Major Drug Introductions☆

Major Drug Introductions☆ KT Ingram, Washington State University - Spokane, WA, USA PD Kennewell, Swindon, UK ã 2014 Elsevier Inc. All rights reserved.

Introduction Anti-Infectives Antivirals Abacavir sulfate Adefovir dipivoxil Amprenavir Atazanavir Boceprevir Cidofovir Clevudine Darunavir Delavirdine mesylate Efavirenz Emtricitabine Enfuvirtide Entecavir Etravirine Famciclovir Formivirsen sodium Fosamprenavir Imiquimod Indinavir sulfate Interferon alfacon-1 Lamivudine Laninamivir octanoate Lopinavir Maraviroc Nelfinavir mesylate Nevirapine Oseltamivir phosphate Penciclovir Peramivir Propagermanium Raltegravir Rilpivirine Ritonavir Saquinavir mesylate Stavudine Telaprevir Telbivudine Tenofovir disoproxil fumarate Tipranavir Valacyclovir hydrochloride Valganciclovir hydrochloride Zanamivir Antibiotics Balofloxacin Besifloxacin Biapenem

12 16 16 16 17 17 18 18 19 19 20 20 21 21 22 22 23 23 24 24 25 25 26 26 26 27 27 28 28 29 29 30 30 31 31 32 32 33 33 34 34 35 35 36 36 37 37 37 38

☆ Change History: October 2013. KT Ingram updated the work by PT Kennewell and wrote composed entries for drugs from 2003 to 2011, provided all graphics, figures, tables, and updated the introduction and table of contents. KT Ingram also updated the Abstract, Extended index, consolidated Tables 1 and 2 to Table 1, Updated Table 3 (now Table 2), Updated synopsis to describe drugs introduced to market between 2004 and 2011, Updated body of article to include drugs introduced to market from 2004 to 2011, Created section for Genitourinary Agents in body, Updated the reference section.

Reference Module in Chemistry, Molecular Sciences and Chemical Engineering

http://dx.doi.org/10.1016/B978-0-12-409547-2.10977-1

1

2

Major Drug Introductions

Cefcapene pivoxil Cefditoren pivoxil Cefoselis Cefozopran hydrochloride Ceftaroline fosamil Ceftobiprole medocaril Dalfopristin, quinupristin Daptomycin Doripenem Faropenem Fidaxomicin Flurithromycin ethylsuccinate Garenoxacin Gatifloxacin Gemifloxacin Linezolid Meropenem Moxifloxacin hydrochloride Panipenem, betamipron Pazufloxacin Prulifloxacin Retapamulin Sitafloxacin hydrate Telavancin Telithromycin Tigecycline Trimetrexate glucuronate Trovafloxacin mesylate Antifungals Anidulafungin Caspofungin acetate Eberconazole Flutrimazole Fosfluconazole Lanoconazole Liranaftate Luliconazole Micafungin Posaconazole Voriconazole Antimalarials Arteether Bulaquine Antispesis Drotrecogin alfa Anticancer Agents Anticancer Drugs Abarelix Alemtuzumab Alitretinoin Arglabin Belotecan Bevacizumab Bexarotene Bortezomib Brentuximab vedotin Cabazitaxel Catumaxomab Cetuximab Clofarabine

38 39 39 40 40 41 41 42 43 43 44 44 45 45 46 46 47 47 48 48 49 49 50 50 51 51 52 52 53 53 53 54 54 55 55 56 56 57 57 58 58 58 59 59 59 59 60 60 60 61 61 62 62 63 63 63 64 64 64 65

Major Drug Introductions

Degarelix acetate Denileukin diftitox Denosumab Eribulin mesylate Erlotinib Exemestane Fulvestrant Gemtuzumab ozogamicin Ibritumomab tiuxetan Ipilimumab Ixabepilone Lapatinib Letrozole Mifamurtide Nilotinib Nimotuzumab OCT-43 Ofatumumab Oxaliplatin Panitumumab Pazopanib Pemetrexed Plerixafor hydrochloride Pralatrexate Raltitrexed Romidepsin Ruxolitinib SKI-2053R Sorafenib Sunitinib Talaporfin sodium Tamibarotene Tasonermin Temozolomide Temsirolimus Topotecan hydrochloric acid Tositumomab Trabectedin Valrubicin Vandetanib Vemurafenib Vorinostat Antineoplastic Drugs Abiraterone acetate Amrubicin hydrochloride Anastrozole Azacitidine Bicalutamide Capecitabine Crizotinib Dasatinib Decitabine Docetaxel Fadrozole hydrochloride Gemcitabine hydrochloride Gefitinib Imatinib mesilate Irinotecan hydrochloride Lenalidomide Nedaplatin

3

65 66 66 66 67 67 68 68 68 69 69 70 70 71 71 72 72 72 72 73 73 73 74 74 75 75 76 76 76 77 77 78 78 78 79 79 80 80 81 81 82 82 83 83 83 84 84 85 85 85 86 86 87 87 88 88 88 89 89 89

4

Major Drug Introductions

Nelarabine Pegaspargase Sipuleucel-T Sobuzoxane Temoporfin Vinflunine ditartrate Zinostatin stimalamer Antiemetic Agents Aprepitant Dolasetron mesylate Fosaprepitant dimeglumine Indisetron Nazasetron hydrochloride Palonosetron Ramosetron Cytoprotective Agents Amifostine 5a-Reductase Inhibitor Dutasteride Chemotherapy-Induced Leukopenia Nartograstim Anticancer Adjuvant Angiotensin II Hypercalcemia Zoledronate Cardiovascular Agents Antihypertensives Aliskiren Ambrisentan Aranidipine Azelnidipine Azilsartan medoxomil Bosentan Candesartan cilexetil Cilnidipine Clevidipine Efonidipine hydrochloride ethanol Eplerenone Eprosartan Fenoldopam mesylate Irbesartan Lercanidipine Losartan Potassium Mibefradil Hydrochloride Moexipril hydrochloride Nebivolol Olmesartan medoxomil Sitaxsentan Spirapril hydrochloride Telmisartan Temocapril hydrochloride Treprostinil sodium Valsartan Zofenopril calcium Antithrombotic Agents Apixaban Bivalirudin Clopidogrel hydrogen sulfate Dabigatran etexilate Edoxaban

90 90 90 91 91 92 92 93 93 93 94 94 95 95 95 96 96 96 96 97 97 97 97 98 98 98 98 98 99 99 100 100 101 101 102 102 103 103 104 104 105 105 106 106 107 107 108 108 109 109 110 110 111 111 112 112 113 114 114 115

Major Drug Introductions

Eptifibatide Fondaparinux sodium Prasugrel Rivaroxaban Ticagrelor Tirofiban hydrochloride Ximelgatran Hypocholesterolemic Agents Atorvastatin calcium Cerivastatin Choline fenofibrate Colesevelam hydrochloride Colestimide Ezetimibe Fluvastatin sodium Pitavastatin Rosuvastatin Antiarrhythmic Dofetilide Dronedarone Ibutilide fumarate Landiolol Nifekalant hydrochloride Pirmenol hydrochloride Vernakalant Heart Failure Carperitide Levosimendan Nesiritide Pimobendan Anticoagulants Duteplase Lepirudin Thrombomodulin Hematological Anagrelide hydrochloride Eltrombopag Romiplostim Anti-Anginals Ivabradine Ranolazine Cardiostimulants Docarpamine Loprinone hydrochloride Iron Chelation Deferasirox Deferiprone Cardiotonic Colforsin daropate hydrochloride Drug-eluting Stent Biolimus drug-eluting stent Fibrinolytic Reteplase Hemophilia Factor vIIa Subarachnoid Hemorrhage Tirilazad mesylate Nervous System (Both Central and Peripheral) Antidepressants Desvenlafaxine succinate

5

115 116 116 117 117 118 118 119 119 119 120 120 121 121 121 122 122 123 123 123 124 124 125 125 125 126 126 126 126 127 127 127 127 127 128 128 128 129 129 129 129 130 130 130 131 131 131 132 132 132 132 133 133 133 133 133 133 134 134 134

6

Major Drug Introductions

Duloxetine Escitalopram oxalate Milnacipran Mirtazapine Nefazodone hydrochloride Pivagabine Reboxetine Venlafaxine hydrochloride Vilazodone hydrochloride Antiepileptics Eslicarbazepine acetate Fosphenytoin sodium Gabapentin enacarbil Lacosamide Levetiracetam Rufinamide Pregabalin Retigabine, ezogabine Tiagabine Topiramate Neuroleptics Aripiprazole Asenapine Blonanserin Lurasidone Olanzapine Paliperidone Perospirone Quetiapine fumarate Sertindole Ziprasidone hydrochloride Antiparkinsonian Agents Budipine CHF-1301 Entacapone Pramipexole hydrochloride Rasagiline Ropinirole hydrochloride Rotigotine Talipexole Tolcapone Antimigraine Agents Almotriptan Eletriptan Frovatriptan Lomerizine hydrochloride Naratriptan hydrochloride Rizatriptan benzoate Zolmitriptan Multiple Sclerosis Dalfampridine Interferon b-1a Fingolimod hydrochloride Glatiramer acetate Natalizumab Antihistamines Desloratadine Bilastine Mizolastine Levocetirizine

134 135 135 136 136 137 137 138 138 139 139 139 140 140 141 141 141 142 142 143 143 143 144 144 145 145 146 146 147 147 148 148 148 148 149 149 149 150 150 151 151 152 152 152 153 153 154 154 155 155 155 155 156 156 156 157 157 157 158 158

Major Drug Introductions

Hypnotic Eszopiclone Ramelteon Zaleplon Muscle Relaxation Cisatracurium besylate Rapacuronium bromide Rocuronium bromide Neuroprotective Agents Edaravone Fasudil hydrochloride Riluzole Anti-Alzheimer’s Disease Donepezil hydrochloride Rivastigmine tartrate Attention Deficit Hyperactivity Atomoxetine Lisdexamfetamine Local Anesthesia Levobupivacaine hydrochloride Ropivacaine Narcolepsy Armodafinil Modafinil Anxiolytic Tandospirone Central Nervous System Diagnosis Ioflupane Central Nervous System Stimulants Taltirelin Dependence Treatment Nalmefene hydrochloride Muscle Relaxation Reversal Sugammadex Psychostimulants Dexmethylphenidate hydrochloride Sedative Dexmedetomidine hydrochloride Gastrointestinal Tract Related Antiulcerative Agents Dexlansoprazole Dosmalfate Ebrotidine Egualen Sodium Esomeprazole magnesium Lafutidine Pantoprazole sodium Polaprezinc Rabeprazole sodium Ranitidine bismuth citrate Irritable Bowel Syndrome Alosetron hydrochloride Tegaserod maleate Itopride hydrochloride Ulcerative Colitis Balsalazide disodium Silodosin Constipation/Irritable Bowel Syndrome Lubiprostone Crohn’s Disease

7

159 159 159 160 160 160 161 161 162 162 162 162 163 163 163 164 164 164 165 165 165 166 166 166 167 167 167 167 168 168 168 168 169 169 170 170 170 170 170 171 171 171 172 172 173 173 173 174 174 175 175 175 176 176 176 176 177 177 177 178

8

Major Drug Introductions

Certolizumab pegol Gastroprokinetic Agents Mosapride citrate Genitourinary Related Urinary Incontinence Fesoterodine Imidafenacin Mirabegron Solifenacin Dysuria Naftopidil Darifenacin Lung Related (Including Antiallergics) Antiallergics Betotastine besilate Epinastine hydrochloride Fexofenadine Fluticasone furoate Loteprednol etabonate Olopatadine hydrochloride Omalizumab Ramatroban Rupatadine fumarate Suplatast tosylate Antiasthmatic Agents Ciclesonide Levalbuterol hydrochloride Montelukast sodium Pranlukast Seratrodast Zafirlukast Zileuton Bronchodilator Arformoterol Indacaterol Roflumilast Tiotropium bromide Expectorants Erdosteine Fudosteine Cystic Fibrosis Dornase alfa Idiopathic Pulmonary Fibrosis Pirfenidone Lung Surfactant Pumactant Mucopolysaccharides Laronidase Joints and Bones Antirheumatic Agents Abatacept Actarit Adalimumab Anakinra Celecoxib Etoricoxib Golimumab Iguratimod Leflunomide Lumiracoxib

