伏格列波糖片剂药品说明书(英文)

Revised: October 2009 (12th version) Standard Commodity Classification No. of Japan873969- Improving agent for postprandial hyperglycemia –<Japanese Pharmacopoeia, Voglibose tablets>BASEN®Tablets 0.2BASEN®Tablets 0.3Prescription drugCaution - Use only pursuant to the prescription of a physician etc.CONTRAINDICATIONS (BASEN® Tablets are contra-indicated in the following patients.)(1) Patients with severe ketosis, or in a state of diabeticcoma or pre-coma [Since it becomes essential to quickly rectify hyperglycemia with administration of intrave-nous fluid or insulin, the use of BASEN® Tablets is not suitable.](2) Patients with severe infections, before or after operation,or with serious trauma [It is desirable to control plasma glucose with the injection of insulin. Therefore, ad-ministration of this drug is not appropriate.](3) Patients with a history of hypersensitivity to any of theingredients of this drugDESCRIPTION351 352Upper Lower Side Upper Lower Side7.1 8.12.63.1 Inactive ingredients:Corn Starch, Hydroxypropylcellulose, Magnesium Stearate, Lactose INDICATIONS○I mprovement of postprandial hyperglycemia in diabetes mel-litus (However, BASEN® Tablets should be used only when sufficient effect has not been obtained in patients already un-dergoing dietary treatment and/or exercise therapy, or when sufficient effect has not been obtained in patients who have been using oral hypoglycemic drugs or insulin preparations, in addition to dietary treatment and/or exercise therapy.)○P revention of onset of type 2 diabetes mellitus in impaired glucose tolerance (only for BASEN® Tablets 0.2) (However, BASEN® Tablets should be used only when im-paired glucose tolerance has not been improved in patients al-ready undergoing appropriate dietary treatment and/or exercise therapy.)< Precautions >Prevention of onset of type 2 diabetes mellitus in impaired glucose tolerance (only for BASEN® Tablets 0.2) Administration of BASEN® Tablets should be limited to those who is judged as impaired glucose tolerance (fasting plasma glucose is <126mg/dL and two-hour plasma glucose levels is 140 to 199mg/dL in 75 grams oral glucose tolerance test) and has not improved by dietary treatment and/or exercise therapy, which are the basics for the prevention of onset of diabetes mellitus, for three to six months and has any of followings; hypertension, dyslipidemia (hypertriglyceridemia, low HDL cholesterolemia etc.), obesity (Body Mass Index: BMI ≥25kg/m2) or a family history of diabetes mellitus in first-degree or second-degree relatives.DOSAGE AND ADMINISTRATION○I mprovement of postprandial hyperglycemia in diabetes mellitusStorageStore at room temperature.Expiration dateDo not use after the expiration date in-dicated on the package. (Use as soon as possible after unsealing, even before the expiration date.)Tablets 0.2 Tablets 0.3 Approval No.(6AM)1120(6AM)1121 Date of listing in the NHI reimbursement price August 1994August 1994 Date of initial marketing in Japan September 1994September 1994 Date of latest reexamination September 2004September 2004 Date of latest approval of indications October 2009 -Usually, for adults, BASEN® Tablets are orally administered in a single dose of 0.2 mg as voglibose, three times a day, just before each meal. If the effect is not sufficient enough, the single dose may be increased up to 0.3 mg, under close obser-vation of the course of disease.○P revention of onset of type 2 diabetes mellitus in impaired glucose tolerance (only for BASEN® Tablets 0.2)Usually, for adults, BASEN® Tablets are orally administered in a single dose of 0.2 mg as voglibose, three times a day, just before each meal.< Precautions >Prevention of onset of type 2 diabetes mellitus in impaired glucose tolerance (only for BASEN® Tablets 0.2)During administration of BASEN® Tablets, the examination of glycemic control should be made at appropriate intervals and careful attention should always be paid to the necessity for continuous administration of this drug. (See 2. Important Pre-cautions)PRECAUTIONS1. Careful Administration (BASEN® Tablets should beadministered with care in the following patients.)(1) Patients who are receiving other antidiabetic drugs[Hypoglycemia may occur.] (See 4. (1) Clinically sig-nificant adverse reactions.)