Differences in Pharmacogenomic Information Reflected in Approved Drug Labels of Korea and the United States

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Supplementary Table 1. Whether drugs, including pharmacogenomic information from the US FDA, are reflected on drug labels in Korea (Antineoplastic and immunomodulating agents)

ingredient (biomarker) MFD S

ingredient (biomarker) MFD

S

ingredient (biomarker) MFD S Abemaciclib (ESR, HER2) ○ Enfortumab Vedotin-ejfv (NECTIN4) - Nivolumab (BRAF,

PD-L1, Microsatellite Instability, Mismatch Repair)

○

Ado-Trastuzumab Emtansine (HER2)

○ Entrectinib (ROS1, NTRK) ○ Obinutuzumab (CD20 antigen) ○

Afatinib (EGFR) ○ Erdafitinib (FGFR, CYP2C9) - Olaparib (BRCA) ○

Alectinib (ALK) ○ Eribulin (HER2, ESR, PGR) X Olaratumab (PDGFRA) ○

Alpelisib (ESR, HER2, PIK3CA)

- Erlotinib (EGFR) ○ Omacetaxine (BCR-ABL1) -

Anastrozole (ESR, PGR) ○ Everolimus (HER2, ESR) ○ Osimertinib (EGFR) ○

Arsenic Trioxide (PML-RARA) ○ Exemestane (ESR, PGR) ○ Palbociclib (ESR, HER2) ○ Atezolizumab (PD-L1) ○ Fam-Trastuzumab Derauxtecan-

nxki (ERBB2)

- Panitumumab (RAS) ○

Avapritinib (PDGFRA) - Fluorouracil (DPYD) ○ Pazopanib (UGT1A1) X

Avelumab (PD-L1) ○ Flutamide (G6PD) - Pembrolizumab (PD-L1, EGFR,

ALK Microsatellite Instability, Mismatch Repair)

○

Azathioprine (TPMT, NUDT15) ○ Fulvestrant (HER2, ESR, PGR) ○ Pemigatinib (FGFR2) -

Belinostat (UGT1A1) - Gefitinib (EGFR) ○ Pertuzumab (HER2) ○

Binimetinib (BRAF, UGT1A1)

- Gemtuzumab Ozogamicin (CD33) - Ponatinib (BCR-ABL1) ○

Blinatumomab (BCR-ABL1) ○ Gilteritinib (FLT3) - Raloxifene (ESR) Ⅹ

Bosutinib (BCR-ABL1) - Goserelin (ESR, PGR) ○ Ramucirumab (EGFR, RAS) Ⅹ

Brentuximab Vedotin (CD30) ○ Ibrutinib (Chromosome 17p) ○ Regorafenib (RAS) ○ Brigatinib (ALK) ○ Imatinib (KIT, BCR-ABL1, PDGFRB,

FIP1L1-PDGFRA)

○ Ribociclib (ESR, PGR, HER2) -

Busulfan (BCR-ABL1) X Inotuzumab Ozogamicin (BCR-ABL1) ○ Rituximab (CD20 antigen) ○ Cabozantinib (RET) ○ Ipilimumab (HLA-A, Microsatellite

Instability, Mismatch Repair)

○ Rucaparib (BRCA) -

Capecitabine (DPYD) ○ Irinotecan (UGT1A1) ○ Sacituzumab Govitecan-hziy (UGT1A1)

-

Capmatinib (MET) - Isatuximab- irfc (Chromosome 17p, Chromosome 4p;14q, Chromosome 14q;16q)

Ⅹ Selpercatinib (RET) -

Ceritinib (ALK) ○ Ivosidenib (IDH1) - Siponimod (CYP2C9) -

Cetuximab (EGFR, RAS) ○ Ixabepilone (HER2, ESR, PGR) ○ Talazoparib (BRCA, HER2) -