178 178 178 178 179 179 179 180 180 181 181 181 181 182 182 182 183 183 184 184 184 185 185 186 186 186 187 187 188 188 189 189 190 190 190 191 191 191 191 192 192 192 193 193 193 193 194 194 194 194 194 194 195 195 195 196 196 197 197 198

Major Drug Introductions

Meloxicam Parecoxib sodium Rofecoxib Valdecoxib Osteoporosis Eldecalcitol Ibandronic acid Incandronic acid Minodronic acid Raloxifene hydrochloride Risedronate sodium Strontium ranelate Tiludronate disodium Trimegestone Anti-Inflammatory Agents Ampiroxicam Betamethasone butyrate propionate Bromfenac sodium Dexibuprofen Lornoxicam Rimexolone Sivelestat Vitamin D Cinacalcet Doxercalciferol Falecalcitriol Maxacalcitol Paricalcitol Analgesia Mofezolac Remifentanil hydrochloride Zucapsaicin Antihyperuricemic Febuxostat Osteoinductor OP-1 Hypocalcemic Neridronic acid Immunology (Including Vaccines) Immunosuppressants Belatacept Belimumab Everolimus Gusperimus trihydrochloride Mycophenolate mofetil Mycophenolate sodium Pimecrolimus GMDP Vaccines Influenza virus (live) Lyme disease vaccine Hormone Related Antidiabetic Alogliptin Exenatide Glimepiride Insulin lispro Linagliptin Liraglutide Miglitol

9

198 199 199 200 200 200 201 201 202 202 203 203 204 204 205 205 205 206 206 206 207 207 208 208 208 209 209 210 210 210 211 211 212 212 212 212 212 212 213 213 213 213 214 214 215 215 216 216 217 217 217 217 218 218 218 219 219 220 220 221

10

Major Drug Introductions

Mitiglinide Nateglinide Pioglitazone hydrochloride Pramlintide Repaglinide Rosiglitazone Saxagliptin Sitagliptin Troglitazone Vildagliptin Voglibose Acromegaly Lanreotide acetate Pegvisomant Growth Hormone Somatomedin-1 Somatotropin Reproduction and Fertility Fertility Enhancer Cetrorelix Corifollitropin alfa Follitropin alpha Follitropin beta Ganirelix acetate Contraceptive Drospirenone Norelgestromin Ulipristal acetate Hyperprolactinemia Quinagolide hydrochloride Preterm Labor Atosiban Skin Related Antipsoriasis Alefacept Efalizumab Tazarotene Ustekinumab Wound Healing Acemannan Prezatide copper acetate Dermatological Kinetin Photosenstization Verteporfin Eye Related Antiglaucoma Bimatoprost Brimonidine Brinzolamide Dorzolamide hydrochloride Latanoprost Tafluprost Travoprost Unoprostone isopropyl ester Antiangiogenic Aflibercept Pegaptanib Ranibizumab Antihistamines

221 221 222 222 223 223 224 224 225 225 226 226 226 227 227 227 227 228 228 228 228 228 229 229 230 230 230 231 231 231 232 232 232 232 232 232 233 233 233 233 234 234 234 235 235 235 235 235 236 236 237 237 238 238 239 239 239 240 240 241

Major Drug Introductions

Alcaftadine Anti-Inflammatory Nepafenac Moistening Agents Diquafosol Miscellaneous Male Sexual Dysfunction Avanafil Dapoxetine Sildenafil citrate Tadalafil Udenafil Vardenafil Antiobesity Dexfenfluramine Orlistat Rimonabant Sibutramine Antidote Antidigoxin polyclonal antibody Crotalidae polyvalent immune fab Fomepizole Hyponatremia Conivaptan Mozavaptan Tolvaptan Analgesics Tapentadol hydrochloride Ziconotide Cryopyrin-Associated Periodic Syndromes (CAPS) Canakinumab Rilonacept Heredity Angioedema Ecallantide Icatibant Type 1 Gaucher’s Disease Imiglucerase Miglustat Antixerostomia Cevimeline hydrochloride Antityrosinemia Nitisinone Fabry’s Disease Agalsidase alfa Hematological Thrombin alfa Hepatoprotectant Mivotilate HIV Lipodystrophy Tesamorelin acetate Magnetic Resonance Imaging (MRI) Contrast Agent Gadoversetamide Mucopolysaccharidosis II (Hunter Syndrome) Idursulfase Mucopolysaccharidosis VI Galsulfase Opioid Induced Constipation Methylnaltrexone bromide Paroxysmal Nocturnal Hemoglobinuria Eculizumab

11

241 241 241 242 242 242 242 242 243 243 244 244 245 245 245 246 246 247 247 247 247 248 248 248 248 249 249 249 250 250 250 250 251 251 251 252 252 252 252 252 253 253 253 253 253 253 254 254 254 254 255 255 255 255 255 255 256 256 256 256

12

Major Drug Introductions

Pompe Disease Alglucosidase alfa Postoperative Ileus Prophylaxis Alvimopan Pruritus Nalfurafine hydrochloride Smoking Cessation Varenicline Stomatitis Palifermin Transthyretin Familial Amyloid Polyneuropathy Tafamidis meglumine References

257 257 257 257 258 258 258 258 259 259 259 259 259

Introduction Volume 6 and 7 of Comprehensive Medicinal Chemistry II contains a listing complete of compounds that have been studied as medicinal agents in humans.1,2 This chapter is less comprehensive in scope and only focuses on new molecular entity introductions over the last 18 years (1994 to 2011) as listed in Annual Reports of Medicinal Chemistry.3–20 This chapter is an update of Major Drug Introductions from Comprehensive Medicinal Chemistry II and compounds introduced from 1994 to 2003 are were produced by P.D. Kennewell.21 Compounds included in this chapter are both new chemical entities (NCEs) and new biological entities (NBEs). From 1994 to 2011, 530 compounds were introduced to market; at a yearly range of 19 to 44 compounds per year (an average of approximately 30 per year) as seen in Table 1. From this data set a downward trend in compounds introduced to market over this time period can be observed. Additionally Table 1 lists the countries of origin of the new molecular entities. The overall dominance of the United States of America (USA) in drug discovery followed by Japan, United Kingdom (UK), Germany, Switzerland, and France is apparent from this table. Over the 18 year time period the USA and Japan exhibit an inverse relationship in new molecular entity origination. Lastly, from 2005 to 2011 there has been a general reduction in number of countries bringing new molecular entities to market than observed from 1994 to 2004. Agents have been grouped into categories shown in Table 2 and have been organized descending by number of compounds in each category and secondly alphabetically. Within these 530 drugs, there are a number that represent scientific and commercial breakthroughs. For example, the use of statins in cardiovascular disease, which resulted in atorvastatin calcium (Lipitor) becoming the first drug to achieve sales of US$1 billion in its first year, and overall sales of US$125 billion since approval, becoming one of the bestselling compound in pharmaceutical history. The introduction of the COX-2 inhibitors, which offered the possibility control of pain and inflammation in patients with osteo- and rheumatoid-arthritis, lacking the adverse gastrointestinal effects of NSAIDs. Although, rofecoxib (Vioxx) has been withdrawn from the market because of cardiovascular effects, at this time it does not appear to be a class effect and innovative COX-2 inhibitors continue to be produced. With the introduction of sildenafil (Viagra) as a totally novel therapy for erectile dysfunction, five new drugs with a similar mechanism of action have followed. Perhaps less well known there has been a trending increase in the last decade in the number of treatments produced for many rare, albeit serious disease states. Dornase alfa (Pulmozyme) was the first new treatment for 30 years for cystic fibrosis; a recombinant form of the enzyme a-galactosidase A were introduced for the treatment of Fabry’s disease; imiglucerase (Cerezyme) and miglustat (Zavesca) was introduced as a recombinant enzyme replacement therapy for type I Gaucher’s disease; deferiprone (Kelfer) is the first oral iron chelator that provides life-saving benefits for patients with thalassemia; and interferon b-1a (Avonex), glatiramer acetate (Copaxone), dalfampridine (Ampyra), fingolimod (Gilenya), and natalizumab (Tysabri) were marketed for multiple sclerosis. Conivaptan (Vaprisol), Mozavaptan (Physuline), and tolvaptan (Samsca) were approved for the treatment of hyponatremia and/or inappropriate antidiuretic hormone secretion syndrome. Canakinumab (Ilaris) and rilonacept (Arcalyst) are two biologics introduced for the treatment of cryopyrin-associated periodic syndromes; Ecallantide (Kalbitor) and icatibant (Firazyr) for the hereditary angioedema, which is a rare genetic disorder. Alglucosidase alfa (Myozyme) a recombinant protein for Pompe disease; and lastly, idursulfase (Elaprase) and galsulfase (Naglazyme) were introduced for the treatment of mucopolysaccharidosis II (Hunter syndrome) and mucopolysaccharidosis IV, respectively. In the anti-infective domain, 30 new antiviral agents were produced between 1994 and 2003, and 13 between 2004 and 2012 mainly for the continued treatment of human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). Other compounds targeted at viruses included: two agents against hepatitis B, one of which was the first organogermanium compound to be marked as a pharmaceutical; two neuramidase inhibitors for a wide variety of influenza strains; and the first agent based on antisense technology, which was launched for the treatment of cytomegalovirus infections. The 1994 and 2003 period has seen the introduction of protease inhibitors, second-generation non-nucleoside reverse transcriptase inhibitors, and the first agent to block the uptake of the virus into CD4 T cells, while the 2004 to 2011 period has seen the development of clevudine (Levovir) and entecavir (Baraclude) for the treatment of HBC; a protease inhibitor darunavir (Prezista) and the NNRTI etravirine (Intelence) for HIV therapy; a protease inhibitor boceprevir (Victrelis) for HCV treatment; and lastly maraviroc (Selzentry) the second agent that blocks viral uptake into cells.

44

1

11 21 2 3 2 2 2

1994

Year

35

1

1

7 10 5 1 4 3 1 1 1

1995

38

1

1

3

10 4 8 5 4 1 1

1996

39

1

1

1

2

1

10 7 6 4 3 3

1997

27

1

12 3 1 5 3 2

1998

1 36

1

1 2

1 2

14 7 3 4

1999

35

1 2 2 1

1

2 1

12 6 4 2 1

2000

25

4 2

14 3 2

2001

Countries of origin of new molecular entities between 1994 and 2011[3-20]

USA Japan UK Germany Switzerland France Netherlands Spain Canada Denmark Italy South Korea Sweden Finland India Israel Australia Belgium Austria Cuba Norway Kazakhstan Total by Year

Country

Table 1

32

1

1 1

1

11 9 7 1

2002

27

1

1 1

21 3

2003

19

2

8 6 1 1 1

2004

24

1

1

2

1 2 1

12 4

2005

27

1

2 1

19 3 1

2006

20

2

16 2

2007

24

1

12 4 2 4 1

2008

31

1 1 1

16 7 1 2 1 1

2009

21

8 4 1 2 1 1 1 1 2

2010

26

1

16 5 2 2

2011 229 108 46 28 30 20 9 9 5 5 5 5 4 3 3 3 2 2 1 1 1 1 530

Total by country

Major Drug Introductions 13

14

Major Drug Introductions

Table 2

Number of new agents discovered in each category between 1994 and 2011[3-20]

Category

Number of new agents discovered

Anti-infectives Cancer related Cardiovascular Nervous system Gastrointestinal tract related Genitourinary related Lung related Joints and bones Immunology (including vaccines) Hormone related Reproduction and fertility Skin related Eye related Miscellaneous

87 91 76 79 18 6 27 41 10 22 10 8 14 41

Adapted from P.D. Kennewell. Major Drug Introductions. In Comprehensive Medicinal Chemistry II; John B. Taylor and David J. Triggle.; 2007; Vol. 1, pp 97–249.

