1/21. Veriguat-(VERQUVO)- (Jan 2021)- to treat chronic heart failure
Drug Name:1/21. Veriguat-(VERQUVO)- (Jan 2021)- to treat chronic heart failure
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS-(summary)
PDE-5 Inhibitors: Concomitant use is not recommended.
DRUG INTERACTIONS-(details)-
1. Other Soluble Guanylate Cyclase Stimulators VERQUVO is contraindicated in patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators [see Contraindications (
2. PDE-5 Inhibitors Concomitant use of VERQUVO with PDE-5 inhibitors is not recommended because of the potential for hypotension.
Indication:
BRIEF DETAILS
VERQUVO- (Jan 2021)
Indn- To treat chronic heart disease
Comp- Tablets: 2.5 mg, 5 mg and 10 mg. The recommended starting dose is 2.5 mg orally once daily with food.
ADR- Most common adverse reactions reported in =5% are hypotension and anemia.
CI- Patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators. Pregnancy
Pat inform-
Dosing Instructions- If a dose is missed, it should be taken as soon as the patient remembers on the same day of the missed dose. Patients should not take two doses on the same day.
Advise pregnant women and females of reproductive potential of the potential risk to a fetus and to inform their healthcare person of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with and for one month after the final dose
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U.S. FDA APPROVED DRUGS DURING 2021
Sr.No- 1
Adverse Reaction:
ADVERSE REACTIONS -
Most common adverse reactions reported in =5% are hypotension and anemia.
Contra-Indications:
CONTRAINDICATIONS-
Patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators. Pregnancy
Dosages/ Overdosage Etc:
Patient Information:
PATIENT COUNSELING INFORMATION
Dosing Instructions- If a dose is missed, it should be taken as soon as the patient remembers on the same day of the missed dose. Patients should not take two doses of VERQUVO on the same day. 14 Reference ID: 4733497
Embryo-Fetal Toxicity-
Advise pregnant women and females of reproductive potential of the potential risk to a fetus and to inform their healthcare provider of a known or suspected pregnancy.
Advise females of reproductive potential to use effective contraception during treatment with VERQUVO and for one month after the final dose
Pregnancy- Advise women who are exposed to VERQUVO during pregnancy to report their pregnancy to their healthcare provider.
Lactation - Advise women not to breastfeed during treatment
Manufactured by: Bayer AG Leverkusen, Germany For patent information: www.merck.com/product/patent/home.html Copyright © 2021 Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. uspi-mk1242-t-2101r001
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
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.
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 NTproBNP at week 32 was greater in patients who received VERQUVO compared with placebo
Cardiac Electrophysiology- There was no evidence of proarrhythmic risk in an in vitro assessment of vericiguat or its major Nglucuronide metabolite. No inhibition of cardiac ion channels (hERG, hNav1.5, or hKvLQT1/mink) was observed at substantial multiples of their unbound Cmax 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.
There is limited experience with concomitant use of VERQUVO and PDE-5 inhibitors in patients with heart failure.
3. Pharmacokinetics- Vericiguat steady-state mean (coefficient of variation %) Cmax 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.
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 Tmax from about 1 hour (fasted) to about 4 hours (fed), reduces PK variability, and increases vericiguat AUC by 44% and Cmax 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/1.73m2 at treatment initiation or on dialysis ..
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.
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
Pregnancy and lactation:
8 USE IN SPECIFIC POPULATIONS -
1. Pregnancy 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
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.
If a patient becomes pregnant while receiving VERQUVO, healthcare providers should report VERQUVO exposure by calling 1-877-888-4231.
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
Because of the potential for serious adverse reactions in breastfed infants from VERQUVO, advise women not to breastfeed during treatment with VERQUVO.
3 Females and Males of Reproductive Potential- Pregnancy Testing- Verify the pregnancy status in females of reproductive potential prior to initiating VERQUVO .
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)].
4. Pediatric Use - Safety and effectiveness of VERQUVO have not been established in pediatric patients.
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)]. 4 Reference ID: 4733497
6. Renal Impairment - No dosage adjustment of VERQUVO is recommended in patients with estimated glomerular filtration rate (eGFR) =15 mL/min/1.73m2 who are not on dialysis.
VERQUVO has not been studied in patients with eGFR <15 mL/min/1.73m2 at treatment initiation or on dialysis .
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)
OVERDOSAGE- Limited data are available with regard to overdosage in human patients treated with VERQUVO. In VICTORIA, doses up to 10 mg have been studied.
In a study of patients with preserved ejection fraction heart failure (left ventricular ejection fraction =45%), multiple doses of VERQUVO 15 mg have been studied and were generally well tolerated.
In the event of an overdose, hypotension may result. Symptomatic treatment should be provided. VERQUVO is unlikely to be removed by hemodialysis because of high protein binding.
