100 Sporanox Capsules 100 mg 022816

SPORANOX / itraconazole 100 mg Onychomycosis Tinea Capitis SPORANOX / / 1

SPORANOX 2

SPORANOX 200mg 200mg / / 1 3 3

200 mg 200 mg 7 15 200 mg 7 200 mg 30 200 mg 7 100 mg 15 AIDS SPORANOX itraconazole 4

200 mg 21 / 200 mg 5

1 2 3 1 2 200 mg 3 6

Itraconazole 2 4 1 200 mg 2-5 200 mg 100-200 mg 3-7 200 mg 7

200 mg 2-1 200 mg 2-1 200 mg 200 mg 8 100 mg 200 mg 6 100 mg 3 100 mg 6 AIDS SPORANOX 8

100-200 mg 1 6 SPORANOX SPORANOX SPORANOX SPORANOX 9

itraconazole itraconazole itraconazole itraconazole itraconazole SPORANOX SPORANOX CYP3A4 QT astemizole bepridil 10

cisapride dofetilide levacetylmethadol levomethadyl mizolastine pimozide quinidine sertindole terfenadine SPORANOX QT torsade de pointes CYP3A4 HMG-CoA 酶 lovastatin simvastatin Triazolam midazolam Ergot dihydroergotamine ergometrine ergonovine ergotamine methylergometrine methylergonovine Nisoldipine SPORANOX CYP3A4 itraconazole QT 11

SPORANOX CHF CHF SPORANOX SPORANOX SPORANOX IV 12

Itraconazole SPORANOX 400 mg itraconazole SPORANOX / SPORANOX 13

itraconazole itraconazole itraconazole Itraconazole itraconazole / itraconazole Itraconazole azole SPORANOX azole SPORANOX 14

itraconazole quinidine itraconazole fluconazole itraconazole itraconazole SPORANOX SPORANOX 15

SPORANOX / SPORANOX 16

itraconazole itraconazole itraconazole itraconazole CYP3A4 SPORANOX SPORANOX itraconazole aluminium hydroxide H2 17

SPORANOX itraconazole itraconazole itraconazole itraconazole SPORANOX SPORANOX SPORANOX SPORANOX 18

itraconazole itraconazole AIDS SPORANOX SPORANOX AIDS 19

AIDS itraconazole 2.5 mg/kg 14 itraconazole 16 50% 250 ng/ml 16 SPORANOX Itraconazole itraconazole 20

itraconazole Itraconazole CYP3A4 CYP3A4 itraconazole itraconazole CYP3A4 itraconazole hydroxyitraconazole itraconazole CYP3A4 itraconazole itraconazole itraconazole itraconazole itraconazole itraconazole Itraconazole hydroxy-itraconazole CYP3A4 21

Itraconazole P-glycoprotein breast cancer resistance protein BRCP Itraconazole CYP3A4 P-glycoprotein / BRCP itraconazole / itraconazole itraconazole 7-14 CYP3A4 itraconazole itraconazole 22

CYP3A4 / itraconazole / itraconazole CYP3A4 itraconazole 2 CYP3A4/P-gp/BCRP itraconazole 2 itraconazole itraconazole / itraconazole 23

CYP3A4 CYP3A4/P-gp/BCRP α Alfuzosin Silodosin 24 / Alfuzosin Cmax, AUC a Silodosin Cmax, AUC a itraconazole 2 alfuzosin/silodosin/tamsulosin c

Tamsulosin Alfentanil Tamsulosin Cmax, AUC a Alfentanil AUC a Buprenorphine Buprenorphine Cmax, AUC a Oxycodone Oxycodone Cmax, AUC Sufentanil Sufentanil a,b c alfentanil/buprenorphine/ oxycodone/sufentanil 25

Fentanyl Levacetylmethadol levomethadyl Fentanyl IV AUC a Fentanyl a,b Levacetylmethadol Cmax, AUC a itraconazole 2 fentanyl c itraconazole 2 levacetylmethadol QT TdP 26

