Designation of Pharmaceuticals Required securing

Pharmaceutical Equivalence

Ministry of Food & Drug Safety Notification No. 2014- 189 (Nov. 26, 2014, Amended)

Article 1 (Purpose) In accordance with Article 31(2) and 42(1) of the 「Pharmaceutical Affairs Act」, Articles 4(1)(3) of the 「Regulation on Safety of Medicinal Products, etc.」 and Article 57 of the 「Narcotics Control Act.」, the purpose of this Notification is to set forth the appropriate standards for Pharmaceuticals approval by providing for designates pharmaceuticals required to submit bioequivalence study results and comparative clinical study results, and also designates pharmaceuticals required to submit test results of not using biological matters such as comparative dissolution test in the approval of pharmaceutical manufacturing/marketing and import. Article 2 (Designation of pharmaceuticals requiring pharmaceuticals equivalence test) ① In accordance with Article 4(1)(3)(b) of the 「Regulation on Safety of Medicinal Products,

etc..」, Tablets, capsules, or suppository of which ingredients are the same as previously approved pharmaceuticals for manufacturing/marketing and import, are one of the following subparagraph.

1. Conventional pharmaceuticals, their salts and derivatives comprised of a single active

pharmaceutical ingredient as listed in the attached Table 1, which are determined by the claim quantity of medical expense of health insurance submitted to the President of Health Insurance Review and Assessment Service by the healthcare institutions as

described in Article 43 of the 「National Health Insurance Act」.

2. Expensive pharmaceuticals, their salts and derivatives comprise of a single active pharmaceutical ingredient as listed in the attached Table 2, which are determined by the invoiced amounts of medical expense of health insurance divided by the claim quantity submitted to the President of Health Insurance Review and Assessment

Service by the healthcare institutions as described in Article 43 of the 「National Health Insurance Act」.

3. Other pharmaceuticals required securing pharmaceutical equivalence, their salts and isomers comprise of a single active pharmaceutical ingredient as listed in the attached Table 3.

4. Fixed-dose combination of pharmaceuticals containing ingredients, their salts and isomers as listed in the attached Table 1, 2, and 3.

② In accordance with the partial clues with Article 4(1)(3) of the 「Regulation on Safety of Medicinal Products, etc.」, Pharmaceuticals needed to submit test results of comparative dissolution test, etc., in which biological matters are not used, are one of the following subparagraphs. 1. Pharmaceuticals, their salts and their derivatives comprised of single ingredients listed in the attached Table 4. 2. Fixed-dose combination of pharmaceuticals comprising of ingredients listed in the attached Table 4, their salts and derivatives.

Article 3 (Review Period) According to Article 8 of the 「Framework Act on Administrative Regulations」 and the 「Regulation on Issuance and Management of Instructions and Rules」 (Presidential Instruction No. 248), validity of regulations must be reviewed and

other relevant actions accompanied by every 3 years (by December 31 of every third year) starting January 1, 2014.

ADDENDA Article 1 (Enforcement Date) This Notification is to be effective from the date of notification. Provided, That pharmaceutical approval or notification application on ingredients falling into No. 49 to 64 of Appendix 3 shall be effective from January 1, 2016.

Article 2 (Example of Application) This Notification submitted to Minister of Food and Drug Safety or Commissioner of Regional office of Food and Drug Safety after the enforcement date of this notification applies to application (including amendment) for approval or notification (including amendment) of pharmaceutical manufacturing·marketing and import. Provided, that this notification can be applied in the case that a pharmaceutical is approved or notified for manufacturing·marketing and import even before the enforcement date of this notification. [Attached Table 1] Conventional Pharmaceuticals

