Vocinti

Vocinti

vonoprazan

Manufacturer:

Takeda

Distributor:

Takeda
Full Prescribing Info
Contents
Vonoprazan fumarate.
Description
Each tablet contains 10mg or 20mg Vonoprazan (as fumarate).
Action
Pharmacology: Mechanism of action: Vonoprazan does not require activation by acid and inhibits H+, K+-ATPase in a reversible and potassium-competitive manner. Vonoprazan has a strong basicity and resides on the acid production site of gastric parietal cells for a long time, thereby inhibiting gastric acid production. Vonoprazan exerts a strong inhibitory effect on formation of mucosal damage in upper part of the gastrointestinal tract. Vonoprazan does not exhibit anti-Helicobacter pylori activity nor inhibitory activity against Helicobacter pylori ureas.
Inhibiting activity on gastric acid secretion: Following consecutive administration of Vonoprazan at a dose of 10mg or 20mg in healthy adult male subjects for 7 days, proportions of the time exhibiting gastric pH of 4 or above within 24 hours were 63±9% and 83±17%, respectively.
Adjunctive effect on eradication of Helicobacter pylori: The role of Vonoprazan in the Helicobacter pylori eradication is considered to increase intragastric pH leading to the enhancement of antibacterial activity of amoxicillin hydrate, clarithromycin and metronidazole which are concomitantly administered.
Pharmacokinetics: Pharmacokinetics at single administration: The following table shows pharmacokinetic parameters of Vonoprazan following single administration of Vonoprazan to healthy adult male subjects at 20mg under fasting and after meal. (See Table 1 and figure.)

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Pharmacokinetics at consecutive administration: At consecutive administration of a daily dose of 10mg or 20mg of Vonoprazan in healthy adult male subjects once daily for 7 days, AUC(0-tau) and Cmax increase as the dose increases. The degree of these increases is slightly higher than the dose ratio. It is considered that the steady state has been reached by day 3 of administration, since the trough level of the blood concentration of Vonoprazan is constant between day 3 and day 7 of administration. In addition, it is considered that pharmacokinetics of Vonoprazan at consecutive administration may not be time-dependent, as the result of the evaluation of accumulation with regard to AUC(0-tau) and T1/2 of Vonoprazan. The following table shows pharmacokinetic parameters of Vonoprazan on day 7 of administration. (See Table 2.)

