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Revision: October 2015 (3rd version) Standard Commodity Classification No. of Japan 871169 Storage: Store at a room temperature Expiration date: Do not use after the expiration date indicated on the package. Regulatory classification: Prescription-only drug* Adenosine A2A Receptor Antagonist NOURIAST® Tablets 20 mg NOURIAST® Tablets Istradefylline Tablets Approval No. Date of NHI drug price listing Launch date International birth date 22500AMX00875 May 2013 May 2013 March 2013 * Caution - Use only pursuant to prescription CONTRAINDICATIONS (NOURIAST® is contraindicated in the following patients.) 1) Patients with a history of hypersensitivity to any of the ingredients of this product. 2) Pregnant women or women who may possibly be pregnant (See “Use during Pregnancy, Delivery, or Lactation”.) 3) Patients with severe hepatic impairment [Since NOURIAST® is metabolized mainly in the liver, the blood concentration of this drug may be increased. There is no experience of the use of this product in patients with severe hepatic impairment.] DESCRIPTION 1. Composition Active 20 mg of istradefylline in each tablet ingredient Yellow ferric oxide, carnauba wax (JP), crospovidone, crystalline cellulose (JP), Inactive titanium oxide (JP), magnesium stearate (JP), triacetin, lactose hydrate (JP), ingredients hypromellose (JP), polyvinyl alcohol (partially saponified), macrogol 4000 (JP) 2. Product description Diameter Thickness (mm) (mm) 7.1 3.3 Weight (g) Face 0.14 KH 131 Reverse Lateral Description Yellow-brown film-coated tablets Identification code KH131 (Printed on the tablets and PTP) INDICATIONS Improvement of wearing-off phenomena in patients with Parkinson’s disease on concomitant treatment with levodopa-containing products. -1- Revision: October 2015 (3rd version) Precautions related to INDICATIONS NOURIAST® should be used in patients with wearing-off phenomena even after adjustment of dose and dosing frequency of levodopa-containing products. DOSAGE AND ADMINISTRATION To be administered concomitantly with levodopa-containing products. The usual adult dosage of istradefylline is 20 mg orally administered once daily. According to symptoms, 40 mg of istradefylline can be orally administered once daily. Precautions related to DOSAGE AND ADMINISTRATION 1. NOURIAST® at 40 mg can be given once daily for the expected response on improving motor function during ON time. However, the efficacy on decreasing OFF time at 40 mg has not been shown to be higher than that at 20 mg. (See “CLINICAL STUDIES”.) 2. The maximum dosage of NOURIAST® should be limited to 20 mg once daily in the following patients since the blood concentration of istradefylline may increase. Patients with moderate hepatic impairment (see “Careful Administration” and "PHARMACOKINETICS”.) Patients on treatment with strong CYP3A4 inhibitors (see “Drug Interactions” and “PHARMACOKINETICS”.) PRECAUTIONS 1. Careful Administration (NOURIAST® should be administered with care in the following patients.) (1) Patients with hepatic impairment [Since NOURIAST® is metabolized mainly in the liver, the blood concentration of this drug may be increased.] (See “PHARMACOKINETICS”.) (2) Patients with ischemic heart disease [Arrhythmia may be aggravated.] 2. Important Precautions (1) NOURIAST® should be administered under close observation in patients with dyskinesia, since the treatment may aggravate dyskinesia in such patients. In the case that dyskinesia is aggravated, appropriate measures such as dose reduction, interruption, or discontinuation should be taken as needed. (2) Since sudden onset of sleep without preceding signs, sleep attacks, orthostatic hypotension, somnolence, dizziness, loss of consciousness, syncope, etc. may occur, caution should be exercised to avoid patients on treatment with NOURIAST® from engaging in potentially hazardous activities including car driving, machinery operation, and work at height. (3) In non-clinical studies, inflammatory changes in the lung characterized by infiltrating macrophages were noted. The patient’s condition should be closely observed after starting the administration of NOURIAST®. If shortness of breath/dyspnoea or dry cough occurs, imaging tests including chest