Serial number Ingredient 1 acarbose 2 acebrophylline 3 aceclofenac 4 acemetacin 5 acepifyline 6 acetylcarnitine HCl 7 aclatonium napdisilate 8 acyclovir 9 afloqualone 10 alibendol 11 allopurinol 12 alprazolam 13 14 15 16 17 18 amoxicillin 19 atenolol 20 atorvastatin(calcium) 21 azelastine HCl 22 bacampicillin HCl 23 baclofen 24 barnidipine HCl 25 benexate betadex 26 benidipine HCl 27 28 benztropine mesylate 29 bepotastine besilate 30 beraprost sodium 31 betaxolol HCl 32 bethanechol chloride 33 biphenyl dimethyl dicarboxylate 34 bisoprolol hemifumarate 35 bromazepam 36 buspirone HCl 37 calcitriol 38 39 candesartan cilexetil 40 captopril 41 carbamazepine 42 caroverine HCl 43 carvedilol 44 cefaclor 45 cefadroxil 46 cefatrizine propylene glycol 47 cefdinir 48 cefditoren pivoxil 49 cefixime 50 celecoxib 51 cephradine 52 cetraxate HCl 53 chlordiazepoxide HCl 54 chlorphenesin carbamate 55 56 ciclacillin 57 cilazapril 58 cilnidipine 59 cilostazol 60 cimetidine 61 cimetropium bromide 62 ciprofloxacin HCl 63 clarithromycin 64 clonazepam 65 cloperastine HCl 66 clopidogrel 67 clotiazepam 68 codeine phosphate 69 colchicine 70 collinalpocereate 71 72 dextromethorphan Hbr 73 diacerhein 74 diazepam 75 diclofenac sodium 76 diethylamine ethyl theophylline 77 difemerine HCl 78 digoxin 79 80 diphenylhydantoin sodium 81 dipyridamole 82 divalproex sodium 83 dobesilate calcium 84 domperidone 85 domperidone maleate 86 doxazocin mesylate 87 88 doxofylline 89 doxycycline 90 ebastine 91 emedastine fumarate 92 enalapril maleate 93 eperisone HCl 94 eprosartan mesylate 95 erdosteine 96 erythromycin estolate 97 erythromycin(enteric coated 215mg) 98 estrogens(conjugated) 99 etizolam 100 etodolac 101 famotidine 102 felodipine 103 fenofibrate 104 fenoprofen calcium 105 fenoterol Hbr 106 fexofenadine 107 finasteride 108 flavoxate HCl 109 fluconazole 110 flunarizine HCl 111 flunitrazepam 112 fluoxetine HCl 113 formoterol fumarate 114 fosinopril sodium 115 furosemide 116 gabapentin 117 118 gliclazide 119 glimepiride 120 haloperidol 121 hexoprenaline sulfate 122 hydrochlorothiazide 123 124 hydroxychloroquine sulfate 125 hydroxyzine HCl 126 ibudilast 127 imidapril HCl 128 imipramine HCl 129 indapamide 130 irbesartan 131 isoniazid 132 133 isosorbide mononitrate 134 itopride 135 itraconazole 136 137 ketotifen fumarate 138 lacidipine 139 lamivudine 140 lamotrigin 141 lecithin iodide 142 lercanidipine HCl 143 levofloxacin 144 levosulpiride 145 levothyroxine sodium 146 limaprost alpha-cyclodextrin 147 lisinopril 148 lithium carbonate 149 loperamide HCl 150 loratadine 151 lorazepam 152 lornoxicam 153 losartan potassium 154 lovastatin 155 loxoprofen sodium 156 manidipine HCl 157 medroxyprogesterone acetate 158 meloxicam 159 mequitazine 160 mesalazine 161 metformin HCl 162 methimazole 163 methocarbamol 164 methotrexate 165 methylphenidate HCl 166 methylprednisolone 167 metoclopramide HCl 168 metronidazole 169 microemulsion cyclosporine 170 midecamycin acetate 171 misoprostol 172 moexipril HCl 173 molsidomin 174 montelukast sodium 175 mosapride citrate 176 mycophenolate mofetil 177 nabumetone 178 nateglinide 179 neltenexine monohydrate 180 nicergoline 181 nicorandile 182 nifedipine 183 nimesulide 184 nimodifine 185 nitrendifine 186 nizatidine 187 norfloxacin 188 nortryptiline HCl 189 octylonium bromide 190 ofloxacin 191 olmesartan medoxomil 192 olopatadine HCl 193 omeprazole 194 orphenadrine HCl 195 oxcarbazepin 196 oxiracetam 197 paroxetine HCl 198 pentoxifylline 199 perphenazine 200 phenobarbital 201 