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Ganaton

PRODUCT DESCRIPTION
Itopride hydrochloride is an orally active gastroprokinetic agent. Itopride hydrochloride tablets contain 50 mg of itopride hydrochloride. The tablet has been formulated to provide immediate release. It is chemically designated as N-[4-[2-(Dimethylamino)ethoxy]benzyl]-3,4-dimethoxybenzamide hydrochloride. Itopride hydrochloride is a substituted benzamide. It has an empirical formula of C20H26N2O4•HCI, molecular weight of 394.89 g/mol, and structural formula as shown:


Itopride hydrochloride is a white to pale yellowish white crystal or crystalline powder. It is odorless and has a bitter taste. It is very soluble in water, freely soluble in methanol or in glacial acetic acid, sparingly soluble in ethanol and practically insoluble in acetic anhydride or in ether. The pH of the solution is 4.0 to 5.0. The melting point is 193 to 198°C.

Inactive Ingredients
Itopride hydrochloride tablets are available for oral administration in a strength of 50 mg with the following inactive ingredients: lactose, corn starch, carmellose, light anhydrous silicic acid, magnesium stearate, hydroxypropylmethylcellu lose 2910 (6 mm2/s), macrogol 6000, titanium oxide and carnauba wax.

INDICATIONS
Itopride hydrochloride is used in the treatment of gastrointestinal symptoms of functional, nonulcer dyspepsia (chronic gastritis) i.e., sensation of bloating, early satiety, upper abdominal pain or discomfort, anorexia, heartburn, nausea and vomiting.

DOSAGE AND ADMINISTRATION
Adults
The recommended dose of itopride hydrochloride for adult patients is 150 mg daily [one tablet (50 mg) taken orally three times a day before meals]. The dose may be reduced according to the patient's age and symptoms (see PRECAUTIONS).

Duration of Treatment
In clinical studies, itopride hydrochloride has been administered up to 8 weeks.

CLINICAL STUDIES
The activity of Itopride hydrochloride has been evaluated in two pivotal studies; a dose finding study and a comparative study.

Dose-Finding Study of a Gastroprokinetic Agent, HSR-803, on Gastrointestinal Complaints - Late Phase II Study

A double blind comparative study evaluated 204 patients diagnosed with functional, non-ulcer dyspepsia (chronic gastritis), acute gastric mucosal lesions (AGML), gastric polyps with complaints of upper abdominal digestive symptoms such as upper abdominal fullness, heaviness of the stomach, epigastric pain, nausea, vomiting, heartburn, loss of appetite, discomfort, etc. The purpose of this study was to determine the optimal dosage of this drug. Using 3 treatment groups with a daily dosage level of 75 mg, 150 mg, or 300 mg, respectively, 188 cases were evaluated for drug efficacy.

The Final Global Improvement Ratings showed that the degree of improvement was "moderate improvement" or better in 53.3% in the 75 mg group, 73.7% in the 150 mg group, and 66.2% in the 300 mg group, and a trend (p-value = 0.065) was observed between the 3 groups using the chi-square test for differences in scores of "moderate improvement" or better, with the 150 mg group showing a higher degree of improvement than the 75 mg group by Tukey-type multiple comparison (p-value = 0.036).

When analyzed by symptom, the degree of improvement ("moderate improvement" or better) was higher at 2 weeks administration or at discontinuation compared to at 1 week administration for all symptoms, and with the exception of 'heartburn, which showed a low incidence, the 150 mg group showed the highest degree of improvement for every symptom.

The Usefulness Rating was "useful" or better, in 53.3% in the 75 mg group, 71.9% in the 150 mg group, and 69.0% in the 300 mg group.

From the above results, it was concluded that the optimal dosage of this drug is a daily dose of 150 mg.

Clinical Evaluatin of Itopride Hydrochloride for Gastrointestinal Symptoms Associated with Chronic Gastritis - Multicenter Double Blind Comparative Study Using Cisapride as a Control Drug

A multi-center, double-blind clinical trial, compared itopride hydrochloride with cisapride in 251 patients for upper abdominal digestive symptoms associated with functional, non-ulcer dyspepsia (chronic gastritis). The purpose of this study was to evaluate the efficacy, safety, and usefulness of itopride hydrochloride. Patients received either cisapride 2.5 mg t.i.d. or itopride hydrochloride 50 mg t.i.d. for a period of two weeks.