Cisplatin (TPMT) X Lapatinib (HER2) ○ Tamoxifen (ESR, PGR) ○

Cobimetinib (BRAF) ○ Larotrectinib (NTRK) - Thioguanine (TPMT, NUDT15) - Crizotinib (ALK, ROS1) ○ Lenalidomide (Chromosome 5q) ○ Toremifene (ESR) ○ Dabrafenib (BRAF, G6PD,

RAS)

X Lenvatinib (Microsatellite Instability, Mismatch Repair)

○ Trametinib (BRAF, RAS) ○

Dacomitinib (EGFR) ○ Letrozole (ESR, PGR) ○ Trastuzumab (HER2, ESR, PGR)

○

Dasatinib (BCR-ABL1) ○ Lorlatinib (ALK) - Tretinoin (PML-RARA) ○

Denileukin Diftitox (CD25 antigen)

○ Lutetium Dotatate Lu-177 (SSTR) ○ Tucatinib (ERBB2) -

Dinutuximab (MYCN) - Mercaptopurine (TPMT, NUDT15) ○ Upadacitinib (CYP2D6) - Docetaxel (ESR, PGR) ○ Midostaurin (FLT3) ○ Ustekinumab (IL12A, IL12B,

IL23A)

○

Durvalumab (PD-L1) ○ Mycophenolic Acid (HPRT1) ○ Vemurafenib (BRAF) ○

Duvelisib (Chromosome 17p) - Neratinib (HER2) - Venetoclax (Chromosome 17p, Chromosome 11q, TP53, IDH1,

○

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Enasidenib (IDH2) - Nilotinib (BCR-ABL1, UGT1A1) ○ Vincristine (BCR-ABL1) ○

Encorafenib (BRAF) - Niraparib (BRCA) ○

○: Consistent with FDA, △: Some missing, X: Not included, -: Not manufactured

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Supplementary Table 2.

Whether drugs, including pharmacogenomic information from the US FDA, are reflected on drug labels in Korea (Nervous system)

ingredient (biomarker) MFDS ingredient (biomarker) MFDS ingredient (biomarker) MFDS

Amifampridine (NAT2) - Diazepam (CYP2C19) X Nefazodone (CYP2D6) -

Amifampridine Phosphate (NAT2)

- Donepezil (CYP2D6) X Nortriptyline (CYP2D6) X

Amitriptyline (CYP2D6) X Doxepin (CYP2D6, CYP2C19) X Oxcarbazepine (HLA-B) ○ Amoxapine (CYP2D6) ○ Duloxetine (CYP2D6) ○ Oxymetazoline and Tetracaine

(Nonspecific, G6PD)

-

Amphetamine (CYP2D6) - Eculizumab (ACHR, AQP4) Ⅹ Paliperidone (CYP2D6) X

Aripiprazole (CYP2D6) ○ Escitalopram (CYP2D6) X Paroxetine (CYP2D6) X

Aripiprazole Lauroxil (CYP2D6)

- Eteplirsen (DMD) - Patisiran (TTR) -

Articaine and Epinephrine (G6PD, Nonspecific)

X Fluoxetine (CYP2D6) ○ Perphenazine (CYP2D6) X

Atomoxetine (CYP2D6) ○ Fluvoxamine (CYP2D6) X Phenytoin (HLA-B, CYP2C9, CYP2C19)

X

Brexpiprazole (CYP2D6) - Fosphenytoin (HLA-B) ○ Pimozide (CYP2D6) ○

Brivaracetam (CYP2C19) ○ Galantamine (CYP2D6) X Pitolisant (CYP2D6) -

Bupropion (CYP2D6) ○ Golodirsen (DMD) - Protriptyline (CYP2D6) -

Carbamazepine (HLA-B, HLA-A)

○ Iloperidone (CYP2D6) - Rimegepant (CYP2C9) -

Cariprazine (CYP2D6) - Imipramine (CYP2D6) X Risperidone (CYP2D6) X

Cevimeline (CYP2D6) - Inebilizumab-cdon (AQP4) - Ropivacaine (G6PD, Nonspecific) ○ Chloroprocaine (G6PD,

Nonspecific)