X-ray and an appropriate work-up, etc. should be performed, and appropriate measures such as dose reduction, interruption, or discontinuation should be taken as needed. (See “Other Precautions”.) -2- Revision: October 2015 (3rd version) 3. Drug Interactions Istradefylline is mainly metabolized by CYP1A1, CYP3A4, and CYP3A5. Istradefylline has an inhibitory effect on CYP3A4/5 and P-glycoprotein. (See “PHARMACOKINETICS”.) Precautions for concomitant use (NOURIAST® should be administered with care in concomitant use.) Drugs Strong CYP3A4 inhibitors Itraconazole Clarithromycin, etc. CYP3A4 inhibitors Erythromycin Fluconazole, etc. CYP3A4 inducers Rifampicin Carbamazepine, etc Signs, Symptoms and Treatment Concomitant use of istradefylline at a dose of 40 mg with ketoconazole increased AUC0-∞ and t1/2 of istradefylline by 2.47 times and 1.87 times, respectively. The effects of istradefylline may be enhanced. The maximum dosage of NOURIAST® in combination with strong CYP3A4 inhibitors should be limited to 20 mg once daily. The effects of istradefylline may be enhanced. Mechanism and Risk Factors Concomitant use with CYP3A4 inhibitors may inhibit the metabolism of NOURIAST®, resulting in elevated blood concentration of istradefylline. The effects of istradefylline may Concomitant use with CYP3A4 inducers be impaired. may promote the metabolism of NOURIAST®, resulting in lowered blood concentration of istradefylline. Foods containing St. John’s Wort CYP3A4 substrates The effects of these drugs may be Concomitant use with NOURIAST® Midazolam, may inhibit the metabolism of CYP3A4 enhanced. Atorvastatin, etc. substrates, resulting in elevated blood concentration of these drugs. P-glycoprotein substrates The effects of these drugs may be Concomitant use with NOURIAST® Digoxin may inhibit P-glycoprotein, resulting in enhanced. Atorvastatin, etc. elevated blood concentration of P-glycoprotein substrates. Tobacco (smoking) The effects of istradefylline may Smoking may induce CYP1A1 and be impaired. CYP1A2 and promote the metabolism of NOURIAST®, resulting in lowered blood concentration of istradefylline. Entacapone Concomitant use with entacapone The mechanism is unknown. increased the incidence of dyskinesia. 4. Adverse Reactions Of a total of 649 patients enrolled in Japanese clinical studies, adverse reactions including laboratory data abnormalities occurred in 322 patients (49.6%). Common adverse reactions included dyskinesia in 110 patients (16.9%), constipation in 33 patients (5.1%), visual hallucination in 29 patients (4.5%), hallucination in 21 patients (3.2%), somnolence in 18 patients (2.8%), nausea in 16 patients (2.5%), blood CK (CPK) increased in 13 patients (2.0%), and weight decreased in 13 patients (2.0%). [Data from NDA submissions.] -3- Revision: October 2015 (3rd version) (1) Clinically significant adverse reactions Psychiatric disorders such as visual hallucination (4.5%), hallucination (3.2%), delusion (0.8%), delirium (0.6%), anxiety disorder (0.5%), aggravation of depression/depression (0.5%), persecutory delusion (0.3%), auditory hallucination (0.2%), somatic hallucination (0.2%), mania (0.2%), agitation (0.2%), impulse-control disorder (0.2%), etc. may occur. If any of these symptoms occurs, appropriate measures such as dose reduction, interruption, or discontinuation should be taken. (2) Other adverse reactions >5% 1% to <5% Cardiac disorders Gastrointestinal disorders Constipation Nausea, gastrooesophageal reflux Chest discomfort General disorders and administration site conditions Hepatobiliary disorders Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Vascular disorders <0.5% Myocardial infarction, ventricular extrasystoles Abdominal distension, vomiting, abdominal pain upper Malaise, peripheral edema, thirst, gait disorder Hepatic function abnormal Infections and infestations Injury, poisoning and procedural complications Investigations (laboratory test abnormality) Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Nervous system disorders 0.5% to <1% Supraventricular extrasystoles, atrial fibrillation, palpitations Gastritis, dyspepsia, gastric ulcer Bronchitis Contusion Weight decreased, blood CK (CPK) increased, blood trypsin increased, lipase increased, blood urine present, protein