Among the new antibiotics introduced were a number with improved spectra of activity against Gram-positive bacteria responsible for life-threatening infections. These included eight new quinolones two intravenously administered cephalosporins for complicated skin and skin structure infections; additionally ceftaroline was launched for pneumonia; a carbapenem with broad spectrum activity; and three new classes of agents; the oxazolidin-2-ones, the cyclic lipopeptides, and the ketolides. Fidaxomicin was launched as the 2nd oral therapy for Clostridium difficile-associated diarrhea. Tigecycline is the first glycylcycline antibiotic for skin and intraabdominal infections. Retapamulin the first pleuromutilin based topical antibiotic and telavancin, a derivative of vancomycin for skin infections. In addition, a new treatment for severe sepsis was introduced. Finally, the eleven new antifungals included and three representatives of the echinocandins, a new class of such compounds. The introduction of two new antimalarials, arteether (Artemotil) and bulaquine (Aablaquin), appear to be the only examples of drugs for use predominantly in the less developed countries. In the oncology field, as a general trend most NCEs and NBEs are first marketed in the USA from approximately 2000 to 2011. One of the most remarkable compounds is imatinib mesylate (Gleevec), introduced for the treatment of chronic myelogenous leukemia (CML), additionally nilotinib (Tasigna), dasatinib (Sprycel) and ofatumumab (Arzerra) are therapies for CML that were released. Also introduced were inhibitors of topoisomerase I, third-generation orally active aromatase inhibitors for breast cancer, and eribulin (Halaven), and lapatinib (Tykerb) for metastatic breast cancer. Pazopanib (Votrient) and sorafenib (Nexavar) are VEGF inhibitors for the treatment of renal cell carcinoma. Three treatments for malignant melanoma included one biologic and two NCEs ipilimumab (Yervoy) and vemurafenib (Zelboraf ). Three GnRH releasing hormone antagonists for prostate cancer, abarelix (Plenaxis), degarelix (Firmagon) and clofarabine (Clolar), additionally cabazitaxel (Jevtana) and abiraterone (Zytiga) were approved for prostate cancer. Lastly, one of the most innovative drugs launched for the treatment of prostate cancer, sipuleucel-T (Provenge) is the first cancer vaccine that is produced from each individual patients own blood. Treatments released for T cell lymphoma include pralatrexate (Folotyn), romidepsin (Istodax) and vorinostat (Zolinza). Panitumumab (Vectibix) is a NBE released for colon cancer and bevacizumab (Avastin) for metastatic colorectal cancer. Other NCEs were released for the following: Hodgkin’s lymphoma, pediatric acute lymphoblastic leukemia, non-small-cell lung cancer, osteosarcoma, myelofibrosis, renal cell carcinoma, and medullary thyroid cancer. Biological agents for cancer therapy included recombinant tumor necrosis factor (TNF) for soft tissue sarcomas and, two radiolabeled antibodies for non-Hodgkin’s lymphoma, antibody-targeted antineoplastics for acute myeloid leukemia, a humanized monoclonal antibody for B-cell chronic lymphocytic leukemia, and a monoclonal antibody against epidermal growth factor receptor for colorectal cancer. Lastly to aid in management of nausea and vomiting side effects produced as a result of chemotherapy seven new antiemetic agents were introduced. Agents for various forms of cardiovascular disease figured highly over this time period. The role of the statins in controlling blood cholesterol levels was well established and Lipitor made waves in the marketplace followed by the even more potent Crestor. Choline fenofibrate (TriLipix) was released to reduce triglycerides in combination with a statin. Three different approaches to the treatment of acute heart failure appeared, namely, colforsin daropate (Adele), an activator of adenylate cyclase, levosemendan (Simdax), a Caþ2 sensitizer, and nesiritide (Natrecor), a recombinant form of human B-type natriuretic peptide. Other therapies for management of hypertension included: losartan potassium (Cozaar), the first selective nonpeptide angiotensin II antagonist; azilsartan (Edarbi) a new angiotensin II receptor antagonist; aliskiren (Tekturna) a first in class renin inhibitor; ambrisentan (Letaris) and sitaxsentan (Thelin) and bosentan (Tracleer), which is the first endothelin receptor antagonist for pulmonary hypertension; and clevidipine (Cleviprex) injectable short acting calcium channel blocker for acute hypertension. New hematologic and clot prevention therapies include: tirilazad (Freedox), a peroxidation inhibitor for the reduction of tissue damage following subarachnoid hemorrhage in men; anagrelide hydrochloride (Agrylin), the first therapy for raised platelet counts with essential thrombocytopenia; and fondaparinux sodium (Arixtra), an agent against deep vein thrombosis. From 2004 to 2011 the

Major Drug Introductions

15

market for oral treatments for clot prevention was introduced. These therapies give patients an alternative to warfarin which has more than 50 years of use for similar indications. Three oral direct inhibitor of factor Xa inhibitors were approved, apixaban (Eliquis), edoxaban (Lixiana), rivaroxaban (Xarelto) for VTE prophylaxis for patients following hip or knee replacements. Additionally, two oral direct thrombin inhibitors dabigatran (Pradaxa) and ximelgatran (Exanta) were introduced for the same indication. These agents are also being studied for thrombus prophylaxis in patients with atrial fibrillation. Prasugrel (Effient), ticagrelor (Brilique/Possia) are two oral platelet aggregation inhibitors for prevention of atherothrombotic events following PCI. In this time frame, two oral antiarrhythmic agents were introduced dofetilide (Tikosyn), and dronedarone (Multaq) a close analogue of amiodarone with a more predictable kinetic profile. Vernakalant (Brinavess) and landiolol (Onoact) are both shorting acting NCEs for the acute management of arrhythmias that manifest during procedures. Lastly ivabradine (Procoralan) and ranolazine (Ranexa) are therapies released in 2006 for reducing the frequency of angina symptoms. Within the central nervous system (CNS) domain a number of agents have been introduced with novel mechanisms of action. For the treatment of depression: duloxetine (Cymbalta) venlafaxine (Effexor) and desvenlafaxine (Pristiq), the active metabolite of venlafaxine, are antidepressants with dual serotonin/norepinephrine reuptake inhibitory activity; mirtazapine (Remeron) which is void of anticholinergic side effects; and Vilazodone (Viibryd) belongs to a new class of antidepressants and is both a serotonin reuptake inhibitor and serotonin receptor agonist. Other introductions include topiramate (Topomax) belongs to a new class of antiepileptics, gabapentin enacarbil (Horizan) is a new formulation of gabapentin with a more predictable bioavailability; pregabalin (Lyrica) is structurally similar to gabapentin but does not influence GABA uptake, retigabine (Trobalt) is a novel potassium channel opener for the adjuvant treatment epilepsy. Tolcapone (Tasmar) (subsequently withdrawn) and entacopone (Comtess) are the first examples of catechol O-methyl transferase inhibitors acting as anti- Parkinsonian agents. In this time frame 7 atypical antipsychotics were released, all for the treatment of schizophrenia. Rasagiline (Azilect), rotigotine (Neupro), tolcapone (Tasmar) and ropinirole (ReQuip) are all mechanistically different but each were launched to play a role in the management of Parkinson’s disease. Two agents, interferons b-1a (Avonex) and glatiramer acetate (Copaxone), were introduced for the treatment of relapsing multiple sclerosis (MS). Also for the treatment of MS dalfampridine (Ampyra) is a first in class potassium channel blocker with the treatment intent to increase walking distance; fingolimod hydrochloride (Gilenya) is the first oral NCE for the treatment of relapsing-remitting MS and natalizumab (Tysabri) is a monocloncal antibody to reduced inflammation associated with MS. Lomerizine (Teranas, Migsis) is the first dual sodium and calcium channel blocker to be launched for the treatment of migraine. For the treatment of insomnia zaleplon (Sonata) and eszopiclone (Lunesta) represents a non-benzodiazepine class and ramelteron (Rozerem) is an innovative and selective melatonin receptor agonist. Taltirelin (Ceredist) is an orally active drug against ataxia due to cerebrospinal degeneration, and edaravone (Radicut) is a lipophilic antioxidant for the improvement of neurologic impairment following acute brain infarction. Sugammadex (Bridion) provides an option for acute reversal of neuromuscular blockade. Lisdexamfetamine (Vyvanse) is a prodrug of dextroamphetamine which has a reduced potential for misuse and abuse. The number of new agents affecting the gastrointestinal tract was relatively modest over this time period. These induced included ranitidine bismuth citrate (Pylorid), the first therapy specifically tailored to attack Helicobacter pylori, and orlistat, which prevents the absorption of dietary fat and is used for the treatment of obesity. Five proton pump inhibitors for gastro esophageal reflux were launched; three agents, alosetron (Lotronex), lubiprostone (Amitiza) and tegaserod maleate (Zelmac), were launched for the treatment of irritable bowel syndrome, although alosetron was rapidly withdrawn in response to the occurrence of ischemic colitis. Certolizumab pegol is a TNF-a blocker for Crohn’s disease There were a number of agents launched for the management of urinary incontinence: fesoterodine (Toviaz), imidafenacin (Staybla), mirabegron (Betanis) and solifenacin (Vesicare) offer greater selectivity and therefore are associated with fewer anticholinergic effects. Novel antiasthmatics included seratrodast (Bronica), the first thromboxane A2 antagonist; zafirlukast (Accolate), the first LTD4 antagonist; zileuton (Zyflo), a reversible, orally active direct inhibitor of 5-lipoxygenase; omalizumab (Xolair), a humanized antiIgE antibody. Corticosteroids such as fluticasone furoate (Veramyst) nasal spray for allergic rhinitis and ciclesonide (Alvesco) inhalation for persistent asthma. Two inhaled long acting bronchodilators arformoterol (Brovana) and indacaterol (Onbrez/ Arcapta) for the management of chronic obstructive pulmonary disorder (COPD) and roflumilast (Daxas/Daliresp) a novel phosphodiesterase-4 inhibitor for the oral management of COPD. Two lung-active biologically derived agents are dornase alfa (Pulmozyme) for cystic fibrosis and pumactant (ALEC), a lung surfactant for the treatment of respiratory distress syndrome in premature infants, an inhaled fibrinolytic for the treatment of idiopathic pulmonary fibrosis. Introductions in the field of osteoarthritis treatments have been dominated by the appearance of the COX-2 inhibitors, celecoxib (Celebrex), rofecoxib (Vioxx), etoricoxib (Arcoxia), lumiracoxib (Prexige), valdecoxib (Bextra), and parecoxib (Dynastat). Treatments for joint decay in rheumatoid arthritis include leflunomide (Arava), abatacept (Orencia), a T cell activation inhibitor fusion protein, anakinra (Kineret), a human interleukin-1 (IL1) receptor antagonist, golimumab (Simponi), a tumor necrosis factor binder, and adalimumab (Humira), a humanized monoclonal antibody that binds human TNF-alpha. Another biological agent of great interest is OP-1 (Novos), a combination of human recombinant osteogenic protein and a bovine bonederived collagen carrier that is used to promote bone growth in long bone nonunion fractures. Strontium ranelate (Protelos) was adequately formulated for the treatment of osteoporosis, while strontium was associated with strengthening of bones for many years. Lastly, febuxostat (Uloric) is the first oral treatment for patients with gout launched since the 1960s. In the immunology field, a vaccine against Lyme disease and a nasally administered influenza vaccine was introduced. Three parentally administered immunosuppressants were introduced, belatacept (Nulojix), everolimus (Certican) and belimumab (Benlysta) with the two former for kidney transplant rejection prophylaxis and the latter for treatment of systemic lupus erythematosus (SLE).