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Protein binding rate: The protein binding rate is 85.2 to 88.0% when [14C] Vonoprazan in the range of 0.1 to 10μg/mL is added to human plasma (in vitro).
Metabolism: Vonoprazan is metabolized mainly by hepatic drug-metabolizing enzyme CYP3A4 and partially by CYP2B6, CYP2C19 and CYP2D6. Vonoprazan is also metabolized by sulfotransferase SULT2A1 (in vitro).
Vonoprazan exhibits time-dependent inhibitory effect on CYP2B6, CYP2C19 and CYP3A4/5 (in vitro). In addition, Vonoprazan shows a slight concentration-dependent inductive effect on CYP1A2, but it shows little inductive effect on CYP2B6 and CYP3A4/5 (in vitro).
Excretion: When radioactive-labeled drug (15mg as Vonoprazan) is orally administered to non-Japanese healthy adult male subjects, 98.5% of the radioactivity administered is excreted into urine and feces by 168 hours after administration: 67.4% into urine and 31.1% into feces.
Pharmacokinetics in patients with hepatic disorders: The clinical trial conducted in Caucasian population to evaluate the effect of hepatic disorders or pharmacokinetics in subjects with normal hepatic function and patients with mild, moderate and severe hepatic disorder when administered with the drug as Vonoprazan 20mg shows that AUC(0-inf) and Cmax were higher by 1.2 to 2.6 times and 1.2 to 1.8 times, respectively, in patient with mild, moderate and severe hepatic disorder, compared to subjects with normal hepatic function.
Pharmacokinetics in patients with renal disorders: The clinical trial conducted in Caucasian population to evaluate the effect of renal disorders on pharmacokinetics of Vonoprazan in subjects with normal renal function, patients with mild, moderate and severe renal function, patients with mild, moderate and severe renal disorder and patients with end-stage renal disorders (ESRD) when administered the drug as Vonoprazan 20mg shows that AUC(0-inf) and Cmax were higher by 1.3 to 2.4 times and 1.2 to 1.8 times, respectively, in patients with mild, moderate and severe renal disorder compared to subjects with normal renal function. AUC(0-inf) and Cmax were higher by 1.3 times and 1.2 times, respectively, in ESRD patients compared to those in subjects with normal renal function.
Drug Interactions: Pharmacokinetics at concomitant administration of Vonoprazan and clarithromycin: The drug interaction study in non-Japanese healthy adult male subjects administered with single dose of Vonoprazan 40mg 30minutes after breakfast on day 1 and day 8, and with repeated dose of clarithromycin 500mg (potency) 2 times daily 30 minutes before breakfast and dinner on day 3-9, shows that AUC(0-inf) and Cmax of Vonoprazan when concomitantly administered with clarithromycin increased by 1.6 times and 1.4 times, respectively, compared to those of Vonoprazan when administered alone.
Pharmacokinetics at concomitant administration of Vonoprazan, amoxicillin hydrate and clarithromycin: The drug interaction study in healthy adult male subjects administered with twice daily of Vonoprazan 20mg, amoxicillin hydrate 750mg (potency) and clarithromycin 400mg (potency) concomitantly for 7 days shows that no effect on pharmacokinetics of unchanged amoxicillin, however, AUC(0-12) and Cmax of Vonoprazan increased by 1.8 times and 1.9 times, respectively, and AUC(0-12) and Cmax of unchanged clarithromycin increased 1.5 times and 1.6 times, respectively.
Pharmacokinetics at concomitant administration of vonoprazan, low-dose aspirin or Vonoprazan, NSAIDs: The drug interaction study in healthy adult male subjects administered with Vonoprazan 40mg and aspirin 100mg or NSAID (loxoprofen sodium 60mg, diclofenac sodium 25mg or meloxicam 10mg) concomitantly showed no clear effect of low-dose aspirin or NSAIDs on pharmacokinetics of Vonoprazan and of Vonoprazan on pharmacokinetics of low-dose aspirin or NSAIDs.
Indications/Uses
Gastric ulcer, duodenal ulcer, reflux esophagitis, prevention of recurrence of gastric ulcer or duodenal ulcer during low-dose aspirin administration, or prevention of recurrence of gastric ulcer or duodenal ulcer during NSAIDs administration.
Adjunct to Helicobacter pylori eradication in the following: Gastric ulcer, duodenal ulcer, gastric MALT lymphoma, idiopathic thrombocytopenic purpura, the stomach after endoscopic resection of early stage gastric cancer, or Helicobacter pylori gastritis.
Precautions for Indications: Prevention of recurrence of gastric ulcer or duodenal ulcer during low-dose aspirin administration: This drug should be administered to the patients who are under continuous administration of low-dose aspirin for prevention of blood clots and emboli formation. History of gastric ulcer or duodenal ulcer should be confirmed before starting administration.
Prevention of recurrence of gastric ulcer or duodenal ulcer during NSAIDs administration: This drug should be administered to the patients who are under continuous administration of NSAIDs for purpose such as pain management of rheumatoid arthritis or osteoarthritis, etc. History of gastric ulcer or duodenal ulcer should be confirmed before starting administration.
Adjunct to Helicobacter pylori eradication: The efficacy of Helicobacter pylori eradication in the advanced stage of gastric MALT lymphoma has not been established.
Helicobacter pylori eradication should be conducted in the idiopathic thrombocytopenic purpura patients only if Helicobacter pylori eradication is considered appropriate with referring to the guidelines etc.
The efficacy on the prevention of gastric cancer by Helicobacter pylori eradication has not been established other than the stomach after endoscopic resection of early stage gastric cancer.
It should be confirmed that Helicobacter pylori is positive and Helicobacter pylori gastritis should be diagnosed by endoscopy before starting administration for patients with Helicobacter pylori gastritis.
Dosage/Direction for Use
