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

U.S. FDA APPROVED DRUGS SURING 2021                                          

Serial No 1

Name of the Drug-    VERGUVO

Active Ingredient -     Vericiguat

Pharmacological Classification-   To treat chronic heart failure

Date of Approval-          1/19/2021

 ADVERSE REACTIONS-

 Most common adverse reactions reported in =5% are hypotension and anemia. 

 CONTRAINDICATIONS-

 Patients with concomitant use of other soluble guanylate cyclase (sGC) stimulators.  Pregnancy 

PATIENT COUNSELING INFORMATION-                                                                         Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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. 

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 1) 

Pregnancy-                                                                                                                Advise women who are exposed to VERQUVO during pregnancy to report their pregnancy to their healthcare provider. [See Use in Specific Populations (8.1)].

Lactation Advise women not to breastfeed during treatment with VERQUVO 

Manufactured by: Bayer AG Leverkusen, Germany For patent information: www.merck.com/product/patent/home.html

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.

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.

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.

.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.

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-                                                                                                       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

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 coadministration 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 (Pgp substrate), warfarin, sildenafil, or the combination of sacubitril (including metabolite LBQ657)/valsartan were observed when coadministered with VERQUVO in healthy subjects

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

 There are no available data with VERQUVO use in pregnant women.

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.

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. 

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 .7

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) [see Clinical Pharmacology (12.3)].

 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.