Vonoprazan

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. 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. 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.

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 vonoprazan.

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.

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.

• Acute Tubulointerstitial Nephritis
• Clostridioides difficile-Associated Diarrhea
• Bone Fracture
• Severe Cutaneous Adverse Reactions
• Vitamin B12 (Cobalamin) Deficiency
• Hypomagnesemia and Mineral Metabolism
• Fundic Gland Polyps

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 vonoprazan 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.

Adverse reactions reported in at least 2% of patients in the vonoprazan arm in the healing phase are presented in Table 1.

Table 1. Adverse Reactions* in a Clinical Trial of Adult Patients with All Grades of Erosive Esophagitis^† (2 to 8 Week Healing Phase):

^* Reported in at least 2% of patients in the vonoprazan arm.
^† The trial was not designed to support comparative claims for vonoprazan for the adverse reactions reported in this table.
^‡ Represents a grouped term and includes related terms.

Adverse reactions reported in at least 3% of patients in the vonoprazan arm of the maintenance phase are shown in Table 2.

Table 2. Adverse Reactions* in a Clinical Trial of Adult Patients with All Grades of Erosive Esophagitis^† (24 Week Maintenance Phase):

^* Reported in at least 3% of patients in the vonoprazan arm.
^† The trial was not designed to support comparative claims for vonoprazan for the adverse reactions reported in this table.
^‡ Represents grouped term and includes related terms.

COVID-19

COVID-19 was reported in the healing phase in 11 (2%) vonoprazan-treated subjects and 9 (2%) lansoprazole-treated subjects; and in the maintenance phase in 18 (6%) vonoprazan-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 vonoprazan-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 vonoprazan, 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 vonoprazan 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 vonoprazan, amoxicillin and clarithromycin (triple therapy) and vonoprazan 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.

Adverse Reactions Leading to Discontinuation

Treatment discontinuation due to an adverse reaction occurred in 2.3% (8/346) of the patients treated with vonoprazan, amoxicillin and clarithromycin, 0.9% (3/348) of the patients treated with vonoprazan 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 vonoprazan, amoxicillin and clarithromycin were diarrhea (0.6%) and hypertension (0.6%) and the most common adverse reaction leading to discontinuation of vonoprazan 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 3.

Table 3. Adverse Reactions* in Adult Patients with H. pylori Infection^†:

^* Reported in at least 2% of patients in any treatment arm.
^† These trials were not designed to support comparative claims for vonoprazan-containing treatment arms for the adverse reactions reported in this table.
^‡ Represents grouped term and includes related terms.

Less Common Adverse Reactions

Other adverse reactions reported in less than 2% of patients treated with vonoprazan, amoxicillin, and clarithromycin or vonoprazan and amoxicillin are listed 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.

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

Infections and infestations: C. difficile (with concomitant antibacterials)

Investigation: hypomagnesemia, hypokalemia, hypocalcemia, vitamin B12 deficiency

Hepatobiliary disorders: hepatic injury, hepatic failure, jaundice

Skin and subcutaneous tissue disorders: drug eruption, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis