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  • CLASSES

    Guanylate Cyclase Stimulants

    BOXED WARNING

    Pregnancy

    Vericiguat is contraindicated for use in pregnancy. There are no available data on the use of vericiguat in human pregnancy; however, based on animal reproductive studies, vericiguat may cause fetal harm when administered to a pregnant woman. When administered to pregnant rabbits during organogenesis from gestation day 6 to 20, an increased incidence of cardiac malformations (cardiac ventricular septal defect), major vessel malformations (truncus arteriosus communis), late spontaneous abortions and resorptions occurred with vericiguat doses of 4 times or more than the human exposure at the maximum recommended human dose (MRHD). In reproduction study of rats administered vericiguat from gestational day 6 through lactation day 21, maternal toxicity (e.g., decreased food consumption and body weight) resulted in decreased pup weight at doses 10 times or more than the MRHD and pup mortality at 24 times the MRHD. Following oral administration to pregnant rats, vericiguat was found to transfer across the placenta resulting in a fetal plasma concentration of approximately 67% of the maternal concentration. Females of reproductive potential should be informed of the potential risk to a fetus. If a pregnancy occurs during vericiguat therapy, health care providers should report the exposure to 1-877-888-4231.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral soluble guanylate cyclase (sGC) stimulator
    For adults with symptomatic, chronic heart failure and an ejection fraction less than 45% following heart failure hospitalization or need for outpatient intravenous diuretics
    Contraindicated for use during pregnancy; females must be use effective contraception during and for one month after treatment

    COMMON BRAND NAMES

    VERQUVO

    HOW SUPPLIED

    VERQUVO Oral Tab: 2.5mg, 5mg, 10mg

    DOSAGE & INDICATIONS

    For the reduction of cardiovascular mortality and reduction of heart failure hospitalizations in adults with chronic, symptomatic heart failure and ejection fraction less than 45% following a hospitalization for heart failure or outpatient treatment with intravenous diuretics.
    Oral dosage
    Adults

    2.5 mg PO once daily with food. Double the dose approximately every 2 weeks as tolerated to the target maintenance dose of 10 mg PO once daily. In the VICTORIA study, vericiguat was superior to placebo in reducing the incidence of the primary composite endpoint of first hospitalization for heart failure or death from cardiovascular causes (HR 0.9 [95% CI 0.82, 0.98], p = 0.02); total hospitalizations for heart failure (HR 0.91[95% CI 0.84, 0.99], p = 0.02); and secondary composite outcome of death from any cause or first hospitalization for heart failure (HR 0.9 [0.83, 0.98], p = 0.02).

    MAXIMUM DOSAGE

    Adults

    10 mg/day PO.

    Geriatric

    10 mg/day PO.

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Mild or moderate hepatic impairment (Child-Pugh A or B): No dosage adjustment is necessary.
    Severe hepatic impairment (Child-Pugh C): Vericiguat has not been studied.

    Renal Impairment

    eGFR 15 mL/minute/1.73 m2 or more and not on dialysis: No dosage adjustment necessary.
    eGFR less than 15 mL/minute/1.73 m2 at treatment initiation or on dialysis: Vericiguat has not been studied in this patient population.

    ADMINISTRATION

    Oral Administration

    Vericiguat should be taken with food.
    For patients unable to swallow whole tablets, vericiguat may be crushed and mixed with water immediately prior to administration.
    If a dose is missed, it should be taken as soon as remembered on the same day of the missed dose. Patients should not take 2 doses on the same day.

    STORAGE

    VERQUVO:
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    Pregnancy

    Vericiguat is contraindicated for use in pregnancy. There are no available data on the use of vericiguat in human pregnancy; however, based on animal reproductive studies, vericiguat may cause fetal harm when administered to a pregnant woman. When administered to pregnant rabbits during organogenesis from gestation day 6 to 20, an increased incidence of cardiac malformations (cardiac ventricular septal defect), major vessel malformations (truncus arteriosus communis), late spontaneous abortions and resorptions occurred with vericiguat doses of 4 times or more than the human exposure at the maximum recommended human dose (MRHD). In reproduction study of rats administered vericiguat from gestational day 6 through lactation day 21, maternal toxicity (e.g., decreased food consumption and body weight) resulted in decreased pup weight at doses 10 times or more than the MRHD and pup mortality at 24 times the MRHD. Following oral administration to pregnant rats, vericiguat was found to transfer across the placenta resulting in a fetal plasma concentration of approximately 67% of the maternal concentration. Females of reproductive potential should be informed of the potential risk to a fetus. If a pregnancy occurs during vericiguat therapy, health care providers should report the exposure to 1-877-888-4231.