phloroglucinol 202 pinaverium bromide 203 pioglitazone HCl 204 piroxicam 205 pranlukast hydrate 206 pravastatin sodium 207 prednisolone 208 procaterol HCl 209 proglumetacin maleate 210 propiverine HCl 211 propranolol HCl 212 propylthiouracil 213 pyrazinamide 214 quinupramine 215 rabeprazole sodium 216 ramipril 217 ranitidine HCl 218 rebamipide 219 repaglinide 220 rifampicin 221 risperidone 222 ropinirole HCl 223 rosiglitazone maleate 224 rosuvastatin calcium 225 roxatidine acetate HCl 226 roxithromycin 227 s-adenosyl-l-methionine sulfate-p-toluene sulfonate 228 229 simvastatin 230 sodium alendronate 231 sodium valproate 232 sofalcone 233 spironolactone 234 235 sulfasalazine 236 sulodexide 237 talniflumate 238 tamoxifen citrate 239 tamsulosin HCl 240 telmisartan 241 teprenone 242 terazosin HCl 243 terbinafine 244 thenothiola sodium 245 theophylline 246 tibolone 247 ticlopidine HCl 248 tipepidine hibenzate 249 tiropramide HCl 250 tizanidine HCl 251 tofisopam 252 tolperisone HCl 253 tolterodine tartrate 254 topiramate 255 torasemide 256 tramadol HCl 257 trazodone HCl 258 triamcinolone 259 triazolam 260 triflusal 261 trimebutine maleate 262 trimetazidine 2HCl 263 tripotassium dicitrato bismuthate 264 troxipide 265 ubidecarenone 266 valsartan 267 verapamil HCl 268 voglibose 269 warfarin sodium 270 zaltoprofen 271 zolpidem 272 α-lipoic acid 273 γ-linoleic acid [Attached Table 2] Expensive Pharmaceuticals Serial number Ingredient 1 5-hydroxytriptophan 2 abacavir sulfate 3 acitretin 4 adefovir dipivoxil 5 alfuzosin HCl 6 allylestrenol 7 altretamine 8 amisulpiride 9 anagrelide HCl 10 anastrozole 11 aripiprazole 12 atazanavir sulfate 13 atorvastatin calcium 14 auranofin 15 azasetron HCl 16 azathioprine 17 azithromycin 18 balofloxacin 19 bambuterol HCl 20 benazepril HCl 21 bicalutamide 22 bucillamine 23 budesonide 24 bupropion HCl 25 camostat mesilate 26 capecitabine 27 carmofur 28 cefaclor 29 cefadroxil 30 cefetamet pivoxil HCl 31 cefotiam hexetyl HCl 32 cefpodoxime proxetil 33 cefprozil 34 cefroxadine 35 cefteram pivoxil 36 ceftibuten 37 cefuroxime axetil 38 chlormadinone acetate 39 cicletanine HCl 40 ciclopirox olamine 41 citalopram 42 citicoline sodium 43 clozapine 44 cycloserine 45 cyclosporine 46 cyproterone acetate 47 cytochrome C 48 danazol 49 desmopressin acetate 50 didanosine 51 dihydrocodeine tartrate 52 dihydroergocriptine mesylate 53 dinoprostone 54 dirithromycin 55 dolasetron mesilate 56 donepezil HCl 57 dutasteride 58 efavirenz 59 entacapone 60 epinastine HCl 61 erythromycin stinoprate 62 esomeprazol magnesium 63 estramustine sod. Phosphate 64 etoposide 65 exemestane 66 ezetimibe 67 famciclovir 68 fleroxacin 69 fluconazole 70 fludrocortisone acetate 71 fluoxetine HCl 72 flurbiprofen 73 flutamide 74 fluvastatin 75 gabapentin 76 galantamine hydrobromide 77 gatifloxacin 78 gefitinib 79 gemifloxacin mesylate 80 glycophosphopeptical 81 granisetron (HCl) 82 imatinib mesylate 83 indinavir sulfate 84 isotretinoin 85 isradipine 86 lamivudine 87 lansoprazole 88 leflunomide 89 letrozole 90 levamisole HCl 91 linezolid 92 lomefloxacin HCl 93 lomustine 94 loracarbef 95 medroxyprogesterone acetate 96 mefloquine HCl 97 melphalan 98 memantine HCl 99 mercaptopurine 100 mesalazine 101 mesoglycan sodium 102 metergoline 103 methylol cephalexin lysinate 104 methylphenidate HCl 105 mirtazapine 106 mizoribine 107 moclobemide 108 modafinil 109 molindone HCl 110 morphine sulfate 111 moxifloxacin HCl 112 mycophenolate sodium 113 naltrexone HCl 114 naratriptan HCl 115 nelfinavir mesylate 116 