Methadone R -methadone Cmax, AUC a itraconazole 2 methadone QT TdP Digoxin Digoxin Cmax, AUC digoxin digoxin c 27

Disopyramide Dofetilide Dronedarone 28 Disopyramide a,b Dofetilide Cmax, AUC a itraconazole 2 disopyramide TdP itraconazole 2 dofetilide TdP Dronedarone itraconazole Cmax, AUC a 2

Quinidine Bedaquiline Quinidine Cmax, AUC dronedarone QT itraconazole 2 quinidine QT TdP Bedaquiline Cmax, bedaquiline AUC 2 bedaquiline a 2 bedaquiline c 29

Ciprofloxacin Erythromycin Clarithromycin Delamanid Trimetrexate Itraconazole Cmax, AUC Clarithromycin a,b Itraconazole Cmax, AUC ; Delamanid a,b Trimetrexate a,b itraconazole itraconazole itraconazole / clarithromycin c itraconazole / clarithromycin delamanid/ trimetrexate delamanid/ trimetrexate c 30

Isoniazid Rifampicin Rifabutin Telithromycin Isoniazid itraconazole a,b Rifampicin itraconazole AUC Rifabutin a,b Itraconazole Cmax, AUC telithromycin Cmax, AUC itraconazole 2 itraconazole itraconazole 2 2 itraconazole rifabutin c itraconazole 2 31

telithromycin telithromycin AUC a QT TdP telithromycin a,b telithromycin telithromycin c Apixaban Rivaroxaban 32 Apixaban Cmax, AUC a Rivaroxaban Cmax, AUC a itraconazole 2 apixaban/rivaroxaban/ vorapaxar c

Vorapaxar Coumarins warfarin Cilostazol Dabigatran Vorapaxar Cmax, AUC a Coumarins warfarin a,b Cilostazol Cmax, AUC a Dabigatran Cmax, AUC a coumarins/ cilostazol coumarins/cilostazol c dabigatran dabigatran c 33

Ticagrelor Carbamazepine Phenobarbital Phenytoin 34 Ticagrelor Cmax, AUC a Carbamazepine a,b Itraconazole a,b itraconazole 2 ticagrelor itraconazole 2 itraconazole carbamazepine c Phenobarbital itraconazole itraconazole a,b 2

Repaglinide Saxagliptin Phenytoin itraconazole itraconazole AUC Repaglinide Cmax, AUC Saxagliptin Cmax, AUC a Artemether Cmax, AUC a Lumefantrine Cmax, AUC a repaglinide/ saxagliptin repaglinide/ saxagliptin c Artemetherlumefantrine artemetherlumefantrine/quinine c 35

Quinine Halofantrine Isavuconazole 36 Quinine Cmax, AUC Halofantrine a,b Isavuconazole Cmax, AUC a itraconazole 2 halofantrine QT itraconazole 2 isavuconazole hypersensitivity reactions

Praziquantel Astemizole Bilastine Ebastine Rupatadine Praziquantel Cmax, AUC a Astemizole Cmax, AUC a Bilastine Cmax, AUC a Ebastine Cmax, AUC praziquantel praziquantel c itraconazole 2 astemizole QT TdP bilastine/ ebastine/rupatadine c bilastine/ 37

Mizolastine Terfenadine Rupatadine a,b Mizolastine Cmax, AUC a Terfenadine b ebastine/rupatadine itraconazole 2 mizolastine QT itraconazole 2 terfenadine QT TdP 38

Eletriptan Eletriptan Cmax, AUC a Ergot Ergot dihydroergotamine a,b ergometrine ergotamine methylergometrine eletriptan c eletriptan itraconazole 2 ergot ergotism 39

