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VOQUEZNA Dailymed

  1. Human Prescription
  2. Proton Pump Inhibitors
  3. Phathom Pharmaceuticals Inc.

Generic: vonoprazan fumarate

VOQUEZNA tablet - image

  1. FDA Adverse Reactions

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1 Indications And Usage


VOQUEZNA is indicated:
  • for healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults.
  • to maintain healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults.
  • in combination with amoxicillin and clarithromycin for the treatment of Helicobacter pylori (H. pylori) infection in adults.
  • in combination with amoxicillin for the treatment of H. pylori infection in adults.


VOQUEZNA is a potassium-competitive acid blocker indicated:
  • for healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults. (1)
  • to maintain healing of all grades of erosive esophagitis and relief of heartburn associated with erosive esophagitis in adults. (1)
  • in combination with amoxicillin and clarithromycin for the treatment of Helicobacter pylori (H. pylori) infection in adults. (1)
  • in combination with amoxicillin for the treatment of H. pylori infection in adults. (1)

2 Dosage And Administration



Recommended Dosage:
  • Healing of Erosive Esophagitis: 20 mg once daily for 8 weeks. (2.1)
  • Maintenance of Healed Erosive Esophagitis: 10 mg once daily for up to 6 months. (2.1)
  • Treatment of H. pylori Infection: see full prescribing information. (2.1)
  • See also full prescribing information for the recommended dosage by indication for patients with renal or hepatic impairment. (2.2, 2.3)

Administration Instructions:
  • Take with or without food. (2.4)
  • Swallow whole; do not chew or crush. (2.4)


Healing of Erosive Esophagitis and Relief of Heartburn
  • The recommended adult oral dosage is VOQUEZNA 20 mg once daily for 8 weeks.


Maintenance of Healed Erosive Esophagitis and Relief of Heartburn
  • The recommended adult oral dosage is VOQUEZNA 10 mg once daily for up to 6 months.


Treatment of H. pylori Infection
  • Triple Therapy: The recommended adult oral dosage is VOQUEZNA 20 mg plus amoxicillin 1,000 mg plus clarithromycin 500 mg, each given twice daily (in the morning and evening, 12 hours apart) for 14 days.
  • Dual Therapy: The recommended adult oral dose is VOQUEZNA 20 mg given twice daily (in the morning and evening) plus amoxicillin 1,000 mg three times daily (in the morning, mid-day, and evening) for 14 days.
  • Also refer to the amoxicillin and clarithromycin full prescribing information.



Healing of Erosive Esophagitis

The recommended dosage of VOQUEZNA in adult patients with renal impairment is described in Table 1 below [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Table 1: Recommended VOQUEZNA Dosage in Patients with Renal Impairment: Healing of Erosive Esophagitis
Estimated glomerular filtration rate (GFR) Recommended Dosage
30 mL/minute or greater 20 mg once daily
Less than 30 mL/minute 10 mg once daily


Maintenance of Healed Erosive Esophagitis

The recommended dosage of VOQUEZNA in adult patients with renal impairment is the same as for adult patients with normal renal function [see Dosage and Administration (2.1)].


Treatment of H. pylori Infection

The recommended dosage of VOQUEZNA in adult patients with renal impairment is described in Table 2 below [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
Table 2: Recommended VOQUEZNA Dosage in Patients with Renal Impairment: Treatment of H. pylori InfectionAlso refer to the Dosage and Administration section of the amoxicillin and clarithromycin prescribing information for dosage recommendations in patients with renal impairment.
Estimated GFR Recommended Dosage
30 mL/minute or greater 20 mg twice daily
Less than 30 mL/minute Use is not recommended



Healing of Erosive Esophagitis

The recommended dosage of VOQUEZNA in adult patients with hepatic impairment is described in Table 3 below [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Table 3: Recommended VOQUEZNA Dosage in Patients with Hepatic Impairment: Healing of Erosive Esophagitis
Classification Recommended Dosage
Child-Pugh Class A 20 mg once daily
Child-Pugh Class B 10 mg once daily
Child-Pugh Class C 10 mg once daily


Maintenance of Healed Erosive Esophagitis

The recommended dosage of VOQUEZNA in adult patients with hepatic impairment is the same as for patients with normal hepatic function [see Dosage and Administration (2.1)].


Treatment of H. pylori Infection

The recommended dosage of VOQUEZNA in adult patients with hepatic impairment is described in Table 4 below [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].
Table 4: Recommended VOQUEZNA Dosage in Patients with Hepatic Impairment: Treatment of H. pylori Infection
Classification Recommended Dosage
Child-Pugh Class A 20 mg twice daily
Child-Pugh Class B Use is not recommended
Child-Pugh Class C Use is not recommended

2.4 Administration Instructions

  • Take VOQUEZNA with or without food [see Clinical Pharmacology (12.3)].
  • Swallow VOQUEZNA tablets whole; do not chew or crush the tablet.
  • Missed doses:
    • For the healing or maintenance of healed erosive esophagitis: If a dose is missed, administer VOQUEZNA as soon as possible within 12 hours after the missed dose. If more than 12 hours have passed, skip the missed dose and administer the next dose at the regularly scheduled time.
    • For the treatment of H. pylori infection: If a dose is missed, administer VOQUEZNA as soon as possible within 4 hours after the missed dose. If more than 4 hours have passed, skip the missed dose and administer the next dose at the regularly scheduled time. Continue the normal dosing schedule until the treatment is completed.

3 Dosage Forms And Strengths


Tablets:
  • 10 mg of vonoprazan: pale yellow, oval, film-coated tablets debossed V10 on one side and plain on the other side.
  • 20 mg of vonoprazan: pale red, oval, film-coated tablets debossed V20 on one side and plain on the other side.


Tablets: 10 mg and 20 mg of vonoprazan. (3)

4 Contraindications

  • VOQUEZNA is contraindicated in patients with a known hypersensitivity to vonoprazan or any component of VOQUEZNA. Reactions have included anaphylactic shock [see Adverse Reactions (6.2) and Description (11)].
  • VOQUEZNA is contraindicated with rilpivirine-containing products [see Drug Interactions (7)].
  • For information about contraindications of antibacterial agents (clarithromycin and amoxicillin) indicated in combination with VOQUEZNA, refer to the Contraindications section of the corresponding prescribing information.