nevirapine 117 nomegestrol acetate 118 olanzapine 119 ondansetron hydrochloride dihydrate 120 oseltamivir phosphate 121 oxandrolone 122 oxycodone HCl 123 ozagrel HCl 124 pamidronate disodium 125 pantoprazol sodium sesquihydrate 126 pefloxacin methanesulfonate 127 pentosan polysulfate sodium 128 pergolide mesylate 129 perindopril tetrabutylamine 130 pilocarpine HCl 131 pitavastatin calcium 132 polysaccharide-K 133 pramipexole dihydrochloride 134 praziquantel 135 procarbazine HCl 136 propafenone HCl 137 quetiapine fumarate 138 raloxifene HCl 139 ramipril 140 ramosetron HCl 141 ranitidine bismuth citrate 142 rifabutin 143 riluzole 144 risedronate sodium 145 ritodrine HCl 146 ritonavir 147 rivastigmine 148 rufloxacin HCl 149 sarpogrelate HCl 150 selegiline HCl 151 sertaconazole nitrate 152 sertraline HCl 153 sevelamer HCl 154 sodium fusidate 155 156 sparfloxacin 157 158 standardized lyophilized mixed bacterial lysates 159 stavudine 160 sulfomucopolysaccharide 161 sultamicillin tosylate 162 sumatriptan succinate 163 tacrolimus 164 tamsulosin HCl 165 tegaserod hydrogen maleate 166 telithromycin 167 temocapril hydrochloride 168 testosterone undecanoate 169 tetrahydrobiopterin l-biopterin 170 thioguanine 171 tolterodine tartrate 172 topiramate 173 toremifene citrate 174 tosufloxacin tosylate 175 tramadol HCl 176 tretinoin 177 tropisetron 178 valsartan 179 vancomycin HCl 180 venlafaxin HCl 181 vigabatrin 182 voriconazole 183 zafirlukast 184 zidovudine 185 ziprasidone hydrochloride monohydrate 186 zolmitriptan [Attached Table 3] Other Pharmaceuticals Required Securing Pharmaceutical Equivalence Serial number Ingredient 1 albuterol sulfate(salbutamol sulfate) 2 aminophylline 3 amitriptyline HCl 4 chlorpromazine HCl 5 chlorthalidone(chlorphthalidolone, hthalamudine, phthalamodine) 6 cortisone acetate 7 cyclosporine 8 dexamethasone 9 10 diltiazem HCl 11 disulfiram 12 dyphylline(diprophylline) 13 estrogen esterified 14 fluoxymesterone 15 fluphenazine HCl 16 glyburide(glibenclamide) 17 hydrocortisone 18 isosorbide dinitrate 19 leucovorin calcium(calcium folinate) 20 levodopa 21 mazindol 22 medroxyprogesterone acetate 23 methyltestosterone 24 nifedipine 25 nortriptyline HCl(desmethylamitriptyline HCl) 26 phendimetrazine tartrate 27 phenytoin sodium, prompt(diphenylhydantoin sodium, prompt) 28 potassium chloride 29 prednisolone 30 prednisone 31 procainamide HCl 32 promethazine HCl 33 propantheline Br 34 propylthiouracil 35 36 reserpine 37 terbutaline sulfate 38 theophylline 39 triamcinolone 40 trichlormethiazide(hydrotrichlorothiazide) 41 verapamil HCl 42 amlodipine 43 cefuroxime Axetil 44 clarithromycin 45 cefpodoxim proxetyl 46 47 sibutramine 48 clopidogrel 49 nebivolol hydrochloride 50 loperamide oxide 51 paliperidone 52 valacyclovir 53 ibandronate sodium 54 cefalexin 55 mefenamic acid 56 bromperidol 57 piracetam 58 sulindac 59 oxybutynin hydrochloride 60 migritol 61 doxycycline hyclate hydrate 62 ibuprofen 63 ketorolac tromethamine 64 ribavirin [Attached Table 4] Pharmaceuticals Required to Submit Test Results not using Biological Matters

Serial number Ingredient Test method 1 benzonatate comparative dissolution test 2 calcium polycarbophil comparative disintegration test 3 diethylpropion HCl(amfepramone HCl) comparative dissolution test 4 doxifluridine comparative dissolution test 5 kallidinogenase comparative disintegration test 6 streptodornase-streptokinase comparative disintegration test 7 standardized lyophilizate of bacterial lysate physicochemical equivalence test