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Major Drug Introductions

Many new treatments for both type 1 and type 2 diabetes have appeared on the market with insulin lispro (Humalog) being claimed to mimic the normal human response in type 1 diabetes. A new class of therapy for type 2 diabetes, the incretin mimetics were introduced, they are structurally similar to the active portion of endogenous GLP-1 but have a half-life that is magnitudes longer and act on receptors on beta-cells to potentiate glucose-stimulated insulin secretion, these agents are: exenatide (Byetta), liraglutide (Victoza)Alogliptin (Nesina), linagliptin (Tradjenta), saxagliptin (Onglyza), sitagliptin (Januvia) and vildagliptin (Galvus) are 5 new oral inhibitors of dipeptidyl peptidase-4 (DPP-4) and work to delay the breakdown of GLP-1. Lanreotide (Somatuline) and pegvisomant (Somavert) have been introduced as treatments for acromegaly (overproduction of growth hormone), while somatomedin-1 (Igef ) and somatotropin (Nutropin) are now available for the treatment of growth hormone insensitivity and failure to grow. In the field of dermatology, three interesting new biological agents are alefacept (Amevine), ustekinumab (Stelara) and efalizumab (Raptiva), which are used in the treatment of plaque psoriasis. In obstetrics 5 fertility enhancers introduced are cetrorelix (Cetrotide), corifollitropin alfa (Elonva), follitropin alpha (Gonal-F), follitropin beta (Puregon) and ganirelix (Orgalutran). Ulipristal Acetate (ellaOne) is a single dose post-coital contraceptive which is effect up to 120 hours after unprotected intercourse. Finally, a number of new treatments for glaucoma have been introduced in for treatment of ocular conditions including brimonidine (Alphagan), a selective a2a-adrenergic agonist; the prostaglandin analogs bimatoprost (Lumigan), latanoprost (Xalatan), travoprost (Travatan), unoprostone (Rescula), and tafluprost (Taflotan); and the carbonic anhydrase inhibitors, brinzolamide (Azopt) and dorzolamide (Trusopt). Three antiangiogenics for the treatment of macular degeneration that are each administered via intraocular injection; aflibercept (Eylea), pegaptanib (Macugen) and ranibizumab (Lucentis). To reduce inflammation the topical NSAID nepafenac (Nevanac); and diquafosol (Diquas) is a moistening agent.

Anti-Infectives This category includes 31 new antibiotics (including one specific for Clostridium difficile infection), 42 antivirals, 11 antifungals, 2 antimalarials, and 1 agent acting against sepsis.

Antivirals Abacavir sulfate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ziagen Glaxo Wellcome United Kingdom 1999 USA 188062-50-2

Abacavir is a carbocyclic nucleoside reverse transcriptase inhibitor and is a potent and selective inhibitor of HIV-1 and HIV-2 replication. Resistance to abacavir appears to develop only slowly and, when used in combination with other antiretroviral drugs such as amprenavir, produces durable suppression of viral loads.

Major Drug Introductions

17

Adefovir dipivoxil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Hepsera Institute of Organic Chemistry and Biochemistry of the Academy of Sciences in the Czech Republic and the REGA Stichting, Research Institute, Gilead Belgium, Czech Republic 2002 USA 142340-99-6

Adefovir dipivoxil was launched as a treatment for hepatitis B viral infections. It is also a prodrug of adefovir, which is phosphorylated twice to give the active species in vivo. Its relatively long half-life enables once daily dosing but nephrotoxicity restricts the possible level of dosing.

Amprenavir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Agenerase Vertex USA 1999 USA 161814-49-9

Amprenavir was the fifth nonpeptidic inhibitor of HIV-1 protease to be marketed and was intended for the treatment of AIDS patients in combination with approved antiretroviral nucleoside analogs. It potently inhibits HIV-1 aspartyl protease and displays a good oral bioavailability in humans with penetration into the CNS. In combination it considerably decreases viral load and restores CDþ T-cell counts in patients with HIV infection.

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Major Drug Introductions

Atazanavir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Reyataz Novartis USA 2003 USA 198904-31-3

Atazanavir is an inhibitor of HIV-1 protease and is potently active against indanavir- and saquinavir-resistant strains. Recommended dosage is 400 mg once daily and it appears to be well tolerated. It showed marked activity in reducing HIV RNA levels in patients who had not responded to previous treatments.

Boceprevir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Victrelis Merck USA 2011 USA 394730-60-0

Boceprevir (SCH-503034), was launched to be for the treatment of patients with chronic hepatitis C genotype 1 viral infection given in combination with peginterferon alfa plus ribavirin in patients who are treatment-naive or who have had inadequate

Major Drug Introductions

19

responded to interferon therapy. Boceprevir is an NS3/4A protease inhibitor, which prevents manufacture of functional hepatitis C viral proteins, which reduces replication.

Cidofovir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vistide Gilead USA 1996 USA 113852-37-2

Cidofovir is rapidly converted to its active diphosphate metabolite, which inhibits viral DNA polymerase. It was launched for the treatment of cytomegalovirus retinitis in AIDS patients and is sufficiently long lived to require dosing only once every 1–2 weeks.

Clevudine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Levovir Bukwang USA 2007 South Korea 163252-36-6

Clevudine is an oral nucleoside or nucleotide analog to be marketed for the treatment of chronic HBV infection. A unique characteristic of clevudine in comparison to similar agents is the slow rebound of viral load after cessation of treatment.

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Major Drug Introductions

Darunavir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Prezista Tibotec, Johnson & Johnson USA 2006 USA 206361-99-1

Darunavir is a second generation anti-retroviral protease inhibitor launched for the treatment of non-treatment naı¨ve patients infected with human immunodeficiency virus (HIV) in combination with low dose ritonavir.

Delavirdine mesylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Rescriptor Pharmacia & Upjohn USA 1997 USA 147221-93-0

Delaviridine mesylate is a second-generation non-nucleoside HIV-1 reverse transcriptase inhibitor, which acts as an allosteric mixed inhibitor of both RNA- and DNA-directed polymerase domains of reverse transcriptase and binds more strongly to the enzyme–substrate complex than to the free enzyme.

Major Drug Introductions

21

Efavirenz Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sustiva Merck USA 1998 USA 154598-52-4

Efavirenz is a non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infections in combination with other antiretroviral agents. It readily crosses the blood–brain barrier resulting in an increased concentration in the cerebrospinal fluid. The pharmacokinetic profile appears to be better than other drugs in this class.

Emtricitabine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Emtriva Emory University, Gilead USA 2003 USA 143491-57-0

Emtricitabine is a synthetic nucleoside inhibitor of HIV-1 reverse transcriptase. Recommended treatment is 200 mg day1; there are mild to moderate side effects at this dose. Cross-resistance to lamivudine and zalcitabine is seen.

22

Major Drug Introductions

Enfuvirtide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Fuzeon Duke University, Roche, Trimeris USA 2003 USA 159519-65-0

Enfuvirtide is the first of a new class of HIV therapeutics that interferes with the entry of HIV-1 by inhibiting fusion of viral and cellular membranes. Because of this unique mechanism it does not show cross-resistance to known agents. The dose is 90 mg twice daily by subcutaneous injection, and it is used in a cocktail with other anti-HIV agents.

Entecavir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Baraclude BristolMyersSquibb USA 2005 USA 142217-69-4

Entecavir is the 3rd nucleoside or nucleotide analog to be marketed for treatment of chronic hepatitis B (HBV) infection, and is a once-daily oral treatment. Entecavir is effective in suppressing HBV replication in patients with a history of lamivudine resistant HBV infection and also treatment-naive patients.

Major Drug Introductions

23

Etravirine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Intelence Janssen, Tibotec USA 2008 USA 269055-15-4

Etravirine is a second generation non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV and the 4th NNRTI brought to market. It was launched for concomitant use with antiretroviral regimen in patients infected with HIV strains that are resistant to other NNRTIs. Etravirine is associated with severe and potentially life-threatening rashes during initial therapy.

Famciclovir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Famvir SmithKlineBeecham United Kingdom 1994 United Kingdom, USA 104227-87-4

Famciclovir is an orally active prodrug of penciclovir and was launched for the treatment of herpes zoster. Selectivity is achieved by virtue of the fact that penciclovir is only phosphorylated, and hence activated in herpesvirus-infected cells. The metabolite is a strong inhibitor of herpesvirus DNA polymerases and viral DNA synthesis.

24

Major Drug Introductions

Formivirsen sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vitravene Isis Pharmaceuticals USA 1998 USA

Vitravene is indicated for the treatment of cytomegalovirus-induced retinitis in patients with AIDS. It acts by an antisense mechanism and targets an intermediate early mRNA of cytomegalovirus, thus inhibiting the expression of two regulatory proteins. Vitravene was thus the first agent based on antisense technology to reach the market.

Fosamprenavir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lexiva Vertex, GlaxoSmithKline USA 2003 USA 226700-81-8

Fosamprenavir is a prodrug of the HIV protease inhibitor amprenavir that is highly active but its low water solubility reduces its utility. Fosamprenavir is rapidly hydrolyzed by phosphatases in the gut epithelium to give good levels of amprenavir. In the clinic, 700–1400 mg are administered daily in conjunction with ritonavir.

Major Drug Introductions

25

Imiquimod Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Aldara 3M Pharmaceuticals USA 1997 USA 99011-02-6

Imiquimod was launched for the topical treatment of genital warts caused by human papillomavirus. It works by the induction of cytokines, in particular interferon alpha, possibly by interaction with a kinase modulating the transduction pathway leading to cytokine genes.

Indinavir sulfate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Crixivan Merck USA 1996 USA 150378-17-9

Indinavir sulfate was launched as an orally bioavailable HIV-1 protease inhibitor. It appears to be relatively safe and well tolerated.

26

Major Drug Introductions

Interferon alfacon-1 Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Infergen Amgen USA 1997 USA 74899-72-2

Infergen was introduced for the treatment of chronic hepatitis C. It is more effective than other interferons in its antiproliferative effects, in activating natural killer (NK) cells, and in immunomodulation.

Lamivudine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Epivir Biochem Pharma Canada 1995 USA 134678-17-4

Lamivudine is a new generation orally active nucleoside analog that was launched for use in combination with AZT as a first-line therapy for patients infected with HIV. Its phosphorylated metabolite is an inhibitor of reverse transcriptase. It is less toxic than AZT and appears also to have activity against hepatitis B virus.

Laninamivir octanoate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Inavir Daiichi Sankyo Japan 2010 Japan 203120-17-6

Major Drug Introductions

27

Laninamivir octanoate is the 4nd neuraminidase inhibitor launched for the treatment of influenza and the one of two approved in 2010. Laninamivir octanoate is an intranasally administered prodrug of laniamivir which inhibits the neuraminidases of influenza A and influenza B. Laninamivir acts extracellularly and binds to influenza neuraminidase that results in competitive inhibition of the enzyme resulting in the blockade of the release of virions from infected cells.

Lopinavir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Kaletra Abbot USA 2000 USA 192725-17-0

Lopinavir was launched as a joint formulation with ritonavir, an established HIV protease inhibitor. Ritonavir inhibits the cytochrome P450 isoenzyme CYP3A4 and thus the microsomal metabolism of lopinavir resulting in increased plasma levels and duration of action of lopinavir. In patients with AIDS, the plasma HIV RNA level was reduced and the CD4þ T-cell counts increased after administration of lopinavir with relatively small doses of ritonavir.

Maraviroc Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Selzentry Pfizer USA 2007 USA 376348-65-1

Maraviroc is the first CCR5 receptor antagonist antiretroviral agent. Maraviroc blocks the entry of HIV into human CD4 T cells via inhibition of the CCR5 receptor, however, it is only effective at reducing viral load in patients with CCR5-tropic HIV strains.

28

Major Drug Introductions

Nelfinavir mesylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Viracept Agouron USA 1997 USA 159989-65-8

Viracept is an orally available, nonpeptidic HIV protease inhibitor with low toxicity and a resistance profile different from other protease inhibitors. In combination with zidovudine and lamivudine, it generated a 98% mean reduction from baseline in viral load after 24 weeks compared to zidovudine and lamivudine alone.

Nevirapine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Viramune Boehringer Ingelheim Germany 1996 USA 71125-38-7

Nevirapine was launched for use in combination with nucleoside analogs to treat HIV-infected patients who had experienced clinical and/or immunologic deterioration. It is a noncompetitive non-nucleoside inhibitor of HIV-1 reverse transcriptase.

Major Drug Introductions

29

Oseltamivir phosphate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tamiflu Gilead USA 1999 Switzerland 204255-11-8

Oseltamivir phosphate was launched for the treatment of influenza infections by all common strain viruses. It is a prodrug of the acid GS-4071, which is a potent inhibitor of both influenza A and B virus muramidase isoenzymes. Forming the ester greatly improves the oral bioavailability and clinical trials show that it significantly reduces the severity and duration of clinical symptoms including fever, cough, and general malaise.

Penciclovir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vectavir SmithKlineBeecham United Kingdom 1996 United Kingdom 39809-25-1

Penciclovir was launched for the treatment of herpes labialis. It acts as a competitive inhibitor of DNA polymerase and is relatively long acting.