Bortezomib Bortezomib AUC a Brentuximab vedotin Brentuximab vedotin AUC a c Busulfan Busulfan Cmax, AUC Erlotinib Erlotinib Cmax, AUC a Gefitinib Gefitinib Cmax, AUC Imatinib Imatinib Cmax, AUC a Ixabepilone Ixabepilone Cmax, AUC a 40

Nintedanib Nintedanib Cmax, AUC a Panobinostat Panobinostat Cmax, AUC a Ponatinib Ponatinib Cmax, AUC a Ruxolitinib Ruxolitinib Cmax, AUC a Sonidegib Sonidegib Cmax, AUC a Vandetanib Vandetanib Cmax, AUC 41

Idelalisib Axitinib Bosutinib Cabazitaxel Cabozantinib 42 Idelalisib Cmax, AUC a Itraconazole a,b Axitinib Cmax, AUC a Bosutinib Cmax, AUC a Cabazitaxel Cmax, AUC a Cabozantinib Cmax, AUC a itraconazole / idelalisib c itraconazole / idelalisib itraconazole 2 c cabazitaxel ketoconazole

Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Ceritinib Cmax, AUC a Cobimetinib Cmax, ibrutinib AUC Crizotinib Cmax, AUC a Dabrafenib AUC a Dasatinib Cmax, AUC a Docetaxel AUC a Ibrutinib Cmax, AUC a 43

Lapatinib Lapatinib Cmax, AUC a Nilotinib Nilotinib Cmax, AUC a Olaparib Olaparib Cmax, AUC Pazopanib Pazopanib Cmax, AUC a Sunitinib Sunitinib Cmax, AUC a Trabectedin Trabectedin Cmax, AUC a 44

Trastuzumab emtansine Vinca Regorafenib Irinotecan Trastuzumab emtasine a,b Vinca a,b Regorafenib AUC itraconazole a 2 Regorafenib Irinotecan a,b itraconazole 2 irinotecan 45

Alprazolam Alprazolam Cmax, AUC Aripiprazole Aripiprazole Cmax, AUC Brotizolam Brotizolam Cmax, AUC Buspirone Buspirone Cmax, AUC Haloperidol Haloperidol Cmax, AUC c 46

Midazolam Perospirone Quetiapine Ramelteon Risperidone Suvorexant Zopiclone Midazolam b Perospirone Cmax, AUC Quetiapine Cmax, AUC a Ramelteon Cmax, AUC a Risperidone b Suvorexant Cmax, AUC a Zopiclone Cmax, AUC 47

Lurasidone Lurasidone Cmax, AUC a Midazolam Midazolam Cmax, AUC itraconazole 2 lurasidone circulatory collapse itraconazole 2 midazolam 48

Pimozide Sertindole Pimozide Cmax, AUC a Sertindole a,b itraconazole 2 pimozide QT TdP itraconazole 2 sertindole QT TdP 49

Triazolam Asunaprevir boosted Tenofovir disoproxil fumarate TDF Boceprevir 50 Triazolam Cmax, AUC Asunaprevir Cmax, AUC a Tenofovir a,b Boceprevir Cmax, AUC a itraconazole 2 triazolam itraconazole / boceprevir c

Cobicistat Daclatasvir Vaniprevir Itraconazole a,b Cobicistat a,b Itraconazole a,b Daclatasvir Cmax, AUC a Vaniprevir Cmax, AUC a itraconazole boceprevir itraconazole itraconazole daclatasvir/ vaniprevir c daclatasvir/vaniprevir 51

Darunavir Ritonavir-boosted itraconazole boosted darunavir itraconazole Fosamprenavir Cmax, AUC a itraconazole ritonavir-boosted Ritonavir-boosted Telaprevir fosamprenavir itraconazole Cmax, AUC a Telaprevir: itraconazole Cmax, AUC a Elvitegravir boosted 52 Elvitegravir Cmax, AUC a itraconazole / elvitegravir ritonavirboosted c