The cases subjected to efficacy evaluation consisted of 111 cases in group H (itopride hydrochloride) and 114 cases in group C (cisapride), for a total of 225 cases.

The Final Global Improvement Ratings showed that the improvement rate was "moderate improvement" or better, in 79.3% in group H, 71.9% in group C, and there were no significant differences observed between the 2 groups.

When analyzed by symptom, the improvement rate scored as "moderate" or better was 64.8 to 78.6% in group H and 57.8 to 81.3% in group C, and the disappearance rate for each symptom (within 14 days) was 58.0 to 92.9% in group H and 63.9 to 86.7% in group C.
There were no significant differences observed between the 2 groups. However, for "vomiting", group H showed a tendency to be superior to group C (p value = 0.052) in the Global Improvement Rating at 1 week administration.

The usefulness rating was "useful" or better, in 74.6% in group H and 69.6% in group C, with no significant differences observed between the 2 groups. From the above results, it was concluded that itopride hydrochloride is a clinically useful drug for the treatment of upper abdominal digestive symptoms associated with chronic gastritis.

PHARMACOLOGIC PROPERTIES
Mechanism of Action
Itopride hydrochloride activates gastrointestinal propulsive motility due to its dopamine D2 antagonizing activity and acetylcholinesterase inhibitory activity. Itopride activates acetylcholine release and inhibits its degradation.

Pharmacodynamics
Itopride hydrochloride also has antiemetic action through interaction with D2 receptors located in the chemoreceptor trigger zone. This was demonstrated by dose dependent inhibition of apomorphine-induced vomiting in dogs.

In conscious dogs, itopride hydrochloride activates propulsive gastric motility through dopamine D2-receptor antagonistic actions and dose-dependent inhibition of acetylcholinesterase.

Itopride hydrochloride has been shown to accelerate gastric emptying in humans, dogs and rats.

In single-dose studies in dogs, itopride hydrochloride was shown to promote gastric emptying.

The action of itopride hydrochloride is highly specific for the upper gastrointestinal tract.

Itopride hydrochloride does not affect serum gastrin levels.

Pharmacokinetic Properties
Absorption
Itopride hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. Relative bio-availability is calculated to be 60% due to liver first pass metabolism. There is no effect of food on bioavailability. Peak plasma levels (Cmax 0.28 g/mL) are reached after 0.5 to 0.75 hours after 50 mg of itopride hydrochloride. Following multiple oral doses ranging from 50 mg to 200 mg tid, itopride hydrochloride and its metabolites showed linear pharmacokinetics over a treatment period of seven days, with minimal accumulation.

Distribution
Approximately 96% of itopride hydrochloride is bound to plasma proteins. Albumin accounts for most of the binding. Alpha-1-acid-glycoprotein accounts for less than 15% of binding. In rats, itopride is distributed extensively (Vdβ = 6.1 L/kg) with high concentrations in the kidneys, small intestines, liver, adrenal glands, and stomach. Protein binding in the rat was lower than that seen in humans (78 vs 96%) . The transfer into the central nervous system, including brain and spinal cord, was minimal. Itopride distributes into the breast milk of rats.

Metabolism
Itopride undergoes extensive hepatic metabolism in humans. Three (3) metabolites have been identified, of which only one exerts minor activity without pharmacological relevance (approximately 2-3% of that of itopride). The primary metabolite in humans is the N-oxide, generated by oxidation of the tertiary amine N-dimethyl group.

Itopride is metabolized by a flavin-dependent monooxygenase (FMO3). The abundance and efficiency of the human FMO-isozymes can be subject to genetic polymorphisms, which can lead to a rare autosomal recessive condition known as trimethylaminuria (fish odor syndrome). The half-life of itopride may therefore be longer in trimethylaminuria patients.

In vivo pharmacokinetic studies on CYP-mediated reactions revealed that itopride showed neither inhibitory nor inductory effect on CYP2C19 and CYP2E1. CYP content and uridine diphosphate glucuronosyl transferase activity were not altered with the administration of itopride.

Excretion
Itopride hydrochloride and its metabolites are primarily excreted in the urine. The urinary excretions of itopride and its N-oxide were 3.7% and 75.4%, respectively, in healthy subjects after oral administration of a single therapeutic dose.

The terminal phase half-life of itopride hydrochloride was approximately six (6) hours.

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