    Breast-feeding

    There are no data on the presence of vericiguat in human milk, effects on the breastfed infant, or the effects on milk production. Vericiguat was present in the milk of rats following intravenous administration. Due to the potential for serious adverse reactions related to vericiguat in the breastfed infant, discontinue breast-feeding or discontinue vericiguat therapy.

    Contraception requirements, pregnancy testing, reproductive risk

    Discuss the reproductive risk, contraception requirements, and the need for pregnancy testing prior to initiation of therapy with vericiguat in female patients of childbearing potential. Before using vericiguat in females of childbearing potential, exclude pregnancy. To prevent pregnancy, females of childbearing potential must use effective forms of contraception during treatment and for 1 month after discontinuation. Advise females of childbearing potential to contact their health care provider immediately if they become pregnant or suspect they may be pregnant.

    ADVERSE REACTIONS

    Moderate

    hypotension / Rapid / 16.0-16.0
    anemia / Delayed / 10.0-10.0

    Mild

    syncope / Early / 4.0-4.0

    DRUG INTERACTIONS

    Avanafil: (Major) Coadministration of vericiguat and phosphodiesterase type 5 (PDE5) inhibitors is not recommended due to the risk of hypotension. Limited data are available on the concurrent use of vericiguat and PDE5 inhibitors in patients with heart failure.
    Phosphodiesterase inhibitors: (Major) Coadministration of vericiguat and phosphodiesterase type 5 (PDE5) inhibitors is not recommended due to the risk of hypotension. Limited data are available on the concurrent use of vericiguat and PDE5 inhibitors in patients with heart failure.
    Riociguat: (Contraindicated) Coadministration of vericiguat with other soluble guanylate cyclase (sGC) stimulators, such as riociguat, is contraindicated.
    Sildenafil: (Major) Coadministration of vericiguat and phosphodiesterase type 5 (PDE5) inhibitors is not recommended due to the risk of hypotension. Limited data are available on the concurrent use of vericiguat and PDE5 inhibitors in patients with heart failure.
    Tadalafil: (Major) Coadministration of vericiguat and phosphodiesterase type 5 (PDE5) inhibitors is not recommended due to the risk of hypotension. Limited data are available on the concurrent use of vericiguat and PDE5 inhibitors in patients with heart failure.
    Vardenafil: (Major) Coadministration of vericiguat and phosphodiesterase type 5 (PDE5) inhibitors is not recommended due to the risk of hypotension. Limited data are available on the concurrent use of vericiguat and PDE5 inhibitors in patients with heart failure.

    PREGNANCY AND LACTATION

    Pregnancy

    Vericiguat is contraindicated for use in pregnancy. There are no available data on the use of vericiguat in human pregnancy; however, based on animal reproductive studies, vericiguat may cause fetal harm when administered to a pregnant woman. When administered to pregnant rabbits during organogenesis from gestation day 6 to 20, an increased incidence of cardiac malformations (cardiac ventricular septal defect), major vessel malformations (truncus arteriosus communis), late spontaneous abortions and resorptions occurred with vericiguat doses of 4 times or more than the human exposure at the maximum recommended human dose (MRHD). In reproduction study of rats administered vericiguat from gestational day 6 through lactation day 21, maternal toxicity (e.g., decreased food consumption and body weight) resulted in decreased pup weight at doses 10 times or more than the MRHD and pup mortality at 24 times the MRHD. Following oral administration to pregnant rats, vericiguat was found to transfer across the placenta resulting in a fetal plasma concentration of approximately 67% of the maternal concentration. Females of reproductive potential should be informed of the potential risk to a fetus. If a pregnancy occurs during vericiguat therapy, health care providers should report the exposure to 1-877-888-4231.

    Discuss the reproductive risk, contraception requirements, and the need for pregnancy testing prior to initiation of therapy with vericiguat in female patients of childbearing potential. Before using vericiguat in females of childbearing potential, exclude pregnancy. To prevent pregnancy, females of childbearing potential must use effective forms of contraception during treatment and for 1 month after discontinuation. Advise females of childbearing potential to contact their health care provider immediately if they become pregnant or suspect they may be pregnant.