  • Known hypersensitivity to vonoprazan or any component of VOQUEZNA. (4)
  • Rilpivirine-containing products. (4, 7)

5 Warnings And Precautions


  • Gastric Malignancy: Symptomatic response to treatment does not preclude the presence of gastric malignancy; consider additional follow-up and diagnostic testing. (5.1)
  • Acute Tubulointerstitial Nephritis: Discontinue treatment and evaluate patients. (5.2)
  • Clostridioides difficile-Associated Diarrhea (CDAD): May be associated with an increased risk; use the shortest duration of treatment appropriate to the condition. (5.3)
  • Bone Fracture, including Osteoporosis-related Fracture: Use the shortest duration of treatment appropriate to the condition. (5.4)
  • Severe Cutaneous Adverse Reactions: Discontinue at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation. (5.5)
  • Vitamin B12 (Cobalamin) Deficiency: Long-term use may lead to malabsorption or deficiency; consider further workup if clinical symptoms are present. (5.6)
  • Hypomagnesemia and Mineral Metabolism: Consider monitoring magnesium levels prior to starting treatment and periodically if prolonged treatment is expected, or if concomitant use of digoxin or other drugs that cause hypomagnesemia. (5.7)
  • Interactions with Investigations for Neuroendocrine Tumors: Increased chromogranin A (CgA) levels may interfere with diagnostic investigations; temporarily stop VOQUEZNA at least 14 days before assessing CgA levels. (5.8, 7)
  • Fundic Gland Polyps: Risk increases with long-term use; use the shortest duration of treatment appropriate to the condition. (5.9)

5.1 Presence of Gastric Malignancy


In adults, symptomatic response to therapy with VOQUEZNA does not preclude the presence of gastric malignancy. Consider additional follow-up and diagnostic testing in patients who have a suboptimal response or an early symptomatic relapse after completing treatment with VOQUEZNA. In older patients, also consider endoscopy.

5.2 Acute Tubulointerstitial Nephritis


Acute tubulointerstitial nephritis (TIN) has been reported with VOQUEZNA [see Adverse Reactions (6.1)]. If suspected, discontinue VOQUEZNA and evaluate patients with suspected acute TIN.

5.3 -Associated Diarrhea


Published observational studies suggest that proton pump inhibitors (PPIs) may be associated with an increased risk of Clostridioides difficile-associated diarrhea (CDAD), especially in hospitalized patients. VOQUEZNA, another drug that blocks the proton pump to inhibit gastric acid production, may also increase the risk of CDAD. Consider CDAD in patients with diarrhea that does not improve [see Adverse Reactions (6.2)]. Use the shortest duration of VOQUEZNA appropriate to the condition being treated.

CDAD has been reported with use of nearly all antibacterial agents. For more information specific to antibacterial agents (clarithromycin and amoxicillin) indicated for use in combination with VOQUEZNA, refer to Warnings and Precautions section of the corresponding prescribing information.

5.4 Bone Fracture


Several published observational studies suggest that PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term therapy (a year or longer). Bone fracture, including osteoporosis-related fracture, has also been reported with vonoprazan. Use the shortest duration of VOQUEZNA appropriate to the condition being treated [see Dosage and Administration (2.1)]. Patients at risk for osteoporosis-related fractures should be managed according to the established treatment guidelines.

5.5 Severe Cutaneous Adverse Reactions


Severe cutaneous adverse reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported with VOQUEZNA [see Adverse Reactions (6.2)].

Discontinue VOQUEZNA at the first signs or symptoms of severe cutaneous adverse reactions or other signs of hypersensitivity and consider further evaluation.

5.6 Vitamin B12 (Cobalamin) Deficiency


Long-term use of acid-suppressing drugs can lead to malabsorption of Vitamin B12 caused by hypo- or achlorhydria. Vitamin B12 deficiency has been reported postmarketing with vonoprazan [see Adverse Reactions (6.2)]. If clinical symptoms consistent with Vitamin B12 deficiency are observed in patients treated with VOQUEZNA consider further workup.

5.7 Hypomagnesemia and Mineral Metabolism


Hypomagnesemia has been reported postmarketing with vonoprazan [see Adverse Reactions (6.2)]. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients.

Consider monitoring magnesium levels prior to initiation of VOQUEZNA and periodically in patients expected to be on prolonged treatment, in patients taking drugs that may have increased toxicity in the presence of hypomagnesemia (e.g., digoxin), or drugs that may cause hypomagnesemia (e.g., diuretics). Treatment of hypomagnesemia may require magnesium replacement and discontinuation of VOQUEZNA.

Consider monitoring magnesium and calcium levels prior to initiation of VOQUEZNA and periodically while on treatment in patients with a preexisting risk of hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium, as necessary. If hypocalcemia is refractory to treatment, consider discontinuing VOQUEZNA.

5.8 Interactions with Diagnostic Investigations for Neuroendocrine Tumors


Serum chromogranin A (CgA) levels increase secondary to drug-induced decreases in gastric acidity. The increased CgA level may cause false positive results in diagnostic investigations for neuroendocrine tumors. Temporarily discontinue VOQUEZNA treatment at least 14 days before assessing CgA levels and consider repeating the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), the same commercial laboratory should be used for testing, as reference ranges between tests may vary [see Drug Interactions (7) and Clinical Pharmacology (12.2)].

5.9 Fundic Gland Polyps


Use of VOQUEZNA is associated with a risk of fundic gland polyps that increases with long-term use, especially beyond one year. Fundic gland polyps have been reported with vonoprazan in clinical trials and postmarketing use with PPIs. Most patients who developed fundic gland polyps were asymptomatic and fundic gland polyps were identified incidentally on endoscopy. Use the shortest duration of VOQUEZNA appropriate to the condition being treated [see Dosage and Administration (2.1)].

6 Adverse Reactions


The following serious adverse reactions are described elsewhere in labeling:


Most common adverse reactions in VOQUEZNA-treated patients are:
  • Healing of Erosive Esophagitis (≥2%): gastritis, diarrhea, abdominal distension, abdominal pain, and nausea. (6.1)
  • Maintenance of Healed Erosive Esophagitis (≥3%): gastritis, abdominal pain, dyspepsia, hypertension, and urinary tract infection. (6.1)
  • Treatment of H. pylori Infection (≥2%): diarrhea, dysgeusia, vulvovaginal candidiasis, abdominal pain, headache, hypertension, and nasopharyngitis. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Phathom Pharmaceuticals, Inc. at toll-free phone 1-888-775-7428 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience


Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.