Efavirenz Nevirapine Indinavir Itraconazole a,b Efavirenz itraconazole Cmax, AUC Nevirapine itraconazole Cmax, AUC itraconazole elvitegravir itraconazole 2 Itraconazole Itraconazole b itraconazole / Indinavir Cmax, AUC indinavir c itraconazole / indinavir 53

Maraviroc Ritonavir Saquinavir 54 Maraviroc Cmax, AUC a Itraconazole Cmax, AUC a Ritonavir Cmax, AUC a c maraviroc itraconazole / ritonavir c itraconazole ritonavir Saquinavir unboosted itraconazole / Cmax, AUC saquinavir c Itraconazole itraconazole boosted saquinavir Cmax, AUC a saquinavir

Simeprevir β Nadolol Bepridil Simeprevir Cmax, AUC a Nadolol Cmax, AUC Bepridil a,b itraconazole 2 nadolol c nadolol itraconazole 2 bepridil TdP 55

Diltiazem Felodipine Lercanidipine Nisoldipine Other dihydropyridines 56 Diltiazem & Itraconazole a,b Felodipine Cmax, AUC Lercanidipine AUC a Nisoldipine Cmax, AUC a Dihydropyridine a,b itraconazole / diltiazem c itraconazole / diltiazem itraconazole 2 dihydropyridine dihydropyridine/verapamil

Verapamil Aliskiren Riociguat Verapamil a,b Sildenafil Sildenafil / Tadalafil Tadalafil a,b c dihydropyridine/verapamil Aliskiren Cmax, AUC itraconazole 2 c Riociguat Cmax, AUC a 57

Bosentan Guanfacine Ivabradine Ranolazine Bosentan Cmax, AUC a Guanfacine Cmax, AUC a Ivabradine Cmax, AUC a Ranolazine Cmax, AUC a bosentan/ guanfacine c bosentan/guanfacine itraconazole 2 ivabradine itraconazole 2 58

Dienogest Ulipristal Eplerenone Dienogest Cmax, AUC a Ulipristal Cmax, AUC a Eplerenone Cmax, AUC a ranolazine QT c dienogest/ulipristal itraconazole 2 eplerenone 59

Aprepitant Loperamide Netupitant Cisapride 60 Aprepitant AUC a Loperamide Cmax, AUC Netupitant Cmax, AUC a Cisapride a,b aprepitant/ loperamide/netupitant c aprepitant/loperamide netupitant itraconazole 2 cisapride QT TdP

Domperidone Domperidone Cmax, AUC Itraconazole Cmax, AUC itraconazole 2 domperidone H2 61

Naloxegol Saccharomyces boulardii Naloxegol Cmax, AUC a S. boulardii Sporanox 2 2 itraconazole 2 naloxegol itraconazole 2 S. boulardii 62

Budesonide Ciclesonide Cyclosporine Budesonide Cmax, AUC ; c Budesonide a,b Ciclesonide Cmax, AUC a Cyclosporine b Cyclosporine a,b 63

Dexamethasone Dexamethasone Cmax, AUC Fluticasone Fluticasone b Fluticasone a,b Methylprednisolone Methylprednisolone Cmax, AUC Methylprednisolone AUC 64

Tacrolimus Temsirolimus Everolimus Sirolimus rapamycin Tacrolimus b Tacrolimus Cmax, AUC a Temsirolimus Cmax, AUC a Everolimus Cmax, AUC a Sirolimus Cmax, AUC a itraconazole 2 c everolimus/sirolimus 65

Atorvastatin Lomitapide Lovastatin Atorvastatin Cmax, AUC atorvastatin c atorvastatin Lomitapide Cmax, itraconazole AUC a 2 lomitapide Lovastatin Cmax, AUC itraconazole 2 66

Simvastatin Meloxicam Salmeterol Simvastatin Cmax, AUC Meloxicam Cmax, AUC Salmeterol Cmax, AUC a lovastatin/simvastatin meloxicam meloxicam itraconazole 2 salmeterol c 67

