Vonoprazan – Uses, Dosage, Side Effects, Interactions

Vonoprazan is a potassium-competitive acid blocker (PCAB) that inhibits H⁺, K⁺-ATPase-mediated gastric acid secretion. PCBs represent an alternative to proton-pump inhibitors for the treatment of acid-related disorders. Unlike proton-pump inhibitors, PCABs are not affected by CYP2C19 genetic polymorphisms and do not require acid-resistant formulations. Furthermore, vonoprazan is 350 times more potent than the proton-pump inhibitor [lansoprazole], thanks to its ability to accumulate in the gastric corpus mucosa, specifically in the parietal cells. In February 2015, vonoprazan was first marketed in Japan for the treatment of acid-related disorders and as an adjunct to Helicobacter pylori (H. pylori) eradication. In May 2022, the FDA approved the use of vonoprazan in a co-packaged product containing amoxicillin and clarithromycin for the treatment of H. pylori infection. Studies have shown that the concomitant use of vonoprazan, amoxicillin, and clarithromycin leads to an H. pylori eradication rate of approximately 90%.

Vonoprazan drug is an antiulcer drug that is used for the treatment of gastroesophageal reflux (GERD), heartburn, indigestion, gastritis, dyspepsia, etc. The potassium-competitive acid blocker vonoprazan is as effective as proton-pump inhibitors (PPIs) in healing gastric and duodenal ulcers  To determine if it is also as effective as PPIs in reducing the risk for recurrent nonsteroidal anti-inflammatory drug Vonoprazan fumarate is a first-in-class potassium-competitive acid blocker. It was approved in the Japanese market in February 2015.

Vonoprazan Fumarate is the fumarate salt form of vonoprazan, a pyrrole derivative and reversible potassium-competitive acid blocker (P-CAB), with potential antacid activity. Upon administration, vonoprazan specifically and competitively binds to the gastric hydrogen-potassium ATPase (H+/K+ ATPase) proton pump at or, more likely, near its potassium ion (K+) binding site and sterically inhibits K+ binding. This blocks the activation of the H+/K+ ATPase by K+, inhibits the proton pump and prevents gastric acid secretion, thereby lowering gastric acid levels.

The fumarate salt form of vonoprazan, a pyrrole derivative and reversible potassium-competitive acid blocker (P-CAB), with potential antacid activity. Upon administration, vonoprazan specifically and competitively binds to the gastric hydrogen-potassium ATPase (H+/K+ ATPase) proton pump at or, more likely, near its potassium ion (K+) binding site and sterically inhibits K+ binding. This blocks the activation of the H+/K+ ATPase by K+, inhibits the proton pump, and prevents gastric acid secretion, thereby lowering gastric acid levels.

Mechanism of Actions

Vonoprazan is a potassium-competitive acid blocker (PCAB) that inhibits the H⁺, K⁺-ATPase enzyme system in a potassium-competitive manner. Through this mechanism, vonoprazan suppresses basal and stimulated gastric acid secretion at the secretory surface of gastric parietal cells. Although both classes of drugs inhibit the H⁺, K⁺-ATPase, the mechanism of action of PCABs differs from that of proton-pump inhibitors (PPIs). PPIs form a covalent disulfide bond with a cysteine residue on the H⁺, K⁺-ATPase, which leads to the inactivation of the enzyme, while PCABs interfere with the binding of K⁺ to the H⁺, K⁺-ATPase.

The use of vonoprazan leads to an increase in intragastric pH. The inhibitory effect of vonoprazan on acid secretion increases with repeated daily dosing. Although the antisecretory effect of vonoprazan decreases after drug discontinuation, intragastric pH remains elevated for 24 to 48 hours. Vonoprazan does not have a clinically significant effect on QT prolongation. Compared to other potassium-competitive acid blockers (PCABs), vonoprazan has a higher point-positive charge (pKa of 9.06). This allows vonoprazan to accumulate at higher concentrations in the canalicular space of the gastric parietal cells, where it binds H⁺, K⁺-ATPase in a K⁺-competitive and reversible manner. Compared to other PCABs, such as SCH28080, or proton-pump inhibitors, such as lansoprazole, vonoprazan has a more potent H⁺, K⁺-ATPase inhibitory activity.

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 concentrates in the parietal cells in both the resting and stimulated states. Vonoprazan binds to the active proton pumps in a non-covalent and reversible manner. Amoxicillin is an antibacterial drug. Clarithromycin is a macrolide antimicrobial drug [see Microbiology (12.4)]. Acid suppression enhances the replication of H. pylori bacteria and the stability and effectiveness of antimicrobials in the treatment of H. pylori infection.

