericiguat was administered orally at doses of 7.5, 15 or 30 mg/kg/day from GD 6 through lactation day 21. Maternal toxicity (decreases in food consumption and body weight gain) was observed at all dose levels ≥6 times the human exposure (total AUC) at the MRHD and resulted in decreased pup body weight gain at ≥15 mg/kg/day (≥10 times the human exposure at the MRHD) and pup mortality at 30 mg/kg/day (24 times the MRHD). [ 14 C]-vericiguat was administered orally to pregnant rats at a dose of 3 mg/kg. Vericiguat-related material was transferred across the placenta, with fetal plasma concentrations of approximately 67% maternal concentrations on GD 19.

8.2 Lactation Risk Summary There are no data on the presence of vericiguat in human milk, the effects on the breastfed infant, or the effects on milk production. Vericiguat is present in the milk of lactating rats and it is likely that vericiguat or its metabolites are present in human milk (see Data ). Because of the potential for serious adverse reactions in breastfed infants from VERQUVO, advise women not to breastfeed during treatment with VERQUVO. Data [ 14 C]-vericiguat was administered intravenously to lactating rats at a dose of 1 mg/kg. Vericiguat-related material was excreted into milk at concentrations approximately 12% maternal plasma concentrations on LD 8.

8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status in females of reproductive potential prior to initiating VERQUVO [see Dosage and Administration (2.2) , Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Contraception Females VERQUVO may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment and for one month after the final dose [see Warnings and Precautions (5.1) ].

8.4 Pediatric Use Safety and effectiveness of VERQUVO have not been established in pediatric patients.

8.5 Geriatric Use No dosage adjustment of VERQUVO is required in geriatric patients. In VICTORIA, a total of 1,596 (63%) patients treated with VERQUVO were 65 years and older, and 783 (31%) patients treated with VERQUVO were 75 years and older. No overall differences in safety or efficacy of VERQUVO were observed between patients aged 65 years and older compared to younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] .

8.6 Renal Impairment No dosage adjustment of VERQUVO is recommended in patients with estimated glomerular filtration rate (eGFR) ≥15 mL/min/1.73m 2 who are not on dialysis. VERQUVO has not been studied in patients with eGFR <15 mL/min/1.73m 2 at treatment initiation or on dialysis [see Clinical Pharmacology (12.3) and Clinical Studies (14) ] .

8.7 Hepatic Impairment No dosage adjustment of VERQUVO is recommended in patients with mild or moderate hepatic impairment (e.g., Child-Pugh A or B). VERQUVO has not been studied in patients with severe hepatic impairment (e.g., Child-Pugh C) [see Clinical Pharmacology (12.3) ] .

12.1 Mechanism of Action Vericiguat is a stimulator of soluble guanylate cyclase (sGC), an important enzyme in the nitric oxide (NO) signaling pathway. When NO binds to sGC, the enzyme catalyzes the synthesis of intracellular cyclic guanosine monophosphate (cGMP), a second messenger that plays a role in the regulation of vascular tone, cardiac contractility, and cardiac remodeling. Heart failure is associated with impaired synthesis of NO and decreased activity of sGC, which may contribute to myocardial and vascular dysfunction. By directly stimulating sGC, independently of and synergistically with NO, vericiguat augments levels of intracellular cGMP, leading to smooth muscle relaxation and vasodilation.

12.2 Pharmacodynamics The mean reduction in systolic blood pressure was approximately 1 to 2 mm Hg greater in patients who received VERQUVO compared with placebo. VERQUVO demonstrated a dose-dependent reduction in NT-proBNP, a biomarker in heart failure, at 12 weeks compared to placebo when added to standard of care. The estimated reduction from baseline NT-proBNP at week 32 was greater in patients who received VERQUVO compared with placebo [see Clinical Studies (14) ] . Cardiac Electrophysiology There was no evidence of proarrhythmic risk in an in vitro assessment of vericiguat or its major N-glucuronide metabolite. No inhibition of cardiac ion channels (hERG, hNav1.5, or hKvLQT1/mink) was observed at substantial multiples of their unbound C max values at the recommended target dose of 10 mg. The integrated risk assessment of nonclinical and clinical data supports that administration of vericiguat 10 mg is not associated with clinically meaningful QTc prolongation. Drug Interaction Studies No clinically significant differences on bleeding time or platelet aggregation were observed when a single dose of vericiguat 15 mg was used concomitantly with 500 mg of aspirin. No clinically significant differences in prothrombin time or the activities of Factors II, VII, and X were observed when multiple doses of VERQUVO 10 mg once daily were used concomitantly with a single dose of warfarin 25 mg. No clinically significant differences on seated blood pressure (BP) were observed when multiple doses of VERQUVO 2.5 mg were used concomitantly with sacubitril/valsartan in healthy subjects. No clinically significant differences on seated BP were observed when multiple doses of VERQUVO 10 mg were used concomitantly with short- and long-acting nitrates (nitroglycerin spray and isosorbide mononitrate [ISMN] modified release 60 mg) in patients with coronary artery disease. In patients with heart failure, concomitant use with short-acting nitrates was well tolerated, but there is limited experience with long-acting nitrates. Concomitant use of VERQUVO 10 mg with single doses of sildenafil (25, 50, or 100 mg) was associated with additional seated BP reduction of up to 5.4 mm Hg (systolic/diastolic BP, MAP), compared to administration of VERQUVO alone. There is limited experience with concomitant use of VERQUVO and PDE-5 inhibitors in patients with heart failure.

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

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