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Kyorin Pharmaceutical Co., Ltd. 1 Revised: March 2010 (9th version) Standard Commodity Classification No. of Japan 872329 - Agent for gastritis and gastric ulcer- ® APLACE Tablets 100 mg < The Japanese Pharmacopoeia Troxipide tablets > ® APLACE Fine Granules 20% < The Japanese Pharmacopoeia Troxipide fine granules > Storage Tablets 100mg Fine Granules 20% Store at room temperature. Approval No. 16100AMZ03249000 22000AMX00662000 Date of listing in the NHI June 1986 June 2008 reimbursement price Expiration date Date of initial marketing in Japan July 1986 February 1989 This product should be used before Date of latest reexamination September 1993 the expiration date specified on the Date of latest approval of indications September 1991 package. International birth date July 1986 DESCRIPTION Taste Slightly sweet at Product description - first, then tasteless APLACE APLACE Fine or slightly bitter Tablets 100 mg Granules 20% Odor - Faint odor Active ingredient JP Troxipide 100 JP Troxipide 200 mg (in one mg (in 1g) INDICATIONS tablet) Gastric ulcers Inactive ingredient Corn starch, less Less substituted Amelioration of gastric mucosal lesions (erosion, hemorrhage, substituted hydroxypropyl- redness and edema) in the following diseases: acute gastritis, hydroxypropyl- cellulose, sodium acute exacerbation stage of chronic gastritis. cellulose, alginate, calcium magnesium lactate hydrates, DOSAGE AND ADMINISTRATION stearate, corn starch, The usual adult dosage for oral use is 100 mg of troxipide (one hypromellose, aspartame (L- tablet or 0.5 g of fine granules) three times daily after meals. carnauba wax phenylalanyl The dosage may be adjusted depending on the patient's age and compound), flavor symptoms. Type of tablet Film-coated Fine granules tablet PRECAUTIONS Color White Faint to pale 1. Adverse Reactions yellow <At the end of the re-examination period> Adverse reactions to this drug, including abnormal laboratory tests, were reported in 91 (0.75%) of 12,092 Diameter patients treated. The most freqently observed adverse 8.1 mm reactions were gastrointestinal symptoms including Size Thickness constipation 23 patients (0.19%), increased AST(GOT) levels in 21 patients (0.17%) and increased ALT(GPT) 4.1 mm levels in 30 patients (0.25%). Weight About 200mg Identification code KP-315 (1) Clinically significant adverse reactions (on package) 1) Shock, anaphylactoid symptoms (on tablet) Shock, anaphylactoid symptoms may occur. If any of KP-296 abnormal findings (such as urticaria, dyspnoea, blood (on package) pressure fell, etc.) are observed, administration should 2 Kyorin Pharmaceutical Co., Ltd. be discontinued and appropriate therapeutic measures 6. Other Precautions must be taken. 1) Urinary occult blood which might be caused by 2) Hepatic dysfunctions, jaundice inflammation and haemorrhage in the urinary bladder Hepatic dysfunction or jaundice with increased AST were observed more frequently than in the control group (GOT), ALT (GPT), Al-P, γ -GTP and/or LDH may at an oral dose of 1,000 mg/kg/day in rat repeated dose occur. Patients should be carefully monitored. If any toxicity study, which is 170 times or more higher dose symptoms are observed, administration should be than recommended human clinical dose. 1) discontinued and appropriate therapeutic measures must 2) Oestrous cycle disorder which might be caused by the be taken. abnormal parasecretion of prolactin was reported in animal experiments 2). Therefore, patients must (2) Other adverse reactions therefore be carefully monitored for abnormal 5% > <0.1% Incidence menstruation and lactation. If abnormal findings are ≥0.1% unknown observed, appropriate measures, such as reducing the Gastro - Constipation Feeling of enlarged dose, should be taken. If any abnormalities are observed, intestinal abdomen, heartburn, the appropriate measures such as suspension or nausea, etc. discontinuance of the dose should be taken. Hepatic Elevation of Elevation of ALP, r- AST (GOT), GTP, etc. PHARMACOKINETICS 3) 4) ALT (GPT) 1) Blood concentrations Hyper- Pruritus, rash, etc. Blood concentrations and pharmacokinetic parameters of sensitivity troxipide after a single oral dose of 100 mg to the healthy Others Headache dull, heart Edema adults are shown below. pounding, generalized fatigability, etc. Note) Incidence from voluntary reports could not be determined. 2. Use in the Elderly In general, elderly patients often have physiological hypofunction, therefore these products should be administered carefully. 3. Use during Pregnancy, Delivery or Lactation 1) The safety of this product in pregnant women has not Pharmacokinetic parameters been established. Therefore, these drugs should be used Dose Tmax Cmax t1/2 AUC0->24 in pregnant women or in women who may possibly be (mg) (h) (µg/mL) (h) (µg•h/mL) pregnant only if the expected therapeutic benefits Tablets 100 2.1 0.84 7.4 7.13 outweigh the possible risks associated with treatment. Fine 100 2.7 1.09 7.0 7.94 2) Breast-feeding must be discontinued during treatment. granule Troxipide is shown to be excreted in breast milk in animal studies with rats. 2) Metabolism 5) Following a single oral administration of 100 mg troxipide 4. Pediatric Use to the healthy adults, more than 96% of the metabolites The safety of these products in children has not been excreted in urine were unchanged compound, and only one established. (insufficient clinical data ) metabolite was observed. 