Gaslon N OD Tablets

Gaslon N OD Tablets 4 mg: Each tablet contains 4 mg of irsogladine maleate (INN: irsogladine). (See Table 1.)

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Nonproprietary name: Irsogladine maleate (JAN).
INN: Irsogladine.
Chemical name: 2,4-Diamino-6-(2,5-dichlorophenyl)-s-triazine maleate.
Molecular formula: C₉H₇Cl₂N₅·C₄H₄O₄.
Molecular weight: 372.16.
Irsogladine maleate occurs as white crystals or crystalline powder. It is odorless, and has a slightly bitter taste. It is sparingly soluble in 2-methoxyethanol, in glacial acetic acid and in ethylene glycol, slightly soluble in ethanol, and practically insoluble in water.
Melting point: 175-183°C (decomposition).
Partition coefficient: 1.4 [n-octanol/buffered solution (pH 1.2)]; 54.0 [n-octanol/buffered solution (pH 6.8)].
Excipients/Inactive Ingredients: Lactose hydrate, D-mannitol, corn starch, hydroxypropylcellulose, magnesium stearate and yoghurt flavor (aroma chemicals, glycerin and dextrin).

Pharmacotherapeutic group: Agents for peptic ulcer (Other) group. ATC Code: A02BX.
Pharmacology: Pharmacodynamics: Mechanism of action: Irsogladine, a mucosal protective agent, has effect based on a mechanism apparently different from those of antisecretory drugs.
Irsogladine increased intercellular cyclic adenosine 3',5'-monophosphate (cAMP) content via non-selective inhibition of phosphodiesterase (PDE) isozymes and exhibited gastric cytoprotection partly mediated by endogenous nitric oxide (NO).
These effects may account for variety actions of Irsogladine in the gastrointestinal tract, including facilitation of gap junctional intercellular communication (GJIC), inhibition of the reduced gastric mucosal blood flow response, suppression of reactive oxygen generation.
Pharmacodynamic effects: Effects on experimentally-induced ulcer: Irsogladine maleate showed antiulcer effects dose-dependently at low doses of 1-10 mg/kg in acute experimental ulcers such as water-immersion stress-induced ulcers in rats, ethanol-induced ulcers in rats, Shay ulcers in rats, indomethacin-induced ulcers in rats, histamine-induced ulcers in guinea pigs and rats, and aspirin-induced ulcers in rats, monochloramine-induced ulcers in rats and ischemia-reperfusion induced-injury of gastric mucosa in rats and in chronic experimental ulcers such as acetic acid-induced ulcers in rats and electric thermocauterization ulcers in dogs.
Effects on experimentally-induced gastritis: Irsogladine maleate showed the effects that this drug dose-dependently inhibited or promoted the healing for the ethanol-induced gastritis, taurocholic acid-induced atrophic gastritis and NH₄OH-induced gastric mucosa lesion in rats.
Cytoprotective effect: Irsogladine maleate inhibited the desquamation and exfoliation of gastric mucosal epithelial cells induced by intragastric infusion of 0.2N hydrochloric acid and inhibits the expansion of intercellular spaces in rats.
Irsogladine maleate inhibited the exfoliation and desquamation of gastric mucosal epithelial cells induced by oral administration of dehydrated ethanol in rats.
Irsogladine maleate inhibited the penetration of gastric mucosal lesion-inducing substances such as 0.2N hydrochloric acid, ethanol and etc. through the gastric mucosa in rats.
Improving effect on blood flow rate of gastric mucosa: Irsogladine maleate increased dose-dependently mucosal blood flow at the marginal area of acetic acid-induced ulcer in dogs. Irsogladine maleate also inhibited monochloramine-induced decrease of gastric mucosal blood flow in rats.
Anti-inflammatory effects: Irsogladine maleate inhibited the production of reactive oxygen species induced by stimulants in activated human neutrophil (in vitro).
Irsogladine maleate inhibited the production of TNF-α in gastric mucosa injured by ischemia-reperfusion and also inhibited the infiltration of inflammatory cells into gastric mucosa in rats indicated with MPO activity.
Irsogladine maleate inhibited dose-dependently the production of IL-8 and RANTES in co-cultivation of human gastric mucosa epithelial cells and Helicobacterium pylori (in vitro).
Effect on activation of intercellular communication: Irsogladine maleate activated the intercellular communication in Dye Coupling method using rabbit fetal gastric mucosa epithelial cells (in vitro).
Clinical study: Gastric ulcer: As a result of the clinical studies conducted in patients with gastric ulcer (the disease stage: A1-H1) in 165 domestic institutions, the healing rate by endoscopic evaluation at 8 weeks of administration was 62.6% (311/497 cases). In the overall improvement rating, evaluation of moderately improved or better was 74.4% (406/546 cases). The efficacy of this drug was also demonstrated in the double blind clinical studies.
Acute gastritis and acute exacerbation stage of chronic gastritis: As a result of the clinical studies conducted in patients with acute gastritis or acute exacerbation stage of chronic gastritis in 201 domestic institutions, in the overall improvement rating, evaluation of moderately improved or better was 85.2% (283/332 cases). The efficacy of this drug was also demonstrated in the double blind clinical studies. (See Table 2.)

