Ganaton

Ganaton

itopride

Manufacturer:

Abbott

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Itopride HCl.
Description
Each film-coated tablet also contains the following inactive ingredients: Lactose, cornstarch, carmellose, light anhydrous silicic acid, magnesium stearate, hydroxypropylmethylcellulose 2910 (6 mm2/s), macrogol 6000, titanium oxide and carnauba wax.
The film-coated tablet is formulated to provide immediate release.
Itopride hydrochloride is N-(4-(2(dimethylamino)ethoxy)benzyl)-3,4-dimethoxybenzamide hydrochloride. Itopride hydrochloride is a substituted benzamide. It has an empirical formula of C20H26N2O4·HCl and a molecular weight of 394.89 g/mol.
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 4-5. The melting point is 193°-198°C.
Action
Pharmacology: 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 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. It does not affect serum gastrin levels.
Pharmacokinetics: Absorption: Itopride hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. Relative bioavailability 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 0.5-0.75 hr after 50 mg of itopride hydrochloride. Following multiple oral doses ranging from 50-200 mg 3 times daily, itopride hydrochloride and its metabolites showed linear pharmacokinetics over a treatment period of 7 days, with minimal accumulation.
Distribution: Approximately 96% of itopride hydrochloride is bound to plasma proteins. Albumin accounts for most of the binding. α1-acid glycoprotein accounts for <15% of binding. In rats, itopride is distributed extensively (V=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 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 6 hrs.
Clinical Studies: The activity of itopride hydrochloride has been evaluated in 2 pivotal studies: A dose-finding study and a comparative study.
Dose-Finding Study of 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 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, 150 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 the scores of "moderate improvement" or better, with the 150 mg group showing a higher degree of improvement than the 75 mg group by Turkey-type multiple comparison (p-value=0.038).
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% in the 300 mg group.
From the previous results, it was concluded that the optimal dosage of this drug is a daily dose of 150 mg.
Clinical Evaluation of Itopride hydrochloride for Gastrointestinal Symptoms Associated with Chronic Gastritis - Multicenter Double-Blind Comparative Study Using Cisapride as a Control Drug: A multicenter, 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 3 times daily or itopride hydrochloride 50 mg 3 times daily for a period of 2 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 64.8-78.6% in group H and 57.8-81.3% in group C and the disappearance rate for each symptom (within 14 days) was 58-92.9% in group H and 63.9-86.7% 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 previous results, it was concluded that itopride hydrochloride is a clinically useful drug for the treatment of upper abdominal digestive symptoms associated with chronic gastritis.
Toxicology: Preclinical Safety Data: Preclinical effects were observed only at dosages in excess of human dose indicating little relevance to human use. Moreover, humans are less susceptible to the hormonal effects observed in animal models.
High dosages (30 mg/kg/day) of itopride hydrochloride produced reversible mammary hyperplasia in rats, secondary to hyperprolactinemia, albeit not in dogs (to 100 mg/kg/day) or primates (to 300 mg/kg/day) dosages.
A 3-month oral toxicity study in dogs, prostatic atrophy was observed at 30 mg/kg/day of itopride, albeit not after 6 months treatment with higher (100 mg/kg/day) dosages nor in rats or monkeys at even higher (300 mg/kg/day) dosages.
Long-term animal studies of itopride hydrochloride have not been conducted to evaluate carcinogenic potential. No clastogenic or mutagenic effects of itopride hydrochloride were observed in a battery of in vitro and in vivo assays.
In the fertility study, prolonged estrous cycle was seen in females receiving ≥30 mg/kg/day, secondary to hyperprolactinemia. In addition, a prolonged precoital interval was also seen at 300 mg/kg/day. There was no adverse effect on copulation or fertility.
No teratogenic effect was observed in preclinical studies.
Indications/Uses