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Major Drug Introductions

Peramivir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Rapiacta, PeramiFlu BioCryst Pharmaceuticals USA 2010 Japan 330600-85-6

Peramivir is the 3rd neuraminidase inhibitor launched and one of two introduced to market in 2010. Peramivir is the only neuraminidase inhibitor available for intravenous use and was launched for the treatment of influenza. Additionally, peramivir was given emergency use authorization in the United States from October 2009 to June 2010, for treatment of hospitalized patients with suspected or confirmed cases of H1N1. Peramivir is a transition-state analogue inhibitor of influenza neuraminidase and inhibits virions from emerging from infected cells.

Propagermanium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Serosion Sanwa Kagaku Japan 1994 Japan 12758-40-6

This is the first organogermanium compound to be marketed as a pharmaceutical; it was launched for the treatment of chronic hepatitis B. Its activity is thought to be the result of an enhanced immune response due to the production of interferon a/b.

Major Drug Introductions

31

Raltegravir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Isentress Merck USA 2007 USA 871038-72-1

Raltegravir is a first in class HIV integrase strand transfer inhibitor type antiretroviral agent for the treatment of infection. Raltegravir slows the advancement of HIV infection by blocking the HIV integrase enzyme needed for integration of viral DNA into the genome of the host cell. Raltegravir can be combined with other antiretroviral treatments and provides an additional treatment option for patients with resistant strains.

Rilpivirine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Edurant Tibotec Belgium 2011 USA 500287-72-9 (free base)

Rilpivirine is an oral, diarylpyrimidine, non-nucleoside reverse transcriptase inhibitor (NNRTI). Rilpivirine was launched for the treatment of human immunodeficiency virus (HIV) 1 infection in treatment-naı¨ve adults with baseline HIV-1 RNA concentrations less than 100 000 copies/mL in combination with other antiretroviral agents. Rilpivirine is also supplied in a fixed dose combination with emtricitabine, and tenofovir.

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Major Drug Introductions

Ritonavir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Norvir Abbott USA 1996 USA 155213-67-5

Ritonavir is an inhibitor of HIV aspartic protease. It was launched for the treatment of advanced HIV in combination with antiretroviral nucleoside analogs. Its selectivity for the viral enzyme over the human form is greater than 500-fold, and it has good oral bioavailability.

Saquinavir mesylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Invirase Roche Switzerland 1995 USA 127779-20-8

Saquinavir mesylate was the first HIV protease inhibitor to reach the market. Initial use was with approved nucleoside analogs for the treatment of advanced HIV infections. It is well tolerated alone and in combination with AZT.

Major Drug Introductions

33

Stavudine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zerit Bristol-Meyers Squibb USA 1994 USA 3056-17-5

Stavudine is orally active with good bioavailability and its 5’-triphosphate is highly active against reverse transcriptase. It was introduced for the treatment of late-stage patients with AIDS refractory to other treatments.

Telaprevir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Incivek Vertex, Eli Lilly USA 2011 USA 402957-28-2

Telaprevir is the 2nd oral protease inhibitor launched for the treatment of genotype 1 chronic hepatitis C who are treatmentnaı¨ve in combination with peginterferon alfa and ribavirin. Telaprevir blocks the proteolytic of HCV serine protease which is responsible for the conversion of HCV polyproteins to functional viral proteins

34

Major Drug Introductions

Telbivudine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sebivo Idenix, Novartis USA 2006 Switzerland 003424-98-4

Telbivudine is oral, once daily, beta-L-thymidine nucleoside analog launched for the treatment of chronic hepatitis B virus infection. It is the 4th nucleoside or nucleotide analog to be marketed for chronic hepatitis B virus infection.

Tenofovir disoproxil fumarate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Viread Gilead USA 2001 USA 201238-50-9

Tenofovir disproxil fumarate was the first nucleotide analog reverse transcriptase inhibitor to be launched in the US as an oral treatment for HIV infection. It is a prodrug, which rapidly hydrolyzes to form the free tenofovir. This undergoes two phosphorylation steps to give the active metabolite, a potent inhibitor of reverse transcriptase. Because of rapid cellular uptake, the prodrug is more active than tenofovir reducing the level of HIV in the blood for up to 48 weeks when added to existing antiretroviral regimens. This activity has been seen in patients bearing resistant strains of HIV. It is eliminated by the kidneys, is not metabolized by the liver, and the half-life is such that once daily dosing is possible.

Major Drug Introductions

35

Tipranavir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Aptivus Boehringer Ingelheim, Pharmacia & Upjohn USA 2005 USA 174484-41-4

Tipranavir is a first in class oral, non-peptidic, HIV protease inhibitor (PI). The targeted patient population includes HIV-1 infected adults with evidence of viral replication and demonstrated resistance to multiple PIs. As with other PIs, tipranavir binds at the HIV-1 protease’s active site inhibits the virus-specific processing of the Gag and Gag-Pol polyproteins in HIV-1-infected cells resulting in the production of non-infectious virions. Additionally, the non-peptidic structure theoretically exhibits greater conformity to the binding site and may also decrease the rate of development of resistance.

Valacyclovir hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Valtrex Glaxo Wellcome United Kingdom 1995 United Kingdom 124832-27-5

Valacyclovir is an orally active L-valyl ester of the known antiviral acyclovir. It was launched for the treatment of herpes simplex infections of skin and mucous membranes. It is readily absorbed following oral treatment and hydrolyzed in the first pass effect to acyclovir. The phosphorylated metabolite is generated in virus-infected cells and inhibits viral DNA polymerase.

36

Major Drug Introductions

Valganciclovir hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Valcyte Roche Switzerland 2001 USA 175865-59-5

Valganciclovir hydrochloride is a prodrug of the antiviral ganciclovir. It had been marketed for the treatment of cytomegalovirus retinitis. It is rapidly hydrolyzed by intracellular esterases in the intestinal mucosal cells and by hepatic esterases. Oral treatment at 900 mg twice daily for 3 weeks followed by 900 mg once a day for a week was as effective as intravenous ganciclovir (5 mg kg1 twice a day for 3 weeks followed by 5 mg kg1 once a day for a week).

Zanamivir Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Relenza Biota Scientific Australia 1999 Australia 139110-80-8

Zanamivir is a potent and specific inhibitor of neuraminidase, a key viral surface glycohydrolase essential for viral replication and disease progression and was launched for the treatment of human influenza A and B virus infections.

Major Drug Introductions

37

Antibiotics Balofloxacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Q-Roxin Choongwae Pharma Corporation Japan 2002 South Korea 127294-70-6

Balofloxacin is an orally active fluoroquinolone antibiotic introduced for the treatment of urinary tract infections. In vitro antibacterial activity against Gram-positive bacteria (Staphylococcus aureus including methicillin-resistant S. aureus (MRSA), Staphylococcus epidermis, Streptococcus pyrogenes, and Streptococcus pneumonia) was almost equal to that of sparfloxacin or tosufloxacin, while activity against Gram-negative bacteria was at least twofold lower. Clinically, it is well tolerated and shows activity against urinary tract infections similar to that of ofloxacin. Following oral administration it is well absorbed and eliminated in the urine unchanged with a half-life of approximately 8 h.

Besifloxacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Besivance Bausch & Lomb, SSP Co. Ltd Japan 2009 USA 141388-76-3 (free base)

Besifloxacin is a fluoroquinolone for ophthalmic use. Besifloxacin is an ophthalmic suspension launched for the treatment of bacterial conjunctivitis. Besifloxacin is effective against organisms that are resistant to ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin, or moxifloxacin

38

Major Drug Introductions

Biapenem Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Omegacin Meiji Seika USA 2002 Japan 120410-24-4

Biapenem is a bacterial cell wall synthesis inhibitor with a broad spectrum of antibiotic activity in vitro. It is stable to hydrolysis by human renal dihydropeptidase I and showed good clinical and microbiological efficacy in the treatment of patients with intraabdominal, lower respiratory tract, and complicated urinary tract infections. After intravenous administration it is widely distributed, has linear pharmacokinetics, and is mainly eliminated in the urine with a half-life of approximately 1 h. Biapenem is well tolerated with the most common adverse side effects being skin eruptions/rashes, nausea, and diarrhea.

Cefcapene pivoxil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Flomox Shionogi Japan 1997 Japan 105889-45-0

Cefcapene pivoxil functions as a cell wall synthesis inhibitor and is highly active against a wide variety of Gram positive and Gram-negative bacteria. It is not effective against strains such as Pseudomonas aeruginosa and enterococci. It was launched as an orally active cephalosporin for respiratory and urinary tract infections, skin/soft tissue infections, and for use in gynecology, dentistry, and oral surgery. This is a prodrug with loss of the pivaloyloxymethyl group giving rise to the active acid.

Major Drug Introductions

39

Cefditoren pivoxil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Meiact Meiji Seika Japan 1994 Japan 117467-28-4

Cefditoren pivoxil is an orally active third-generation cephalosporin that is reported to have a broad spectrum of activity against both Gram-positive and Gram-negative organisms. It was introduced for the treatment of a broad range of bacterial infections including dermatological and other community-acquired infections. Its potency is reported to be greater than many existing agents in this class. It is a prodrug and the free acid, cefditoren, is produced in vivo.

Cefoselis Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Wincef Fujisawa Japan 1998 Japan 122841-12-7

Cefoselis is a fourth-generation cephalosporin, which was launched as a parenteral antibiotic against a variety of infections including methicillin-resistant MRSA and P. aeruginosa.

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Major Drug Introductions

Cefozopran hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Firstcin Takeda Japan 1995 Japan 125905-00-2

Cefozopran hydrochloride is a third-generation cephalosporin that was launched for the treatment of severe infections in immunocompromised patients caused by staphylococci and enterococci. While it shows a very broad antibacterial spectrum against Gram-positive and Gram-negative organisms, it is particularly potent against S. aureus, Enterococcus faecalis, P. aeruginosa, and Citrobacter freundii. It is resistant to hydrolysis by most chromosomal and plasmid mediated b-lactamases and is reported to be active against respiratory, urinary tract, obstetrical, gynecological, soft tissue, and surgical infections.

Ceftaroline fosamil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Teflaro Takeda, Forest Japan 2010 USA 402741-13-3

Ceftaroline fosamil is a fourth-generation, intravenously administered cephalosporin launched for the treatment of acute bacterial skin and skin structure infections and community acquired pneumonia. Ceftaroline fosamil is the prodrug of ceftaroline and is effective against most Gram-positive and few Gram-negative organisms (mainly respiratory pathogens).

Major Drug Introductions

41

Ceftobiprole medocaril Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zeftera Basilea, Johnson & Johnson, Roche Switzerland 2008 Canada 376653-43-9

Ceftobiprole medocaril is an injectable cephalosporin antibiotic with broad spectrum activity against Gram-positive and Gramnegative bacteria, and hospital and community acquired infections and MRSA. Ceftobiprole medocaril was launched for treatment of complicated skin and skin structure infections, including diabetic foot infections.

Dalfopristin, quinupristin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Synercid Rhone-Poulenc-Rorer France 1999 United Kingdom 126602-98-9

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Major Drug Introductions

Dalfopristin and quinupristin are two well-defined semisynthetic antibacterials and are combined in the ratio of 70:30 to produce an injectable antibiotic. The combination of the two antibiotics, which are bacteriostatic in their own right, acts at the ribosomal level to inhibit protein synthesis. This is the first antibiotic in its class to reach the market and appears to be effective in the treatment of severe or life-threatening infections such as Gram-positive nosocomial sepsis, including those caused by vancomycin-resistant E. faecium or MRSA.

Daptomycin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cubicin Eli Lilly USA 2003 USA 103060-53-2

Daptomycin is the first example of a new class of lipopeptide antibiotics that work by disrupting bacterial membrane function at a number of points, i.e., disruption of membrane potential and amino acid transport, inhibition of lipoteichoic acid synthesis, and inhibition of peptidoglycan synthesis. It is indicated for the treatment of complicated skin and skin structure infections caused by a range of Gram-positive bacteria and, due to its novel mode of action, cross-resistance with other antibiotics has not been noted. Dosing is once per day (4 mg kg1 day1) by intravenous infusion; the drug has a half-life of 8.1 h. As it is excreted renally, dosing adjustments are required for those with severe renal insufficiency. Clinical trials indicate a more rapid activity in skin and soft tissue infections than was found for vancomycin or semisynthetic penicillins such as cloxacillin, oxacillin, or flucloxacillin.

