Precautions for Use

1. Contraindications
1) Patients who have a history of hypersensitivity to the Product or its components
2) Patients taking a drug containing atazanavir, nelfinavir, or rilpivirine (refer to ‘5. Interactions’)
3) Pregnant and lactating women (refer to '6. Administration to Pregnant and Lactating Women’)
4) Patients who have congenital conditions for lactose such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, as this medicine contains lactose

 

2. The following patients should be administered with care.
1) Patients with hepatic impairment (no experience of use)
2) Patients with renal impairment (no experience of use)
3) Elderly (refer to ‘8. Geriatric Use’)
4) Patients who have a history of hypersensitivity or allergy to Yellow 5 (Sunset Yellow FCF)

 

3. Adverse Event
1) A total of two clinical trials were conducted in patients with erosive esophagitis (EE). Of the subjects who participated in the clinical trials, 183 received 40 mg of the Product. Adverse events reported in clinical trials are as follow. Adverse events (1% or more) and adverse drug reactions (*) commonly reported in the Product administration group are shown in the following Table 1.

Table 1. Adverse events reported by 1% or more in clinical trials

System Organ Class (SOC)	Adverse Event
Gastrointestinal disorders	Indigestion*, diarrhea*, nausea*, abdominal discomfort*, chronic gastritis, gastritis, erosive gastritis
Skin and subcutaneous tissue disorders	Erythema*
Nervous system disorders	Headache*
Musculoskeletal and connective tissue disorders	Low back pain

Other adverse events reported in clinical trials with an incidence of less than 1?ter administration of the Product are listed according to the major system organ class as follows.
- Gastrointestinal disorders: Hiatal hernia, Brunner’s gland hyperplasia
- Infections and infestations: Bronchitis, herpes simplex, influenza, periodontitis, pharyngitis, vaginal infections
- Skin and subcutaneous tissue disorders: Contact dermatitis, pruritus*, systemic pruritus*, facial edema
- General disorders and administration site conditions: Chest discomfort, strange feeling*, edema, pain, fever
- Nervous system disorders: Dizziness, dysgeusia
- Musculoskeletal and connective tissue disorders: Myalgia*, musculoskeletal pain, neck pain
- Eye disorders: Cataract, septum bleeding*, retinal laceration
- Ear and labyrinth disorders: Ear discomfort*
- Respiratory, thoracic and mediastinal disorders: Runny nose
- Metabolic and nutritional disorders: Hypertriglyceridemia

2) A double-blind, randomized, placebo-controlled, therapeutic confirmatory clinical trial with 10mg of the Product or placebo for up to 14 days was conducted in with 325 patients with acute gastritis or chronic gastritis. As a study result, adverse events occurred 9 patients (8.33%, 15 cases) in the study group 1), 9 patients (8.26%, 11 cases) in the study group 2 and 5 patients (4.63%, 6 cases) in the placebo group. Out of the cases, adverse drug reactions related to the Product occurred 3 patients (2.78%, 4 cases) in the study Group 1 and 4 patients (3.67%, 6 cases) in the study Group 2.
The adverse event and adverse drug reactions (*) reported in the Product administration group are shown in the following Frequency of occurrence was defined by the following criteria: very common (≥10%), common (≥1% <10>

 

Table 2. Adverse events reported in clinical trials

MedDRA System Organ Class	Group 1 (N=108) Twice/day, 10mg/once		Group 2 (N=109) Once/day, 20mg/once
	common	uncommon	common	uncommon
Various gastrointestinal disorders		Dyspepsia, abdominal distension* , Abdominal pain lower, Abdominal pain upper*		Indigestion* , abdominal pain* , change in bowel habits
Various nervous system disorders	Headache		Headachea)*	Somnolence*
Musculoskeletal and connective tissue disorders	Myalgia			Rotator cuff syndrome
Investigations		Hepatic enzyme increased*		Blood cholesterol increased, Blood creatine phosphokinase increase
General disorders and administration site condition		Chest pain, pyrexia
Neoplasms benign, malignant and unspecified (incl cysts and polyps)				Leiomyoma
Renal and urinary disorders				Calculus urinary*
Blood and lymphatic system disorder		Leukopenia
Injury, poisoning and procedural complications		Ligament sprain
Reproductive System and Breast Disorders		Dysmenorrhea
a) In test group 2, headache occurred in 2 patients (1.83%, 2 cases), and one adverse drug reaction occurred in 1 case (0.92%, 1 case).