Gastric ulcer, duodenal ulcer: Usually, for adults, a daily oral dose of 20mg of Vonoprazan is administered once a day. For the treatment of gastric ulcer, the usual administration should be limited up to 8 weeks, and for duodenal ulcer, up to 6 weeks.
Reflux esophagitis: Usually, for adults, a daily oral dose of 20mg of Vonoprazan is administered once a day. The usual administration should be limited up to 4 weeks. However, when the effect if insufficient, the drug may be administered up to 8 weeks. In addition, for the maintenance of healing of reflux esophagitis in patients who repeat recurrence and relapse of the condition, a daily oral dose of 10mg is administered once a day, however, when the efficacy is inadequate, a daily oral dose of 20mg may be administered once a day.
Prevention of recurrence of gastric ulcer or duodenal ulcer during low-dose aspirin administration: Usually, for adults, a daily oral dose of 10mg of Vonoprazan is administered once a day.
Prevention of recurrence of gastric ulcer or duodenal ulcer during NSAIDs administration: Usually, for adults, a daily oral dose of 10mg of Vonoprazan is administered once a day.
Adjunct to Helicobacter pylori eradication: Usually, for adults, the following 3 drugs are orally administered at the same time twice daily for 7 days: 20mg/dose of Vonoprazan, amoxicillin hydrate, and clarithromycin. The dose of clarithromycin may be properly increased as the occasion demands, however, the upper limit is 400mg (potency) twice daily).
When Helicobacter pylori eradication treatment with 3 drugs consist of a proton pump inhibitor, amoxicillin hydrate, and clarithromycin fails, alternative treatment with the following 3 drugs is given as follows; usually, for adults, 20mg/dose of Vonoprazan, 750mg (potency)/dose of amoxicillin hydrate, and 250mg/dose of metronidazole are orally administered at the same time twice daily for 7 days.
Contraindications
Vonoprazan (Vocinti) tablets are contraindicated in the following patients: Patients with a history of hypersensitivity to any of the ingredients of this drug.
Patients who are receiving atazanavir sulphate or rilpivirine hydrochloride (see Interactions).
Special Precautions
Careful Administration: Vonoprazan (Vocinti) tablets should be administered with care in the following patients. Vonoprazan has not been studied in patients under 18 years of age.
Patients with hepatic disorders [A delay in the metabolism and excretion of Vonoprazan (Vocinti) tablets may occur, which may result in an increase in the concentration of Vonoprazan in blood.] See Pharmacology: Pharmacokinetics under Actions.
Patients with renal disorders [A delay in the excretion of Vonoprazan (Vocinti) tablets may occur, which may result in an increase in the concentration of Vonoprazan in blood.] See Pharmacology: Pharmacokinetics under Actions.
Elderly patients (see Use in Elderly as follows).
Important Precautions: At the treatment, the course of the disease should closely be observed and the minimum therapeutic necessity should be used according to the disease condition.
In the long-term, treatment with Vonoprazan (Vocinti) tablets, close observation by such means as endoscopy should be made.
In the maintenance of healing of reflux esophagitis, Vonoprazan (Vocinti) tablets should be administered only to the patients who repeat recurrence and recrudescence of the condition. Administration to the patients who do not necessitate maintenance of healing should be avoided.
When the healing is maintained over a long period, and when there is no risk of recurrence, the dose reduction to a dose of 10mg from a dose 20mg, or suspension of administration should be considered.
When Vonoprazan (Vocinti) tablets are used as an adjunct to Helicobacter pylori eradication, precautions such as contraindications, careful administration and clinically significant adverse reactions listed in the package inserts of the other drugs used in the eradication should be rechecked without fail.
Precautions concerning Use: When dispensing the drug: The patient must be instructed to remove the tablets from the press-through package (PTP) before they are ingested. [It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet may puncture the esophageal mucosa, and this could result in serious complications such as mediastinitis.]
Other Precautions: In 2-year carcinogenicity studies in mice and rats, following observations were made: neuroendocrine tumors in the stomach with the similar exposure (AUC) at the clinical dose (20mg/day) of vonoprazan, adenoma in the stomach (mouse) at the exposure approximately 300 times of the clinical exposure, and hepatic tumor at approximately more than 13 times (mouse) and approximately more than 58 times (rat) of the clinical exposure.
It has been reported that benign gastric polyp was observed in long-term administration of this drug.
The administration of Vonoprazan (Vocinti) tablets may mask the symptoms of gastric cancer. It is therefore, necessary to ascertain the ulcer is not of a malignant nature before initiating the administration of this drug.
In several observational studies in overseas, an increased risk for osteoporosis-related fractures of the hip, wrist or spine under the treatment with proton pump inhibitors has been reported. The risk of fracture was especially increased in the patients receiving high dose or long term (a year or longer) treatment.
In several overseas observational studies, mainly in hospitalized patients, increased risk of gastrointestinal infection caused by Clostridium difficile was reported in patients who receive proton pump inhibitors.
Use in Children: The safety of Vonoprazan (Vocinti) tablets in low birth weight infants, neonates, infants, young children or children has not been established (No clinical experience).
Use in the Elderly: Since the physiological functions such as hepatic or renal function are decreased in elderly patients in general, Vonoprazan (Vocinti) tablets should be carefully administered.
Use In Pregnancy & Lactation