Healing of Erosive Esophagitis and Maintenance of Healed Erosive Esophagitis

The safety of VOQUEZNA was evaluated in a randomized, active-controlled, double-blind two phase trial for the healing of erosive esophagitis (2 to 8 weeks) and maintenance of healed erosive esophagitis (through 24 weeks) conducted in the United States and Europe [see Clinical Studies (14.1), (14.2)].

Adverse reactions reported in at least 2% of patients in the VOQUEZNA arm in the healing phase are presented in Table 5.
Table 5: Adverse ReactionsReported in at least 2% of patients in the VOQUEZNA arm. in a Clinical Trial of Adult Patients with All Grades of Erosive EsophagitisThe trial was not designed to support comparative claims for VOQUEZNA for the adverse reactions reported in this table. (2 to 8 Week Healing Phase)
Adverse Reactions VOQUEZNA20 mg Once DailyN=514% Lansoprazole30 mg Once DailyN=510%
GastritisRepresents a grouped term and includes related terms. 3 2
Diarrhea 2 3
Abdominal distension 2 1
Abdominal pain 2 1
Nausea 2 1

Adverse reactions reported in at least 3% of patients in the VOQUEZNA arm of the maintenance phase are shown in Table 6.
Table 6: Adverse ReactionsReported in at least 3% of patients in the VOQUEZNA arm. in a Clinical Trial of Adult Patients with All Grades of Erosive EsophagitisThe trial was not designed to support comparative claims for VOQUEZNA for the adverse reactions reported in this table. (24 Week Maintenance Phase)
Adverse Reactions VOQUEZNA10 mg Once DailyN=296% Lansoprazole15 mg Once DailyN=297%
GastritisRepresents grouped term and includes related terms. 6 3
Abdominal pain 4 2
Dyspepsia 4 3
Hypertension 3 2
Urinary tract infection 3 2


COVID-19

COVID-19 was reported in the healing phase in 11 (2%) VOQUEZNA-treated subjects and 9 (2%) lansoprazole-treated subjects; and in the maintenance phase in 18 (6%) VOQUEZNA-treated subjects and 20 (7%) lansoprazole-treated subjects.


Other Clinical Trials of Erosive Esophagitis

Adverse reactions reported in the United States trial were similar to those reported in 4 additional randomized, active-controlled, double-blind studies of vonoprazan compared to lansoprazole conducted outside of the United States (two eight-week trials of healing of erosive esophagitis and two 24-week maintenance of healed erosive esophagitis trials).


Less Common Adverse Reactions

Adverse reactions reported in 1% or less of VOQUEZNA-treated patients in the healing or maintenance phase of the United States trial are:

Blood and lymphatic system disorders: anemia, lymphocytosis

Cardiac disorders: tachycardia

Ear and labyrinth disorders: vertigo

Gastrointestinal disorders: duodenal polyp, dry mouth, dysphagia, eructation, flatulence, gastric polyps, vomiting

General disorders and administrative site conditions: asthenia, peripheral edema

Infections and infestations: upper respiratory infection

Investigations: increased liver function test

Metabolism and nutritional disorders: diabetes mellitus

Musculoskeletal system: bone fracture

Nervous system disorders: dizziness, headache, syncope

Psychiatric disorders: depression, insomnia

Renal and urinary disorders: tubulointerstitial nephritis

Skin and subcutaneous tissue disorders: eczema, rash, urticaria


Treatment of H. pylori Infection

The safety of VOQUEZNA, amoxicillin and clarithromycin was evaluated in 675 adult patients (aged 20 to 82 years) in clinical trials in the United States, Europe and Japan and VOQUEZNA and amoxicillin was evaluated in 348 adult patients (aged 20 to 80 years) in a clinical trial in the United States and Europe. All of the patients were screened and found to be positive for H. pylori infection.

The safety of VOQUEZNA, amoxicillin and clarithromycin (triple therapy) and VOQUEZNA and amoxicillin (dual therapy) was 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 [see Clinical Studies (14.3)].


Adverse Reactions Leading to Discontinuation

Treatment discontinuation due to an adverse reaction occurred in 2.3% (8/346) of the patients treated with VOQUEZNA, amoxicillin and clarithromycin, 0.9% (3/348) of the patients treated with VOQUEZNA and amoxicillin, and 1.2% (4/345) of the patients treated with lansoprazole, amoxicillin and clarithromycin. The most common adverse reactions leading to discontinuation of VOQUEZNA, amoxicillin and clarithromycin were diarrhea (0.6%) and hypertension (0.6%) and the most common adverse reaction leading to discontinuation of VOQUEZNA and amoxicillin was rash (0.6%).


Most Common Adverse Reactions

Adverse reactions reported in at least 2% of patients in any treatment arm are described in Table 7.
Table 7: Adverse ReactionsReported in at least 2% of patients in any treatment arm. in Adult Patients with H. pylori InfectionThese trials were not designed to support comparative claims for VOQUEZNA-containing treatment arms for the adverse reactions reported in this table.
Adverse Reactions VOQUEZNA and Amoxicillin VOQUEZNA, Amoxicillin, and Clarithromycin Lansoprazole, Amoxicillin, and Clarithromycin
N=348% N=346% N=345%
Diarrhea 5 4 10
DysgeusiaRepresents grouped term and includes related terms. 1 5 6
Vulvovaginal candidiasis 2 3 1
Abdominal pain 3 2 3
Headache 1 3 1
Hypertension 1 2 1
Nasopharyngitis 2 <1 1


Less Common Adverse Reactions

Other adverse reactions reported in less than 2% of patients treated with VOQUEZNA, amoxicillin, and clarithromycin or VOQUEZNA and amoxicillin are uled below by body system:

Blood and lymphatic system disorders: anemia, leukocytosis, leukopenia, neutropenia

Cardiac disorders: QT prolongation, tachycardia

Eye disorders: orbital edema

Gastrointestinal disorders: abdominal distension, constipation, dry mouth, duodenal polyp, duodenal ulcer, dyspepsia, flatulence, gastric ulcer, gastroesophageal reflux disease, hematochezia, large intestine polyp, rectal polyp, nausea, stomatitis, tongue discomfort, vomiting

