Dosage & Administration
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Verquvo Prescribing Information
Obtain a pregnancy test in females of reproductive potential prior to initiating treatment with VERQUVO
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
Verify the pregnancy status in females of reproductive potential prior to initiating VERQUVO
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
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%
VICTORIA was a randomized, parallel-group, placebo-controlled, double-blind, event-driven, multi-center trial comparing VERQUVO and placebo in 5,050 adult patients with symptomatic chronic heart failure (New York Heart Association [NYHA] class II-IV) and left ventricular ejection fraction (LVEF) less than 45% following a worsening heart failure event. A worsening heart failure event was defined as heart failure hospitalization within 6 months before randomization or use of outpatient IV diuretics for heart failure within 3 months before randomization.
Patients were randomized to receive VERQUVO 10 mg or matching placebo. VERQUVO was initiated at 2.5 mg once daily and increased at approximately 2 week intervals to 5 mg once daily and the target dose of 10 mg once daily, as tolerated. Placebo doses were similarly adjusted. After approximately 1 year, 90% of patients in both treatment groups were treated with the 10 mg target dose.
The primary endpoint was a composite of time to first event of CV death or hospitalization for heart failure. The median follow-up for the primary endpoint was 11 months.
The population was 64% Caucasian, 22% Asian, and 5% Black. The mean age was 67 years and 76% were male. At randomization, 59% of patients were NYHA Class II, 40% were NYHA Class III, and 1% were NYHA Class IV. The mean left ventricular ejection fraction (EF) was 29%. Approximately half of all patients had an EF <30%, and 14% had an EF between 40% and 45%. The most frequently reported medical history conditions other than heart failure included hypertension (79%), coronary artery disease (58%), hyperlipidemia (57%), diabetes mellitus (47%), atrial fibrillation (45%) and myocardial infarction (42%). At randomization, the mean eGFR was 62 mL/min/1.73 m2; the majority of patients (88%) had an eGFR >30 mL/min/1.73 m2. Sixty-seven percent of the patients were enrolled within 3 months of a HF-hospitalization index event; 17% were enrolled within 3 to 6 months of HF hospitalization, and 16% were enrolled within 3 months of outpatient treatment with IV diuretics for worsening HF. The median NT-proBNP level was 2800 pg/mL at randomization.
At baseline, 93% of patients were on a beta blocker, 73% of patients were on an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), 70% of patients were on a mineralocorticoid receptor antagonist (MRA), 15% of patients were on a combination of an angiotensin receptor and neprilysin inhibitor (ARNI), 28% of patients had an implantable cardiac defibrillator, and 15% had a biventricular pacemaker. Ninety-one percent of patients were treated with 2 or more heart failure medications (beta blocker, any renin-angiotensin system [RAS] inhibitor or MRA) and 60% of patients were treated with all 3. At baseline, 6% of patients were on ivabradine and 3% of patients were on a sodium glucose co-transporter 2 (SGLT2) inhibitor.
In VICTORIA, VERQUVO was superior to placebo in reducing the risk of CV death or heart failure hospitalization based on a time-to-event analysis (hazard ratio [HR]: 0.90, 95% confidence interval [CI], 0.82-0.98; p=0.019). Over the course of the study, there was a 4.2% annualized absolute risk reduction (ARR) with VERQUVO compared with placebo. The treatment effect reflected a reduction in both cardiovascular death and heart failure hospitalization (see Table 2).
| VERQUVO N=2,526 | Placebo N=2,524 | Treatment Comparison | |||||
|---|---|---|---|---|---|---|---|
| n (%) | Event rate: % of patients per yearTotal patients with an event per 100 patient years at risk. | n (%) | Event rate: % of patients per year | Hazard Ratio (95% CI)Hazard ratio (VERQUVO over Placebo) and confidence interval from a Cox proportional hazards model. | p-valueFrom the log-rank test. | ARRAbsolute risk reduction, calculated as difference (Placebo-VERQUVO) in event rate per 100 patient years. | |
| N=Number of patients in Intent-to-Treat (ITT) population; n=Number of patients with an event. | |||||||
| Primary endpoint | |||||||
Composite of cardiovascular death or heart failure hospitalizationFor patients with multiple events, only the first event contributing to the composite endpoint is counted. | 897 (35.5) | 33.6 | 972 (38.5) | 37.8 | 0.90 (0.82, 0.98) | 0.019 | 4.2 |
| Secondary endpoints | |||||||
| Cardiovascular death | 414 (16.4) | 12.9 | 441 (17.5) | 13.9 | 0.93 (0.81,1.06) | ||
Heart failure hospitalization | 691 (27.4) | 25.9 | 747 (29.6) | 29.1 | 0.90 (0.81,1.00) | ||
The Kaplan-Meier curve shows time to first occurrence of the primary composite endpoint of CV death or heart failure hospitalization.
