Vonoprazan is an oral potassium-competitive acid blocker (PCAB) that is similar to the proton-pump inhibitors (PPIs). Vonoprazan is indicated for the healing and maintenance treatment of all grades of erosive esophagitis (EE) and relief of heartburn associated with EE in adults. During a randomized, active-controlled double-blind study, vonoprazan (n=514) was showed to be non-inferior to its comparator, lansoprazole (n=510), in complete healing of all grades of erosive esophagitis at week 2 or week 8 (8% treatment difference; 95% CI: 4.5 to 12.2). In maintenance of healed erosive esophagitis and relief of heartburn, vonoprazan (n=293) demonstrated non-inferiority and superiority to lansoprazole (n=294) through week 24 in all grades of disease severity (7% treatment difference; 95% CI: 0.2 to 14.1). Vonoprazan may also be used in combination with amoxicillin and clarithromycin or with amoxicillin alone for the treatment of Helicobacter pylori (H. pylori) infection in adults. Appropriate treatment of H. pylori reduces symptoms, improves gastric healing, helps prevent future ulceration, and reduces the risk of complications from peptic ulcer disease (e.g., bleeding). Vonoprazan reduces intragastric acidity and may affect the oral absorption of certain oral medications, leading to changes in safety and/or effectiveness; review drug interactions.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
Tablets:
-May administer with or without food.
-Administer whole, do not crush or chew the tablet.
-Missed doses:-For healing or maintenance of erosive esophagitis (EE): Administer the missed dose 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 on the regularly scheduled time. Patients should continue the normal dosing schedule until the medication is completed.
-For H. pylori eradication: Administer the missed dose 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 on the regularly scheduled time. Patients should continue the normal dosing schedule until the medication is completed.
Hypersensitivity and dermatologic reactions may occur with the use of vonoprazan. Vonoprazan has been reported to cause hypersensitivity or dermatologic reactions during postmarketing use such as anaphylactic shock, drug eruption, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN). Eczema, rash, and urticaria were reported in less than 1% of patients receiving vonoprazan monotherapy. If hypersensitivity is suspected or a skin reaction occurs, discontinue vonoprazan and institute appropriate evaluation and treatment.
C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with vonoprazan. PPI therapy, such as vonoprazan, may be associated with an increased risk of CDAD, especially in hospitalized patients. The use of gastric acid suppressive therapy, such as PPIs, may increase the risk of enteric infection or superinfection by encouraging the growth of gut microflora. If pseudomembranous colitis is suspected or confirmed, institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Other infections reported include urinary tract infection (3%) and upper respiratory infection (1% or less). During clinical trials, COVID-19 was reported in 2% to 6% of vonoprazan treated patients compared to 2% to 7% of lansoprazole comparator treated patients.
During the 2 to 8 week healing phase of clinical trails with vonoprazan monotherapy (n=514), gastritis (3%), diarrhea (2%), abdominal distension (2%), abdominal pain (2%), and nausea (2%) were the most commonly reported gastrointestinal (GI) adverse reactions. In a 24-week maintenance phase clinical trial with vonoprazan monotherapy (n=296), gastritis (6%), abdominal pain (4%), and dyspepsia (4%) were commonly reported. These trials were not designed to compare adverse reactions for vonoprazan to its comparator. Other GI adverse reactions occurring in less than 1% of patients included, duodenal polyp, xerostomia (dry mouth), dysphagia, eructation, flatulence, gastric polyps, and vomiting. Vonoprazan is also associated with a risk of fundic gland polyps with long term use, especially beyond 1 year. Fundic gland polyps have been reported with vonoprazan in clinical trials and postmarketing use with PPIs. Most patients were asymptomatic and the polyps were identified on incidentally on endoscopy.
Acute tubulo- interstitial nephritis and diabetes mellitus have been reported in less than 1% of patients treated with vonoprazan.
Proton pump inhibitor therapy may be associated with an increased risk of osteoporosis related bone fractures of the hip, wrist, and spine. The risk for fracture is increased in patients who take high-dose or multiple daily doses, and treatment longer than a year. Manage patients at risk for osteoporosis related fractures according to guidelines. Asthenia and bone fracture have each been reported in less than 1% of vonoprazan treated patients.