General disorders and administration site conditions: fatigue, pyrexia

Immune system disorders: drug hypersensitivity

Infections and infestations: anal fungal infection, gastrointestinal viral infection, oral fungal infection, pneumonia, tongue fungal infection, upper respiratory tract infection, urinary tract infection, viral infection

Investigations: increased liver function test

Metabolism and nutrition disorders: decreased appetite

Musculoskeletal system: bone fracture

Nervous system disorders: ageusia, dizziness, tension headache

Psychiatric disorders: anxiety, depression, insomnia

Renal and urinary disorders: renal hypertrophy, tubulointerstitial nephritis

Reproductive system and breast disorders: vaginal discharge

Respiratory, thoracic and mediastinal disorders: cough, nasal polyps, oropharyngeal pain

Skin and subcutaneous tissue disorders: dermatitis, dry skin, rash

For more information on adverse reactions and laboratory changes with amoxicillin or clarithromycin, refer to Adverse Reactions section of the corresponding prescribing information.

6.2 Postmarketing Experience


The following additional adverse reactions have been identified during post-approval use of vonoprazan outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: thrombocytopenia

Immune system disorders: anaphylactic shock [see Contraindications (4)]

Infections and infestations: C. difficile (with concomitant antibacterials) [see Warnings and Precautions (5.3)]

Investigation: hypomagnesemia, hypokalemia, hypocalcemia, vitamin B12 deficiency [see Warnings and Precautions (5.6), (5.7)]

Hepatobiliary disorders: hepatic injury, hepatic failure, jaundice

Skin and subcutaneous tissue disorders: drug eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [see Warnings and Precautions (5.5)]

7 Drug Interactions


Table 8 and Table 9 include drugs with clinically important drug interactions and interaction with diagnostics when administered concomitantly with VOQUEZNA and instructions for preventing or managing them.

These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse reactions or loss of efficacy [see Clinical Pharmacology (12.3)].

Consult the labeling of concomitantly used drugs to obtain further information about interactions with vonoprazan.
Table 8: Drug Interactions Affecting Drugs Co-Administered with VOQUEZNA and Interactions with Diagnostics
Drugs Dependent on Gastric pH for Absorption
Antiretrovirals
Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2)] which may alter the absorption of antiretroviral drugs leading to changes in the safety and/or effectiveness.
Prevention or Management Rilpivirine-containing products Concomitant use with VOQUEZNA is contraindicated.
Atazanavir Avoid concomitant use with VOQUEZNA.
Nelfinavir
Other antiretrovirals See the prescribing information of other antiretroviral drugs dependent on gastric pH for absorption prior to concomitant use with VOQUEZNA.
Other Drugs (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole)
Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2)], which may decrease the absorption of drugs reducing their effectiveness.
Prevention or Management See the prescribing information for other drugs dependent on gastric pH for absorption.
Combination Therapy with Clarithromycin and/or Amoxicillin
Clinical Effect Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Amoxicillin also has drug interactions.
Prevention or Management See Contraindications and Warnings and Precautions in the prescribing information for clarithromycin.See Drug Interactions in the prescribing information for amoxicillin.
Certain CYP3A Substrates where minimal concentration changes may lead to serious toxicities
Clinical Effect Vonoprazan is a weak CYP3A inhibitor [see Clinical Pharmacology (12.3)].Vonoprazan may increase exposure of CYP3A4 substrates, which may increase the risk of adverse reactions related to these substrates.
Prevention or Management Frequent monitoring for concentrations and/or adverse reactions related to the substrate drugs when used with VOQUEZNA. Dosage reduction of substrate drugs may be needed.See prescribing information for the relevant substrate drugs.
CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol)
Clinical Effect Vonoprazan is a CYP2C19 inhibitor [see Clinical Pharmacology (12.3)]. Vonoprazan may reduce plasma concentrations of the active metabolite of clopidogrel and may cause reduction in platelet inhibition. Vonoprazan may increase exposure of CYP2C19 substrate drugs (e.g., citalopram, cilostazol).
Prevention or Management Clopidogrel Carefully monitor the efficacy of clopidogrel and consider alternative anti-platelet therapy.
Citalopram and Cilostazol Carefully monitor patients for adverse reactions associated with citalopram and cilostazol. See the prescribing information for dosage adjustments.
Chromogranin (CgA) Test for Neuroendocrine Tumors
Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2)], which increases CgA levels and may cause false positive results in diagnostic investigations for neuroendocrine tumors.
Prevention or Management Assess CgA levels at least 14 days after stopping VOQUEZNA treatment and repeat the test if initial CgA levels are high. If serial tests are performed (e.g., for monitoring), use the same commercial laboratory for testing, as reference ranges between tests may vary.
Interaction with Secretin Stimulation Test
Clinical Effect Hyper-response in gastrin secretion in response to secretin stimulation test, falsely suggesting gastrinoma.
Prevention or Management Temporarily stop VOQUEZNA at least 14 days before assessing to allow gastrin levels to return to baseline [see Clinical Pharmacology (12.2)].
Table 9: Drug Interactions Affecting VOQUEZNA When Co-Administered with Other Drugs
Strong or Moderate CYP3A4 Inducers
Clinical Effect Vonoprazan is a CYP3A substrate. Strong or moderate CYP3A inducers decrease vonoprazan exposure [see Clinical Pharmacology (12.3)], which may reduce the effectiveness of VOQUEZNA.
Prevention or Management Avoid concomitant use with VOQUEZNA.


See full prescribing information for a ul of clinically important drug interactions. (7)

8 Use In Specific Populations



Lactation: Breastfeeding not recommended during treatment. (8.2)

8.1 Pregnancy


Risk Summary

There are no adequate and well-controlled studies of vonoprazan in pregnant women. Available data from pharmacovigilance reports with vonoprazan-containing products use in pregnant women are not sufficient to evaluate for a drug-associated risk for major birth defects, miscarriage, or other adverse maternal or fetal outcomes.

In pregnant rats, no adverse effects were noted after oral administration of vonoprazan during organogenesis at approximately 27-times the maximum recommended human dose (MRHD) based on AUC exposure comparisons.