Major Drug Introductions

43

Doripenem Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Finibax Shinogi, Peninsula Japan 2005 Japan 148016-81-3

Doripenem is a parenteral carbapenem antibiotic and is the fourth analog to be marketed in the series. Doripenem is a bacterial cell wall synthesis inhibitor with a broad spectrum of antibiotic activity similar to that of other carbapenems, however, doripenem superior activity against Pseudomonas aeruginosa as compared with meropenem and imipenem. After intravenous or intramuscular administration it is widely distributed and is mainly eliminated in the urine with a half-life of approximately 1 h.

Faropenem Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Farom Suntory Japan 1997 Japan 106560-14-9

Faropenem is a b-lactamase stable, broad-spectrum oral carbapenem antibiotic with activity against anaerobes, Gram-positive, and Gram-negative bacteria, and the Enterobacteriaceae. It was launched for the treatment of common respiratory tract infections.

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Major Drug Introductions

Fidaxomicin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Dificid Optimer Pharmaceuticals USA 2011 USA 873857-62-6

Fidaxomicin is an oral macrolide antibiotic used to treat Clostridium difficile-associated diarrhea. Fidaxomicin inhibits bacterial RNA polymerase, thereby inhibiting bacterial protein synthesis and is bactericidal against C. difficile. Similar to vancomycin, fidaxomicin also is minimally systemically absorbed. Additionally, fidaxomicin was found to produces a lower rate of infection recurrence than vancomycin.

Flurithromycin ethylsuccinate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ritro Pharmacia & Upjohn United Kingdom 1997 Italy 82730-23-2

Major Drug Introductions

45

Flurithromycin is used for the treatment of serious nosocomial respiratory infections. The presence of the fluorine atom gives it improved acid stability, prolonged serum half-life, higher tissue penetration, and better bioavailability over erythromycin.

Garenoxacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Geninax Toyama, Taisho, Astellas Japan 2007 Japan 194804-75-6

Garenoxacin is an oral quinolone antimicrobial agent that was launched as an oral treatment for respiratory tract and otorhinolaryngological infections. Garenoxacin exhibits a broad spectrum of activity against both Gram-negative, Gram-positive, and resistant organisms, including S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, multidrug-resistant S. pneumoniae, methicillin-resistant S. aureus (MRSA), and vancomycin-resistant enterococci (VRE).

Gatifloxacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tequin Kyori Japan 1999 USA 160738-57-8

Gatifloxacin is a novel, orally active antibiotic that shows good activity in the treatment of respiratory tract and urinary infections, particularly community-acquired infections including bronchitis, pneumonia, and the common sexually transmitted diseases.

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Major Drug Introductions

Gemifloxacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Factive Oscient South Korea 2004 USA 210353-53-0

Gemifloxacin is an oral once daily fluoroquinolone antimicrobial that is effective against gram-positive and gram-negative bacteria. It was launched as an oral treatment for bacterial respiratory infections such as community acquired pneumonia.

Linezolid Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zyvox Pharmacia Corp. USA 2000 USA 165800-03-3

Linezolid can be considered as the first of a new class of antibacterials, the oxazolidinones, which act by inhibiting early ribosomal protein synthesis without directly inhibiting DNA or RNA synthesis. In vitro, linezolid is as potent as vancomycin against staphylococcal, streptococcal, and pneumococcal infections, and enterococcal species. It was launched for the treatment of patients with infections caused by serious Gram-positive pathogens, particularly skin and soft tissue infections, communityacquired pneumonia, and vancomycin-resistant enterococcal infections.

Major Drug Introductions

47

Meropenem Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Merrem Sumitomo, Zeneca Japan 1994 Italy 96036-03-2

Meropenem has a broad spectrum of antibacterial activity against most clinically important Gram-positive and Gram-negative aerobic and anaerobic bacteria with especially high potency against multiresistant members of the Enterobacteriaceae and P. aeruginosa. It is dehydropeptidase 1 stable and is proposed for the intravenous treatment of hospital infections such as lower respiratory tract, urinary tract, intra-abdominal, gynecological, and polymicrobial infections.

Moxifloxacin hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Avelox Bayer Germany 1999 Germany 186826-86-8

Moxifloxacin is a fluoroquinolone carboxylic acid-derived antibiotic that was introduced for the treatment of respiratory tract infections such as community acquired pneumonia, acute exacerbations of bronchitis, or acute sinusitis. It shows a favorable pharmacokinetic profile with good tissue penetration and plasma concentrations above minimum inhibitory concentrations (MICs), and a lack of phototoxicity.

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Major Drug Introductions

Panipenem, betamipron Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Carbenin Sankyo Japan 1994 Japan 138240-65-0

Panipenem is a semisynthetic carbapenem antibiotic that is efficacious in patients with severe infections complicating hematological disorders and in children where other antibiotics have been ineffectual. Betamipron, when mixed with panipenem in a 1:1 ratio, blocks the incorporation of panipenem into renal tubules, thus preventing renal dysfunction.

Pazufloxacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Pasil, Pazucross Toyama, Mitsubishi Japan 2002 Japan 127045-41-4

Pazufloxacin displays broad-spectrum activity against Gram-positive and Gram-negative bacteria, although it is less active than ciprofloxacin against pneumococci and is not active against ciprofloxacin-resistant bacteria. Good clinical responses have been seen in patients with urinary tract infections and, to a lesser extent, with respiratory tract infections. It has a short half-life of 2 to 2.5 h with phototoxicity equal to that of ciprofloxacin.

Major Drug Introductions

49

Prulifloxacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sword Nippon Shinyaku Japan 2002 Japan 123447-62-1

Prulifloxacin is another fluoroquinolone carboxylic acid-derived antibiotic, which was introduced for the oral treatment of urinary tract infections, respiratory tract infections, and bacterial pneumoniae. It is a prodrug that is rapidly hydrolyzed by paraoxonase-type enzymes in the blood and liver to give the DNA gyrase inhibitor NM 394. This metabolite accounts for all the antibiotic activity. Overall, activity against Gram-positive bacteria is similar to ciprofloxacin but greater in the case of Gram-negative bacteria. Plasma half-life is around 8 h and any adverse effects are similar to those of other fluoroquinolones.

Retapamulin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Altabax GlaxoSmithKline USA 2007 USA 224452-66-8

Retapamulin is the first pleuromutilin based antibiotic approved for human use. Retapamulin is a semisynthetic derivative of pleuromutilin, a tricyclic diterpenoid from the edible mushroom Pleurotus mutilus. Retapamulin applied topically in the treatment of skin infections caused by Staphylococcus aureus and Streptococcus pyogenes.

Sitafloxacin hydrate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Gracevit Daiichi Sankyo Japan 2008 Japan 127254-12-0

Sitafloxacin hydrate is a fourth generation oral fluoroquinolone antibiotic and has broad spectrum activity against Grampositive, Gram-negative, and anaerobic bacterial isolates. Like other fluoroquinolones, sitafloxacin hydrate inhibits bacterial topoisomerase type II, DNA gyrase and topoisomerase IV. Sitafloxacin hydrate is dosed twice daily.

Telavancin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Arbelic, Vibativ Therevance, Astellas USA 2009 USA 372151-71-8

Major Drug Introductions

51

Telavancin is a semisynthetic derivative of vancomycin and was launched for the treatment of adults with complicated skin and skin structure infections caused by susceptible Gram-positive organisms. Telavancin interferes with bacterial cell wall synthesis in two ways, by both binding to peptidoglycan precursors and interfering with polymerization and crosslinking of peptidoglycan. Similar to vancomycin, telavacin is primarily excreted renally.

Telithromycin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ketek Aventis France 2001 Germany 191114-48-4

Telithromycin was introduced as a once daily oral treatment for respiratory infections including community-acquired pneumonia, acute bacterial exacerbations of chronic bronchitis, acute sinusitis, and tonsillitis/pharyngitis. It is a semisynthetic derivative of the macrolide erythromycin and acts by preventing bacterial protein synthesis by binding to two domains of the 50S subunit bacterial ribosomes. It does not form a stable inhibitory cytochrome P450 Fe2þ -nitrosoalkene metabolite complex and therefore should not show hepatotoxicity.

Tigecycline Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tygacil Wyeth USA 2005 USA 220620-09-7

Tigecycline is the first glycylcycline antibiotic to launch for the parenteral treatment of bacterial infection, including complicated intra-abdominal and skin infections. The spectrum of activity of tigecycline is similar to that of tetracycline, doxycycline, and minocycline; however, tigecycline shows activity against tetracycline-resistant organisms, and methicillin-resistant Staphylococcus aureus and S. epidermidis. Tigecycline was later approved for the treatment of community-acquired pneumonia.

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Major Drug Introductions

Trimetrexate glucuronate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

NeuTrexin Warner-Lambert, US Bioscience USA 1994 USA, Canada 82952-64-5

Trimetrexate glucuronate is a nonclassical antifolate that inhibits dihydrofolate reductase and was introduced for the treatment of Pneumonocystis carinii pneumonia in patients with AIDS. It is also in clinical trials against a number of cancers.

Trovafloxacin mesylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Trovan Pfizer Switzerland 1998 USA, Switzerland 157605-25-9

Trovafloxacin mesylate is a fluoroquinolone-derived antibiotic that is given once a day for the treatment of diverse acute bacterial infections, particularly community-acquired respiratory infections. Doses of 200 mg day1 demonstrated advantages over amoxicillin, cephalosporins, and clarithromycin.

Antifungals Anidulafungin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Eraxis Eli Lilly USA 2006 USA 166663-25-8

Anidulafungin is an intravenous semi-synthetic derivative of echinocandin B, and classified as an echinocandin antifungal. Anidulafungin is the 4nd echinocandin release and was launched for treatment of serious fungal infections such as candidemia, Candida-derived peritonitis, intra-abdominal abscesses, and esophageal candidiasis. Anidulafungin is a non-competitive inhibitor of 1,3-b-D-glucan synthase, which forms the cell wall of most pathogenic fungi.

Caspofungin acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cancidas Merck USA 2001 USA 179463-17-3

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Major Drug Introductions

Caspofungin acetate was the first in a new class of antifungal agents, the echinocandins, to be launched for the parenteral treatment of invasive aspergillosis in patients refractive to other antifungal therapies. It inhibits the synthesis of 1,3-beta-D-glucans, which is present only in fungal cell walls, and thus is fungicidic. It is active both in vitro and in vivo against a range of Candida species and also Aspergillus. Its half-life in humans is around 10 h.

Eberconazole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ebernet Chiesi Wassermann, Laboratorios SALVAT SA Spain 2005 Spain 128326-82-9

Eberconazole is an azole antifungal agent, and works as an inhibitor of fungal lanosterol 14-alpha-demethylase and in turn affects the structure of the fungal cell wall. Eberconazole had good in vitro activity against a wide range of Candida species, and is indicated for the topical treatment of cutaneous fungal infections, including tinea corporis, tinea cruris and tinea pedis infections.

Flutrimazole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Micetal Urlach Spain 1995 Spain 119006-77-8

Flutrimazole displays broad-spectrum activity against dematophytes, filamentous fungi, and yeasts, which are saprophytic and pathogenic to animals and humans. Mode of action is inhibition of fungal lanosterol 14a-emethylase. Its main indication is mycosis of the skin.

Major Drug Introductions

55

Fosfluconazole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Prodif Pfizer Japan 2004 Japan 194798-83-9

Fosfluconazole is a phosphate prodrug of fluconazole and was launched as an intravenous injection for the treatment of candidiasis and cryptococcosis infections. Fosfluconazole has a water solubility that is 40-times greater than fluconazole; therefore, it requires a smaller infusion volume.

Lanoconazole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Astat Nihon Nohyaku, Tsumura Japan 1994 Japan 101530-10-3

Lanoconazole is an inhibitor of egosterol biosynthesis and thus affects the ultrastructure of the cell wall. It acts against a wide range of fungi and is used in the treatment of dermal mycoses.

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Major Drug Introductions

Liranaftate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zefnart Tosoh Japan 2000 Japan 088678-31-3

Liranaftate was launched as a topical antifungal for the treatment of dermatophycoses. It is a potent and specific inhibitor of squalene epoxidase, but has no effect on mammalian cholesterol biosynthesis.