Vitamin B12 deficiency has been reported in post marketing experience in patients treated with vonoprazan. Consider further workup in patients experiencing vitamin B12 deficiency. Hypomagnesemia has been reported in post marketing experience with vonoprazan and can lead to hypocalcemia and/or hypokalemia. In at risk patients, hypomagnesemia can exacerbate underlying hypocalcemia. Consider magnesium replacement and discontinue vonoprazan to treat hypomagnesemia. Consider discontinuing vonoprazan if hypocalcemia is refractory to treatment.
Hypertension was reported in 4% of patients during a 24-week maintenance phase study with vonoprazan (n=296). Sinus tachycardia and peripheral edema have been reported in less than 1% of patients treated with vonoprazan during clinical trails.
Dizziness, headache, syncope, vertigo, depression, and insomnia have been reported in less than 1% of vonoprazan treated patients.
Less than 1% of vonoprazan treated patients experienced elevated hepatic enzymes (increased liver function test). Hepatic injury, hepatic failure, and jaundice were reported during post marketing experience.
Anemia and lymphocytosis have been reported in less than 1% of patients treated with vonoprazan during clinical trails. Thrombocytopenia has been reported in post marketing experience with vonoprazan.
Vonoprazan is contraindicated for use with rilpivirine-containing products. Review drug interactions prior to prescribing.
Symptomatic response to vonoprazan may not eliminate the possibility of gastric malignancy or gastric cancer. Consider additional follow-up and diagnostic testing in patients who have suboptimal response or an early symptomatic relapse after completing vonoprazan therapy. Consider endoscopy in older patients. Vonoprazan is associated with a risk of fundic gland polyps and polyps have been reported during clinical studies with vonoprazan. The risk for fundic glad polyps increases with long term use, especially beyond 1 year. Most patients were asymptomatic and polyps were identified on endoscopy. Use the shortest duration of vonoprazan appropriate to the condition being treated.
Consider pseudomembranous colitis in patients presenting with diarrhea after PPI use. PPI therapy, such as vonoprazan, may be associated with an increased risk of C. difficile-associated diarrhea (CDAD), especially in hospitalized patients. CDAD may range in severity from mild to life-threatening. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.
Bone fractures and osteoporosis related fractures have been reported with vonoprazan use. Use of proton pump inhibitor therapy has been associated with an increased risk for osteoporosis related fractures of the hip, wrist, or spine. The risk of bone fracture is increased in patients who receive PPI's in multiple daily doses and in long term therapy lasting more than a year. Consider using the shortest duration of vonoprazan appropriate to the condition treated. Patients at risk for osteoporosis related fractures should be managed according to treatment guidelines.
Patients who have a hypersensitivity to vonoprazan are contraindicated to receive this product. Severe cutaneous adverse reactions, such as Steven-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in vonoprazan use. If signs and symptoms of severe cutaneous adverse reactions occur, such as serious rash, discontinue vonoprazan and consider further evaluation.
Long term use of acid suppressing drugs can lead to malabsorption of Vitamin B12 causes by achlorhydria or hypochlorhydria. Vitamin B12 deficiency has been reported in post marketing with vonoprazan. Consider further evaluation in patients with clinical symptoms consistent with Vitamin B12 deficiency.
Hypomagnesemia has been reported in post marketing experience with vonoprazan. Hypomagnesemia may lead to hypocalcemia and/or hypokalemia and may exacerbate underlying hypocalcemia in at-risk patients. Consider monitoring magnesium levels prior to treatment initiation 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 for hypomagnesemia may require magnesium replacement and vonoprazan discontinuation. Consider monitoring magnesium and calcium levels prior to vonoprazan initiation and periodically during treatment in patients with risk for hypocalcemia (e.g., hypoparathyroidism). Supplement with magnesium and/or calcium, as necessary. Consider discontinuing vonoprazan if hypocalcemia is refractory to treatment.
Administration of vonoprazan may result in diagnostic or laboratory test interference. Vonoprazan reduces intragastric acidity, which increases chromogranin A (CgA) levels and may cause false positive results in diagnostic investigations for neuroendocrine tumors. Assess CgA levels at least 14 days after vonoprazan 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.
Acute tubulo- interstitial nephritis has been reported with vonoprazan use. Discontinue vonoprazan if tubulo- interstitial nephritis occurs.
The use of vonoprazan is not recommended for the treatment of H. pylori in patients with severe renal impairment (eGFR less than 30 mL/minute) or renal failure. Dosage reduction is recommended in patients with severe renal impairment (eGFR less than 30 mL/minute) or renal failure for the healing of erosive esophagitis (EE). No dosage adjustment is required for the healing of EE in patients with mild to moderate renal impairment (eGFR 30 to 89 mL/minute), and in patients with any degree of renal impairment for maintenance of healed EE.
