Irribow

Irribow

ramosetron

Manufacturer:

Astellas Pharma

Distributor:

Zuellig Pharma

Marketer:

Daiichi Sankyo
Full Prescribing Info
Contents
Ramosetron HCl.
Description
Ramosetron hydrochloride is (-)-(R)-5-[(1-Methyl-1H-indol-3-yl)carbonyl]-4,5,6,7-tetrahydro-1H-benzimidazole monohydrochloride.
Molecular Formula: C17H17N3O·HCl.
Molecular Weight: 315.80.
Ramosetron hydrochloride occurs as white or pale yellowish white crystalline powder. It is freely soluble in water or methanol, soluble in ethanol (95) or acetic acid (100), very slightly soluble in acetonitrile or acetic anhydride, and practically insoluble in tetrahydrofuran or diethyl ether. It is hygroscopic. It is affected by light.
Excipients/Inactive Ingredients: Microcrystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, anhydrous citric acid, magnesium stearate, hypromellose, macrogol, titanium oxide, talc, yellow ferric oxide.
Action
Pharmacology: Pharmacodynamics: Affinity for 5-HT3 Receptor: This product showed selective affinity for human serotonin 5-HT3 receptor.
5-HT3 Receptor Antagonistic Action: This product dose-dependently and competitively inhibited serotonin-induced contraction of guinea pig isolated colon. This product also inhibited serotonin-induced transient bradycardic reflexes (von Bezold-Jarisch reflexes) in anesthetized rats in a dose-dependent manner.
Effects on Abnormal Defecation: This product inhibited restraint stress-induced diarrhea in rats, conditioned fear stress-induced increase in defecation in rats, and serotonin-induced diarrhea in mice in a dose-dependent manner.
Effects on Large-Bowel Function: This product significantly improved conditioned fear stress-induced acceleration of colonic transit in rats and corticotropin releasing factor-induced abnormal colonic water transport in rats.
Effects on Abdominal Pain: This product improved restraint stress-induced decrease in colonic nociceptive threshold in rats in a dose-dependent manner.
Pharmacodynamics: Clinical Studies: The results from a double-blind, parallel-group, randomized study (controlled trial) in Japan are described as follows. When this product was orally administered at a dose of 5 μg once daily before breakfast, the monthly responder rate in global assessment of relief of IBS symptoms at the final point, the primary endpoint, was higher in the 5 μg group than in the placebo group, with a statistically significant difference. Adverse reactions including abnormal laboratory findings were observed in 65 (24.07%) of 270 patients in the 5 μg group and 36 (13.38%) of 269 patients in the placebo group. Adverse reactions that occurred in at least 5% of patients in the 5 μg group were hard faeces. (See Tables 1 and 2.)

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Reference: Stratified analyses were performed on the data from a Japanese randomized, double-blind, parallel-group comparative study; the efficacy results and adverse reactions by gender are shown as follows.
(1) Male: The monthly responder rate in global assessment of relief of IBS symptoms at the final point, the primary endpoint, was higher in the 5 μg group than in the placebo group, with a statistically significant difference. Adverse reactions including abnormal laboratory findings were observed in 41 (19.07%) of 215 patients in the 5 μg group and 30 (13.22%) of 227 patients in the placebo group. Adverse reactions that occurred in at least 5% of patients in the 5 μg group were faeces hard. (See Tables 3 and 4.)

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(2) Female: No significant difference was observed in monthly responder rate in global assessment of relief of IBS symptoms at the final point, the primary endpoint, between the 5 μg and placebo groups. Adverse reactions including abnormal laboratory findings were observed in 24 (43.64%) of 55 patients in the 5 μg group and 6 (14.29%) of 42 patients in the placebo group. The incidence of adverse reactions was higher in females than in males. Adverse reactions that occurred in at least 5% of patients in the 5 μg group were constipation, faeces hard, and abdominal distension. (See Tables 5 and 6.)