urine present Blood glucose increased, glucose urine present, blood urea increased, blood ALP increased, blood amylase increased, AST (GOT) increased, ALT (GPT) increased, γ-GTP increased LDH increased, blood bilirubin increased, blood pressure increased, electrocardiogram T wave inversion, white blood cell count decreased Pain in extremity Back pain, spinal osteoarthritis, posture abnormal Dystonia, tremor Decreased appetite Dyskinesia Somnolence, Parkinson's disease aggravated Insomnia Dizziness postural, dizziness, headache, syncope Sleep disorder Anxiety Pollakiuria, neurogenic bladder Cough Urticaria Orthostatic hypotension Eczema, rash Hypertension -4- Revision: October 2015 (3rd version) 5. Use in the Elderly Since elderly patients generally have reduced physiological function (renal function, hepatic function, etc.), NOURIAST® should be administered with care under observation on the patient’s condition. 6. Pregnancy, Delivery, and Lactation (1) NOURIAST® should not be administered to pregnant women or women who may be pregnant. [In animal studies (in rats or rabbits), lower fertility and implantation indices, higher total litter loss, teratogenicity (skeletal variation, skeletal anomaly, microphthalmia, and oligodactyly), lower viability index of suckling pups, etc. were noted. In animal studies (in rabbits), where istradefylline and levodopa/carbidopa were concomitantly administered, lower fetal survival rate and the effects on fetuses including teratogenicity (visceral anomaly, skeletal anomaly, and adactyly, brachydactyly, or oligodactyly) were noted at lower doses with concomitant use compared with istradefylline alone.] (2) Breast feeding must be discontinued during treatment with NOURIAST®. [Animal studies (in rats) revealed excretion of istradefylline in breast milk. Lower viability and lower weight gain were also noted in pups of breast-feeding matanal animals administed with istradefylline .] 7. Pediatric Use The safety of NOURIAST® in low-birth-weight babies, newborns, sucklings, infants, or children has not been established (no clinical experience). 8. Overdosage Signs, symptoms: Dyskinesia and hallucination may occur as acute symptoms of overdosage. Treatment: Gastric lavage and symptomatic treatment according to symptoms should be performed. General supportive treatment should be indicated in a hospitalization setting, as needed. 9. Precautions concerning Use Precautions regarding dispensing For the drug that is dispensed in a press-through package (PTP), patients should be instructed to remove the drug from the PTP sheet prior to use. [It has been reported that, if the PTP sheet is swallowed, its sharp corners may stick into and puncture the esophageal mucosa, resulting in serious complications such as mediastinitis.] 10. Other Precautions (1) In repeated-dose toxicity studies in mice, rats, and dogs and carcinogenicity studies in mice and rats, inflammatory changes in the lung characterized by inflammatory macrophages (development, aggregation, or increase of macrophages/foamy macrophages/histiocytes/foamy histiocytes in the alveolar space and pneumonia associated with these changes) were noted at a dose resulting in an exposure about 3 times the clinical exposure based on AUC0-24 (30 mg/kg/day in a carcinogenicity study in rats and 100 mg/kg/day in a 4-week study in dogs) or above. These changes were recovered by drug interruption. In a short-term repeated-dose toxicity study at a high dose (2000 mg/kg/day for 4 weeks) and a carcinogenicity study (100 mg/kg/day) in rats, deaths due to aggravation of the changes in the lung were noted1). -5- Revision: October 2015 (3rd version) (2) A study investigating the reinforcing effect of istradefylline by intravenous self-administration in rhesus monkeys showed a positive reinforcing effect2). (3) In a repeated-dose toxicity study for 13 weeks or more and a carcinogenicity study in rats, mineral deposition in the cerebral arteriolar wall and the capillary wall was noted at a dose resulting in an exposure about 3 times the clinical exposure based on AUC0-24 (30 mg/kg/day in a carcinogenicity study) or above3). (4) In a phototoxicity study in hairless rats, mild skin erythema reaction to high-dose UVA radiation (30 J/cm2 or more with a single