The use of vonoprazan is not recommended for the treatment of H. pylori in patients with moderate or severe (Child-Pugh B or C) hepatic disease. Dosage reduction is required for use of vonoprazan for the healing of erosive esophagitis (EE) in patients with moderate or severe (Child-Pugh B or C) hepatic disease. No dosage adjustment is needed for use of vonoprazan for the healing of EE in patients with mild hepatic impairment (Child-Pugh A), or for the maintenance of healed EE in patients with any degree of hepatic impairment.
There are no adequate and well-controlled studies of vonoprazan during pregnancy or in pregnant women to evaluate for drug-associated risks of 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. The manufacturer requests that pregnancy exposures be reported to the Phathom Pharmaceuticals, Inc. Adverse Event reporting line at 1-888-775-7428.
There are no data regarding the presence of vonoprazan in humans while breast-feeding, 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 maximum recommended human dose (MRHD). 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 therapy.
For Helicobacter pylori (H. pylori) eradication as part of dual or triple therapy:
Oral dosage:
Adults: 20 mg PO twice daily in combination with either amoxicillin or amoxicillin with clarithromycin for 14 days.
For the treatment of erosive esophagitis (EE or erosive GERD) and pyrosis (heartburn) associated with EE:
-for healing of all grades of erosive esophagitis (EE) and relief of heartburn associated with EE:
Oral dosage:
Adults: 20 mg PO once daily for 8 weeks.
-to maintain healing of all grades of erosive esophagitis (EE) and relief of heartburn associated with EE:
Oral dosage:
Adults: 10 mg PO once daily for up to 6 months.
Maximum Dosage Limits:
-Adults
40 mg/day PO.
-Geriatric
40 mg/day PO.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Healing of erosive esophagitis (EE):
Child-Pugh A: 20 mg PO once daily.
Child-Pugh Class B or C: 10 mg PO once daily.
Maintenance treatment for EE: No dosage adjustment needed.
Treatment of H. pylori infection:
Child-Pugh Class A: 20 mg PO twice daily.
Child-Pugh Class B or C: Use not recommended.
Patients with Renal Impairment Dosing
Healing of erosive esophagitis (EE):
eGFR 30 mL/minute or greater: 20 mg PO once daily.
eGFR less than 30 mL/minute: 10 mg PO once daily.
Maintenance treatment of EE: No dosage adjustment needed.
Treatment of H. pylori infection:
eGFR 30 mL/minute or greater: 20 mg PO twice daily.
eGFR less than 30 mL/minute: Use not recommended.
*non-FDA-approved indication
Acalabrutinib: (Major) Avoid concomitant use of acalabrutinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of acalabrutinib reducing its efficacy.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with vonoprazan may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Vonoprazan is a weak inhibitor of CYP3A, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Albuterol; Budesonide: (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If vonoprazan is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alprazolam: (Major) Avoid coadministration of alprazolam and vonoprazan due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration is necessary, consider reducing the dose of alprazolam as clinically appropriate and monitor for an increase in alprazolam-related adverse reactions. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with vonoprazan, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased alprazolam maximum concentration by 82%, decreased clearance by 42%, and increased half-life by 16%.
Amobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Amphetamine: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Amphetamine; Dextroamphetamine Salts: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Amphetamine; Dextroamphetamine: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Apalutamide: (Major) Avoid concomitant use of vonoprazan and apalutamide due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and apalutamide is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Aripiprazole: (Moderate) Monitor for aripiprazole-related adverse reactions during concomitant use of vonoprazan. Patients receiving both a CYP2D6 inhibitor plus vonoprazan may require an aripiprazole dosage adjustment. Dosing recommendations vary based on aripiprazole dosage form, CYP2D6 inhibitor strength, and CYP2D6 metabolizer status. See prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is a CYP3A and CYP2D6 substrate; vonoprazan is a weak CYP3A inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Major) Avoid concomitant use of atazanavir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of atazanavir reducing its efficacy.
Atazanavir; Cobicistat: (Major) Avoid concomitant use of atazanavir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of atazanavir reducing its efficacy.