Indications

• Vonoprazan, in combination with amoxicillin and clarithromycin in a co-packaged product, is indicated for the treatment of _Helicobacter pylori_ (_H. pylori_) infection in adults. Another co-packaged product with only vonoprazan and amoxicillin is also indicated for the treatment of _H. pylori_ infection in adults.
• Treatment of gastroesophageal reflux disease, Treatment of Helicobacter pylori infection.
• Duodenal Ulcer
• Gastric Ulcer
• Gastric or Duodenal Ulcers Caused by Low-dose Aspirin
• Helicobacter Pylori Infection
• Reflux Esophagitis (RE)
• Develop NSAID-induced gastric ulcers

Contraindications

Vonoprazan TRIPLE PAK and VOQUEZNA DUAL PAK:

• Known hypersensitivity to vonoprazan, amoxicillin or any other betalactams, clarithromycin or any other macrolide antimicrobial or any component of VOQUEZNA TRIPLE PAK. (4.1)
•  Known hypersensitivity to vonoprazan, amoxicillin or any other beta-lactams or any component of VOQUEZNA DUAL PAK. (4.1)
• Rilpivirine-containing products. (4.1) VOQUEZNA TRIPLE PAK Due to the Clarithromycin Component:
• Pimozide. (4.2)
• Lomitapide, lovastatin, and simvastatin. (4.2)
• Ergot alkaloids (ergotamine or dihydroergotamine). (4.2)
• Colchicine in renal or hepatic impairment. (4.2)
• History of cholestatic j

Dosage

Voquezna Triple Pak:

Vonoprazan 20 mg plus amoxicillin 1,000 mg plus clarithromycin 500 mg, each given twice daily (morning and evening, 12 hours apart), with or without food, for 14 days Voquezna Dual Pak: vonoprazan 20 mg twice daily (morning and evening) plus amoxicillin 1,000 mg, three times a day (morning, mid-day, and evening), with or without food, for 14 days

VonoprazanTRIPLE PAK:

• The recommended dosage regimen is vonoprazan 20 mg plus amoxicillin 1,000 mg plus clarithromycin 500 mg, each given twice daily (morning and evening, 12 hours apart), with or without food, for 14 days. (2.1)

Vonoprazan DUAL PAK:

• The recommended dosage regimen is vonoprazan 20 mg twice daily (morning and evening) plus amoxicillin 1,000 mg, three times a day (morning, mid-day, and evening), with or without food, for 14 days. (2.2)

VonoprazanTRIPLE PAK:

Carton of 14 daily administration packs for morning and evening dosing, each containing the following three drug products (3.1):

• Tablets: Vonoprazan 20 mg
• Tablets: Clarithromycin 500 mg
• Capsules: Amoxicillin 500 mg

Vonoprazan DUAL PAK:

Carton of 14 daily administration packs for the morning, mid-day, and evening dosing, each containing the following
two drug products (3.2):

• Tablets: Vonoprazan 20 mg
• Capsules: Amoxicillin 500 mg

Side Effects

The Most Common

• diarrhea
• stomach pain
• change in ability to taste food
• headache
• sore throat
• vaginal itching and/or discharge

More Common

• blistering or peeling skin
• rash; hives; itching; swelling of the lips, face, or tongue; shortness of breath; difficulty breathing or swallowing
• yellow eyes or skin, loss of appetite, dark urine; itching, abdominal pain, unexplained bruising or bleeding, or loss of appetite
• severe diarrhea (watery or bloody stools) that may occur with or without fever and stomach cramps (may occur up to 2 months or more after your treatment)