dose of 400 mg/kg and 20 J/cm2 or more with repeated doses at the same dose level for 7 days) was noted4). PHARMACOKINETICS 1. Blood concentrations Single administration5) The plasma concentration-time profile and pharmacokinetic parameters of istradefylline after a single oral dose of 20 mg in healthy adult males under fasting or fed conditions are presented below (in a cross-over study). ● Fasting conditions (n=20) ○ Fed conditions (n=20) Plasma concentration (ng/mL) (1) (h) Pharmacokinetic parameters Dose tmaxa) 20 mg (h) Under fasting conditions 2.00 (n=20) 0.50 to 4.00 Under fed conditions 3.00 (n=20) 0.50 to 8.00 Cmax (ng/mL) 112.9 ±24.1 136.4 ±36.0 AUC0-∞ (ng・h/mL) 4323 b) ±1991 4591 ±1997 t1/2 (h) 57.09 b) ±31.51 53.56 ±22.33 Mean ± standard deviation a): Median, minimum to maximum b): n=19 Cmax and AUC0-∞ were higher when NOURIAST® was administered under fed conditions than when administered under fasting conditions, but without significant clinical implications. -6- Revision: October 2015 (3rd version) (2) Repeated administration6) The pharmacokinetic parameters after repeated oral doses of istradefylline once daily for 14 days at a dose of 20, 40, or 80 mg/day Note) in healthy adult males are presented below. Cmax and AUC0-24 after repeated doses increased in proportion to the dose in a dose range of 20 to 80 mg/day. The trough concentration (Ctrough) almost reached a steady state after repeated doses for 14 days. Note) The approved daily dose of istradefylline is up to 40 mg. Pharmacokinetic parameters Dose Day tmax a) (h) 20 mg 1 2.00 (n=9) 1.00 to 6.00 14 4.00 2.00 to 4.00 40 mg 1 2.00 (n=9) 1.00 to 4.00 14 2.00 0.50 to 4.00 80 mg 1 2.00 (n=9) 2.00 to 4.00 14 2.00 2.00 to 4.00 Cmax (ng/mL) 149.2 ±25.3 257.5 ±88.0 257.3 ±38.7 458.7 ±117.4 391.2 ±120.0 857.3 ±180.5 Ctrough (ng/mL) 33.4 ±11.5 154.6 ±59.4 67.2 ±20.3 284.7 ±66.6 105.2 ±38.0 502.1 ±136.2 AUC0-24 (ng·h/mL) 1319 ±335 4406 ±1598 2638 ±616 7925 ±2047 3966 ±1264 14318 ±3023 t1/2 (h) 75.0 b) ±32.0 59.1 c) ±27.0 51.1 b) ±25.0 Mean ± standard deviation a): Median, minimum to maximum b): n=7 c): n=8 2. Distribution The in vitro serum protein binding was 95% to 97% with albumin being the main binding protein in plasma. The plasma protein binding was 97% to 98%, which was similar in healthy adults, patients with hepatic impairment, and patients with renal impairment (data in non-Japanese). Istradefylline was highly bound to the basal ganglia in the brain and well distributed to the areas known to contain adenosin A2A receptors. The occupancy of adenosin A2A receptors with repeated doses of istradefylline at 20 and 40 mg/day was 90% or more (data in non-Japanese)7). 3. Metabolism A study with human liver microsomes and CYP-expressing microsomes suggested the main CYP isoenzymes involved in istradefylline metabolism were CYP1A1, CYP3A4, and CYP3A5, while CYP1A2, CYP2B6, CYP2C8, CYP2C18, and CYP2D6*1 were partially involved.. Istradefylline showed an irreversible inhibitory effect on CYP3A4/5. About 80% of total radioactivity was detected as unchanged drug in plasma 2 hours after oral administration. Since unchanged drug was not detected in urine, istradefylline was estimated to be primarily eliminated by metabolism (data in non-Japanese)8). -7- Revision: October 2015 (3rd version) 4. Excretion By 18 days after oral administration, 38.9% of the radioactivity was recovered in urine and 48.0% in feces (data in non-Japanese)8). A study using a Caco-2 cell monolayer demonstrated inhibitory effect of istradefylline on P-glycoprotein. 5. Pharmacokinetics in Patients with Hepatic Impairment9) Steady-state Cmax and AUC0-24 after repeated doses of NOURIAST® at 40 mg/day in patients with hepatic imparitment (moderate hepatic impairment according to Child-Pugh classification) were estimated to be about 3 times those in healthy adults (data in non-Japanese). 6. Pharmacokinetics in Patients with Renal Impairment10) Plasma exposures after a single oral dose of NOURIAST® at 40 mg were similar in patients with renal impairment (creatinine clearance by Cockroft-Gault formula: <30 mL/min) and healthy adults (data in non-Japanese). 