 

4. General Cautions

1) Since the Product may relieve symptoms of malignant tumors or delay the diagnosis, if a malignant tumor is suspected by warning symptoms (unintended significant weight loss, recurrent vomiting, dysphagia, hemoptysis, melena, etc.) and a gastric ulcer is present or suspected, it should be administered after confirming that it is not malignant.
2) The number of bacteria usually present in the gastrointestinal tract increases when acidity in the stomach decreases due to proton pump inhibitors (PPIs). The risk of infection of the gastrointestinal tract by bacteria such as Salmonella, Campylobacter and Clostridium difficile may slightly increase when treated with gastric acid inhibitors. This is associated with an increased risk of Clostridium difficile diarrhea and several observational studies have reported that this risk is increased, especially in hospitalized patients. This diagnosis should be considered when diarrhea does not improve. Clostridium difficile diarrhea has been reported with the used of almost all antimicrobial agents.
3) Proton Pump Inhibitor (PPI) treatment has been reported to have the potential of being associated with an increased risk of osteoporosis-related fractures of the hip, wrist and spine. The risk of fracture was increased in patients receiving high doses of PPIs (defined as repeated daily administration) and in patients with long-term use longer than a year. In the case of patients at risk of developing osteoporosis and osteoporotic fractures, appropriate clinical monitoring is recommended according to the latest clinical guidelines.
4) Hypomagnesemia was rarely reported in patients who had been under treatment with a proton pump inhibitor (PPI) for more than 3 months and the most frequent cases were treated for more than a year. In most patients, treatment of hypomagnesemia requires magnesium supplementation and discontinuation of PPI. Patents requiring long-term treatment or co-administering digoxin or drugs that cause hypomagnesemia (e.g., diuretics) require periodic monitoring of magnesium levels, including at the initiation of treatment. Serious adverse events include stiffness, arrhythmia and seizures.
5) Cyanocobalamin (vitamin B12) deficiency: Cyanocobalamin malabsorption may occur due to Hypochlorhydria or Achlorhydria if gastric acid inhibitors are administered daily for a long period of time (eg, more than 3 years). In the literature, there have been rare reports of cyanocobalamin deficiency when taking acid-suppressing drugs. This diagnosis should be considered if clinical symptoms such as cyanocobalamin deficiency are observed.
6) In case of long-term treatment with this drug, the patient should be checked regularly.
7) Benign gastric polyps have been observed with long-term administration of other potassium-competitive gastric acid inhibitors and THIS DRUG.
8) The effect of this drug on the ability to drive or operate machinery has not been studied, and loss of these abilities cannot be predicted from the pharmacological action of this drug. Nevertheless, when considering a patient's ability to drive or operate machinery, the patient's clinical condition and adverse reaction aspects of this drug should be taken into account.
9) Fundic gland polyps: Proton pump inhibitor use is associated with an increased risk of gastric gland polyps. In particular, long-term use of more than 1 year is associated with an increased risk of gastric gland polyps. Most basement polyps are asymptomatic. Proton pump inhibitors or this drug therapy should be used at the lowest dose for the shortest period of time according to the symptom to be treated.

 

5. Interactions

1) Since the administration of the Product raises the pH in the stomach, it can interact with drug absorption in the case of oral drugs, where the pH of the stomach is an important determinant of bioavailability. Therefore, the use of the Product may reduce the bioavailability of drugs that depends on the gastric pH, such as atazanavir and nelfinavir.
2) The Product is mainly metabolized by CYP3A4 and partially by CYP2B6, CYP2C19 and CYP2D6.
3) When 80 mg of the Product and clarithromycin were co-administered, the AUCτ of the Product and clarithromycin were shown to be 1.1 times and 0.77 times, respectively, which were not clinically significant.
4) When the Product, clarithromycin and amoxicillin were co-administered, the AUCτ of amoxicillin was shown to be 0.86 times, but it was not clinically significant.

 

6. Use in Pregnant and Lactating Women

1) Pregnant women There are no clinical trial data of the Product in pregnant and lactating women. As a result of embryo-fetal development tests in rats and rabbits, maternal body weight and feed intake decreased, but there was no effect on embryo-fetal development. For safety reasons, the use of the Product during pregnancy is prohibited.
2) Lactating women Breastfeeding should be discontinued if the Product is used as it is not known if the Product will pass to breast milk in lactating women. In animal studies (rats), it has been reported that the Product passes into breast milk.

 

7. Pediatric Use

The clinical safety and efficacy of the Product in children and adolescents have not been established.

 

8. Geriatric Use

In general, physiological functions such as hepatic functions or renal functions are deteriorated in the elderly, so it should be administered carefully.

 

9. Use in Patients with Renal Impairment

The safety and efficacy of the Product in patients with renal impairment have not been established.

 

10. Use in Patients with Hepatic Impairment

The safety and efficacy of the Product in patients with hepatic impairment have not been established.

 

11. Treatment in Case of Overdose

No cases of severe overdose of the Product have been reported. In clinical trials, there has been experience of single dose of the Product up to 320 mg. In the event of overdose, the patient should be monitored for symptoms of toxicity and if necessary, general adjuvant treatment should be provided.

 

12. Precautions for Storage and Handling

1) Keep out of reach of children.

2) Be aware that changing it to another container may cause an accident or is not desirable in terms of quality maintenance.