Barbiturates: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of vonoprazan with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Bexarotene: (Major) Avoid concomitant use of vonoprazan and bexarotene due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and bexarotene is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Bosentan: (Major) Avoid concomitant use of vonoprazan and bosentan due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and bosentan is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Budesonide: (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Formoterol: (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Monitor for altered response to budesonide in patients receiving vonoprazan with enteric-coated or extended-release formulations of oral budesonide. Enteric-coated budesonide granules (Entocort EC) dissolve at a pH greater than 5.5. Likewise, the dissolution of the coating of extended-release budesonide tablets (Uceris) is pH dependent. Concomitant use of oral budesonide and drugs that increase gastric pH levels, such as vonoprazan, can cause these products to dissolve prematurely, possibly affecting release properties and absorption of the drug in the duodenum.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and vonoprazan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when vonoprazan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping vonoprazan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If vonoprazan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and vonoprazan is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and vonoprazan can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when vonoprazan is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping vonoprazan, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If vonoprazan is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and vonoprazan is a CYP3A inhibitor.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Cabotegravir; Rilpivirine: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Carbamazepine: (Major) Avoid concomitant use of vonoprazan and carbamazepine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase carbamazepine concentrations. Vonoprazan is a CYP3A substrate and weak CYP3A inhibitor and carbamazepine is a CYP3A substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Cefpodoxime: (Moderate) Monitor for altered response to cefpodoxime if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of cefpodoxime reducing its efficacy.
Cefuroxime: (Major) Avoid concomitant use of cefuroxime and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of cefuroxime reducing its efficacy.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with vonoprazan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of vonoprazan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Major) Avoid concomitant use of vonoprazan and cenobamate due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and cenobamate is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with vonoprazan and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor. Coadministration with another CYP2C19 inhibitor did not significantly affect the metabolism of cilostazol, but the systemic exposure to 3,4-dehydro-cilostazol was increased by 69%.
Cisapride: (Major) Avoid concomitant use of cisapride and vonoprazan; use increases cisapride exposure and the risk for adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Concomitant use of cisapride with CYP3A inhibitors is disallowed under the Propulsid Limited Access Program.
Citalopram: (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with vonoprazan. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation or serotonin-related side effects. Citalopram is a sensitive CYP2C19 substrate and vonoprazan is a CYP2C19 inhibitor.
Clopidogrel: (Moderate) Monitor for reduced clopidogrel efficacy during concomitant use of vonoprazan. Clopidogrel is primarily metabolized to its active metabolite by CYP2C19 and vonoprazan is a CYP2C19 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with vonoprazan and monitor for adverse reactions. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A and vonoprazan is a weak CYP3A inhibitor. If vonoprazan is discontinued, monitor for lack of clozapine effect and increase dose if necessary.
Codeine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with vonoprazan may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of vonoprazan could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If vonoprazan is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A to norcodeine; norcodeine does not have analgesic properties. Vonoprazan is a weak inhibitor of CYP3A.
Cyclosporine: (Moderate) Closely monitor cyclosporine whole blood trough concentrations as appropriate and watch for cyclosporine-related adverse reactions if coadministration with vonoprazan is necessary. The dose of cyclosporine may need to be adjusted. Concurrent use may increase cyclosporine exposure causing an increased risk for cyclosporine-related adverse events. Cyclosporine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Dabrafenib: (Major) Avoid concomitant use of vonoprazan and dabrafenib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and dabrafenib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Dacomitinib: (Major) Avoid concomitant use of dacomitinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of dacomitinib reducing its efficacy.
Dasatinib: (Major) Avoid concomitant use of dasatinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of dasatinib reducing its efficacy.
Dextroamphetamine: (Major) Avoid concomitant use of amphetamines and vonoprazan. Vonoprazan reduces intragastric acidity, which may increase the exposure of amphetamines and risk of toxicity.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with vonoprazan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A and CYP2C19 substrate and vonoprazan is a CYP3A and CYP2C19 inhibitor.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with vonoprazan is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with moderate and strong CYP3A inhibitors.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with vonoprazan is necessary as concurrent use may increase dofetilide exposure. Vonoprazan is a weak CYP3A inhibitor. Dofetilide is a minor CYP3A substrate; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A inhibitors may increase the risk of arrhythmia (torsade de pointes).
Dolutegravir; Rilpivirine: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Doxepin: (Moderate) Monitor for an increase in doxepin-related adverse reactions if concomitant use of vonoprazan is necessary. Concomitant use may increase doxepin exposure; doxepin is primarily metabolized by CYP2C19 and CYP2D6 and vonoprazan is a CYP2C19 inhibitor.