7. Drug Interactions (data in non-Japanese) The results of investigating the drug interactions in healthy adults are as follows: (1) Ketoconazole11) Concomitant use of istradefylline (a single dose of 40 mg) with ketoconazole, a CYP3A4 inhibitor, (repeated doses of 200 mg/dose twice daily for 4 days followed by once daily for 7 days), did not affect istradefylline Cmax, but increased AUC0-∞ by 2.47 times and prolonged t1/2 by 1.87 times. (2) Rifampicin12) Concomitant use of istradefylline (a single dose of 40 mg) with rifampicin, a CYP3A4 inducer, (repeated doses of 600 mg/day for 20 days), istradefylline Cmax and AUC0-∞ were decreased to 55.5% and 19.2%, respectively. (3) Midazolam11) Concomitant use of istradefylline (repeated doses of 80 mg/day Note) for 15 days) with midazolam, a CYP3A4 substrate, (a single dose of 10 mg) increased midazolam Cmax by 1.61 times and AUC0-∞ by 2.41 times. (4) Atorvastatin13) Concomitant use of istradefylline (repeated doses of 40 mg/day for 17 days) with atorvastatin, a CYP3A4 and P-glycoprotein substrate, (a single dose of 40 mg) increased atorvastatin Cmax by 1.53 times and AUC0-∞ by 1.54 times. (5) Digoxin14) Concomitant use of istradefylline (repeated doses of 40 mg/day for 21 days) with digoxin, a P-glycoprotein substrate, (a single dose of 0.4 mg) increased digoxin Cmax by 1.33 times and AUC0-∞ by 1.21 times. (6) Smoking15) Cmax and AUC0-24 of istradefylline (repeated doses of 40 mg/day for 14 days) in smokers were 79.3% and 58.4%, respectively, of those in non-smokers. Note) The approved daily dose of istradefylline is up to 40 mg. -8- Revision: October 2015 (3rd version) CLINICAL STUDIES Efficacy16) 1. In a phase 3 double-blind study in Parkinson’s disease patients with motor complications on concomitant levodopa therapy, istradefylline given for 12 weeks at 20 and 40 mg demonstrated efficacy on the primary endpoint compared to placebo, i.e., mean OFF time per day was decreased. Istradeiylline at 40 mg demonstrated efficacy on the secondary endpoint compared to placebo, i.e., the UPDRS part III score (motor examination) during ON time was improved. Change in mean OFF time per day at the final evaluation (12 weeks after administration) Unit: hour Phase 3 double-blind study Number of subjects Baseline Mean ± standard deviation Final evaluation−Baseline Least square mean 95% confidence interval Istradefylline group Least square mean −Placebo group 95% confidence interval P value (Williams’ test) Placebo 123 6.31±2.47 −0.23 −0.62, 0.16 − − − 20 mg 120 6.55±2.72 −0.99 −1.38, −0.60 −0.76 −1.30, −0.22 0.003* 40 mg 123 5.97±2.45 −0.96 −1.35, −0.58 −0.74 −1.27, −0.20 0.003* *: p<0.025 Change in UPDRS part III score in ON time at the final evaluation (12 weeks after administration) Phase 3 double-blind study Number of subjects Baseline Mean ± standard deviation Final evaluation−Baseline Least square mean 95% confidence interval Istradefylline group Least square mean −Placebo group 95% confidence interval P value (Williams’ test) Placebo 123 21.6±11.6 −2.8 −3.8, −1.8 − − − 20 mg 120 21.3±10.8 −3.7 −4.7, −2.8 −0.9 −2.3, 0.4 0.086NS 40 mg 123 20.7±11.0 −4.9 −5.8, −3.9 −2.0 −3.4, −0.7 0.001* *:p<0.025, NS: Not statistically significant 2. Safety In Japanese placebo-controlled comparative studies (early phase 2, late phase 2, and phase 3 studies) where istradefylline was administered for 12 weeks in patients with Parkinson’s disease and motor complications on concomitant levodopa therapy, the incidence of adverse events classified as psychiatric disorders according to System Organ Class of the Medical Dictionary for Regulatory Activities Terminology, Japanese edition (MedDRA/J) was 3.6% (10/275) in the placebo group, 5.5% (15/272) in the istradefylline 20 mg group, and 10.1% (28/277) in the istradefylline 40 mg group. PHARMACOLOGY Istradefylline is an adenosine A2A receptor antagonist. It exhibits therapeutic effects on Parkinson’s disease by blocking adenosine A2A receptors in the striatum and globus pallidus. 1. (1) Pharmacological action Istradefylline improves catalepsy reaction, movement disorders in reserpine-treated mice. Catalepsy-improving effect of istradefylline is enhanced by concomitant use with levodopa17). -9- Revision: October 2015 (3rd version) (2) Istradefylline increases locomotor activity and improves motor dysfunction in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a model of Parkinson’s disease. The effects of levodopa are enhanced and the duration of action of levodopa is prolonged by concomitant use with istradefylline 18),19). (3) Istradefylline does not affect the intensity of levodopa-induced involuntary movements in MPTP-treated marmosets20). 