VOQUEZNA Tablet Ref.[107221] Active ingredients: Vonoprazan

Antisecretory Activity

Following a single 10 mg or 20 mg dose of vonoprazan, the onset of the antisecretory effect as measured by intragastric pH occurs within 2 to 3 hours. The elevated intragastric pH levels compared to placebo increase with dose and are maintained for over 24 hours after dosing. The inhibitory effect of vonoprazan on acid secretion increases with repeated daily dosing and steady state is achieved by Day 4. The antisecretory effect of vonoprazan decreases following drug discontinuation although intragastric pH remained elevated compared to placebo for 24 to 48 hours following the dose on Day 7.

The effects of vonoprazan 10 mg or 20 mg once daily for 7 days on 24-hour intragastric pH in healthy subjects are shown in Table 10.

Table 10. Effect of VOQUEZNA 10 mg or 20 mg Once Daily on 24-Hour Intragastric pH at Baseline and on Days 1 and 7 in Healthy Subjects:

Cardiac Electrophysiology

At a single dose of 120 mg (6-times the maximum recommended dose), vonoprazan does not prolong the QT interval to any clinically relevant extent.

Serum Gastrin Effects

The effect of vonoprazan on serum gastrin concentrations was evaluated in 514 patients for up to 8 weeks (healing phase) and in 592 patients for up to 6 months (maintenance phase). During the healing phase, the mean fasting gastrin levels at Week 2 increased from baseline after treatment with VOQUEZNA 20 mg and levels were similar at Week 2 and Week 8. In the 6-month maintenance phase, the mean gastrin levels remained elevated with VOQUEZNA 10 mg and 20 mg and the mean serum gastrin levels returned to normal within 4 weeks of discontinuation of treatment.

Increased gastrin causes enterochromaffin-like cell hyperplasia and increased serum CgA levels. The increased CgA levels may cause false positive results in diagnostic investigations for neuroendocrine tumors [see Warnings and Precautions (5.8) and Drug Interactions (7)].

Enterochromaffin-Like Cell (ECL) Effects

Human gastric biopsy specimens were obtained from 135 patients treated with vonoprazan 10 mg or 20 mg once daily for up to 260 weeks. An increase in the incidence of hyperplasia of the parietal cells and G-cells was observed, which is consistent with the pharmacological action of a potassium-competitive acid blocker. No neoplastic changes were observed [see Nonclinical Toxicology (13.1), (13.2)].

Steady state pharmacokinetic (PK) parameters for vonoprazan 10 mg or 20 mg following once daily administration and vonoprazan 20 mg following twice daily administration from data collected across multiple studies are summarized in Table 11.

Table 11. Mean (%CV) Steady State Pharmacokinetic Parameters For Vonoprazan Following Once or Twice Daily Dosing:

C_max = Maximum plasma concentration; AUC_0-24h = Area under the plasma concentration-time curve from time 0 to end of the 24-hour dosing interval; AUC_0-12h = Area under the plasma concentration-time curve from time 0 to the end of the 12-hour dosing interval; T_max = Time to reach C_max, t_1/2 = Elimination half-life, CL/F = Apparent oral clearance, V_z/F = Apparent oral volume of distribution
^* AUC_0-24h
^† AUC_0-12h

Absorption

Vonoprazan exhibits time independent pharmacokinetics and steady state concentrations are achieved by Day 3 to 4. After multiple doses of vonoprazan ranging from 10 to 40 mg (twice the maximum recommended dose) once daily for 7 days in healthy subjects, C_max and area under the plasma concentration time curve (AUC) values for vonoprazan increased in an approximately dose-proportional manner.

There is little accumulation in plasma after once daily multiple doses, with an accumulation index ratio of less than 1.2 based on AUC for doses ranging from 10 to 40 mg (twice the maximum recommended dose).

Steady state plasma exposure of vonoprazan following 20 mg twice daily dosing (AUC_0-12h = 273 hr*ng/mL, N=10) was approximately 1.8-fold higher compared to the mean estimate from the same subjects on Day 1 (AUC_0-12h = 155 hr*ng/mL, N=10).