(2) Patients with a history of laparotomy or ileus [Intes-tinal obstruction-like symptoms are liable to developdue to an increase in intestinal gas, etc.](3) Patients with chronic intestinal disease accompanied bya disturbance in digestion and absorption[The actions of this drug may aggravate the pathologiccondition.](4) Patients with Roemheld’s syndrome, severe hernia, orstenosis or ulceration of the large intestine, etc.[Symptoms may worsen due to an increase in intestinalgas, etc.](5) Patients with serious hepatic dysfunction [Because ofpossible changes in metabolic condition, the status ofplasma glucose control may greatly vary. In patientswith severe liver cirrhosis, hyperammonemia mayworsen, followed by disturbance of consciousness.](6) Patients with serious renal dysfunction [Because ofpossible changes in metabolic conditions, the status ofplasma glucose control may greatly vary.](7) Elderly patients (See 5. Use in the Elderly.)2. Important PrecautionsFor all indications(1) The administration of BASEN® Tablets should be lim-ited to the patients who have been definitely diagnosedas having diabetes mellitus or those who are with im-paired glucose tolerance. It should be noted that inaddition to these, there are such diseases as positiveurinary sugar that represent diabetes-like symptoms(renal glucosuria, senile abnormal glucose tolerance,abnormal thyroid function, pancreatic diseases such aschronic pancreatitis and drug-induced impaired glucose tolerance etc.).(2) The administration of BASEN® Tablets should be con-sidered only when sufficient effect has not been ob-tained in patients already undergoing dietary treatment and exercise therapy, which are the basics for diabetes treatment and/or the prevention of onset of diabetes mellitus.(3) In administration of BASEN® Tablets, hypoglycemicsymptoms and measures to be taken should be suffi-ciently explained to patients with diabetes mellitus or with impaired glucose tolerance (See 4. (1) Clinically significant adverse reactions.)Improvement of postprandial hyperglycemia in diabe-tes mellitus(1) For patients who are undergoing only the basic treat-ment for diabetes mellitus, namely, dietary treatment and /or exercise therapy, this drug should be given only when the two-hour postprandial plasma glucose is 200 mg/dL or more.(2) For patients who are using oral hypoglycemic drugs orinsulin preparations, in addition to dietary treatment and/or exercise therapy, a rough standard for admini-stration of this drug is to give it when the fasting plas-ma glucose is about 140 mg/dL or more.(3) During administration of BASEN® Tablets, the patientshould be closely observed with the monitoring of plasma glucose at regular intervals, and careful atten-tion should always be paid to the necessity for con-tinuous administration of this drug. If its effect on postprandial plasma glucose is not satisfactory even after the administration of this drug for 2 to 3 months(e.g. the reduction in the two-hour postprandial glucoselevel in venous plasma to 200 mg/dL or below can not be achieved), such consideration as the change to more possible appropriate treatment should be made.When sufficient control of the postprandial plasma glucose has been attained (the two-hour postprandial glucose level reduced to 160 mg/dL or below in venous plasma), and is judged to be satisfactorily maintained only with dietary treatment and/or exercise therapy, or with additional use of oral hypoglycemic drugs or in-sulin preparations, the administration of BASEN®Tablets should be discontinued and the patient should be observed.Prevention of onset of type 2 diabetes mellitus in im-paired glucose toleranceAfter starting of BASEN® Tablets administration, glu-cose metabolism assessment, such as fasting plasma glucose, casual plasma glucose or HbA1c, etc., and measurement of body weight should be conducted ap-proximately every 1 to 3 months and the patient should be observed with the monitoring of 75 grams oral glu-cose tolerance test approximately every 6 to 12 months, and careful attention should always be paid to the necessity for continuous administration of thisdrug. Since it has been reported that the risk of de-veloping diabetes mellitus increases in the patients with high level of plasma glucose (fasting plasma