In a pre- and postnatal development (PPND) study, pups from dams orally administered vonoprazan during organogenesis and through lactation, exhibited liver discoloration, which in follow-up mechanistic animal studies was associated with necrosis, fibrosis, and hemorrhage at a dose approximately 22-times the MRHD based on AUC comparisons which were likely attributable to exposure during lactation [see Use in Specific Populations (8.2)]. These effects were not observed at the next lower dose in this study, which was approximately equal to the MRHD based on AUC comparison, however they were seen at clinically relevant exposures in dose range finding studies in rats (see Data).

The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the United States general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Report pregnancies to the Phathom Pharmaceuticals, Inc. Adverse Event reporting line at 1-888-775-7428.


Data


Animal Data

Pregnant rats were orally administered vonoprazan at doses of 30, 100, or 300 mg/kg/day (7-, 27-, 130-times the MRHD based on AUC comparison at the same doses from unmated female rats from separate studies) during the period of organogenesis from gestation day (GD) 6 to 17. During maternal dosing, one high-dose female died and decreased body weight and food consumption occurred at the middle and highest doses. No embryo-fetal lethality was observed but decreased fetal body weight was observed in the highest dose group. Fetal abnormalities were limited to the 300 mg/kg/day and included ventricular septal defect and mal-positioned subclavian artery in fetuses in a majority (15/19) of litters, as well as tail abnormalities and small anal opening. No adverse embryo-fetal effects were observed at the 100 mg/kg/day.

Pregnant rabbits were orally administered vonoprazan at doses of 3, 10, or 30 mg/kg/day (0.04-, 1.5-, 10-times the MRHD based on AUC comparison) during the period of organogenesis from GD 6 to 18. Two animals aborted at the highest dose and decreased body weight and food consumption occurred at the mid and high doses. No embryo-fetal mortality or toxicity occurred. There were no external, visceral or skeletal abnormalities.

In a PPND study, pregnant female rats were orally administered vonoprazan at doses of 1, 3, 10, or 100 mg/kg/day (0.01-, 0.18-, 1.1-, 22-times the MRHD based on AUC comparison) from GD 6 to lactation day (LD) 21. Decreased body weight gain and food consumption were present in dams at the highest dose during lactation. Decreased body weight gain compared to controls was observed in the offspring from dams in the high dose group. Liver discoloration occurred in offspring from the high dose group at LD 4 but was not present in animals examined after weaning. Similarly, in dose range finding studies in rats and follow-up mechanistic animal studies, the liver discoloration was observed and characterized as necrosis, fibrosis, and hemorrhage at equal to or greater than clinically relevant exposures based on AUC comparisons. The mechanistic studies further demonstrated the effect was likely attributable to vonoprazan exposure during lactation [see Use in Specific Populations (8.2)]. The clinical relevance of the liver findings is uncertain.

Exposure margins from vonoprazan between the animal and clinical studies for vonoprazan, amoxicillin and clarithromycin used in combination may be lower due to increased vonoprazan exposure from concomitant use with clarithromycin in patients [see Clinical Pharmacology (12.3)].

8.2 Lactation



Risk Summary

There are no data regarding the presence of vonoprazan in human milk, the effects on the breastfed infant, or the effects on milk production. Vonoprazan and its metabolites are present in rat milk. Liver injury occurred in offspring from pregnant and lactating rats administered oral vonoprazan at AUC exposures approximately equal to and greater than the MRHD (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential risk of adverse liver effects shown in animal studies with vonoprazan, advise patients not to breastfeed during treatment with VOQUEZNA.


Data


Animal Data

In a PPND study in rats, in which the dams were administered oral vonoprazan during gestation and through lactation at up to 22-times the MRHD (based on AUC comparison), liver discoloration occurred in offspring from the high dose group [see Use in Specific Populations (8.1)].

Liver discoloration associated with necrosis, fibrosis, and hemorrhage in the offspring of dosed rats was also seen in dose-range finding studies and follow-up, mechanistic studies, including offspring in lactation only studies. These effects were reported in pups on LD 4 at doses from 3 to 100 mg/kg/day (approximately 0.2- to 22-fold the MRHD based on AUC values extrapolated from the PPND study) and on LD 14 at doses from 10 to 100 mg/kg/day dose groups (approximately 1- to 22-fold the MRHD based on an extrapolated AUC comparisons). In mechanistic studies, liver effects were observed in offspring treated only during lactation but not in offspring from animals only treated during gestation. In some of these studies, this finding was associated with increased offspring stomach weights that was reversed along with liver discoloration by concomitant treatment with a gastrointestinal prokinetic agent.

8.4 Pediatric Use


The safety and effectiveness of VOQUEZNA have not been established in pediatric patients.

8.5 Geriatric Use


There were 200 patients aged 65 years and older in the clinical trial for erosive esophagitis and relief of heartburn [see Clinical Studies (14.1)]. Of the total number of vonoprazan-treated patients there were 93 (18%) patients aged 65 years of age and older and 10 (2%) patients aged 75 years of age and older.

There were 218 patients aged 65 years and older in the clinical trial for the treatment of H. pylori infection [see Clinical Studies (14.3)]. Of the total number of vonoprazan-treated patients, there were 153 (22%) patients aged 65 years of age and older and 18 (3%) patients aged 75 years of age and older.

No overall differences in safety or effectiveness were observed between these patients and younger adult patients, and other reported clinical experience has not identified differences in responses between the geriatric and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

No clinically meaningful differences in the pharmacokinetics of vonoprazan are predicted in patients 65 years of age and older compared to younger adult patients [see Clinical Pharmacology (12.3)].

8.6 Renal Impairment



Healing of Erosive Esophagitis

No dosage adjustment of VOQUEZNA for the healing of erosive esophagitis is recommended in patients with mild to moderate renal impairment (eGFR 30 to 89 mL/min). Dosage reduction is recommended in patients with severe renal impairment (eGFR < 30 mL/min) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].


Maintenance of Healed Erosive Esophagitis

No dosage adjustment of VOQUEZNA for the maintenance of healed erosive esophagitis is recommended in patients with any degree of renal impairment.


Treatment of H. pylori Infection

Use of VOQUEZNA is not recommended for the treatment of H. pylori infection in patients with severe renal impairment (eGFR < 30 mL/min) [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment



Healing of Erosive Esophagitis

No dosage adjustment of VOQUEZNA for the healing of erosive esophagitis is recommended in patients with mild hepatic impairment (Child-Pugh A). Dosage reduction is recommended in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].