Luliconazole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lulicon Nihon Nohyaku, Pola Japan 2005 Japan 187164-19-8

Luliconazole is a member of the imidazole class of antifungal agents, for use as a topical antimycotic agent and it is indicated for the treatment of tinea pedis infections. Similar to other azole antifungals, luliconazole inhibits sterol 14-alpha-demethylase, and inhibits ergosterol biosynthesis. In vitro, luliconazole exhibits strong antifungal activity against Trichophyton mentagrophytes and Trichophyton rubrum, and activity against C. albicans, however activity is slightly lower than fluconazole.

Major Drug Introductions

57

Micafungin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Funguard Fujisawa Japan 2002 Japan 235114-32-6

Micafungin was the second member of the echinocandin class of antifungal agents to be introduced for the parenteral treatment of various fungal infections caused by Aspergillus and Candida. Its half-life in humans is 11.7–15.2 h after injection.

Posaconazole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Noxafil Schering-Plough USA 2006 United Kingdom 171228-49-2

Posaconazole is an azole antifungal agent and like other azoles, inhibits fungal ergosterol synthesis through inhibition of lanosterol 14-a demethylase. Posaconazole has greater activity over other members of the azole antifungals and has activity against refractory cases of aspergillosis, fluconazole-resistant Candida, and is the only azole with activity against Zygomycetes.

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Major Drug Introductions

Voriconazole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vfend Pfizer USA 2002 USA 137234-62-9

Voriconazole was introduced for the treatment of acute invasive aspergillosis, candidosis, and other emerging fungal infections seen in immunocompromised patients. It acts by inhibiting the cytochrome P450-dependent enzyme 14a-sterol demethylase of ergosterol biosynthesis. Voriconazole is active against a wide range of fungi including Aspergillus, Cryptococcus neoformans, and various Candida species. It was effective in the treatment of neutropenic patients with acute invasive aspergillosis, non-neutropenic patients with chronic invasive aspergillosis, and HIV-infected patients with oropharyngeal candidiasis.

Antimalarials Arteether Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Artemotil Central Drug Research Institute, Artecef BV India 2000 Netherlands 075887-54-6

Arteether is marketed as a solution in sesame oil. It is administered by i.m. injection for the treatment of severe malaria infections in children and adolescents. It acts rapidly against Plasmodium during the early blood stage of its development. It also shows gametocytocidal activity against Plasmodium falciparium. The initial approval was only for treatment of young people, but clinical trials indicate that the drug acts rapidly and efficiently against Plasmodium in adults.

Major Drug Introductions

59

Bulaquine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ablaquin CDRI India 2000 India 079781-00-3

Bulaquine is used in combination with chloroquine in the treatment of malaria. It kills the latent tissue stage of the parasite Plasmodium vivax, which accumulates in the liver and is responsible for relapses.

Antispesis Drotrecogin alfa Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Xigris Lilly USA 2001 USA 42617-41-4

Drotrecogin alfa was introduced as an intravenous treatment for the reduction of mortality in adult patients with severe sepsis associated with acute organ dysfunction. It is a recombinant activated protein C expressed in human kidney 293 cells. The majority of patients with sepsis have reduced levels of activated protein C, which acts as an antithrombic via inhibition of factor Va and VIIIa and as a promoter of fibrinolysis via inactivation of plasminogen-activator inhibitor-1, and exerts an anti-inflammatory effect by inhibiting the production of inflammatory cytokines.

Anticancer Agents This category includes 55 anticancer drugs, 24 antineoplastic drugs, seven antiemetic agents, one cytoprotective, one 5a-reductase inhibitor, one agent for treating chemotherapy-induced leukopenia, one agent for treating hypercalcemia, and one anticancer adjuvant are included.

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Major Drug Introductions

Anticancer Drugs Abarelix Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Plenaxis Praecis USA 2004 USA 183552-38-7

Abarelix is a synthetic antagonist of gonadotropin releasing-hormone (GnRH). Abarelix is the first FDA-approved sustained-release GnRH antagonist and was released for the palliative treatment of symptomatic prostate cancer. Inhibition of GnRH suppresses luteinizing hormone and follicle stimulating hormone thereby reducing testosterone secretion from the testes.

Alemtuzumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Campath Cambridge University, Millennium, LEX Oncology, Schering AG United Kingdom 2001 United Kingdom 146705-13-7

Alemtuzumab is a humanized monoclonal antibody of the IgG1 isotype specific for the glycoprotein CD52 expressed on the cell surface of over 95% of normal and malignant B and T lymphocytes and monocytes. It was introduced for the treatment of B-cell chronic lymphocytic leukemia in patients who have been treated with alkylating agents and have failed fludarabine therapy.

Major Drug Introductions

61

Alitretinoin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Penretin Ligand USA 1999 USA 5300-03-8

Alitretinoin was introduced for the treatment of cutaneous lesions in patients with Kaposi’s sarcoma. It binds to all isoforms of the intracellular retinoid X and A receptors thus inducing cell differentiation, increasing cell apoptosis, and inhibiting cellular proliferation in experimental models of human cancer.

Arglabin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Unknown NuOncology Labs Kazakhstan 1999 Russia 84692-91-1

Arglabin is a potent and selective inhibitor of farnesyl transferase, which is critical to the function of the Ras oncogene in cancer cell reproduction. It was launched in Russia for the treatment of a range of cancers.

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Major Drug Introductions

Belotecan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Camtobell CKD Pharmaceuticals South Korea 2004 South Korea 213819-48-8

Belotecan is a DNA topoisomerase I inhibitor launched for the treatment of ovarian and small cell lung cancer. The clinical application of belotecan is limited by severe toxicity and poor water solubility.

Bevacizumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Avastin Genentech, Roche USA 2004 USA 216974-75-3

Bevacizumab is a humanized monoclonal IgG1 antibody against vascular endothelial growth factor (VEGF or VEGF-A) produced in a Chinese hamster ovary cell system, and works to inhibit tumor angiogenesis which delays disease progression. Bevacizumab is indirectly cytotoxic; therefore, it needs to be administered with other treatment considered to be cytotoxic. It was initially launched for the treatment of metastatic colorectal cancer when given intravenously in combination with a fluorouracilbased chemotherapy.

Major Drug Introductions

63

Bexarotene Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Targretin Ligand USA 2000 USA 153559-49-0

Bexarotene was launched for the treatment of manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. It is selective for retinoid X rather than retinoid A receptors.

Bortezomib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Velcade Millennium (LeukoSite, Proscript) USA 2003 USA 179324-69-7

Bortezomib is a potent ubiquitin proteasome (26S) inhibitor that is marketed for the treatment of multiple myeloma.

Brentuximab vedotin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Adcetris Seattle Genetics USA 2011 USA 914088-09-8

Brentuximab vedotin was launched for treatment of Hodgkin’s lymphoma in patients who have failed autologous stem cell transplant (ASCT) or ASCT ineligible patients who have failed at least two prior chemotherapy regimens, and for second line treatment of systemic anaplastic large cell leukemia. Brentuximab vedotin targets CD30 expressed on the surface of Hodgkin’s

64

Major Drug Introductions

Reed-Sternberg cells and cells in anaplastic large-cell lymphomas. Brentuximab vedotin is a formulated for intravenous infusion given over 30-min every 3 weeks for up to 16 cycles.

Cabazitaxel Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Jevtana Sanofi-Aventis France 2010 USA 183133-96-2

Cabazitaxel is the 2nd semi-synthetic analog of taxol to enter the market. Cabazitaxel in combination with prednisone was launched for the treatment of late-stage, castration-resistant prostate cancer in patients who were previously treated with a regimen containing docetaxel. Cabazitaxel is a microtubule inhibitor that binds to tubulin which results in micotic blockade and cell death and is effective in cells resistant to docetaxel

Catumaxomab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – trifunctional monoclonal antibody; molecular weight 180 kDa

Removab TRION Pharma Germany 2009 Germany 509077-98-9

Catumaxomab is a bispecific trifunctional antibody. The Fab region of catumaxomab consists of one half of an anti-Ep-CAM antibody and one half of an anti-CD3 antibody. The Fc region selectively binds to macrophages, dendritic cells, and natural killer cells that promote phagocytosis and cytotoxicity. Catumaxomab was launched for the intraperitoneal treatment of malignant ascites caused by Ep-CAM-positive metastatic epithelial-derived tumors.

Cetuximab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Erbitux ImClone USA 2003 Switzerland 205923-56-4

Cetuximab is a human/mouse chimeric monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). It was launched as a combination with irinotecan for the treatment of patients with colorectal cancer who no longer respond to standard chemotherapy.

Major Drug Introductions

65

Clofarabine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Clolar Genzyme, Bioenvision USA 2005 USA 123318-82-1

Clofarabine is a member of the purine nucleoside antimetabolites. It was introduced as an intravenous infusion for treating pediatric patients (1 to 21 years old) with relapsed or refractory acute lymphoblastic leukemia after at least two prior treatment regimens. Clofarabine has a higher potency relative to other purine nucleoside analogs attributed to the higher efficiency of its phosphorylation by deoxycytidine kinase, and longer intracellular half-life of the triphosphate metabolite.

Degarelix acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Firmagon Ferring Pharmaceutical Switzerland 2009 USA 214766-78-6

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Major Drug Introductions

Degarelix acetate is the 2nd gonadotropin releasing hormone (GnRH) antagonist launched for the treatment of prostate cancer. Degarelix acetate is a GnRH receptor antagonist and binds GnRH receptors in the pituitary gland, resulting in a blockade of the release of luteinizing hormone and follicle-stimulating hormone. Degarelix acetate is administered as a subcutaneous injection once every 28 days.

Denileukin diftitox Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Ontak Ligand USA 1999 USA 173146-27-5

Denileukin diftitox is a fusion protein comprising diphtheria toxin fragment A–fragment B genetically fused to a human interleukin-2 (IL2) fragment. It was launched for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma.

Denosumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant monoclonal antibody; molecular weight 147 kDa

Prolia, Xgeva Amgen USA 2010 USA 615258-40-7

Denosumab is a subcutaneous fully humanized IgG2 monoclonal antibody that inhibits bone resorption by blocking the activity of receptor activator of nuclear factor–kB (RANKL) which mediates bone resorption through the RANK receptor found on osteoclasts. Denosumab was launched for the treatment of osteoporosis in post-menopausal women with a high-fracture risk, and for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Denosumab is dosed every 6-months for osteoporosis and every 4-weeks for the treatment of bone metastases.

Eribulin mesylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Halaven Eisai USA 2010 USA 253128-41-5

Major Drug Introductions

67

Eribulin mesylate is a synthetic analogue of the natural marine product, halichondrin B, which is isolated from the sea sponge Halichondria okadai. Eribulin is a microtubule inhibitor and binds close to the vinca-binding site of tubulin. Eribulin was launched for the treatment of metastatic breast cancer in patients that have received at least two previous chemotherapy regimens.

Erlotinib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tarceva OSI Pharmaceuticals, Genentech, Roche USA 2004 USA 183319-69-9

Erlotinib is an oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), and is the second molecule to be marketed with this mechanism of action. It was launched for the treatment of non-small-cell lung cancer.

Exemestane Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Aromasin Farmitalia Carlo Erba, Pharmacia Italy 2000 USA, Canada, Western Europe 107868-30-4

Exemestane is an irreversible inactivator of the aromatase enzyme system that was launched for the treatment of estrogendependent tumors and postmenopausal breast cancer. It has high activity in women failing antiestrogen therapy with tamoxifen.

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Major Drug Introductions

Fulvestrant Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Faslodex AstraZeneca United Kingdom 2002 USA 129453-61-8

Fulvestrant binds to the estrogen receptor. It was launched as a once monthly injectable treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following estrogen therapy. It completely blocks the cell growth in tamoxifen-resistant breast cancer cell lines and prevents growth of tamoxifen-resistant tumors in mice.

Gemtuzumab ozogamicin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Myotarg Celltech Group, Wyeth-Ayerst Research USA, UK 2000 USA 220578-59-6

Gemtuzumab ozogamicin was launched as the first antibody-targeted anticancer agent for the treatment of patients with acute myeloid leukemia. It is an immunoconjugate of anti-CD33 humanized mouse monoclonal antibody linked via a bifunctional link to the cytotoxic antibiotic calicheamicin.