2. (1) Mechanism of action Istradefylline shows high affinity to human recombinant adenosine A2A receptors, but shows low affinity to human recombinant adenosine A1 and A3 receptors (in vitro)21). (2) Istradefylline inhibits cAMP accumulation increase caused by an adenosine A2A agonist CGS21680 in PC-12 cells (in vitro)22). (3) Istradefylline decreases the increased extracellular concentration of gamma-aminobutyric acid (GABA) in the globus pallidus of rats with unilateral destruction of the nigrostriatal pathway, a rat Parkinson’s disease model23). PHYSICOCHEMISTRY Nonproprietary name: Istradefylline Chemical name: (E)-8-(3,4-Dimethoxystyryl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione Molecular formula: C20H24N4O4 = 384.43 Structural formula: O H 3C O N N O CH 3 N N CH3 O CH3 H3 C Description: Istradefylline occurs as a light yellow-green crystalline powder. Melting point: 192.9°C Partition coefficient: log P’OCT =3.5 (measured by the flask-shaking method using n-octanol/pH7.0 buffer solution) PRECAUTIONS FOR HANDLING NOURIAST® Tablets are film-coated to secure photostability and should not be pulverized. PACKAGING NOURIAST® Tablet 20 mg: [PTP] 30 tablets (10 tablets×3), 100 tablets (10 tablets×10) - 10 - Revision: October 2015 (3rd version) PRIMARY REFERENCES AND CORRESPONDING CONTACT < Primary References> 1) Company data: Changes in the lung in a long-term repeated-dose toxicity study and a carcinogenicity study 2) Company data: A study investigating a reinforcing effect by intravenous self-administration 3) Company data: Mineral deposition in the brain in a long-term repeated-dose toxicity study and a carcinogenicity study 4) Company data: Phototoxicity study in hairless rats 5) Company data: Pharmacokinetic study after a single dose (conducted in Japan, in healthy adults) 6) Company data: Pharmacokinetic study after repeated doses (conducted in Japan, in healthy adults) 7) Brooks DJ., et al.: Synapse.; 62(9).671.(2008) <Reference request No. 023-112> 8) Company data: Mass balance study (conducted overseas, in healthy adults) 9) Company data: Pharmacokinetic study (conducted overseas, in patients with decreased hepatic function) 10) Company data: Pharmacokinetic study (conducted overseas, in patients with decreased renal function) 11) Company data: Drug interaction study (conducted overseas, with midazolam/ketoconazole) 12) Company data: Drug interaction study (conducted overseas, with rifampicin) 13) Company data: Drug interaction study (conducted overseas, with atorvastatin) 14) Company data: Drug interaction study (conducted overseas, with digoxin) 15) Company data: Pharmacokinetic study (conducted overseas, in smokers) 16) Company data: A phase 3 double-blind study (conducted in Japan, in patients with Parkinson’s disease) 17) Company data: Effect of improving reserpine-induced catalepsy in mice 18) Company data: Effect of improving motor dysfunction in MPTP-treated marmosets 19) Company data: Effect of concomitant use with levodopa in MPTP-treated marmosets 20) Company data: Effect on involuntary movements in MPTP-treated marmosets 21) Company data: Affinity to adenosine receptors 22) Company data: A study on adenosine A2A receptor function 23) Company data: Measurement of gamma-aminobutyric acid concentration in the globus pallidus of rats with unilateral destruction of the nigrostriatal pathway - 11 - Revision: October 2015 (3rd version) REQUEST FOR LITERATURE OR INQUIRY ABOUT PRODUCT INFORMATION SHOULD BE MADE TO: Please request for the company data as well as literature cited in the “PRIMARY REFERENCE” list above to the following. Medical Information Office Kyowa Hakko Kirin Co., Ltd. 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo 100-8185 toll-free 0120-850-150 TEL: 03 (3282) 0069, FAX: 03 (3282) 0102 Office hours: 9:00-17:30 (except Saturdays, Sundays, national holidays and company holidays) MANUFACTURED AND DISTRIBUTED BY: Kyowa Hakko Kirin Co., Ltd. 1-6-1 Ohtemachi, Chiyoda-ku, Tokyo Japan - 12 -