Vericiguat

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 )

VERQUVO 2.5 mg (vericiguat 2.5 mg) are round, biconvex, white film-coated tablets debossed with “2.5” on one side and “VC” on the other side. VERQUVO 5 mg (vericiguat 5 mg) are round, biconvex, brown-red film-coated tablets debossed with “5” on one side and “VC” on the other side. VERQUVO 10 mg (vericiguat 10 mg) are round, biconvex, yellow-orange film-coated tablets debossed with “10” on one side and “VC” on the other side. Tablets: 2.5 mg, 5 mg and 10 mg ( 3 )

VERQUVO is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators [see Drug Interactions (7.1) ] . VERQUVO is contraindicated in pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators. ( 4 , 7.1 ) Pregnancy ( 4 )

5.1 Embryo-Fetal Toxicity Based on data from animal reproduction studies, VERQUVO may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to a fetus. Obtain a pregnancy test before the start of treatment. Advise females of reproductive potential to use effective contraception during treatment with VERQUVO and for at least one month after the final dose [see Dosage and Administration (2.2) and Use in Specific Populations (8.1 , 8.3) ].

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.

PDE-5 Inhibitors: Concomitant use is not recommended. ( 7.2 )

7.1 Other Soluble Guanylate Cyclase Stimulators VERQUVO is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators [see Contraindications (4) ] . 7.2 PDE-5 Inhibitors Concomitant use of VERQUVO with PDE-5 inhibitors is not recommended because of the potential for hypotension [see Clinical Pharmacology (12.2) ] .

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) ] .

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.