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Pharmacokinetics: Absorption: Single administration: Irsogladine maleate was orally administered at a single dose of 4 mg in 4 healthy male adults. The plasma concentration of unchanged compound reached to maximum (C_max) at 3.5 hours after administration and decreased at a half life of ca.150 hours. (See Figure 1 and Table 3.)

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Repeated administration: Healthy male adults: Irsogladine maleate was orally administered to 6 healthy male adults at a dose of 2 mg once daily for 28 days. The plasma concentration of unchanged compound became steady-state after 14 days. After the administration was finished, the plasma concentration was gradually decreased at a half life of ca.170 hours. (See Figure 2.)

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Gastric ulcer patients: Irsogladine maleate was orally administered to 10 gastric ulcer patients during 4 to 8 weeks at 4 mg in 1 to 2 divided doses a day. The plasma concentration of unchanged compound reached to a steady-state after 2 weeks as repeated administration to healthy male adults at a dose of 2 mg a day.
Distribution: Distribution to the site of action (rat): After ¹⁴C-Irsogladine maleate was intravenously administered, the radioactivity of gastric mucosa was higher than that in plasma.
Protein binding: The binding rate of ¹⁴C-Irsogladine maleate to human serum albumin of 1% solution was 62.4%.
Metabolism: Irsogladine maleate was orally administered to healthy male adults at a dose of 4 mg. The major metabolite in urine was the conjugate of m-hydroxy irsogladine. Also the conjugates of p-hydroxy irsogladine and N-oxide of irsogladine were detected. The pharmacological and toxicological effects of these metabolites were much less than unchanged form of irsogladine or hardly recognized.
Excretion: After the oral administration at a dose of 4 mg of irsogladine maleate in healthy male adults, the cumulative excretion rate into urine within 80 hours was 1.77% in unchanged compound, 3.54% in m-hydroxy conjugate of irsogladine, 0.79% in p-hydroxy conjugate and 0.94% in N-oxide.
Bioavailability: One tablet of Gaslon N OD 2 mg (orally disintegrative preparation) with or without water and Gaslon N 2 mg with water were orally administered in 19 healthy male adults and it was demonstrated that their bioavailabilities were to be equal.
Administration with water: See Figure 3 and Table 4.

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Administration without water: See Figure 4 and Table 5.

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Dissolution profile: For the purpose of securing the bioequivalence between Gaslon N OD Tablets 2 mg (2 tablets) and Gaslon N OD Tablets 4 mg (1 tablet), dissolution profiles of both formulation were compared according to the Guideline for Bioequivalence Studies for Different Strengths of Oral Solid Dosage Forms. The dissolution profiles of both formulations were conformed to the guideline and were judged to be equivalent. (See Figure 5.)

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Toxicology: Preclinical Safety data: Pharmacology Study: Safety Pharmacology Studies: No remarkable general pharmacological effects were observed within the anti-ulcer doses.
Toxicity study: Single-dose toxicity study: Acute toxicity (LD₅₀; mg/kg). (See Table 6.)