Maintenance of Healed Erosive Esophagitis

No dosage adjustment of VOQUEZNA for the maintenance of healed erosive esophagitis is recommended in patients with any degree of hepatic impairment.


Treatment of H. pylori Infection

Use of VOQUEZNA is not recommended for the treatment of H. pylori infection in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C) [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)].

11 Description


Vonoprazan (as the fumarate), is a potassium-competitive acid blocker. Chemically, it is 1H-pyrrole-3-methanamine, 5-(2-fluorophenyl)-N-methyl-1-(3-pyridinylsulfonyl)-, (2E)-2-butenedioate (1:1). Its empirical formula is C17H16FN3O2S•C4H4O4 with a molecular weight of 461.5. Vonoprazan fumarate has the following structure:

Vonoprazan fumarate is white to nearly white crystals or crystalline powder which melts at 194.8°C. Vonoprazan fumarate is soluble in dimethyl sulfoxide; sparingly soluble in N,N–dimethylacetamide, slightly soluble in N,N-dimethylformamide, methanol and water; very slightly soluble in ethanol (99.5%); and practically insoluble in 2-propanol, acetone, 1-octanol, and acetonitrile.

VOQUEZNA (vonoprazan) tablets are available in two dosage strengths for oral administration: 10 mg of vonoprazan (equivalent to 13.36 mg of vonoprazan fumarate) and 20 mg of vonoprazan (equivalent to 26.72 mg of vonoprazan fumarate). Each film-coated tablet contains the following inactive ingredients: ascorbic acid, croscarmellose sodium, ferric oxide red (only in 20 mg tablets), ferric oxide yellow (only in 10 mg tablets), fumaric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol 8000, and titanium dioxide.

12 Clinical Pharmacology


12.1 Mechanism of Action


Vonoprazan suppresses basal and stimulated gastric acid secretion at the secretory surface of the gastric parietal cell through inhibition of the H+, K+-ATPase enzyme system in a potassium competitive manner. Because this enzyme is regarded as the acid (proton) pump within the parietal cell, vonoprazan has been characterized as a type of gastric proton-pump inhibitor, in that it blocks the final step of acid production. Vonoprazan does not require activation by acid. Vonoprazan may selectively concentrate in the parietal cells in both the resting and stimulated states. Vonoprazan binds to the active pumps in a noncovalent and reversible manner.

12.2 Pharmacodynamics



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
Parameter VOQUEZNA10 mg Once Daily(N=9) VOQUEZNA20 mg Once Daily(N=9)
Baseline Day 1 Day 7 Baseline Day 1 Day 7
Mean Intragastric pH 2.0 3.7 4.6 1.9 4.5 5.9
% Time Intragastric pH>4 (hours) 6.8(2 h) 43.1(10 h) 60.2(14 h) 7.4(2 h) 62.7(15 h) 85.2(20 h)
% Time Intragastric pH>6 (hours) 1.3(<1 h) 20.7(5 h) 34.3(8 h) 0.9(<1 h) 29.0(7 h) 57.8(14 h)


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)].

12.3 Pharmacokinetics


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
PK Parameter Vonoprazan 10 mg Vonoprazan 20 mg
Once Daily(N=30) Once Daily(N=68) Twice Daily(N=32)
Cmax = Maximum plasma concentration; AUC0-24h = Area under the plasma concentration-time curve from time 0 to end of the 24-hour dosing interval; AUC0-12h = Area under the plasma concentration-time curve from time 0 to the end of the 12-hour dosing interval; Tmax = Time to reach Cmax, t1/2 = Elimination half-life, CL/F = Apparent oral clearance, Vz/F = Apparent oral volume of distribution
Tmax(h) median (min, max) 1.5 (0.75,3.0) 2.0 (0.75, 5.0) 3.0 (1.0-6.0)
Cmax  (ng/mL) 11.7 (27.5) 26.1 (35.2) 37.8 (36.1)
AUC (hr*ng/mL) 92.9 (33.1)AUC0-24h 230.9 (41.3) 272.5 (30.5)AUC0-12h
 t1/2z (h) 7.7 (27.1) 7.9 (22.6) 6.8 (22.7)
CL/F (L/h) 120.2 (35.2) 100.2 (38.3) 81.3 (35.7)
Vz/F (L) 1270.7 (26.6) 1114.0 (39.6) 782.7 (34.4)


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, Cmax 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 (AUC0-12h = 273 hr*ng/mL, N=10) was approximately 1.8-fold higher compared to the mean estimate from the same subjects on Day 1 (AUC0-12h = 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 Cmax, a 15% increase in AUC, and a delay in median Tmax 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 (AUC0-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), AUC0-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 (AUC0-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


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 Cmax and AUC0-12h increased by 87% and 85%, respectively, and clarithromycin Cmax and AUC0-12h 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 AUC0-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 AUC0-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.

12.4 Microbiology



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.

13 Nonclinical Toxicology


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility


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.

13.2 Animal Toxicology and/or Pharmacology


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 Clinical Studies


14.1Healing 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
Timepoint Treatment Group Treatment Difference(95% Confidence Interval)
VOQUEZNA20 mg Once Daily Lansoprazole30 mg Once Daily
N=514% N=510%
Week 2 or 8 93 85 8Demonstrated noninferiority to lansoprazole. (4.5, 12.2)
Week 2 74 68


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
Parameter Treatment Group Treatment Difference(95% Confidence Interval)
VOQUEZNA20 mg Once DailyN=514% Lansoprazole30 mg Once DailyN=510%
Mean ± SD 67 ± 35 64 ± 35 3 Demonstrated noninferiority to lansoprazole. (-1.6, 7.0)
Median 81 78


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.

14.2Maintenance 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
Baseline Severity Treatment Group Treatment Difference(95% Confidence Interval)
VOQUEZNA10 mg Once Daily Lansoprazole15 mg Once Daily
All LA Grades: N=293 N=294
Week 24 79% 72% 7Demonstrated non-inferiority and superiority to lansoprazole. (0.2, 14.1)
LA Grade C or D: N=95 N=96
Week 24 75% 61% 13Demonstrated superiority to lansoprazole. (0.02, 26.1)

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
Parameter Treatment Group Treatment Difference(95% Confidence Interval)
VOQUEZNA10 mg Once DailyN=293% Lansoprazole15 mg Once DailyN=294%
Mean ± SD 81 ± 29 79 ± 27 2Demonstrated non-inferiority to lansoprazole. (-2.3, 6.8)
Median 95 89

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.