No clinical studies have been conducted to date to evaluate vonoprazan in subjects who are pregnant or lactating. Vonoprazan (Vocinti) tablets should be used in pregnant women or women having possibilities of being pregnant only if the expected therapeutic benefit is thought to outweigh any possible risk. [In animal studies (rats), following exposure of more than approximately 28 times of the exposure (AUC) at the maximum clinical dose (40mg/day) of Vonoprazan, low values of fetal weight and placental weight, external abnormalities (anal stenosis and tail abnormalities) and visceral abnormalities (membranous ventricular septal defect and aberrant subclavian artery) were observed.]
It is advisable to avoid the administration of Vonoprazan (Vocinti) tablets to nursing mothers. However, when the administration is indispensable, nursing should be discontinued. [It has been reported in animal studies (rats) that Vonoprazan is transferred to mother's milk.]
Adverse Reactions
Gastric ulcer, duodenal ulcer, reflux esophagitis: Adverse reactions, including abnormalities in laboratory data, were observed in 186 (8.2%) of 2,271 patients who received once daily administration of 10mg or 20mg of Vonoprazan in the clinical trials performed before approval. The most common adverse reaction was constipation (0.7%).
Prevention of recurrence of gastric ulcer or duodenal ulcer during low-dose aspirin administration: Adverse reactions, including abnormalities in laboratory data, were observed in 73 (16.9%) of 431 patients who received once daily administration of 10mg or 20mg of Vonoprazan in the clinical trials performed before approval. The most common adverse reaction was constipation (1.9%).
Prevention of recurrence of gastric ulcer or duodenal ulcer during NSAIDs administration: Adverse reactions, including abnormalities in laboratory data, were observed in 78 (17.0%) of 460 patients who received once daily administration of 10mg or 20mg of Vonoprazan in the clinical trials performed before approval. The most common adverse reaction was constipation (1.5%).
Adjunct to Helicobacter pylori eradication in the case of gastric ulcer or duodenal ulcer: Adverse reactions, including abnormalities in laboratory data, were observed in 67 (20.4%) of 329 patients administered with Vonoprazan fumarate, amoxicillin and clarithromycin in the clinical trials before approval. The most common adverse reaction was diarrhea (10.6%).
Adjunct to Helicobacter pylori eradication in the case of gastric MALT lymphoma, idiopathic thrombocytopenic purpura, the stomach after endoscopic resection of early stage gastric cancer, or Helicobacter pylori gastritis: Concerning concomitant administration of vonoprazan fumarate, amoxicillin hydrate, and clarithromycin or metronidazole, no study such as clinical trials to determine the frequency of adverse reactions has been conducted.
With Vonoprazan fumarate, amoxicillin and metronidazole, adverse reactions including abnormalities in laboratory data were observed in 8 (16.0%) of 50 patients in the clinical trials before approval.
Clinically significant adverse reactions: Pancytopenia, agranulocytosis, leukocytopenia, and thrombocytopenia (Each incidence unknown) may occur. Therefore, close observation should be made. If any abnormality is observed, Vonoprazan (Vocinti) Tablets should be discontinued and appropriate measures should be taken.
Toxic epidermal necrolysis: TEN, Stevens-Johnson syndrome and Erythema multiforme: (Each incidence unknown) may occur. Therefore, close observation should be made. If any abnormality is observed, Vonoprazan (Vocinti) Tablets should be discontinued and appropriate measures should be taken.
Serious colitis accompanied with bloody stools, such as pseudomembranous colitis, may occur due to amoxicillin hydrate or clarithromycin being used for Helicobacter pylori eradication (incidence unknown). If abdominal pain and frequent diarrhea occur, appropriate measures, such as immediate discontinuation of the treatment, should be taken.
Hepatotoxicity: Hepatic function abnormalities including liver injury have been reported in clinical studies. Post marketing reports have also been received in patients treated with Vonoprazan, many of which occurred shortly after initiation of treatment. Discontinuation of Vonoprazan is recommended in patients who have evidence of liver function abnormalities or if they develop signs or symptoms suggestive of liver dysfunction.
Other adverse reactions: When the following adverse reactions are observed, appropriate measures should be taken according to the symptoms: (See Tables 3 and 4.)

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Postmarketing: Following is a list of ADRs which have been observed in postmarketing and are not included as previously mentioned: (See Table 5.)

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Drug Interactions
Vonoprazan (Vocinti) are metabolized mainly by hepatic drug-metabolizing enzyme CYP3A4 and partially by CYP2B6, CYP2C19 and CYP2D6.
Gastric antisecretory effect of Vonoprazan (Vocinti) tablets may promote or inhibit absorption of concomitant drugs. The use of Vonoprazan is therefore not recommended with some of these drugs for which absorption is dependent on acidic intragastric pH.
Contraindications for Co-administration: [Vonoprazan (Vocinti) tablets should not be co-administered with the following drugs.] (See Table 6.)

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Precautions for co-administration: [Vonoprazan (Vocinti) tablets should be administered with care when co-administered with the following drugs.] (See Table 7.)

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Storage
Store at temperature not exceeding 30°C.
ATC Classification
A02BC08 - vonoprazan ; Belongs to the class of potassium-competitive acid blocker. Used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).
Presentation/Packing
FC tab 10 mg x 30's. 20 mg x 30's.
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