glucoseand two-hour plasma glucose levels in 75 grams oralglucose tolerance test) or with decreased insulin secre-tion in initial phase following glycemic load, patients should be observed closely. When a patient is diagnosed as type 2 diabetes melli-tus, such consideration as the change to appropriate treatment should be made. In case impaired glucose tolerance improved after starting of BASEN ®Tablets administration and it is considered that dietary treat-ment and/or exercise therapy alone would provide suf-ficient effects, the administration of BASEN ®Tablets should be discontinued and the patient should be ob-served with glucose metabolism assessment etc.3. Drug InteractionsPrecautions for coadministration (BASEN ®Tablets should be administered with care when coadministeredwith the following drugs.)Drugs Signs, Symptoms, Treatment, Mecha-nisms, etc. Antidiabetic drugs Derivatives of sulfonylamide and sul-fonylurea, biguanide derivatives, in-sulin preparations and improvingagents for insulin resistance It has been reported that hypoglycemiaoccurred in the concomitant use ofBASEN ® Tablets with insulin prepara-tions or sulfonylurea derivatives. There-fore, when this drug is used in combina-tion with any of the left-listed drugs, such careful caution as starting from a lowerdose should be exercised, taking into ac-count the possible development of hypo-glycemia.For the concomitant use of antidia-betic drugs and the drugs which en-hance or diminish the hypoglycemic action of antidiabetic drugs ◊ Drugs enhancing the hypoglyce-mic action of antidiabetic drugs: β- blockers, salicylic acid prepa-rations, monoamine oxidase in-hibitors, fibrate derivatives for treatment of hyperlipemia, war-farin, etc.◊ Drugs diminishing the hypoglyce-mic action of antidiabetic drugs:Adrenaline, adrenocortical hor-mone, thyroid hormone, etc. When BASEN ® Tablets are further ad-ministered concurrently, in addition to the concomitant use among any of the left -listed drugs, careful attention should bepaid to the drug interactions listed in thepackage inserts of these antidiabeticdrugs. Further cautious attention shouldalso be paid to the influence that might be additionally caused by the delaying action of this drug on the absorption of carbo-hydrates. 4. Adverse Reactions Improvement of postprandial hyperglycemia in diabe-tes mellitus Adverse reactions, including abnormalities in laboratory data, were observed in 154 (16.0%) of 965 patients given the daily doses of 0.6 mg or 0.9 mg of BASEN ® Tablets in the studies performed up to the time of approval, and in 460 (10.3%) of 4,446 patients in the postmarketing inves-tigation of the results of drug use (as of the end of reex-amination). Major adverse reactions were diarrhea(4.0%), increased flatus (4.0%) and abdominal distension(3.5%), etc.Prevention of onset of type 2 diabetes mellitus in im-paired glucose toleranceAdverse reactions, including abnormalities in laboratory data, were observed in 452 (47.5%) of 951 patients given the daily doses of 0.6 mg of BASEN ® Tablets in the stud-ies performed up to the time of approval. Major adverse reactions were flatulence (17.4%), abdominal distension (13.1%) and diarrhea (12.0%), etc.Adverse reactions listed below have been found in theabove-mentioned studies, investigations or spontaneousreports, etc. (1) Clinically significant adverse reactions1) When BASEN ® Tablets are used in combination with other antidiabetic drugs, hypoglycemia mayoccur (0.1% - < 5%). Furthermore, hypoglyce-mia has been reported to occur (< 0.1%) even when other antidiabetic drug was not concomi-tantly used with this drug. This drug delays the digestion and absorption of disaccharides. Therefore, if any hypoglycemic symptom is ob-served, appropriate measures, such as the admini-stration of glucose instead of sucrose, should betaken. 2) Abdominal swelling, increased flatus, etc., may occur, and intestinal obstruction-like symptomdue to an increase in intestinal gas, etc., may occur (<0.1%). Therefore, close observation should bemade, and if any of such symptoms occurs, appro-priate measures, such as discontinuation of BASEN ® Tablets, should be taken. 