Efavirenz: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Avoid concomitant use of vonoprazan and efavirenz due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and efavirenz is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Elagolix: (Major) Avoid concomitant use of vonoprazan and elagolix due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Elagolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of vonoprazan and elagolix due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and elagolix is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Eliglustat: (Major) Coadministration of eliglustat and vonoprazan is not recommended in poor CYP2D6 metabolizers (PMs). In extensive CYP2D6 metabolizers (EM) with mild hepatic impairment, coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. Eliglustat is a CYP3A and CYP2D6 substrate; vonoprazan is a weak CYP3A inhibitor. Because CYP3A plays a significant role in the metabolism of eliglustat in CYP2D6 PMs, coadministration of eliglustat with CYP3A inhibitors may increase eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Encorafenib: (Major) Avoid concomitant use of vonoprazan and encorafenib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and encorafenib is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A inducer.
Enzalutamide: (Major) Avoid concomitant use of vonoprazan and enzalutamide due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and enzalutamide is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Erlotinib: (Major) Avoid concomitant use of erlotinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of erlotinib reducing its efficacy.
Eslicarbazepine: (Major) Avoid concomitant use of vonoprazan and eslicarbazepine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and eslicarbazepine is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Etravirine: (Major) Avoid concomitant use of vonoprazan and etravirine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and etravirine is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Felodipine: (Moderate) Concurrent use of felodipine and vonoprazan should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Concurrent use of another weak CYP3A inhibitor increased felodipine AUC and Cmax by approximately 50%.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If vonoprazan is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Ferric Maltol: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Finerenone: (Moderate) Monitor serum potassium during initiation or dose adjustment of either finerenone or vonoprazan; a finerenone dosage reduction may be necessary. Concomitant use may increase finerenone exposure and the risk of hyperkalemia. Finerenone is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. Coadministration with another weak CYP3A inhibitor increased overall exposure to finerenone by 21%.
Flibanserin: (Moderate) The concomitant use of flibanserin and multiple weak CYP3A inhibitors, including vonoprazan, may increase flibanserin concentrations, which may increase the risk of flibanserin-induced adverse reactions. Therefore, patients should be monitored for hypotension, syncope, somnolence, or other adverse reactions, and the potential outcomes of combination therapy with multiple weak CYP3A inhibitors and flibanserin should be discussed with the patient.
Fosamprenavir: (Major) Avoid concomitant use of vonoprazan and fosamprenavir due to altered plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and fosamprenavir is both a strong CYP3A inhibitor and moderate CYP3A inducer. The net effect on CYP3A4 substrates is unclear. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Fosphenytoin: (Major) Avoid concomitant use of vonoprazan and fosphenytoin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase fosphenytoin concentrations. Vonoprazan is a CYP3A substrate and CYP2C19 inhibitor and fosphenytoin is a CYP2C19 substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Gefitinib: (Major) Avoid concomitant use of gefitinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of gefitinib reducing its efficacy.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. Hydrocodone is a CYP3A substrate, and coadministration with CYP3A inhibitors like vonoprazan can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If vonoprazan is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Infigratinib: (Major) Avoid concomitant use of infigratinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of infigratinib reducing its efficacy.
Iron Salts: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Iron: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Avoid concomitant use of vonoprazan and rifampin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Isoniazid, INH; Rifampin: (Major) Avoid concomitant use of vonoprazan and rifampin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with vonoprazan is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Itraconazole: (Moderate) Administer vonoprazan at least 2 hours before or 2 hours after itraconazole 100 mg capsules. Monitor for increased itraconazole-related adverse effects if vonoprazan is administered with itraconazole 65 mg capsules; a dose reduction may be needed. Drugs that reduce gastric acidity, such as vonoprazan, may decrease the systemic exposure of the 100 mg itraconazole capsule formulation. Conversely, exposure to itraconazole is increased when gastric acid reducers are administered with the 65 mg itraconazole capsule.
Ixabepilone: (Moderate) Monitor for ixabepilone toxicity and reduce the ixabepilone dose as needed if concurrent use of vonoprazan is necessary. Concomitant use may increase ixabepilone exposure and the risk of adverse reactions. Ixabepilone is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Ketoconazole: (Major) Avoid concomitant use of ketoconazole and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ketoconazole reducing its efficacy.
Ledipasvir; Sofosbuvir: (Major) Avoid concomitant use of ledipasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ledipasvir reducing its efficacy.