Drugs Interactions

Pregnancy and Lactation

Pregnancy

Based on findings from animal studies and observational studies in pregnant women with the use of clarithromycin, the use of VOQUEZNA TRIPLE PAK is not recommended in pregnant women except in clinical circumstances where no alternative therapy is appropriate. There are no adequate and well-controlled studies of VOQUEZNA TRIPLE PAK in pregnant women to evaluate for drug-associated
risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. If VOQUEZNA TRIPLE PAK is used during pregnancy, advise pregnant women of the potential risk to a fetus. No reproductive and developmental toxicity studies with the combination of vonoprazan, amoxicillin, and/or clarithromycin were conducted.
VOQUEZNA DUAL PAK
There are no adequate and well-controlled studies of VOQUEZNA DUAL PAK in pregnant women to evaluate for drug-associated risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Individual Components of VOQUEZNA TRIPLE PAK and VOQUEZNA DUAL PAK
Clarithromycin:
Published observational studies in pregnant women have demonstrated adverse effects on pregnancy outcomes, including an increased risk of miscarriage and in some studies an increased incidence of fetal malformations (see Data). In animal reproduction studies, administration of oral clarithromycin to pregnant mice, rats, rabbits, and monkeys during the period of organogenesis produced malformations in rats (cardiovascular anomalies) and mice (cleft palate) at clinically relevant doses. Fetal effects in mice, rats, and monkeys (e.g., reduced fetal survival, body weight, body weight gain) and implantation losses in rabbits were generally considered to be secondary to
maternal toxicity (see Data).
Vonoprazan:
Available data from pharmacovigilance reports with vonoprazan 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 of 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
Amoxicillin:
Available data from published epidemiologic studies and pharmacovigilance case reports over several decades with amoxicillin use have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Reproduction studies with amoxicillin have been performed in mice and rats (5 and 10 times the human dose 2 g human dose for mice and rats, respectively, 3 and 6 times the 3 g human dose for mice and rats, respectively). There was no evidence of harm to the fetus due to amoxicillin. The estimated background risks of major birth defects and miscarriage for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the US 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 1-800-775-

Clarithromycin:
Available data from prospective and retrospective observational studies with clarithromycin use in pregnant women demonstrate an increased risk of miscarriage. Data from these same studies regarding major congenital malformations are inconsistent, with some studies reporting an increased risk (atrioventricular septal defects, genital malformations, orofacial clefts) and others finding no
difference between those exposed to clarithromycin and those exposed to nonteratogenic controls. Available studies have methodologic limitations, including small sample size, under-capture of nonlive births, exposure misclassification and inconsistent comparator groups.

Lactation

No information is available on the clinical use of vonoprazan during breastfeeding. Because of liver damage that occurred in nursing rodents, the manufacturer recommends that nursing mothers should pump and discard human milk while taking and for 2 days after the last dose. An alternate drug may be preferred. Relevant published information was not found as of the revision date. Relevant published information was not found as of the revision date.

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. The 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, a woman should pump and discard human milk for the duration of VOQUEZNA TRIPLE PAK or VOQUEZNA DUAL PAK therapy, and for 2 days after therapy ends, and feed her infant stored human milk (collected prior to therapy) or formula.
Based on data from a published lactation study, clarithromycin and its active metabolite 14-OH clarithromycin are present in human milk at less than 2% of the maternal weight-adjusted dose (see Data). In a separate observational study of lactating women exposed to clarithromycin, reported adverse effects on breastfed children (rash, diarrhea, loss of appetite, somnolence) were comparable to amoxicillin. No data are available to assess the effects of clarithromycin or 14-OH clarithromycin on milk production.

Toxicology

Overdose with vonoprazan has not been reported. No serious adverse reactions were observed during clinical studies in subjects given a single dose of 120 mg of vonoprazan. Vonoprazan is not removed from the circulation by hemodialysis. In case of overdose, the FDA label for Voquezna Triple Pak and Voquezna Dual Pak recommends symptomatic and supportive treatment. Animal studies evaluating vonoprazan mutagenicity (Ames test) have reported negative results. No effects on fertility and reproductive performance were observed in rats given 300 mg/kg/day of vonoprazan orally (133, the maximum recommended human dose). Mice given 6, 20, 60, and 200 mg/kg/day of vonoprazan orally (0.4, 4, 19, and 93 times the maximum recommended human dose) developed hyperplasia of neuroendocrine cells, gastropathy and benign and/or malignant neuroendocrine cell tumors (carcinoids) in the stomach.

Vonoprazan is metabolized by several cytochrome P450 (CYP) isoforms, mainly CYP3A4, and to a lesser extent CYP3A5, CYP2B6, CYP2C19, CYP2C9 and CYP2D6. Sulfo- and glucuronosyl-transferases also participate in the metabolism of vonoprazan, and all metabolites are pharmacologically inactive. CYP3A4 converts vonoprazan into metabolites M-I and M-II, which are then converted to glucuronic-acid-conjugated products M-I-G and M-II-G, respectively. Unlike proton pump inhibitors, the presence of CYP2C19 polymorphisms does not have a significant effect on the pharmacokinetics of vonoprazan.

References

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