Figure 2: Kaplan-Meier Curve for the Primary Composite Endpoint |
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A wide range of demographic characteristics, baseline disease characteristics, and baseline concomitant medications were examined for their influence on outcomes. The results of the prespecified subgroup analysis for the primary composite endpoint are shown in Figure 3.
Figure 3: Primary Composite Endpoint (CV Death or HF Hospitalization) – Subgroup Analysis |
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As shown above in Figure 3, the results of the primary composite endpoint were generally consistent across subgroups. However, among patients in the highest baseline NT-proBNP quartile, the estimated HRs for both CV death (HR: 1.16; 95% CI: [0.95, 1.43]) and first HF hospitalization (HR:1.19; 95%CI: [0.9,1.44]) were unfavorable, in contrast to the estimated HRs for patients in the three quartiles with lower NT-proBNP levels.
Secondary endpoints other than the components of the primary endpoint were tested according to a hierarchical testing procedure to control the family wise type I error rate. VERQUVO was superior to placebo in reducing the risk of total (first and recurrent) events of HF hospitalization and the first occurrence of either all-cause mortality or HF hospitalization (see Table 3).
| VERQUVO N=2,526 | Placebo N=2,524 | Hazard Ratio (95% CI) | |||
|---|---|---|---|---|---|
| n (%) | Rate | n (%) | Rate | ||
| N=Number of patients in ITT population; n=Total number of events of heart failure hospitalization, or number of patients with ≥1 event for all other rows. | |||||
Total events of heart failure hospitalization | 1,223 | 38.3Event rate (total events, including recurrent events in the same patient, per 100 patient years at risk). | 1,336 | 42.4 | 0.91Hazard ratio (VERQUVO over Placebo), based on an Andersen-Gill model. (0.84, 0.99) |
Composite of all- cause mortality or heart failure hospitalizationFor patients with multiple events, only the first event contributing to the composite endpoint is counted in this row and the applicable subsequent rows. Thus, any deaths occurring after a heart failure hospitalization are not counted. | 957 (37.9) | 35.9Incidence rate (total patients with ≥1 event per 100 patient years at risk). | 1,032 (40.9) | 40.1 | 0.90Hazard ratio (VERQUVO over Placebo), based on a Cox proportional hazards model. (0.83, 0.98) |
| - All-cause mortality | 266 (10.5) | 285 (11.3) | |||
| - Heart failure hospitalization | 691 (27.4) | 747 (29.6) | |||
- The recommended starting dose of VERQUVO is 2.5 mg orally once daily with food. ()
2.1 Recommended DosageThe recommended starting dose of VERQUVO is 2.5 mg orally once daily with food.
Double the dose of VERQUVO 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)]. - Double the dose of VERQUVO approximately every 2 weeks to reach the target maintenance dose of 10 mg once daily, as tolerated by the patient. ()
2.1 Recommended DosageThe recommended starting dose of VERQUVO is 2.5 mg orally once daily with food.
Double the dose of VERQUVO 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)]. - Tablets may be crushed and mixed with water for patients who have difficulty swallowing. ()
2.1 Recommended DosageThe recommended starting dose of VERQUVO is 2.5 mg orally once daily with food.
Double the dose of VERQUVO 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)].
- 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.
- Lactation: Breastfeeding is not recommended ()
8.2 LactationRisk SummaryThere 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[14C]-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.
VERQUVO is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators
VERQUVO is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators
VERQUVO is contraindicated in pregnancy
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
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.
Based on data from animal reproduction studies, VERQUVO may cause fetal harm when administered to a pregnant woman and is contraindicated during pregnancy
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.
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).
[14C]-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.