Lemborexant: (Major) Limit the dose of lemborexant to 5 mg PO once daily if coadministered with vonoprazan as concomitant use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A substrate; vonoprazan is a weak CYP3A inhibitor. Coadministration with a weak CYP3A inhibitor is predicted to increase lemborexant exposure by less than 2-fold.
Levoketoconazole: (Major) Avoid concomitant use of ketoconazole and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of ketoconazole reducing its efficacy.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Levothyroxine: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Levothyroxine; Liothyronine (Porcine): (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Levothyroxine; Liothyronine (Synthetic): (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with vonoprazan is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Liothyronine: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Lomitapide: (Major) Decrease the dose of lomitapide by one-half not to exceed 30 mg/day PO if coadministration with vonoprazan is necessary. Concomitant use may significantly increase the serum concentration of lomitapide. Vonoprazan is a weak CYP3A inhibitor; the exposure to lomitapide is increased by approximately 2-fold in the presence of weak CYP3A inhibitors.
Lonafarnib: (Major) Avoid coadministration of lonafarnib and vonoprazan; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing vonoprazan. Lonafarnib is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Lorlatinib: (Major) Avoid concomitant use of vonoprazan and lorlatinib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and lorlatinib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of vonoprazan and lumacaftor; ivacaftor due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of vonoprazan and lumacaftor; ivacaftor due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and lumacaftor; ivacaftor is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Mavacamten: (Major) Reduce the mavacamten dose by 1 level (i.e., 15 to 10 mg, 10 to 5 mg, or 5 to 2.5 mg) in patients receiving mavacamten and starting vonoprazan therapy. Avoid initiation of vonoprazan in patients who are on stable treatment with mavacamten 2.5 mg per day because a lower dose of mavacamten is not available. Initiate mavacamten at the recommended starting dose of 5 mg PO once daily in patients who are on stable vonoprazan therapy. Concomitant use increases mavacamten exposure, which may increase the risk of adverse drug reactions. Mavacamten is a CYP2C19 substrate and vonoprazan is a weak CYP2C19 inhibitor. Concomitant use with another weak CYP2C19 inhibitor in CYP2C19 normal and rapid metabolizers increased overall mavacamten exposure by 48%.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with vonoprazan is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse events. Mefloquine is a substrate of CYP3A and vonoprazan is a weak CYP3A inhibitor.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A and vonoprazan is a weak CYP3A inhibitor. Concomitant use with vonoprazan can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; vonoprazan is a weak CYP3A and CYP2C19 inhibitor. Concomitant use with vonoprazan can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Methohexital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Midazolam: (Moderate) Use caution when midazolam is coadministered with vonoprazan. Concurrent use may increase midazolam exposure leading to prolonged sedation. Midazolam is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Mitotane: (Major) Avoid concomitant use of vonoprazan and mitotane due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and mitotane is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Mycophenolate: (Moderate) Monitor for altered mycophenolate efficacy when coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of mycophenolate reducing its efficacy.
Nafcillin: (Major) Avoid concomitant use of vonoprazan and nafcillin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and nafcillin is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Major) Reduce the nab-sirolimus dose to 56 mg/m2 during concomitant use of vonoprazan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Nelfinavir: (Major) Avoid concomitant use of nelfinavir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of nelfinavir reducing its efficacy.
Neratinib: (Major) Avoid concomitant use of neratinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of neratinib reducing its efficacy.
Nilotinib: (Major) Avoid concomitant use of nilotinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of nilotinib reducing its efficacy.
Nimodipine: (Moderate) Monitor blood pressure and reduce the dose of nimodipine as clinically appropriate if coadministration with vonoprazan is necessary. Concurrent use may increase nimodipine exposure. Nimodipine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with vonoprazan due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and vonoprazan is a CYP3A inhibitor. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Octreotide: (Moderate) Concomitant use of oral octreotide with vonoprazan may require increased doses of octreotide. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral octreotide reducing its efficacy.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of vonoprazan and rifabutin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A substrate, and coadministration with weak CYP3A inhibitors like vonoprazan can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If vonoprazan is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Pazopanib: (Major) Avoid concomitant use of pazopanib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of pazopanib reducing its efficacy.
Pentobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Pexidartinib: (Major) Avoid concomitant use of vonoprazan and pexidartinib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Additionally, vonoprazan reduces intragastric acidity, which may decrease the absorption of pexidartinib reducing its efficacy. Vonoprazan is a CYP3A substrate and pexidartinib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Phenobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Phenytoin: (Major) Avoid concomitant use of vonoprazan and phenytoin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Concomitant use may also increase phenytoin concentrations. Vonoprazan is a CYP3A substrate and CYP2C19 inhibitor and phenytoin is a CYP2C19 substrate and strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Pimozide: (Major) Avoid concomitant use of pimozide and vonoprazan. Concomitant use may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Polysaccharide-Iron Complex: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Primidone: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with vonoprazan; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and vonoprazan with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A and CYP2D6 substrate and vonoprazan is a weak CYP3A inhibitor.
Repotrectinib: (Major) Avoid concomitant use of vonoprazan and repotrectinib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and repotrectinib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A inducer.
Rifabutin: (Major) Avoid concomitant use of vonoprazan and rifabutin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifabutin is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
Rifampin: (Major) Avoid concomitant use of vonoprazan and rifampin due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifampin is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Rifapentine: (Major) Avoid concomitant use of vonoprazan and rifapentine due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and rifapentine is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Rilpivirine: (Contraindicated) Concomitant use of vonoprazan with rilpivirine is contraindicated due to the potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. Vonoprazan reduces intragastric acidity, which may decrease the absorption of rilpivirine reducing its efficacy.
Risedronate: (Major) Avoid concomitant use of vonoprazan with delayed-release risedronate tablets (Atelvia). Concomitant use of drugs that raise gastric pH, such as vonoprazan, increases risedronate bioavailability due to faster release of the drug from the enteric coated tablet. This interaction does not apply to risedronate immediate-release tablets.
Secobarbital: (Major) Avoid concomitant use of vonoprazan and barbiturates due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and barbiturates are strong CYP3A inducers. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Selpercatinib: (Major) Avoid concomitant use of selpercatinib and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of selpercatinib reducing its efficacy.
Sirolimus: (Moderate) Monitor sirolimus concentrations and adjust sirolimus dosage as appropriate during concomitant use of vonoprazan. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Moderate) Monitor for decreased efficacy of oral iron salts if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of iron reducing its efficacy.
Sofosbuvir; Velpatasvir: (Major) Avoid concomitant use of velpatasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of velpatasvir reducing its efficacy. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid concomitant use of velpatasvir and vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of velpatasvir reducing its efficacy. Velpatasvir solubility decreases as pH increases; therefore, drugs that increase gastric pH are expected to decrease the concentrations of velpatasvir, potentially resulting in loss of antiviral efficacy.
Sotorasib: (Major) Avoid concomitant use of vonoprazan and sotorasib due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Additionally, vonoprazan reduces intragastric acidity, which may decrease the absorption of sotorasib reducing its efficacy. Vonoprazan is a CYP3A substrate and sotorasib is a moderate CYP3A inducer. Vonoprazan exposures are predicted to be 50% lower when coadministered with a moderate CYP3A4 inducer.
St. John's Wort, Hypericum perforatum: (Major) Avoid concomitant use of vonoprazan and St. John's Wort due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if vonoprazan must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of vonoprazan is necessary. If vonoprazan is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A substrate, and coadministration with a weak CYP3A inhibitor like vonoprazan can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If vonoprazan is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Tacrolimus: (Moderate) Monitor tacrolimus serum concentrations as appropriate and watch for tacrolimus-related adverse reactions if coadministration with vonoprazan is necessary. The dose of tacrolimus may need to be reduced. Tacrolimus is a sensitive CYP3A substrate with a narrow therapeutic range; vonoprazan is a weak CYP3A inhibitor.
Thyroid hormones: (Moderate) Monitor for altered response to thyroid hormones if coadministered with vonoprazan. Vonoprazan reduces intragastric acidity, which may decrease the absorption of oral thyroid hormones reducing their efficacy.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with vonoprazan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of vonoprazan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with vonoprazan is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of vonoprazan, a weak CYP3A inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Triazolam: (Moderate) Monitor for signs of triazolam toxicity during coadministration with vonoprazan. Coadministration may increase the exposure of triazolam. Consider appropriate dose reduction of triazolam when coadministered with weak CYP3A inhibitors, as clinically indicated. Triazolam is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Ubrogepant: (Major) Limit the initial and second dose of ubrogepant to 50 mg if coadministered with vonoprazan. Concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with vonoprazan is necessary. Vinorelbine is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with vonoprazan is necessary as concurrent use may increase the exposure of warfarin leading to increased bleeding risk. The R-enantiomer of warfarin is a CYP3A substrate and vonoprazan is a weak CYP3A inhibitor. The S-enantiomer of warfarin exhibits 2 to 5 times more anticoagulant activity than the R-enantiomer, but the R-enantiomer generally has a slower clearance.