3) Fulminant hepatitis , serious hepatic dysfunctionwith increased AST (GOT), ALT (GPT), etc., orjaundice may occur (each < 0.1%). Therefore,close observation should be made, and if any ab-normality is found, the administration should be discontinued and appropriate measures should be taken. 4) When BASEN ® Tablets are administered to thepatients with serious liver cirrhosis , hyperam-monemia may worsen with the development of constipation, etc., followed by disturbance ofconsciousness (frequency unknown). Therefore, the condition of bowel movement, etc., shouldbe observed closely, and if any abnormality is ob-served, appropriate measures, such as immediatediscontinuation of this drug, should be taken.sea,vomiting, heart-burn or thirsttestinalis2) Hyper-sensitivityNote 1)Rash, pruri-tus or photo-sensitivity3) Hepatic IncreasedAST(GOT),ALT(GPT),LDH, γ- GTP orALP4) Psycho-neurologic DizzinessHeadache,light-headedness or sleepi-ness5) Hema-tologic AnemiaThrombocy-topeniaGranulo-cytopenia6) Others Numbness, ede-ma of face etc.,blurred vision,hot flushes, ma-laise, weakness,hyperkalemia,increased serumamylase, de-creased HDLcholesterol, dia-phoresis or alo-peciaNote 1) In such a case, administration of BASEN® Tablets should be discontinued.5. Use in the ElderlySince the elderly have a physiological hypofunction in general, the administration of BASEN® Tablets should be initiated at a lower dose (e.g. single dose of 0.1 mg).Furthermore, this drug should be carefully administered under close observation of the course of disease, such as careful attention to the plasma glucose level and the onset of gastrointestinal symptoms.6. Use during Pregnancy, Delivery or Lactation(1) BASEN® Tablets should be administered to pregnantwomen or women having possibilities of being preg-nant only if the expected therapeutic benefit is thoughtto outweigh any possible risk. [The safety of thisdrug in pregnant women has not been established.](2) It is desirable to avoid the administration of this drug tonursing mothers. However, if the administration isindispensable, nursing should be discontinued. [Ani-mal studies (rats) have revealed a suppressive action ofthis drug on body weight increase in newborns, pre-sumably due to suppression of milk production result-ing from inhibition of carbohydrate absorption inmother animals.1-2)]7. Pediatric UseThe safety of BASEN® Tablets in children has not been established (no clinical experience).8. Precautions concerning UseWhen dispensing the drug:The patient must be instructed to remove the tabletsfrom the press-through package (PTP) before they areingested. [It has been reported that, if the PTP sheet isswallowed, the sharp corners of the sheet may puncturethe esophageal mucosa, and this could result in seriouscomplications such as mediastinitis.] PHARMACOKINETICS(1) When BASEN® Tablets were repeatedly administered tohealthy male adults (6 subjects) in a single dose of 0.2 mg, three times a day, for 7 consecutive days, no voglibose was detected in plasma or urine.3)(For reference) In administration of this drug to healthymale adults (10 subjects) in a single dose of 2 mg, no vo-glibose was detected in plasma or urine.(2) In a study in which a single dose of 1 mg/kg of [14C] vo-glibose was administered to rats, the transfer of voglibose to fetus and mother's milk was observed, and the rates of excretion into urine and feces were about 5% and 98%, re-spectively.4)CLINICAL STUDIES5-21)1. Improvement of postprandial hyperglycemia in diabetes mellitusIn various clinical studies, including double-blind comparative controlled clinical trials, in which BASEN® Tablets were ad-ministered in daily doses of 0.6 mg or 0.9 mg to patients with non-insulin-dependent diabetes mellitus or insulin-dependent diabetes mellitus, the improvement rates by the type of diabe-tes mellitus in 877 patients, who were included in the analysis of the final global improvement rating in plasma glucose, were as shown in the table.Type of diabetesmellitusNumber ofpatientsImprovement orbettter evaluationSlight improvementor better evaluation Non-insulin-dependentdiabetes mellitus812 371 (45.7) 613 (75.5) Insulin-dependent dia-betes mellitus65 31 (47.7) 47 (72.3)Total 877 402 (45.8) 660 (75.3) Figures denote the number of patients, and figures in parentheses indicate the cumulative %.Improvement or better evaluation: "marked improvement" + "improvement" Slight improvement or