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Repeated-dose toxicity study: Subacute toxicity: Repeated doses of 3, 60 and 1,200 mg/kg/day were orally administered to rats for 13 weeks. Salivation, suppression of body weight gain and decreased food consumption were observed at 60 mg/kg or more. Moreover, increased liver weight, hyperplasia of smooth endoplasmic reticulum, and renal pelvic calculus were observed.
It was concluded that the no observed effect level (NOEL) was 3 mg/kg/day.
Repeated doses of 2.5, 10, 40, and 160 mg/kg/day were orally administered to dogs for 13 weeks. Vomiting, salivation, and suppression of body weight gain and decreased food consumption were observed at 40 mg/kg or more. Moreover, hyperplasia of smooth endoplasmic reticulum in the liver and foot process fusion of the glomerular epithelial cells in the kidney were observed.
It was concluded that the NOEL was 10 mg/kg/day.
Chronic toxicity: Repeated doses of 1.5, 9, 54, and 324 mg/kg/day were orally administered to rats for 52 weeks. The results showed some changes similar to those observed in the subacute toxicology study. It was concluded that the NOEL was 1.5 mg/kg/day.
Repeated doses of 2, 10, and 50 mg/kg/day were orally administered to dogs for 52 weeks. The results showed some changes similar to those observed in the subacute toxicology study. It was concluded that the NOEL was 2 mg/kg/day.
Reproduction toxicity studies: As the result of oral administration to rats in pre-pregnancy, early pregnancy and organogenesis period, and rabbits in organogenesis period, no effect on embryo, fetus and neonate were observed at the maximum dose of 30 mg/kg/day. A decreased survival rate of neonates at 8 mg/kg/day or more and suppression of body weight gain of neonates at 30 mg/kg/day was observed after oral administration to rats in perinatal and lactation period.
Dependency study: Physical or psychological dependency was not indicated in the study of single dose acute central nervous system effects, barbital withdrawal syndrome suppression test, continuous intragastric self-administration experiments, and drug discrimination study (monkey).
Antigenicity study: Antigenicity studies, active systemic anaphylaxis (ASA) studies, active cutaneous anaphylaxis (ACA) studies, passive cutaneous anaphylaxis (PCA) studies, and agar gel precipitation reaction were conducted. Antigenicity was not observed in these test (guinea pig).
Mutagenicity study: No mutagenicity was observed in bacterial reverse mutation test, chromosomal aberration test (hamster derived cell), and micronucleus test (mouse).

Gastric ulcer; Improvement of gastric mucosal lesion (erosion, hemorrhage, redness and edema) caused by the following diseases: Acute gastritis and acute exacerbation stage of chronic gastritis.

For adults, usually 4 mg daily as irsogladine maleate (one tablet of Gaslon N OD Tablets 4 mg) is orally administered in 1 to 2 divided doses. Usage in pediatric patient has not been established.
The dosage may be adjusted according to the age of patients and severity of symptoms.
This drug disintegrates in the oral cavity, but is not absorbed from the oral mucosa. It should therefore be swallowed with saliva or water.

In the event of overdosage general symptomatic and general supportive measures are indicated as required.

In patient with hypersensitivity to irsogladine or to any of the excipients.

Other Precautions: The elimination half-life of Irsogladine maleate from plasma in healthy male adults is about 150 hours. The drug should be used with precaution in patients with renal and liver diseases.
Effects on ability to drive and use machine: Effects on ability to drive and use machines have not been studied.
Use in Children: Safety in pediatric patients has not been established (insufficient clinical experience).
Use in the Elderly: Since the elderly patients often have a physiological hypofunction, this drug should be carefully administered such as starting at a low dose (e.g. 2 mg/day) while closely monitoring the patient's condition.

Safety of this drug in pregnant women has not been established.

Adverse drug reactions to this drug, including abnormalities in laboratory data, were reported in 64 of 10,176 patients (0.63%). The most frequently observed adverse drug reactions were hepatic function abnormal in 12 patients (0.12%), increased ALT (GPT) in 12 patients (0.12%), increased AST (GOT) in 7 patients (0.07%), constipation in 6 patients (0.06%), rash in 5 patients (0.05%), itching, diarrhea and increased ALP in each 3 patients (0.03%).
(At the end of the reexamination period of Gaslon N Tablets and Fine Granules.) (See Table 7.)

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There have not been any studies to confirm Irsogladine causes drug interactions with other drugs.

Precaution in dispensing: For drugs that are dispensed in press-through package (PTP), instruct the patient to remove the drug from the package prior to use. (It has been reported that, if the PTP sheet is swallowed, the sharp corners of the sheet puncture the esophageal mucosa, resulting in severe complications such as mediastinitis.)
Precaution in administration: Since this drug disintegrates when it was infiltrated with saliva on tongue, it can be taken without water. It is also possible to take it with water.
Incompatibilities: Not applicable.

Special precautions for storage: Store below 30°C.
Store in a tight container. Avoid humidity at room temperature.

Antacids, Antireflux Agents & Antiulcerants

A02BX16 - irsogladine ; Belongs to the class of other drugs used in the treatment of peptic ulcer and gastro-oesophageal reflux disease (GERD).

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