- Inotersen (TTR) - Sevoflurane (RYR1) X

Citalopram (CYP2C19, CYP2D6)

○ Isoflurane (Nonspecific) ○ Succinylcholine (BCHE) ○

Clobazam (CYP2C19) △ Lacosamide (CYP2C19) X Tafamidis (TTR) ○

Clomipramine (CYP2D6) X Lidocaine, Prilocaine (Nonspecific, G6PD)

○ Tetrabenazine (CYP2D6) -

Clozapine (CYP2D6) X Lidocaine and Tetracaine (G6PD, Nonspecific)

○ Thioridazine (CYP2D6) -

Codeine (CYP2D6) ○ Lofexidine (CYP2D6) - Tramadol (CYP2D6) ○

Desflurane (Nonspecific) ○ Meclizine (CYP2D6) X Trimipramine (CYP2D6) -

Desipramine (CYP2D6) - Meloxicam (CYP2C9) Ⅹ Valbenazine (CYP2D6) -

Desvenlafaxine (CYP2D6) X Mepivacaine (Nonspecific, G6PD) ○ Valproic Acid (POLG, Urea Cycle Disorders)

○

Deutetrabenazine (CYP2D6)

- Mivacurium (BCHE) ○ Venlafaxine (CYP2D6) ○

Dextromethorphan, Quinidine (CYP2D6)

- Modafinil (CYP2D6) ○ Vortioxetine (CYP2D6) ○

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are reflected on drug labels in Korea (Antiinfectives for systemic use and alimentary trac and metabolism)

ingredient (biomarker) MFDS ingredient (biomarker) MFDS

Antiinfectives for systemic use

Abacavir (HLA-B) ○ Nitrofurantoin (G6PD) ○

Boceprevir (IL28B) - Ombitasvir, Paritaprevir, Ritonavir (IL28B) ○ Ceftriaxone (G6PD, Nonspecific) X Peginterferon Alfa-2b (IL28B) -

Chloroquine (G6PD) ○ Primaquine (G6PD, CYB5R) ○

Daclatasvir (IL28B) X Quinine Sulfate (G6PD, CYP2D6) -

Dapsone (G6PD, Nonspecific) O Raltegravir (UGT1A1) X

Dasabuvir, Ombitasvir, Paritaprevir,

and Ritonavir (IL28B) - Simeprevir (IL28B) -

Dolutegravir (UGT1A1) X Sofosbuvir (IL28B) Ⅹ

Efavirenz (CYP2B6) X Sofosbuvir and Velpatasvir (IL28B) -

Elbasvir and Grazoprevir (IL28B) X Sofosbuvir, Velpatasvir, and Voxilaprevir (IL28B) -

Erythromycin, Sulfisoxazole (G6PD) - Sulfadiazine (G6PD) ○

Hydroxychlo-roquine (G6PD) ○ Sulfamethoxazole, Trimethoprim (G6PD, Nonspecific) ○

Isoniazid (Nonspecific) ○ Tafenoquine (G6PD) -

Ledipasvir and Sofosbuvir (IL28B) ○ Telaprevir (IL28B) -

Mafenide (G6PD) ○ Voriconazole (CYP2C19) X

Nalidixic Acid (G6PD) -

Alimentary trac and metabolism

Alglucosidase Alfa (GAA) Ⅹ Lansoprazole (CYP2C19) X

Ascorbic Acid, PEG-3350, KCl

Sod.Ascorbate (G6PD) X Metoclopramide (CYB5R, CYP2D6) ○

Carglumic Acid (NAGS) ○ Migalastat (GLA) ○

Cerliponase Alfa (TPP1) - Omeprazole (CYP2C19) X

Chlorpropamide (G6PD) - Ondansetron (CYP2D6) ○

Dexlansoprazole (CYP2C19) ○ Palonosetron (CYP2D6) ○

Dronabinol (CYP2C9) - Pantoprazole (CYP2C19) X

Eliglustat (CYP2D6) ○ Parathyroid Hormone (CASR) -

Elosulfase (GALNS) ○ Rabeprazole (CYP2C19) X

Esomeprazole (CYP2C19) X Sodium Phenylbutyrate (ASS1, CPS1, OTC) ○ Givosiran (CPOX, HMBS, PPOX) - Sulfasalazine (G6PD, Nonspecific (NAT)) ○