Vonoprazan is a potassium-competitive acid blocker (PCAB). 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 proton pumps in a noncovalent and reversible manner. Following a single 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 compared to placebo is maintained for over 24-hours after dosing. At a dose 6 times the maximum recommended dose, vonoprazan does not prolong the QT interval to any clinically relevant extent.
Vonoprazan is administered orally. 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. Vonoprazan is metabolized in the liver to inactive metabolites via multiple pathways by a combination of cytochrome P450 (CYP) isoenzymes (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. 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.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP3A4/5, CYP2B6, MATE1, and OCT1
In vitro studies have shown that vonoprazan directly and time-dependently inhibits CYP2C19, CYP3A4/5, and CYP2B6. Vonoprazan is a CYP2C19 inhibitor that can produce clinically significant interactions with medications metabolized or activated by this enzyme. Vonoprazan is a weak CYP3A inhibitor and may increase exposure to sensitive CYP3A4 substrates of narrow therapeutic index. Vonoprazan also inhibits multidrug and toxin extrusion protein 1 (MATE1) and organic cation transporter 1 (OCT1), but only at concentrations higher than clinically relevant. Strong CYP3A inducers may decrease vonoprazan exposure by 80%, and moderate CYP3A4 inducers may decrease vanoprazan exposure by 50%
Vonoprazan may also exhibit clinically significant drug interactions by reducing intragastric acidity, which may alter the absorption of certain drugs leading to changes in their safety and/or effectiveness.
-Route-Specific Pharmacokinetics
Oral Route
Vonoprazan exhibits time independent pharmacokinetics and steady-state concentrations are achieved by Day 3 to 4. After multiple doses of vonoprazan ranging from 10 mg to 40 mg once daily for 7 days in healthy subjects, the Cmax and AUC values for vonoprazan increased in an approximately dose-proportional manner. The mean Cmax of once daily vonoprazan 10 mg and 20 mg were 11.7 ng/mL and 26.1 ng/mL, respectively. The Cmax of twice daily vonoprazan 20 mg was 37.8 ng/mL. The Tmax of vonoprazan 10 mg or 20 mg following once daily administration and vonoprazan 20 mg following twice daily administration was 1.5 hours (range: 0.75 to 3 hours), 2 hours (range: 0.75 to 5 hours), and 3 hours (range 1 to 6 hours), respectively. The AUC0-24hours of vonoprazan 10 mg or 20 mg following once daily administration was 92.9 hour*ng/mL and 230.9 hour*ng/mL, respectively. The AUC0-12hours of vonoprazan 20 mg following twice daily administration was 272.5 hour*ng/mL. Steady-state mean plasma exposure of vonoprazan following 20 mg twice daily dosing was approximately 1.8-fold higher compared to Day 1. Administration with a high-fat meal resulted in a 5% increase in Cmax, a 15% increase in AUC, and a delay in median time to maximum concentration (Tmax) of 2 hours. These changes are not considered to be clinically significant.
-Special Populations
Hepatic Impairment
Vonoprazan serum concentrations are increased in patients with hepatic impairment. In patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B), or severe (Child-Pugh Class C) hepatic impairment, there was an approximate 1.2-, 2.4- and 2.6-times greater respectively in mean AUC compared to normal subjects. Protein binding of vonoprazan is not affected by impaired hepatic function.
Renal Impairment
Vonoprazan systemic exposure (AUC) increased by 1.7 times, 1.3-times, and 2.4-times in patients with mild, moderate, and severe renal impairment when compared to patients with normal renal function. The AUC estimates were 1.3-fold greater when compared to patients with normal renal function for patients requiring dialysis. Protein binding of vonoprazan is not affected by impaired renal function. Vonoprazan was present in the dialysate and represented 0.94% of the dose administered in patients requiring dialysis. The use of vonoprazan should be avoided in patients with severe renal impairment (eGFR less than 30 mL/minute/1.73 m2).
Geriatric
There were no clinically significant differences in the pharmacokinetics of vonoprazan in patients 65 years and older.
Gender Differences
There were no clinically significant differences in the pharmacokinetics of vonoprazan based on sex or gender.
Ethnic Differences
There were no clinically significant differences in the pharmacokinetics of vonoprazan based on race or ethnicity.