14.3Treatment of 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
VOQUEZNA Amoxicillin, and Clarithromycin VOQUEZNA and Amoxicillin Lansoprazole, Amoxicillin, and Clarithromycin (LAC)
%(n) %(n) %(n)
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.
Patients with H. pylori infection who did not have a clarithromycin or amoxicillin resistant strain at baselineClarithromycin 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. 85(222) 79(208) 79(201)
Treatment Difference from LAC (95% CI) 6p<0.0001 for test of non-inferiority versus LAC. (-0.8, 12.6) -0.3p<0.01 for test of non-inferiority versus LAC. (-7.4, 6.8)
All randomized patients with H. pylori infection at baseline 81(273) 77(250) 69(226)
Treatment Difference from LAC (95% CI) 12p=0.0003 for test of superiority versus LAC. (5.7, 18.8) 9p=0.01 for test of superiority versus LAC. (1.9, 15.4)
Patients with H. pylori infection who had a clarithromycin resistant strain of H. pylori at baseline 66(48) 70(39) 32(23)
Treatment Difference from LAC (95% CI) 34p<0.0001 for test of superiority versus LAC. (17.7, 48.1) 38 (20.5, 52.6)

16 How Supplied/storage And Handling


VOQUEZNA (vonoprazan) tablets:

10 mg of vonoprazan: pale yellow, oval, film-coated tablets debossed V10 on one side and plain on the other side. Bottles of 30 (NDC 81520-100-30).

20 mg of vonoprazan: pale red, oval, film-coated tablets debossed V20 on one side and plain on the other side. Bottles of 30 (NDC 81520-200-30).

STORAGE AND HANDLING SECTION


Store between 20°C and 25°C (68°F and 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature].

17 Patient Counseling Information


Advise the patient to read the FDA-approved patient labeling (Patient Information).

Advise patients of the following:


Acute Tubulointerstitial Nephritis

To call their healthcare provider if they experience signs and/or symptoms associated with acute tubulointerstitial nephritis [see Warnings and Precautions (5.2)].


Clostridioides difficile-Associated Diarrhea

To immediately call their healthcare provider if they experience diarrhea that does not improve [see Warnings and Precautions (5.3)].


Bone Fracture

To report any fractures, especially of the hip, wrist or spine, to their healthcare provider [see Warnings and Precautions (5.4)].


Severe Cutaneous Adverse Reactions

To discontinue VOQUEZNA and report to their healthcare provider at first appearance of a severe cutaneous adverse reaction or other sign of hypersensitivity [see Warnings and Precautions (5.5)].


Vitamin B12 (Cobalamin) Deficiency

To report any clinical symptoms that may be associated with Vitamin B12 deficiency to their healthcare provider, if they have been receiving VOQUEZNA long-term [see Warnings and Precautions (5.6)].


Hypomagnesemia and Mineral Metabolism

To report any clinical symptoms that may be associated with hypomagnesemia, hypocalcemia, and/or hypokalemia to their healthcare provider [see Warnings and Precautions (5.7)].


Drug Interactions

To report to their healthcare provider if they start treatment with rilpivirine-containing products [see Contraindications (4)].


Pregnancy

To contact Phathom Pharmaceuticals, Inc. if exposed to VOQUEZNA during pregnancy [see Use in Specific Populations (8.1)].


Lactation

To not breastfeed during treatment with VOQUEZNA [see Use in Specific Populations (8.2)].


Important Administration Instructions
  • VOQUEZNA can be taken with or without food [see Dosage and Administration (2) and Clinical Pharmacology (12.3)].
  • Swallow VOQUEZNA tablets whole; do not to chew or crush the tablet.
  • Missed doses:
    • For the healing or maintenance of healed erosive esophagitis: If a dose is missed, administer VOQUEZNA as soon as possible within 12 hours after the missed dose. If more than 12 hours have passed, skip the missed dose and take your next dose at your regularly scheduled time [see Dosage and Administration (2)].
    • For the treatment of H. pylori infection: If a dose is missed, administer VOQUEZNA as soon as possible within 4 hours after the missed dose. If more than 4 hours have passed, skip the missed dose and administer your next dose at the regularly scheduled time. Continue the normal dosing schedule until the treatment is completed [see Dosage and Administration (2)].


VOQUEZNA is manufactured for and distributed byPhathom Pharmaceuticals, Inc.Buffalo Grove, IL 60089, U.S.A.

VOQUEZNA, the VOQUEZNA logo, and Phathom Pharmaceuticals are registered trademarks of Phathom Pharmaceuticals, Inc.

© 2023 Phathom Pharmaceuticals, Inc. All rights reserved.