3) Excretion 6) 5. Precautions concerning Use When a single oral dose of 100 mg troxipide to the healthy Precautions regarding dispensing adults, about 61% of dose was excreted up to 24 hours and For drugs that are dispensed in a press-through package about 67% of dose was excreted up to 48 hours in urine. (PTP), instruct the patient to remove the drug from the package prior to use. CLINICAL STUDIES [It has been reported that, if the PTP sheet is swallowed, 1. Effect on gastritis the sharp corners of the sheet may puncture the esophageal The overall amelioration rate of these products in acute mucosa, resulting in severe complications such as gastritis or acute gastric mucosal lesions of chronic gastritis mediastinitis.] in clinical studies performed in 310 cases, which included double blind clinical trial, was 82.9% (257/310). The clinical usefulness of these products in acute gastritis or Kyorin Pharmaceutical Co., Ltd. 3 acute gastric mucosal lesions of chronic gastritis was 8. Effect on mucosal prostaglandin level proved by double blind clinical trial. Troxipide was shown to increase the levels of 2. Effect on gastric ulcer prostaglandins which exhibited the cytoprotective effect in The amelioration rate of these products in gastric ulcer in gastric mucosa in rats. 23) clinical studies performed in 514 cases, which included double blind clinical trial, was 79.4% (408/514). The PHYSICOCHEMISTRY clinical usefulness of these products in gastric ulcer was Nonproprietary name: Troxipide (JAN) proved by double blind clinical trial Chemical name: 3,4,5-Trimethoxy-N-[(3RS)-piperidin-3-yl]benzamide PHARMACOLOGY Molecular formula: C15H22N2O4 1. Therapeutic and preventive effects on experimental Molecular weight: 294.35 gastritis Structural formula: Troxipide was shown to have therapeutic and preventive effects on experimental chronic gastritis (atrophic) caused by sodium taurocholate in rats. 7) 2. Preventive effect on acute gastric mucosal lesions Troxipide was shown to have a preventive effect on gastric mucosal lesions caused by aspirin, 0.6N HCl, ethanol and enantiomer (99.5) or under water-immersion stress in rats. 8)9)10) 3. Tissue repair-accelerating effect Description: Troxipide was shown to give a well balanced Troxipide occurs as a white crystalline powder. Freely reconstruction of gastric mucosa and growth of collagenous soluble in acetic acid (100), soluble in methanol, sparingly fibers on the basal portion of ulcer in histological studies on soluble in ethanol (99.5), slightly soluble in water. an clamping cortisone ulcer, acetic acid-induced ulcer and Troxipide is soluble in hydrochloric acid solution clamping ulcer in rats, and to accelerte the healing of (0.1mol/L).The hydrochloric acid (1mol/L) solution of chronic ulcers. 11)12) troxipide (1 in 5) shows no optical rotation. Troxipide was observed to have a synergetic effect on the Melting point: 177-181ºC ulcer caused by acetic acid with a concomitant use with 13) cimetidine. Partition coefficient: 4. Preventive activity on various experimental ulcers Partition Troxipide was shown to prevent the formation of ulcers by Organic phase Aqueous phase coefficient under water-immersion stress, stress-reserpine, 1- Octanol Phosphate buffer 17.9 indomethacin, dehematization-aspirin, hydrocortisone and Chloroform Phosphate buffer 159 pylorus-ligated, and to have a protective effect on mucosa (at 25ºC) in rats. 10)14) 5. Gastromucosal blood flow increasing effect PACKAGING Troxipide was observed to increase the gastromucosal 18) APLACE Tablets 100 mg: blood flow in the studies using thermoelectrical method Boxes of 100 tablets (10 tablets x 10), 500 tablets (10 15)(in rabbits and dogs) and the hydrogen clearance tablets x 50), 1,000 tablets (10 tablets x 100) and 1,050 technique (in rats 16) and dogs 17)). tablets (21 tablets x 50) in press-through packages, and And also, troxipide was observed to increase the blood flow bottles of 500 tablets in gastric mucosa and marginal gastric mucosa in acetic APLACE Fine Granules 20%: acid-induced ulcer after bleeding in the studies using organ- Boxes of 0.5g x 600 packets (3 packets x 200) and bottles reflectance-spectrophotometry in rats. 18) of 100g and 500g 6. Metabolism accelerating effect in gastric mucosa Troxipide was observed to activate the energy metabolism REFERENCES of gastric mucosa as a consequence of increased oxygen 1) Imai S et al.: Subacute toxicity study of troxipide in rats consumption and ATP contents in gastric mucosa. (In-house data) These effects were particularly remarkable in the marginal 2) Murayama J et al.: Effects of troxipide on blood prolactin gastric mucosa in which the blood flow was reduced due to and estrous cycle (In-house data) the ulcers. 19)20) 3) Kamijo S et al.: Bioequivalence study of troxipide tablets 7.