Effect of Food

In a food effect study in healthy subjects (N=24) who received vonoprazan 20 mg, a high-fat meal resulted in a 5% increase in C_max, a 15% increase in AUC, and a delay in median T_max of 2 hours. These changes are not considered to be clinically significant [see Dosage and Administration (2.4)].

Distribution

Plasma protein binding of vonoprazan ranged from 85 to 88% in healthy subjects and was independent of concentration from 0.1 to 10 mcg/mL.

Elimination

Metabolism

Vonoprazan is metabolized to inactive metabolites via multiple pathways by a combination of cytochrome P450 (CYP) isoforms (CYP3A4/5, CYP2B6, CYP2C19, CYP2C9 and CYP2D6) along with sulfo- and glucuronosyl-transferases. CYP2C19 polymorphisms have been evaluated in clinical studies and there were no considerable differences in the pharmacokinetics of vonoprazan based on CYP2C19 metabolizer status.

Excretion

Following oral administration of radiolabeled vonoprazan, approximately 67% of the radiolabeled dose (8% as unchanged vonoprazan) was recovered in urine and 31% (1.4% as unchanged vonoprazan) was recovered in feces.

Specific Populations

Geriatric Patients

No clinically meaningful differences in the pharmacokinetics of vonoprazan are predicted in patients 65 years of age and older compared to younger adult patients.

Sex, Race or Ethnicity

There were no clinically significant differences in the pharmacokinetics of vonoprazan based on sex or race/ethnicity.

Patients with Renal impairment

The pharmacokinetics of vonoprazan administered as a single 20 mg dose in patients with mild [eGFR 60 to <90 mL/min/1.73m² (N=8)], moderate [eGFR 30 to <60 mL/min/1.73m² (N=8)], or severe [eGFR 15 to <30 mL/min/1.73m² (N=8)] renal impairment were compared to those with normal renal function [eGFR ≥90 mL/min/1.73m² (N=13)]. Compared to subjects with normal renal function, systemic exposure (AUC_0-inf) was 1.7-, 1.3-, and 2.4-times greater in patients with mild, moderate, and severe renal impairment, respectively. In subjects requiring dialysis (N=8), AUC_0-inf estimates were 1.3-fold greater compared to estimates from subjects with normal renal function [see Dosage and Administration (2.2)]. Protein binding of vonoprazan is not affected by impaired renal function. In patients requiring dialysis, vonoprazan was present in the dialysate and represented 0.94% of the dose administered.

Patients with Hepatic Impairment

The pharmacokinetics of vonoprazan administered as a single 20 mg dose in patients with mild [Child-Pugh Class A (N=8)], moderate [Child-Pugh Class B (N=8)], or severe [Child-Pugh Class C (N=6)] hepatic impairment were compared to those with normal hepatic function (N=12). Compared to subjects with normal hepatic function, systemic exposure (AUC_0-inf) of vonoprazan was 1.2-, 2.4-, and 2.6-times greater in patients with mild, moderate, and severe hepatic impairment, respectively [see Dosage and Administration (2.3)]. Protein binding of vonoprazan is not affected by impaired hepatic function.

Drug Interaction Studies

In Vitro Studies

Cytochrome P450 (CYP450) Enzymes:

In vitro studies have shown that vonoprazan directly and time-dependently inhibits CYP2B6, CYP2C19, and CYP3A4/5.

Transporter Systems:

Vonoprazan inhibits multidrug and toxin extrusion protein 1 (MATE1) and organic cation transporter 1 (OCT1), but only at concentrations higher than clinically relevant.

Clinical Studies

Combination Therapy with Vonoprazan, Amoxicillin, and Clarithromycin:

When vonoprazan 20 mg, amoxicillin 750 mg and clarithromycin 400 mg were co-administered twice daily for 7 days (N=11), there was no effect on pharmacokinetics of amoxicillin compared to amoxicillin alone. However, vonoprazan C_max and AUC_0-12h increased by 87% and 85%, respectively, and clarithromycin C_max and AUC_0-12h increased by 64% and 45% respectively, compared to administration of each component alone.