better evaluation: "marked improvement" + "improvement" + "Slight improvement"The usefulness of BASEN® Tablets has been proved in dou-ble-blind controlled clinical trials in the above-cited patients with non-insulin-dependent diabetes mellitus.5-6) The useful-ness of this drug, including improvement of postprandial hy-perglycemia, has also been recognized not only in patients un-dergoing dietary treatment alone but also in patients using in-sulin preparations7-10) or oral hypoglycemic drugs.11-15) In ad-dition, in long-term administration study (for an average of 7 months), the lasting efficacy of this drug has been confirmed, and stable control of plasma glucose has been attained.16-20)The results of the clinical pharmacological tests have revealed that the typical adverse reactions pertaining to BASEN® Tab-lets, such as increased flatus, feeling of enlarged abdomen, di-arrhea or loose stools, etc, are considered to be attributable to decomposition and fermentation of unabsorbed carbohydrate resulting from pharmacological actions of this drug.2. Prevention of onset of type 2 diabetes mellitus in im-paired glucose toleranceIn the double-blind comparative trial (for an average of 336.7 ± 254.0 days), voglibose were administered in a single dose of 0.2 mg, three times a day to patients with impaired glucose tol-erance and any of followings; hypertension, hyperlipemia, obe-sity (Body Mass Index: BMI ≥25kg/m2) or a family history of diabetes mellitus in a first-degree or second-degree relative. As the result, the number of patients progressing to type 2 dia-betes mellitus was 50 of 897 patients in the voglibose group, and 106 of 881 patients in the placebo group at the end of the study.Hazard ratio of voglibose to placebo group (two-sided 95% CI) was 0.595 (0.4334–0.8177) (stratified log-rank test: p=0.0014).21)The cumulative progression rates to type 2 diabetes mellitus were as shown in the figure and the table.PHARMACOLOGY22-29)Voglibose inhibits the hydrolase (α-glucosidase) for disaccha-rides that catalyzes decomposition of disaccharides into mono-saccharides in the intestine, thereby delaying the digestion and absorption of carbohydrate, resulting in improvement of post-prandial hyperglycemia.1. Mechanism of action22)(1) Voglibose exhibits the inhibitory actions on porcinesmall intestine-derived maltase and sucrase, which areabout 20 and 30 times as strong as acarbose, respec-tively, while the inhibitory actions of voglibose on ratsmall intestine-derived maltase and sucrase are about270 and 190 times as strong as those of acarbose, re-spectively (in vitro). On the other hand, the inhibitoryactions of voglibose on porcine and rat pancreaticα-amylase are about 1/3,000 of those of acarbose, andvoglibose produces no inhibitory action onβ-glucosidase (in vitro).(2) The mode of inhibitory action of voglibose on the di-saccharide hydrolase for the complex of rat small intes-tine-derived sucrase and isomaltase is competitive an-tagonistic (in vitro).2. Suppressive action on increase in plasma glucose(1) When administered orally to normal rats, voglibosesuppresses the plasma glucose increase resulting fromthe loading of starch, maltose and sucrose. However,it is ineffective in suppressing the plasma glucose in-crease resulting from the loading of glucose, fructoseand lactose (in vivo).22)(2) When healthy adults were loaded with sucrose andtheir expired hydrogen gas was measured, suppressiveaction of voglibose on increase in plasma glucose atclinical doses was presumed to be attributable to slightinhibition of the absorption of carbohydrate based onits partial suppressing action on the decomposition ofdisaccharides, resulting in delayed absorption of car-bohydrate.23)PHYSICOCHEMISTRYStructural formula:Nonproprietary name:Voglibose [JAN]Chemical name:3,4-Dideoxy-4-[2-hydroxy-1-(hydroxymethyl)-ethyl amino]-2-C-(hydroxymethyl)-D-epi-inositol Molecular formula:C10H21NO7Molecular weight:267.28Melting point:163-168°CDescription:Voglibose occurs as white crystals or crystalline pow-der. It is very soluble in water, freely soluble in aceticacid (100), slightly soluble in methanol, very slightlysoluble in ethanol (99.5). It is soluble in 0.1mol/L hy-drochloride solution.CONDITIONS FOR APPROVALPrevention of onset of type 2 diabetes mellitus