    MECHANISM OF ACTION

    Vericiguat is a soluble guanylate cyclase stimulator. Soluble guanylate cyclase (sGC) is an enzyme in the cardiopulmonary system and an intracellular receptor for nitric oxide (NO). NO, produced in endothelial cells in response to physiologic stimuli, diffuses to vascular or cardiac muscle cells where it stimulates sGC to catalyze the synthesis of cyclic guanosine monophosphate (cGMP). Production of cGMP plays an important role in the regulation of vascular tone, cardiac contractility, and cardiac remodeling. In heart failure, oxidative stress and inflammation lead to endothelial dysfunction, which reduces NO bioavailability. Reductions in NO bioavailability lead to decreased sGC activity and a subsequent reduction in cGMP synthesis. Both impaired NO synthesis and decreased sGC activity are seen in heart failure, which may contribute to myocardial and vascular dysfunction. Reductions in cGMP may contribute to the progression of heart failure with reduced ejection fraction through negative effects on the heart, kidneys, and vessels. Thus, through direct sGC stimulation, in a manner that is independent of and synergistic with NO, vericiguat increases intracellular cGMP levels, leading to smooth muscle relaxation and vasodilation.

    PHARMACOKINETICS

    Vericiguat is administered orally. Vericiguat demonstrated a dose-dependent reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP), a biomarker in heart failure, when added to standard of care in the VICTORIA study. Vericiguat is highly bound to plasma proteins, primarily albumin, (98%) and has a mean steady-state volume of distribution (Vd) of approximately 44 L in healthy subjects. Vericiguat primarily undergoes glucuronidation via UGT1A9 and, to a lesser extent, UGT1A1 to an inactive N-glucoronide metabolite. Metabolism via the cytochrome P450 (CYP) system is a minor pathway accounting for less than 5% of vericiguat metabolism. In healthy subjects, 53% of the vericiguat dose was excreted in urine, primarily as the inactive metabolite, and 45% in the feces as unchanged drug. The half-life of vericiguat in patients with heart failure is 30 hours and the rate of clearance in healthy subjects is 1.6 L/hour.
     
    Affected cytochrome P450 isoenzymes and drug transporters: UGT1A9, UGT1A1, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)
    Vericiguat undergoes glucuronidation via UGT1A9 (primary) and UGT1A1; CYP isoenzymes account for less than 5% of vericiguat metabolism. In vitro studies have determined that vericiguat is a substrate of both BCRP and P-gp. A drug-drug interaction study found a 13% increase in vericiguat exposure when coadministered with ketoconazole (UGT and CYP3A4 inhibitor); a 29% decrease in AUC and 9% decrease in Cmax for vericiguat when coadministered with rifampin (UGT, CYP1A2, CYP2C9, CYP2C19, and CYP3A4 inducer); and a 20% increase in vericiguat AUC during concurrent use with mefenamic acid (UGT1A9 inhibitor); these changes in vericiguat exposure were deemed clinically insignificant. No clinically significant drug-drug interactions were observed with coadministration of vericiguat with atazanavir (UGT1A1 inhibitor), digoxin (P-gp substrate), midazolam (CYP3A4 substrate), or warfarin (CYP1A2, CYP2C19, CYP2D6,a d CYP3A4 substrate).

    Oral Route

    Following administration to heart failure patients at a dose of 10 mg PO once daily, the steady-state mean Cmax is 350 mcg/L and AUC is 6,680 mcg x hour/L. Plasma accumulation of vericiguat is up to 155 to 171% and time to reach steady-state is approximately 6 days. Increases in the pharmacokinetics of vericiguat occur in a slightly lower than dose-proportional manner. Following oral administration with food, the absolute bioavailability of vericiguat is 93%. Vericiguat oral bioavailability is comparable following administration of the whole tablet or crushed tablet dispersed in water. Vericiguat administration with a high-fat, high-calorie meal reduces pharmacokinetic variability, increases Tmax to 4 hours (versus 1 hour in the fasted state), and increases AUC and Cmax by 44% and 41%, respectively, compared to the fasted state. Pharmacokinetic results were similar when vericiguat was administered with low-fat, low-calorie meal compared to a high-fat, high-calorie meal. It is theorized that the increase in vericiguat exposure following administration with food is related to stimulation of bile salt secretion resulting in enhanced vericiguat solubilization.