Effect of Vonoprazan on CYP3A4 Substrates:

When a single oral dose of midazolam 2 mg was administered following vonoprazan 20 mg twice daily for 7 days (N=20), midazolam AUC_0-inf increased 93% compared to administration of midazolam alone.

Effect of CYP3A Inhibitors on Vonoprazan:

When a single dose of 40 mg vonoprazan (twice the maximum recommended dose) was administered with clarithromycin 500 mg twice daily for 7 days (N=16), vonoprazan AUC_0-inf increased 58% compared to administration of vonoprazan alone.

Coadministration of Vonoprazan with NSAIDs or Low Dose Aspirin:

When a single dose of 40 mg vonoprazan (twice the maximum recommended dose) was co-administered with diclofenac 25 mg, meloxicam 10 mg, or aspirin 100 mg, there were no clinically meaningful changes in exposure of vonoprazan, diclofenac, meloxicam, or aspirin compared to administration of each drug alone.

Model-Informed Approaches

Effect of CYP3A Inducers on Vonoprazan:

Vonoprazan exposures are predicted to be 80% lower when co-administered with a strong CYP3A4 inducer such as rifampicin and 50% lower when co-administered with a moderate CYP3A4 inducer such as efavirenz.

Antimicrobial Activity

Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of H. pylori infection [see Clinical Studies (14.3)]. The following in vitro data are available, but their clinical significance is unknown. Clarithromycin and amoxicillin are active in vitro against most isolates of H. pylori.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

Carcinogenicity

In a 24-month carcinogenicity study in mice, vonoprazan at daily oral doses of 6, 20, 60, and 200 mg/kg/day (approximately 0.4-, 4-, 19-, and 93-times the MRHD based on AUC) produced hyperplasia of neuroendocrine cells, gastropathy and benign and/or malignant neuroendocrine cell tumors (carcinoids) in the stomach at all doses in males and at 60 mg/kg/day and greater in females. In liver, increased incidences of hepatocellular adenoma and carcinomas were observed at doses of 20 mg/kg/day and greater in males and 60 mg/kg/day and greater in females.

In a 24-month carcinogenicity study in Sprague-Dawley rats, vonoprazan at daily oral doses of 5, 15, 50, and 150 mg/kg/day (approximately 0.6-, 4-, 19-, and 65-times the MRHD based on AUC) produced benign and/or malignant neuroendocrine cell tumors in the stomach in both male and female rats at doses of 5 mg/kg/day or more. Increased incidence of hepatocellular adenoma and carcinomas and hepatocholangiocellular adenomas and carcinomas were observed at doses of 50 and 150 mg/kg/day.

In both mice and rats, neuroendocrine tumors in the stomach occurred in association with neuroendocrine hyperplasia and gastropathy in the stomach and increased plasma gastrin concentrations that are consistent with inhibition of gastric acid secretion. Carcinoid tumors have also been observed in rats subjected to fundectomy or long-term treatment with proton pump inhibitors or high doses of H₂-receptor antagonists.

Mutagenesis

Vonoprazan was negative for mutagenicity in the in vitro Ames test, in an in vitro clastogenecity assay in Chinese Hamster cells and in vivo in a rat bone marrow micronucleus study.

Impairment of Fertility

Vonoprazan at oral doses up to 300 mg/kg/day in rats (approximately 133-times the MRHD based on AUC from a separate study in nonpregnant animals administered the same dose) was found to have no effect on fertility and reproductive performance. Elongation of the estrous cycle was observed in rats at doses equivalent to 133-times the MRHD based on AUC.

During lifetime exposure of mice and rats dosed daily with up to 200 mg/kg/day and 150 mg/kg/day of vonoprazan respectively, increases in gastrin levels and marked neuroendocrine hyperplasia and gastropathy were observed followed by formation of carcinoid tumors [see Nonclinical Toxicology (13.1)]. This finding is considered to be a rodent-specific phenomenon.