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Note: This product has been approved for the indication of diarrhea-predominant irritable bowel syndrome in males.
Pharmacokinetics: 1. Plasma Concentration: (1) Single Dose: When this product was administered as a single oral dose of 5 μg to healthy adult male and female subjects under fasting conditions, the plasma unchanged drug concentration reached a peak (Cmax) at approximately 1 to 3 hours after administration, and was eliminated thereafter, with a half-life of approximately 5 to 7 hours. Mean Cmax and AUC were 18.5 to 27.4 pg/mL and 125.3 to 215.9 pg·hr/mL, respectively. After single oral administration of this product at doses of 0.4 to 1.6 mg to healthy adult subjects, Cmax and AUC increased dose-proportionally.
(2) Multiple Dose: When this product was administered as multiple oral doses of 0.6 mg twice daily to 6 healthy adult male subjects for 7 days, no change in the pharmacokinetics was observed, which showed no accumulation.
Note: The approved maximum daily dose of this product is 10 μg.
2. Metabolism: It has been demonstrated in in vitro metabolism studies that hepatic drug metabolizing enzymes CYP1A1, CYP1A2 and CYP2D6 are involved in primary metabolism of ramosetron hydrochloride, which suggests that CYP1A2 and CYP2D6 are involved in primary metabolism of this product in humans.
3. Effects of Food: When this product was administered as a single oral dose of 5 μg under fasting or postprandial conditions to 20 healthy adult male subjects, there were no effects on Cmax or AUC after administration under postprandial conditions, which suggests that food has no effects on bioavailability of this product.
4. Gender Differences: When this product was administered as a single oral dose of 5 μg to healthy adult subjects, 20 males and 20 females, Cmax and AUC were 1.5-fold and 1.7-fold higher in female subjects than in male subjects, respectively.
5. Drug Interactions (Non-Japanese Data): When this product was administered as a single oral dose of 10 μg to 24 healthy non-elderly adult male and female subjects in combination with the administration of fluvoxamine (having a CYP1A2 inhibitory effect) for 10 days (50 mg once daily on the first day, followed by 50 mg twice daily), Cmax and AUC increased by 1.4-fold and 2.8-fold, respectively, compared with those after administration of this product alone. When this product was administered as a single oral dose of 10 μg to 35 healthy non-elderly adult male and female subjects in combination with the administration of paroxetine (having a CYP2D6 inhibitory effect) at 20 mg for 10 days, there were no effects on Cmax or AUC of this product.
Indications/Uses
Diarrhea-predominant irritable bowel syndrome in males.
Precautions: Clinical study results that have been obtained to date showed no efficacy of Irribow Tablet in female patients, and a high incidence of adverse reactions has also been reported in female patients. Therefore, Irribow Tablet should not be administered to female patients (see Pharmacology: Pharmacodynamics: Clinical Studies under Actions).
Dosage/Direction for Use
The recommended oral dose for adult males is 5 μg of ramosetron hydrochloride, once daily.
The dosage may be adjusted according to the patient's symptoms. However, the maximum dosage is 10 μg a day.
Precautions: The change in symptoms in the recent 1 month should be checked before adjusting the dose. Frequent dose adjustment according to the change in symptoms should be avoided.
Overdosage
No appropriate case.
Contraindications
Not applicable.
Special Precautions
Important Precautions: Use of this product should be considered for patients who have followed dietary instructions and lifestyle guidance, which are the basis of treatment of diarrhoea-predominant irritable bowel syndrome, but failed to achieve an improvement in symptoms.
Patients who are prescribed this product should not be those with chronic constipation or constipation predominant irritable bowel syndrome.
Before treatment with this product, it should be confirmed by adequate medical interview that the patient is suffering from repetitive episodes of diarrhea in the absence of constipation.
For patients suspected of having other diseases characterized by similar symptoms (large intestine carcinoma, inflammatory bowel disease, enteritis infectious, etc.), referral for specified testing should be considered whenever necessary.
Caution should be exercised for patients with a history of abdominal operation because ileus may occur according to the development of constipation and faeces hard caused by administration of this product.
Colitis ischaemic and serious constipation may occur. Therefore, patients should be instructed to contact the physician if they experience an abdominal pain, bloody stool, constipation, or faeces hard. (See Adverse Reactions.)
If a continued improvement in the symptoms is observed after treatment with this product, whether to continue or complete treatment should be examined at the time of about 3 months after the start of treatment, and routine administration for a long period of time should be avoided.
Precautions Concerning Use: At the Time of Dispensing: For drugs that are dispensed in a 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 may puncture the esophageal mucosa, resulting in severe complications such as mediastinitis).
Use in Children: The safety of this product has not been established in low-birth-weight infants, newborns, nursing infants, infants, or children. (There are no clinical experiences.)
Use in Elderly: This product should be administered with care to elderly patients, while closely monitoring the patient's condition. If any adverse reaction occurs, appropriate measures such as discontinuing administration should be taken. (Elderly patients often have reduced physiological function.)
Use In Pregnancy & Lactation
No appropriate case.
Adverse Reactions
Of a total of 921 patients assessed for the safety in Japanese clinical trials in patients (males and females) with diarrhea-predominant irritable bowel syndrome, adverse reactions including abnormal laboratory findings were reported in 259 patients (28.1%), and common events include constipation in 63 patients (6.84%) and faeces hard in 65 patients (7.06%) (At the time of approval: July 2008).
Clinically Significant Adverse Reactions: Shock and Anaphylactoid Symptoms (Incidence Unknown): Shock or anaphylactoid symptoms have been reported in patients who were given ramosetron hydrochloride IV for the treatment of gastrointestinal symptoms (nausea, vomiting) induced by antitumor drugs. Patients should be monitored closely, and if any abnormality is observed, Irribow should be discontinued and subsequent appropriate measures should be taken.
Colitis Ischaemic (Incidence Unknown): Colitis ischaemic may occur. Therefore, if symptoms suggestive of ischaemic colitis such as abdominal pain and bloody stool appear, appropriate measures such as drug discontinuation, should be taken.
Serious Constipation: Constipation and faeces hard have been reported with the use of this product. Serious constipation and its complications (intestinal obstruction, ileus, faecal impaction, megacolon toxic, secondary intestinal ischaemia, intestinal perforation) have also been reported outside Japan with analog, and some resulted in a fatal outcome. If constipation or faeces hard occur after treatment with this product, appropriate measures such as drug suspension or discontinuation should be taken according to the patient's symptoms.
Other Adverse Reactions: See Table 7.

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Drug Interactions
Concomitant administration of this product with drugs having CYP1A2 inhibitory effects can lead to increases of plasma concentrations of this product (see Pharmacology: Pharmacokinetics under Actions). (See Table 8.)

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Caution For Usage
Precautions for Handling: In order to maintain quality, this product is packed in a moisture-proof inner pouch.
Storage
Store below 25°C in a tight container. (Store in a dry place after opening.)
ATC Classification
A03AE - Serotonin receptor antagonists ; Used in the treatment of functional bowel disorders.
Presentation/Packing
FC tab 5 mcg (light yellow, 6.6 mm in diameter, 3 mm thick, weighs 0.104 g) x 28's.
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