Glimepiride (G6PD) ○ Tolazamide (G6PD) -

Glipizide (G6PD) ○ Tolbutamide (G6PD) -

Glyburide (G6PD) ○ Triheptanoin (ACADVL, CPT2, HADHA, HADHB) -

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Supplementary Table 4.

Whether drugs, including pharmacogenomic information from the US FDA, are reflected on drug labels in Korea (Cardiovascular system, Genito-urinary system and sex hormones, Blood and blood forming organs, Musculo-skeletal system, Respiratory system and various)

ingredient (biomarker) MFDS ingredient (biomarker) MFDS

Cardiovascular system

Carvedilol (CYP2D6) ○ Procainamide (Nonspecific (NAT)) -

Hydralazine (Nonspecific) X Propafenone (CYP2D6) X

Isosorbide Dinitrate (CYB5R) X Propranolol (CYP2D6) X

Isosorbide Mononitrate (CYB5R) X Quinidine (CYP2D6) -

Metoprolol (CYP2D6) ○ Rosuvastatin (SLCO1B1) ○

Nebivolol (CYP2D6) X

Genito-urinary system and sex hormones

Darifenacin (CYP2D6) - Flibanserin (CYP2C9, CYP2D6) -

Drospirenone, Ethinyl Estradiol (CYP2C19) - Mirabegron (CYP2D6) ○

Elagolix (SLCO1B1) X Ospemifene (CYP2C9) -

Estradiol and Progesterone (PROC, PROS1, SERPINC1)

X Tamsulosin (CYP2D6) X

Fesoterodine (CYP2D6) ○ Tolterodine (CYP2D6) ○

Blood and blood forming organs

Avatrombopag (Prothrombin,Factor V Leiden, PROC, PROS1, Antithrombin III, CYP2C9)

- Prasugrel (CYP2B6, CYP2C9, CYP2C19) X

Clopidogrel (CYP2C19) ○ Rivaroxaban (F5) Ⅹ

Crizanlizumab-tmca (HBB) - Succimer (G6PD) -

Emapalumab-lzsg (PRF1, RAB27A, SH2D1A, STXBP2, STX11, UNC13D, XIAP)

- Ticagrelor (CYP2C19) X

Eltrombopag(Prothrombin, Factor V Leiden, PROC, PROS1, Antithrombin III)

○ Voxelotor (HBB) -

Luspatercept–aamt (HBB/F2) - Warfarin (CYP2C9, VKORC1, PROS1, PROC) ○ Lusutrombopag (Prothrombin, Factor V Leiden,

PROC, PROS1, Antithrombin III)

-

Musculo-skeletal system

Carisoprodol (CYP2C19) X Nusinersen (SMN2) ○

Celecoxib (CYP2C9) △ Pegloticase (G6PD) -

Flurbiprofen (CYP2C9) X Piroxicam (CYP2C9) X

Lesinurad (CYP2C9) - Probenecid (G6PD) ○

Respiratory system and various

Arformoterol (UGT1A1) - Ivacaftor and Tezacaftor (CFTR) -

Elexacaftor, lavacaftor, and Tezacaftor (CFTR) - Methylene Blue (CFTR) ○

Formoterol (CYP2D6, CYP2C19) X Rasburicase (G6PD) ○

Indacaterol (CYP2D6) X Sodium Nitrite (G6PD, CYB5R) ○

Ivacaftor (UGT1A1) - Umeclidinium (G6PD, Nonspecific, CYP2D6) ○

Ivacaftor and Lumacaftor (CFTR) -

○: Consistent with FDA, △: Some missing, X: Not included, -: Not manufactured, BO: boxed warnings