14.1 Healing of Erosive Esophagitis and Relief of Heartburn

The effectiveness and safety of VOQUEZNA was evaluated in a randomized, active-controlled, double-blind, eight-week study conducted in the United States and Europe in 1024 adult patients with endoscopically confirmed erosive esophagitis (NCT04124926). Severity of the disease was classified based on the Los Angeles (LA) Classification Grading System (Grades A through D). Patients were randomized to one of the following treatment groups: VOQUEZNA 20 mg once daily or lansoprazole 30 mg once daily for 2 to 8 weeks. Patients who were positive for H. pylori infection or who had Barrett’s esophagus and/or definite dysplastic changes in the esophagus at baseline were excluded from the study. Based on the LA Classification, 66% of patients had mild erosive esophagitis (Grades A or B) and 34% of patients had moderate to severe erosive esophagitis (Grades C or D) prior to randomization. Patients in the trial had a mean age of 51 years (range 18 to 84 years); 53% were female; 12% identified as Hispanic or Latino; 91% identified as White, 6% as Black or African American, and 3% identified as another racial group.

Healing of erosive esophagitis was assessed at Week 2 and Week 8 and resolution of heartburn symptoms was evaluated daily over the 8-week period. If endoscopic healing of erosive esophagitis was confirmed at Week 2, the patient entered the maintenance phase of the study. If endoscopic healing was not confirmed at Week 2, the patient continued to receive randomized treatment until Week 8. Only patients with confirmed endoscopic healing entered the maintenance phase. All endoscopies were centrally read and adjudicated.

Healing of All Grades of Erosive Esophagitis

The primary endpoint, was endoscopically confirmed complete healing of all grades of erosive esophagitis at Week 2 or Week 8, as shown in Table 12.

Table 12. Rates of Healing of All LA Grades of Erosive Esophagitis at Week 2 or Week 8:

^* Demonstrated noninferiority to lansoprazole.

Healing of Erosive Esophagitis in Subgroups with LA Grade C or D Esophagitis

For the secondary endpoint of complete healing of erosive esophagitis at Week 2, superiority was demonstrated in the subgroup of patients with LA Grade C or D disease, 70% of 177 VOQUEZNA treated patients and 53% of 174 lansoprazole treated patients achieved healing (18% treatment difference; 95% CI 7.4, 27.4).

Complete healing of erosive esophagitis at either Week 2 or Week 8 in the subgroup of patients with LA Grade C or D disease was 92% in patients treated with VOQUEZNA and 72% in patients treated with lansoprazole. This endpoint was not statistically significant under the prespecified multiple testing procedure.

Relief of Heartburn in Patients with Erosive Esophagitis During the Healing Phase

The percentage of 24-hour heartburn-free days through Week 8 was evaluated as a secondary endpoint and results are shown in Table 13.

Table 13. Percentage of 24-Hour Heartburn-Free Days in Patients with Erosive Esophagitis through Week 8:

^* Demonstrated noninferiority to lansoprazole.

Other Healing of Erosive Esophagitis Studies

Two additional randomized, active-controlled, double-blind studies conducted outside of the United States, of similar design to the United States trial, also demonstrated non-inferiority of vonoprazan 20 mg once daily compared to lansoprazole 30 mg once daily for the primary endpoint of healing of all grades of erosive esophagitis by Week 8.

14.2 Maintenance of Healed Erosive Esophagitis and Relief of Heartburn

Patients who completed the healing phase of the erosive esophagitis study (NCT04124926) and showed endoscopically confirmed healed erosive esophagitis at Week 2 or Week 8 were re-randomized in the maintenance phase 1:1:1 to either VOQUEZNA 10 mg once daily, a higher dosage of VOQUEZNA, or lansoprazole 15 mg once daily. Maintenance of healing and resolution of heartburn symptoms were evaluated over 24 weeks. The higher VOQUEZNA dose group did not demonstrate additional treatment benefit compared to VOQUEZNA 10 mg once daily.

Maintenance of Healed Erosive Esophagitis

The primary endpoint was maintenance of healed erosive esophagitis (all grades) through Week 24. A secondary endpoint was maintenance of healed erosive esophagitis in the subgroup of patients with LA Grade C or D disease prior to randomization in the healing phase of the study.

The maintenance rates of healed erosive esophagitis are shown in Table 14.