VOQ222 V1

Spl Patient Package Insert Section

This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 11/2023  
PATIENT INFORMATIONVOQUEZNA® (voe kwez nah)(vonoprazan)tablets, for oral use
What is VOQUEZNA? VOQUEZNA is a prescription medicine called a potassium-competitive acid blocker. VOQUEZNA reduces the amount of acid in your stomach. VOQUEZNA is used in adults:
  • for 8 weeks to heal acid-related damage to the lining of the esophagus (called erosive esophagitis) and for relief of heartburn related to erosive esophagitis.
  • for up to 6 months to maintain healing of erosive esophagitis and for relief of heartburn related to erosive esophagitis.
  • for 14 days with the antibiotics amoxicillin and clarithromycin to treat an infection caused by bacteria called Helicobacter pylori (H. pylori).
  • for 14 days with the antibiotic amoxicillin to treat an infection caused by bacteria called H. pylori.
It is not known if VOQUEZNA is safe and effective in children.
Do not take VOQUEZNA if you are:
  • allergic to vonoprazan or any of the ingredients in VOQUEZNA. See the end of this Patient Information leaflet for a complete ul of ingredients in VOQUEZNA. Allergic reaction symptoms may include trouble breathing, rash, itching and swelling of your face, lips, tongue, or throat.
  • taking a medicine that contains rilpivirine (EDURANT, COMPLERA, JULUCA, ODEFSY, CABENUVA) used to treat HIV-1 (Human Immunodeficiency Virus).
Before taking VOQUEZNA, tell your healthcare provider about all of your medical conditions, including if you:
  • have low magnesium, calcium, or potassium in your blood or you are taking a medicine to increase urine (diuretic).
  • have kidney problems.
  • have liver problems.
  • are pregnant, think you may be pregnant or plan to become pregnant. It is not known if VOQUEZNA will harm your unborn baby. Call the Phathom Pharmaceuticals, Inc. Adverse Event reporting line at 1-888-775-7428 if you become pregnant while taking VOQUEZNA.
  • are breastfeeding or plan to breastfeed. It is not known if VOQUEZNA passes into your breast milk. You and your healthcare provider should decide if you will take VOQUEZNA or breastfeed. You should not do both.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Keep a ul of them to show your healthcare provider and pharmacist when you get a new medicine. VOQUEZNA may affect how other medicines work, and other medicines may affect how VOQUEZNA works.
How should I take VOQUEZNA?
  • Take VOQUEZNA exactly as your healthcare provider tells you to take it.
  • Do not change your dose or stop taking VOQUEZNA without talking to your healthcare provider first.
  • Take VOQUEZNA with or without food.
  • Swallow VOQUEZNA tablets whole. Do not chew or crush the tablet.
  • For the treatment of erosive esophagitis:
    • If you miss a dose of VOQUEZNA, take it as soon as possible within 12 hours after the missed dose. If more than 12 hours have passed, skip the missed dose and take the next dose at the regularly scheduled time.
  • For the treatment of H. pylori infection:
    • If you miss a dose of VOQUEZNA, take it as soon as possible within 4 hours after the missed dose. If more than 4 hours have passed, skip the missed dose and take the next dose at the regularly scheduled time. Continue your regular dosing schedule until the treatment is completed.
What are the possible side effects of VOQUEZNA?VOQUEZNA may cause serious side effects, including:
  • A type of kidney problem (acute tubulointerstitial nephritis). Some people who take VOQUEZNA may develop a kidney problem called acute tubulointerstitial nephritis. Call your healthcare provider right away if you have a decrease in the amount that you urinate or if you have blood in your urine.
  • Diarrhea caused by an infection (Clostridioides difficile) in your intestines. Call your healthcare provider right away if you have watery stools, stomach pain, or fever that does not go away.
  • Bone fractures (hip, wrist, or spine). Bone fractures in the hip, wrist, or spine may happen in people who take multiple daily doses of another type of medicine that reduces acid in your stomach known as proton pump inhibitors (PPI medicines) for a long period of time (a year or longer). Tell your healthcare provider if you have a bone fracture, especially in the hip, wrist, or spine.
  • Severe skin reactions. VOQUEZNA can cause rare but severe skin reactions that may affect any part of your body. These serious skin reactions may need to be treated in a hospital and may be life threatening:
    • Skin rash which may have bulering, peeling or bleeding on any part of your skin (including your lips, eyes, mouth, nose, genital, hands or feet).
    • You may also have fever, chills, body aches, shortness of breath, or enlarged lymph nodes.
    If you have any of these symptoms, stop taking VOQUEZNA and call your healthcare provider right away. These symptoms may be the first sign of a severe skin reaction.
  • Low Vitamin B-12 levels. VOQUEZNA lowers the amount of acid in your stomach. Stomach acid is needed to absorb Vitamin B12 properly. Tell your healthcare provider if you have symptoms of low vitamin B12 levels, including irregular heartbeat, shortness of breath, lightheadedness, tingling or numbness in the arms and legs, muscle weakness, pale skin, feeling tired, or mood changes. Talk with your healthcare provider about the risk of low Vitamin B12 levels if you have been on VOQUEZNA for a long time.
  • Low magnesium levels in the body can happen in people who take VOQUEZNA. Tell your healthcare provider right away if you have symptoms of low magnesium levels, including seizures, dizziness, irregular heartbeat, jitteriness, muscle aches or weakness, or spasms of hands, feet, or voice.
  • Stomach growths (fundic gland polyps). A certain type of stomach growth called fundic gland polyps may happen in people who take VOQUEZNA for a long time (more than a year). Talk with your healthcare provider about the risk of fundic gland polyps if you have been on VOQUEZNA for a long time.
The most common side effects of VOQUEZNA for treatment of erosive esophagitis include:
  • stomach inflammation
  • diarrhea
  • stomach bloating
  • stomach pain
  • nausea
  • indigestion
  • high blood pressure
  • urinary tract infection
The most common side effects of VOQUEZNA when used with antibiotics for treatment of H. pylori infection include:
  • diarrhea
  • temporary changes in sense of taste
  • vaginal yeast infection
  • stomach pain
  • headache
  • high blood pressure
  • cold-like symptoms
These are not all the possible side effects of VOQUEZNA.For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store VOQUEZNA?
  • Store VOQUEZNA at room temperature between 68°F to 77°F (20°C to 25°C).
Keep VOQUEZNA and all medicines out of the reach of children.
General information about the safe and effective use of VOQUEZNA. Medicines are sometimes prescribed for purposes other than those uled in a Patient Information leaflet. Do not use VOQUEZNA for a condition for which it was not prescribed. Do not give VOQUEZNA to other people, even if they have the same symptoms you have. It may harm them.You can ask your healthcare provider or pharmacist for information about VOQUEZNA that is written for health professionals.
What are the ingredients of VOQUEZNA?Active ingredient: vonoprazan Inactive ingredients: ascorbic acid, croscarmellose sodium, ferric oxide red (only in 20 mg tablets), ferric oxide yellow (only in 10 mg tablets), fumaric acid, hydroxypropyl cellulose, hypromellose, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol 8000, and titanium dioxide.
VOQUEZNA is manufactured for and distributed by:Phathom Pharmaceuticals, Inc.Buffalo Grove, IL 60089, U.S.A.VOQUEZNA, the VOQUEZNA logo, and Phathom Pharmaceuticals are registered trademarks of Phathom Pharmaceuticals, Inc.© 2023 Phathom Pharmaceuticals, Inc. All rights reserved.

Principal Display Panel - 10 Mg Tablet Bottle Label


NDC 81520-100-3030 TabletsRx only

VOQUEZNA® (vonoprazan) tablets

10 mg*

Principal Display Panel - 20 Mg Tablet Bottle Label


NDC 81520-200-3030 TabletsRx only

VOQUEZNA® (vonoprazan) tablets

20 mg*

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