SSRIs Reboxetine Reboxetine Cmax, AUC a Venlafaxine Venlafaxine Cmax, AUC a Avanafil Avanafil Cmax, AUC a reboxetine/ venlafaxine c reboxetine/ venlafaxine itraconazole 2 avanafil Dapoxetine Dapoxetine Cmax, itraconazole 68

AUC a 2 dapoxetine Darifenacin Darifenacin Cmax, itraconazole Vardenafil AUC a Vardenafil Cmax, AUC a 2 darifenacin/vardenafil c Dutasteride Imidafenacin Dutasteride a,b Imidafenacin Cmax, AUC c dutasteride 69

Oxybutynin Oxybutynin b sildenafil tadalafil Sildenafil Sildenafil Cmax, AUC a Tadalafil Tadalafil Cmax, AUC a Tolterodine Tolterodine CYP2D6 Cmax, AUC a Udenafil Udenafil Cmax, AUC a 70

Fesoterodine Solifenacin Fesoterodine Cmax, AUC a Solifenacin Cmax, AUC a itraconazole 2 fesoterodine fesoterodine c fesoterodine itraconazole 2 solifenacin 71

Alitretinoin Cabergoline Cannabinoids 72 Alitretinoin Cmax, AUC a Cabergoline Cmax, AUC a Cannabinoids a QT solifenacin c solifenacin alitretinoin/ cabergoline/cannabinoids/ cinacalcet alitretinoin/cabergoline/ cannabinoids/cinacalcet c

Cinacalcet Colchicine Cinacalcet Cmax, AUC a Colchicine Cmax, AUC a itraconazole 2 colchicine itraconazole 2 colchicine c 73

Eliglustat Ergot 74 CYP2D6 EMs: Eliglustat Cmax, CYP2D6 CYP2D6 AUC a EMs/CYP2D6 IMs PMs CYP2D6 itraconazole CYP2D6 IMs/ 2 eliglustat PMs PR QTc / QRS CYP2D6 EMs eliglustat c eliglustat Ergot a,b itraconazole 2 ergot

Ivacaftor Lumacaftor/ Ivacaftor Ivacaftor Cmax, AUC a Ivacaftor Cmax, AUC a Lumacaftor Cmax, AUC a Itraconazole ergotism ivacaftor c ivacaftor itraconazole 2 2 Itraconazole ivacaftor c 75

Conivaptan Conivaptan Cmax, AUC a Tolvaptan Tolvaptan Cmax, AUC a Mozavaptan Mozavaptan Cmax, AUC itraconazole 2 conivaptan/tolvaptan c mozavaptan c mozavaptan EMs extensive metabolizers IMs intermediate metabolizers PMs poor metabolizers TdP Torsade de Pointes 76

< 100% < 2 100-400% 2 < 5 400-900% 5 < 10 10 < 40% 40-80% > 80% prodrug a ketoconazole CYP3A4 77

/ P-glycoprotein BCRP / itraconazole b c itraconazole imipramine propranolol diazepam cimetidine indomethacin tolbutamide sulfamethazine 78

SPORANOX Itraconazole SPORANOX SPORANOX SPORANOX SPORANOX Itraconazole 79

SPORANOX SPORANOX i t r a c o n a z o l e SPORANOX itraconazole 80

itraconazole itraconazole SPORANOX 107 8499 8499 SPORANOX 2104 SPORANOX 8499 SPORANOX 1 SPORANOX 1% 81

1 107 SPORANOX 1% SPORANOX % N=8499 1.6 1.6 1.3 2 SPORANOX < 1% 82

2 107 SPORANOX < 1% 83

84

85

SPORANOX / SPORANOX 86

Dysphonia 87

Alanine aminotransferase Aspartate aminotransferase Blood alkaline phosphatase Blood lactate dehydrogenase Blood urea Gamma-glutamyltransferase Hepatic enzyme SPORANOX 165 14 4 9 1 1-17 1 SPORANOX 88