Table 14. Maintenance Rates of Healed Erosive Esophagitis in Adults through Week 24:

^* Demonstrated non-inferiority and superiority to lansoprazole.
^† Demonstrated superiority to lansoprazole.

Relief of Heartburn During Maintenance of Healed Erosive Esophagitis

The percentage of 24-hour heartburn-free days through Week 24 was evaluated for non-inferiority as a secondary endpoint as shown in Table 15.

Table 15. Percentage of 24-Hour Heartburn-Free Days through Week 24:

^* Demonstrated non-inferiority to lansoprazole.

Other Maintenance of Healed Erosive Esophagitis Studies

Two additional randomized, active-controlled, double-blind studies conducted outside of the United States, of similar design to the United States trial, also demonstrated non-inferiority of vonoprazan 10 mg once daily compared to lansoprazole 15 mg once daily for the primary endpoint of maintenance of healed erosive esophagitis (all grades) through Week 24.

14.3 Treatment of Helicobacter pylori Infection

The effectiveness and safety of VOQUEZNA, amoxicillin and clarithromycin (triple therapy) and VOQUEZNA and amoxicillin (dual therapy) were evaluated in a randomized, controlled, double-blind (triple therapy)/open-label (dual therapy) study conducted in the United States and Europe in treatment-naïve H. pylori-positive adult patients with at least one clinical condition: dyspepsia lasting at least 2 weeks, functional dyspepsia, recent/new diagnosis of peptic ulcer, peptic ulcer not treated for H. pylori infection, or a stable dose of long-term NSAID treatment (NCT04167670). Patients were randomized 1:1:1 to one of the following regimens administered for 14 consecutive days:

• VOQUEZNA 20 mg twice daily plus, amoxicillin 1,000 mg twice daily, and clarithromycin 500 mg twice daily
• VOQUEZNA 20 mg twice daily and amoxicillin 1,000 mg three times daily
• lansoprazole 30 mg twice daily, amoxicillin 1,000 mg twice daily, and clarithromycin 500 mg twice daily

H. pylori infection at baseline was defined as positive by ¹³C urea breath test (UBT) and follow-up upper endoscopy (culture or histology). H. pylori eradication was confirmed with a negative ¹³C UBT test-of-cure at least 27 days post-therapy. Patients with negative test results were considered treatment successes. Patients who tested positive for H. pylori infection and patients with missing results from the test-of-cure visit were considered treatment failures.

A total of 346 patients received VOQUEZNA, amoxicillin, and clarithromycin, 348 patients received VOQUEZNA and amoxicillin, and 345 patients received lansoprazole, amoxicillin, and clarithromycin. These patients had a mean age of 51 years (range 20 to 87 years); 62% were female; 27% identified as Hispanic or Latino; 89% identified as White, 7% as Black or African American, 2% as Asian, and 2% identified as another racial group.

VOQUEZNA, amoxicillin, and clarithromycin and VOQUEZNA and amoxicillin were shown to be noninferior to lansoprazole, amoxicillin, and clarithromycin in patients who did not have a clarithromycin or amoxicillin resistant strain of H. pylori at baseline. VOQUEZNA, amoxicillin, and clarithromycin and VOQUEZNA and amoxicillin were shown to be superior to lansoprazole, amoxicillin, and clarithromycin in patients who had a clarithromycin resistant strain of H. pylori at baseline and in the overall population.

H. pylori eradication rates at least 27 days post-therapy are shown in Table 16.

Table 16. Eradication Rates of H. pylori in Adult Patients at least 27 Days Post-Therapy – mITT:

CI = confidence interval calculated via the Miettinen and Nurminen method
Modified intent to treat (mITT) population: Patients were included in the mITT analysis if they had documented H. pylori infection at baseline.
^* Clarithromycin resistant strains of H. pylori were considered those with an MIC ≥1 mcg/mL; amoxicillin resistant strains were considered those with an MIC >0.125 mcg/mL.
^† p<0.0001 for test of non-inferiority versus LAC.
^‡ p<0.01 for test of non-inferiority versus LAC.
^§ p=0.0003 for test of superiority versus LAC.
^¶ p=0.01 for test of superiority versus LAC.
^# p<0.0001 for test of superiority versus LAC.