in im-paired glucose tolerancePost-marketing clinical trials (including follow-up inves-tigation after discontinuation of this drug) and special post-marketing investigation for long-term use should be conducted in a timely manner and their results should be submitted to regulatory agency. Furthermore, the neces-sary information should be provided to medical institu-tions promptly and thoroughly.PACKAGINGTablets 0.2:100 tablets (10 tablets × 10), 500 tablets (loose, 10 tablets × 50), 1,000 tablets (10 tablets × 100), 2,100 tablets (21 tablets × 100)Tablets 0.3:100 tablets (10 tablets × 10), 500 tablets (loose, 10 tablets × 50), 1,000 tablets (10 tablets × 100), 2,100 tablets (21 tablets × 100)SCOPE OF JAPANESE NATIONAL HEALTH INSURANCE COVERAGEIn administration of BASEN® Tablets for “Prevention of onset of type 2 diabetes mellitus in impaired glucose tol-erance (However, BASEN® Tablets should be used only when impaired glucose tolerance has not been improved in patients already undergoing appropriate dietary treat-ment and/or exercise therapy.)”, Japanese national health insurance coverage should be dealt as followings:1. Japanese national health insurance should onlycover for patients who are judged as impaired glucose tolerance (fasting plasma glucose is <126mg/dL and two-hour plasma glucose levels is 140 to 199mg/dL in75 grams oral glucose tolerance test) and has not im-proved by dietary treatment and/or exercise therapy, which are the basics for the prevention of onset of diabetes mellitus, for three to six months and has any of followings as the underlying condition; hyperten-sion, dyslipidemia (hypertriglyceridemia, low HDL cholesterolemia etc.).2. Basis for diagnosis of impaired glucose tolerance(date of diagnosis and the results), no improvement by dietary treatment and/or exercise therapy for three to six months and/or hypertension or dyslipidemia should be described in the space for notes of the cer-tificates of medical remuneration.REFERENCES1) Morseth, S.L. et al.: Jpn. Pharmacol. Ther., 19: 4325,1991.2) Morseth, S.L. et al.: ibid., 19: 4375, 1991.3) Hiraga, K.: Clinical Report, 26: 283, 1992.4) Maeshiba, Y. et al.: Jpn. Pharmacol. Ther., 19: 3639,1991.5) Goto, Y. et al.: J.Clin. Exp. Med., 160: 943, 1992.6) Kamiya, F. et al.: The Journal of Adult Diseases, 22:573, 1992.7) Ikeda, Y. et al.: Journal of New Remedies & Clinics,41: 20, 1992.8) Nakano, K. et al.: Medical Consultation & New Reme-dies, 28: 2315, 1991.9) Morishima, T. at al.: Jpn. J. Clin. Exp. Med., 69: 3997,1992.10) Kawamori, R. et al.: J. Jpn. Diabetes Society, 35: 633,1992.11) Shibata, A. et al.: Prog. Med., 12: 239, 1992.12) Taminato, A. et al.: Journal of New Remedies & Clin-ics, 41: 193, 1992.13) Nishizawa, Y. et al.: Jpn. J. Med. Pharm. Sci., 27: 123,1992.14) Matsuoka, H. et al.: Medical Consultation & NewRemedies, 29: 255, 1992.15) Kaku, K. et al.: Jpn. Pharmacol. Ther., 20: 887, 1992.16) Mimura, K. et al.: Jpn. J. Clin. Exp. Med., 69: 919,1992.17) Mimura, K. et al.: ibid., 69: 235, 1992.18) Nakamura, M. et al.: Journal of New Remedies &Clinics, 41: 2, 1992.19) Koizumi, J. et al.: Medical Consultation & New Reme-dies, 29: 241, 1992.20) Umeda, F. et al.: Jpn. J. Clin. Exp. Med., 69: 1309,1992.21) Kawamori, R. et al.: Lancet, 373: 1607, 2009.22) Odaka, H. et al.: Journal of Japanese Society of Nutri-tion and Food Science, 45: 27, 1992.23) Goto, Y. et al.: The Journal of Adult Diseases, 22: 451,1992.24) Ikeda, K. et al.: Jpn. Pharmacol. Ther., 19: 4105, 1991.25) Odaka, H. et al.: Journal of Nutritional Science andVitaminology, 38: 27, 1992.26) Ikeda, K. et al.: Jpn. Pharmacol. Ther., 19: 4451, 1991.27) Odaka, H. et al.: Journal of Japanese Society of Nutri-tion and Food Science, 45: 33, 1992.28) Takami, K. et al.: Jpn. Pharmacol. Ther., 19: 4457,1991.29) Odaka, H. et al.: ibid., 19: 4829, 1991.REQUEST FOR LITERATURE SHOULD BE MADE TO: Customer Relations, Pharmaceutical Information Services for Ethical Products DepartmentPharmaceutical Marketing DivisionTAKEDA PHARMACEUTICAL COMPANY LIMITED12-10, Nihonbashi 2-chome, Chuo-ku,Tokyo 103-8668, JapanOpen: 9:00-17:30 (except Saturday, Sunday, national holidays and nonbusiness days)Manufactured and Distributed by:TAKEDA PHARMACEUTICAL COMPANY LIMITED1-1, Doshomachi 4-chome, Chuo-ku,Osaka 540-8645, Japan。