3.0% 3.0% 2.4% 2.4% 1.2% 1.2% 1.2% 1.2% 3 1/10 1/100 < 1/10 1/1,000 < 1/100 1/10,000 < 1/1,000 < 1/10,000 89

3 SPORANOX 3 SPORANOX 90

91

Stevens-Johnson creatine phosphokinase 92

itraconazole 93

Itraconazole triazole ATC code J02A C02 itraconazole 94

Itraconazole triazole Itraconazole triazole itraconazole CLSI M27-A2 CLSI 0.125 0.25-0.5 1 µg/ml CLSI EUCAST Aspergillus flavus A. fumigatus A. nidulans A. terreus itraconazole 1 mg/l > 2 mg/l EUCAST Candida spp. 95

itraconazole 1 µg/ml Candida spp. Candida albicans Candida tropicalis Candida parapsilosis Candida dubliniensis Aspergillus spp. Blastomyces dermatitidis Cladosporium spp. Coccidioides immitis Cryptococcus neoformans Geotrichum spp. Histoplasma spp. H. capsulatum Paracoccidioides brasiliensis Penicillium marneffei Sporothrix schenckii Trichosporon spp. Itraconazole Epidermophyton floccosum Fonsecaea spp. Malassezia spp. Microsporum spp. 96

Pseudallescheria boydii Trichophyton spp. Candida krusei Candida glabrata Candida guillermondii itraconazole itraconazole Zygomycetes Rhizopus spp. Rhizomucor spp. Mucor spp. Absidia spp. Fusarium spp. Scedosporium spp. Scopulariopsis spp. Azole 14α-demethylase ERG1 1 / efflux Azole Candida spp. azole azole Aspergillus fumigatus itraconazole 97

2~5 Itraconazole 15 100 mg 200 mg 200 mg Cmax 0.5 µg/ml 1.1 µg/ml 2.0 µg/ml itraconazole 16-28 34~42 itraconazole 7-14 Itraconazole 278 ml/min Itraconazole Itraconazole 2~5 98

itraconazole 55% Itraconazole H2 - SPORANOX ranitidine H2 - SPORANOX 200 mg itraconazole SPORANOX Itraconazole 99

itraconazole 99.8% 99.6% hydroxy 0.2% itaconazole Itraconazole > 700 L 2-3 4 Itraconazole CYP3A4 itraconazole hydrox-itraconazole itraconazole Hydroxy itraconazole 100

itraconazole 35% 54% hydroxy-itraconazole 1% 3~18% itraconazole itraconazole 2 4 itraconazole Itraconazole 12 6 101

100 mg itraconazole Cmax 47% 37 17 16 5 AUC itraconazole itraconazole itraconazole 200 mg itraconazole 50mg n=7 n=7 n=5 13 ml/min 1.73 m 2 itraconazole Tmax Cmax AUC0-8h 102

itraconazole CrCl 50-79 ml/min CrCl 20-49 ml/min CrCl < 20 ml/min 42-49 48 AUC itraconazole 30% 40% itraconazole itraconazole hydroxy-itraconazole 103

Itraconazole itraconazole itraconazole 104

itraconazole itraconazole Itraconazole itraconazole itraconazole itraconazole 105

itraconazole hypromellose hydroxypropylmethylcellulose 5mPa.s macrogol polyethylene glycol 20,000 sugar spheres sugar spheres 25-30 mesh maize starch, purified water, and sucrose erythrosine sodium Red #3 gelatin 106

indigotin disulfonate sodium Blue#1 titanium dioxide 2-1000 SPORANOX itraconazole 100 mg 107

15 30 Janssen Korea Ltd. 45, Jeyakgongdan 2-gil, Hyangnam-eup, Hwaseong-si, Gyeonggi- Do, Korea 319 8 0800-211-688 CCDS 13Feb2017_v1701 Johnson & Johnson Taiwan Ltd. 2017 1701 108