VOCINTI Film-coated tablet Ref.[50552] Active ingredients: Vonoprazan

Hepatotoxicity

Hepatic function abnormalities including liver injury have been reported in clinical studies (see Section 4.8). 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.

Elevation of intragastric pH

Administration of vonoprazan results in elevation of intragastric pH and is therefore not recommended to be taken with drugs for which absorption is dependent on acidic intragastric pH (See Section 4.5).

Masking of Symptoms Associated with Gastric Malignancy

Gastric malignancy may present with symptoms associated with acid-related disorders which initially respond to drugs that elevate intragastric pH. A symptomatic response to vonoprazan does not exclude the presence of gastric malignancy

Clostridium difficile associated diarrhea, including pseudomembranous colitis

Drugs that elevate intragastric pH may be associated with an increased risk of Clostridium difficile gastrointestinal infection. Pseudomembranous colitis may be due to antibiotics used for Helicobacter pylori eradication in combination with vonoprazan. If abdominal pain and frequent diarrhea occur, appropriate measures, including discontinuation of the treatment, should be taken.

Bone Fracture

An increased risk for osteoporosis-related fractures of the hip, wrist, or spine, predominantly in the elderly or in presence of other recognized risk factors, has been reported with the use of proton pump inhibitors, especially with use of high doses over a long-term period (>1 year). The mechanism is not clear and is likely to be multifactorial.

Administration of vonoprazan results in elevation of intragastric pH, suggesting that it may interfere with the absorption of drugs where gastric pH is an important determinant of oral bioavailability. Use of vonoprazan is therefore not recommended with some of these drugs for which absorption is dependent on acidic intragastric pH such as atazanavir and nelfinavir, due to significant reduction in their bioavailability.

Vonoprazan is metabolized mainly by hepatic drug-metabolizing enzyme CYP3A4 and partially by CYP2B6, CYP2C19 and CYP2D6.

With strong CYP3A4 inhibitors, e.g., clarithromycin, blood concentration of vonoprazan may increase. It has been reported that blood concentration of vonoprazan increased in concomitant use with clarithromycin by 1.5-fold, but no dose adjustment of vonoprazan is considered necessary.

Coadministration of vonoprazan with the antibiotic regimen clarithromycin and amoxicillin increased concentrations of vonoprazan by up to 1.9-fold. No increase was observed with the antibiotic regimen of metronidazole and amoxicillin. No dose adjustment of vonoprazan is considered necessary.

There were no clinically significant effects of low-dose aspirin or NSAIDs on the pharmacokinetics of vonoprazan, and no clinically significant effects of vonoprazan on the pharmacokinetics of low-dose aspirin or NSAIDs. The effect on platelet-aggregating inhibitory activity of low-dose aspirin was not considered clinically meaningful.

Pregnancy

No clinical studies have been conducted to date to evaluate vonoprazan in subjects who are pregnant. In a rat toxicology study, embryo-foetal toxicity was observed following exposure of more than approximately 28 times of the exposure (AUC) at the maximum clinical dose (40 mg/day) of vonoprazan. As a precaution, vonoprazan should not be administered to women who are or may be pregnant, unless the expected therapeutic benefit is thought to outweigh any possible risk.

Lactation

No clinical studies have been conducted to date to evaluate vonoprazan in subjects who are lactating are lactating. It is unknown whether vonoprazan is excreted in human milk. In animal studies it has been shown that vonoprazan was excreted in milk. During treatment with vonoprazan, nursing should be avoided if the administration of this drug is necessary for the mother.

The influence of vonoprazan on the ability to drive or use machines is unknown.

Clinical Trials

Clinical trial data for expected adverse events is based on pooled safety analysis from the following studies: EE healing (CCT-001 and CCT-002), EE maintenance therapy (CCT-003 and OCT-001), GU healing (CCT-101), DU healing (CCT-102), prevention of recurrence of peptic ulcer associated with NSAID use (CCT-301, OCT-301 and OCT-303), prevention of recurrence of peptic ulcer associated with LDA use (CCT-302, OCT-302 and OCT-304) and treatment of non-erosive reflux disease (NERD; CCT201). Although the study in patients with NERD has the placebo arm and is considered as the best data, the number of patients (N=449 and 278 for TAK-438 and placebo, respectively) is relatively small compared to the number of patients of all other active-comparator studies combined (N=3162 and 1392 for TAK-438 and AG-1749 [Lansoprazole], respectively). Therefore, the pooled safety data of activecomparator studies are used for the primary analysis. The safety data of CCT-201 study are analyzed separately. (Note: AG-1749 (Lansoprazole) is the only comparator used in the comparator studies).

The following convention is used for the classification of the frequency of an adverse drug reaction (ADR) and is based on the Council for International Organizations of Medical Sciences (CIOMS) guidelines: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Table 1. Adverse reactions with vonoprazan in clinical studies:

^* ADRs included as preferred terms are based on MedDRA version 21.0.

Post-marketing

Following is a list of ADRs which have been observed in post-marketing (Frequency unknown):

Table 2. Adverse reactions with vonoprazan in post-marketing setting System Organ Class:

Not applicable.