Treatment of gastrointestinal symptoms of functional, non-ulcer dyspepsia (chronic gastritis) ie, sensation of bloating, early satiety, upper abdominal pain or discomfort, anorexia, heartburn, nausea and vomiting.
Dosage/Direction for Use
Adults: Recommended Dose: 50 mg daily (150-mg tab taken orally 3 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 has been administered up to 8 weeks.
Overdosage
There have been no reported cases of overdose in humans. In case of excessive overdose, the usual measures of gastric lavage and symptomatic therapy should be applied.
Contraindications
Known hypersensitivity to itopride hydrochloride or any of the excipients.
Patients in whom an increase in gastrointestinal motility could be harmful eg, gastrointestinal hemorrhage, mechanical obstruction or perforation.
Special Precautions
Itopride hydrochloride enhances the action of acetylcholine and may produce cholinergic side effects. Data on long-term use are not available.
Use in pregnancy: There are no adequate and well-controlled studies in pregnant women. Therefore, itopride hydrochloride should not be used during pregnancy unless the benefits outweigh the potential risks.
Labor and Delivery: There are no known effects of itopride hydrochloride on labor or delivery.
Use in lactation: Because itopride is excreted in milk in rats, and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Use in children: Safety of itopride in children <16 years has not been established.
Use in the elderly: In general, appropriate caution should be exercised in the administration and monitoring of itopride hydrochloride in elderly patients reflecting the greater frequency of decreased hepatic, renal function and of concomitant disease or other drug therapy.
Use In Pregnancy & Lactation
Use in pregnancy: There are no adequate and well-controlled studies in pregnant women. Therefore, itopride hydrochloride should not be used during pregnancy unless the benefits outweigh the potential risks.
Labor and Delivery: There are no known effects of itopride hydrochloride on labor or delivery.
Use in lactation: Because itopride is excreted in milk in rats, and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Adverse Reactions
Reactions During Clinical Trials: In clinical trials (Phase I to Phase III), itopride hydrochloride was well tolerated and no serious adverse reactions were reported. A total of 19 adverse drug reactions in 14 patients were reported out of 572 cases with an incidence of 2.4%. The majority of these adverse reactions occurring in >1 patient consisted of diarrhea in 4 cases (0.7%), headache in 2 cases (0.3%), and abdominal pain in 2 cases (0.3%).
Abnormal laboratory findings observed in the trials include decreased WBC (leukocytopenia) in 4 cases (0.7%), increased prolactin in 2 cases (0.3%).
Post-Marketing Experience and Ongoing Critical Studies: The following adverse events have been reported in patients receiving itopride hydrochloride: Blood and Lymphatic System Disorders: Leukopenia and thrombocytopenia.
Immune System Disorders: Anaphylactoid reaction.
Endocrine Disorders: Increased prolactin level and gynecomastia.
Nervous System Disorders: Dizziness, headache, tremor.
Gastrointestinal Disorders: Diarrhea, constipation, abdominal pain, increased saliva, and nausea.
Hepatobiliary Disorder: Jaundice.
Skin and Subcutaneous Tissue Disorders: Rash, redness, itching.
Investigations: Increased AST (SGOT), increased ALT (SGPT), increased γ-GTP, increased alkaline phosphatase and increased bilirubin.
Drug Interactions
Metabolic interactions are not expected since itopride is primarily metabolized by flavine monooxygenase and not by CYP450.
No changes in protein-binding have been seen with co-administration of warfarin, diazepam, diclofenac sodium, ticlopidine hydrochloride, nifedipine and nicardipine hydrochloride.
Since itopride has gastrokinetic effects it could influence the absorption of concomitantly orally administered drugs. Particular caution should be taken with drugs with a narrow therapeutic index, sustained-release or enteric-coated formulations.
Antiulcer drugs eg, cimetidine, ranitidine, teprenone and cetraxate do not affect the prokinetic action of itopride.
Anticholinergic drugs may reduce the action of itopride.
Storage
Store below 30°C (86°F). Protect from light and moisture.
Shelf-Life: 36 months.
ATC Classification
A03FA - Propulsives ; Used in the treatment of functional gastrointestinal disorders.
Presentation/Packing
FC tab 50 mg (white, scored) x 3 x 10's.
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