Ibritumomab tiuxetan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

90

Zevalin IDEC, Syncor USA 2002 USA 206181-63-7

Y-Ibritumomab tiuxetan is the first commercially available radiolabeled antibody for cancer therapy and more specifically for the treatment of relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin’s lymphoma. Ibritumomab is a murine immunoglobulin G1 kappa isotype monoclonal antibody that targets CD20, a B-lymphocyte antigen. Conjugating with the isothiocyanatobenzyl derivative of diethylene triamine pentaacetate (DTPA) gives ibritumomab tiuxetan, which can then chelate radionucleotides.

Major Drug Introductions

69

Ipilimumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant monoclonal antibody; molecular weight 148 kDa

Yervoy Bristol-Myers Squibb USA 2011 USA 477202-00-9

Ipilimumab is a recombinant human monoclonal antibody launched for the treatment of unresectable or metastatic melanoma. Ipilimumab that binds to the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and blocks the interaction of CTLA-4 with its ligands CD80/CD86. Blockade of CTLA-4 augments T cell activation and proliferation. Treatment with ipilimumab can result in severe, and possibly fatal, immune-related reactions.

Ixabepilone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ixempra Bristol-Myers Squibb USA 2007 USA 219989-84-1

Ixabepilone is a semisynthetic analog of epothilone B and is the first member of the epothilone family of anticancer agents to be approved. Like taxanes, ixabepilones mechanism of action involves binding to and stabilizing microtubules resulting in mitotic arrest and apoptosis. Ixabepilone was launched last year for the treatment of metastatic or locally advanced breast cancer. Ixabepilone in combination with capecitabine is indicated for use in patients who have previously failed treatment with an anthracycline. Additionaly, ixabepilone is approved as monotherapy for the treatment of breast cancer resistant to anthracyclines, taxanes, and capecitabine.

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Lapatinib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tykerb GlaxoSmithKline USA 2007 USA 231277-92-2

Lapatinib is the 3rd 4-anilinoquinazoline RTK inhibitor and was launched as an oral treatment for breast cancer. Lapatinib has dual affinity for EGFR and HER2 tyrosine kinases. Lapatinib in combination with capecitabine is indicated for the treatment of advanced or metastatic breast cancer tumors with overexpressed HER2 and patients who have received prior therapy with anthracycline, a taxane, and trastuzumab.

Letrozole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Femara Novartis Switzerland 1996 France 112809-51-5

Letrozole is a third-generation aromatase inhibitor that specifically inhibits P450arom that catalyzes the conversion of androstenedione to estrone. It was launched for the second-line treatment of advanced breast cancer.

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71

Mifamurtide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Junovan Takeda, Novartis Switzerland 2010 Austria 838853-48-8

Mifamurtide was launched for the treatment of nonmetastatic osteosarcoma combination with postoperative multiagent chemotherapy in patients between the ages of 2 and 30. Mifamurtide is a liposome formulation consisting of synthetic phospholipids dioleoyl phosphatidyl serine and 1-palmitoyl-2-oleoyl phosphatidyl choline in a 3:7 ratio. This liposomal formulation allows for targeting of monocytes and macrophages in the liver, spleen, and lungs leading to the production of proinflammatory cytokines contributing to the tumoricidal properties of mifamurtide.

Nilotinib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tasigna Novartis Switzerland 2007 Switzerland 641571-10-0

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Major Drug Introductions

Nilotinib is the 3rd tyrosine kinase inhibitor that was launched for the treatment of chronic myelogenous leukemia (CML). Nilotinib is an additional an option for the treatment of imatinib-resistant CML. Nilotinib may cause serum lipase and liver enzyme elevations, and electrolyte abnormalities.

Nimotuzumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 150 kDa

BioMab EFGR, Theraloc Center for Molecular Immunology Cuba 2006 India 828933-51-3

Epidermal growth factor receptor (EGFR) is prevalent in malignant tumors of epithelial origin and is especially common in breast, head and neck, colon, and lung cancer. Nimotuzumab is a humanized form of the murine IgG2a monoclonal antibody that has been launched in India for treatment of head and neck cancers overexpressing EGFR.

OCT-43 Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Octin Otsuka Japan 1999 Japan 159074-77-8

This protein is a recombinant variant of IL1beta that was launched for the treatment of mycosis fungoides. It is clinically useful in the treatment of aplastic anemia and myelodysplastic syndrome.

Ofatumumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant monoclonal antibody; molecular weight 149 kDa

Arzerra Genmab, GlaxoSmithKline Denmark 2009 USA 679818-59-8

Ofatumumab is the 2nd monoclonal antibody launched for the treatment of chronic lymphocytic leukemia (CLL). Ofatumumab binds to CD20 expressed on B lymphocytes and on B-cell chronic lymphocytic leukemia which results in B-cell lysis and death. Ofatumumab was approved for the treatment of CLL that is refractory to fludarabine and alemtuzumab.

Oxaliplatin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Eloxatin Bebiopharm/Sanofi Switzerland 1996 France 61825-94-3

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73

Oxaliplatin has an antitumor spectrum similar to cisplatin but is more effective against L1210 leukemia and cisplatin resistant L1210. It was launched for second-line treatment of metastatic colorectal cancer. The mode of action involves binding to guanineN7 leading to bidentate chelation, which results in the bending of DNA.

Panitumumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – humanized monoclonal antibody; molecular weight 147 kDa

Vectibix Amgen USA 2006 USA 339177-26-3

Panitumumab is an immunoglobulin G2 antibody that binds to the extracellular domain of the human EGFR. Panitumumab is the first fully humanized monoclonal antibody indicated for EGFR-expressing colon and rectal cancer.

Pazopanib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Votrient GlaxoSmithKline USA 2009 USA 444731-52-6

Pazopanib is an oral, once-daily, multikinase angiogenesis inhibitor launched for the treatment of renal cell cancer. Pazopanib targets the vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, and VEGFR-3, platelet-derived growth factor receptor, fibroblast growth factor receptor (FGFR)-1 and FGFR-3.

Pemetrexed Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Alimta Eli Lilly USA 2004 USA 150399-23-8

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Major Drug Introductions

Pemetrexed is a pyrimidine-based folate analog that disrupts cell replication and suppresses tumor growth by inhibiting both DNA synthesis and folate metabolism at multiple target enzymes. It was initially launched for the treatment of malignant pleural mesothelioma in conjunction with cisplatin. Pemetrexed is given intravenously over 10 minutes followed by a 30 minute washout period every 21 days.

Plerixafor hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Mozobil Genzyme Canada 2009 USA 110078-46-1

Plerixafor is a novel stem cell stimulator launched for the treatment non-Hodgkin’s lymphoma(NHL) and multiple myeloma (MM). Plerixafor inhibits stromal-derived factor-1, CXC receptor-4, which results in mobilization of hematopoietic stem cells (HSC) into peripheral blood, thereby increasing the quantity of HSCs for collection and subsequent autologous transplantation in patients with NHL and MM.

Pralatrexate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Folotyn Allos, SRI International, Sloan-Kettering USA 2009 USA 146464-95-1

Pralatrexate is an injectable dihydrofolate reductase (DHFR) inhibitor launched for the treatment of refractory or relapsed peripheral T cell lymphoma, which is a form of form of non-Hodgkin’s lymphoma. Inhibition of DHFR reduces levels of tetrahydrofolate, which is required for cellular proliferation, resulting in cellular death.

Major Drug Introductions

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Raltitrexed Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tomudex Zeneca United Kingdom 1996 United Kingdom 112887-68-0

Raltitrexed is a highly selective inhibitor of thymidylate synthase, the key enzyme in the biochemical conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). It was launched for the treatment of advanced colorectal cancer and needs to be given only once every 3 weeks.

Romidepsin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Istodax Celgene, Astellas Japan 2009 USA 128517-07-7

Romidepsin was launched for the treatment of cutaneous T-cell lymphoma (CTCL) for patients who received at least one previous systemic therapy. Romidepsin is a bicyclic depsipeptide histone deacetylase (HDAC) that is a potent inhibitor of class I, II, and IV HDAC. Inhibitors of HDAC cause growth arrest, differentiation, and apoptosis in cancer cells and reverse cancer-related epigenetic changes.

Ruxolitinib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Jakafi Incyte USA 2011 USA 941678-49-5

Ruxolitinib is a kinase inhibitor launched for the treatment of immediate or high-risk myelofibrosis. Myelofibrosis is associated with dysregulated Janus-associated kinases (JAK) 1 and JAK2. Ruxolitinib is an ATP-competitive inhibitor of JAK1 and JAK2 which inhibits myeloproliferation, inducing apoptosis, and reducing cytokine plasma levels.

SKI-2053R Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sunpla SK Pharma Korea 1999 Korea 146665-77-2

SKI-2053R is a third-generation platinum complex alkylating agent that is highly active against various cell lines including cisplatin-resistant tumor cell lines. It was launched for the treatment of unresectable or metastatic gastric adenocarcinoma.

Sorafenib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nexavar Bayer, Onyx Germany 2005 USA 284461-73-0

Major Drug Introductions

77

Sorafenib is a novel small molecule, multi-kinase inhibitor to inhibit angiogenesis. Targeted kinases include Raf kinase, vascular endothelial growth factor (VEGF) receptors VEGFR-2 and VEGFR-3, platelet-derived growth factor receptor-beta (PDGFR-beta), Kit receptor tyrosine kinase (KIT), fms-like tyrosine kinase 3 (FLT-3), and RET. Sorafenib was first indicated for renal cell carcinoma had its indication later expanded to hepatocellular carcinoma.

Sunitinib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sutent Sugen, Pfizer USA 2006 USA 557795-19-4

Sunitinib is an oral, multi-targeted tyrosine kinase inhibitor involved with tumor proliferation and angiogenesis. It was launched for treatment of gastrointestinal stromal tumors and advanced renal-cell carcinoma.

Talaporfin sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Laserohyrin Nippon Petrochem, Light Sciences Corp, Meiji Seika Kaisha Japan 2004 Japan 110230-98-3

Talaporfin sodium is an injectable photosensitizer that was initially approved for photodynamic therapy of early stage lung cancer.

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Major Drug Introductions

Tamibarotene Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Amnolake Toko Yakuhin Kogyo, Nippon Shinyaku Japan 2005 Japan 094497-51-5

Tamibarotene is a selective agonist of the retinoic acid receptor and is an oral treatment for relapsed or refractory acute promyelocytic leukemia (APL).Tamibarotene exhibits an improved selectivity profile as compared with all-trans-retinoic acid (2005 standard of care for APL).

Tasonermin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Beromun Genentech USA 1999 Germany 94948-59-1

Tasonermin is the first tumor necrosis factor launched for the treatment of soft tissue sarcoma of the limbs.

Temozolomide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Temodal CRC Technology, Schering-Plough United Kingdom 1999 United Kingdom 85622-93-1

Temozolomide was introduced for the treatment of patients with glioblastoma multiforme showing recurrence or progression after standard therapy. The mode of action involves inhibition of O-6-alkylguanine-DNA alkyltransferase.

Temsirolimus Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Torisel Wyeth USA 2007 USA 162635-04-3

Temsirolimus is an ester analog of sirolimus, is an inhibitor of mammalian target of rapamycin (mTOR). Temsirolimus is the first approved mTOR antagonist for the treatment of renal cell carcinoma (RCC) and is administered intravenously once weekly. mTOR inhibition prevents phosphorylation of the 4E binding protein-1 and the 40S ribosomal protein S6 kinase which results in cell cycle arrest.

Topotecan hydrochloric acid Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Hycamtin SmithKlineBeecham United Kingdom 1996 USA 123948-87-8

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Major Drug Introductions

Topotecan is an inhibitor of topoisomerase 1 and inhibits its release from DNA where it relaxes super-coiled DNA giving rise to single-strand breaks. When the replication fork eventually reaches this complex double-strand breaks can occur thus signaling apoptosis and eventually giving rise to cell death. Topotecan was launched for the second-line treatment of ovarian cancer.

Tositumomab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Bexxar Corixar, GlaxoSmithKline USA 2003 USA 192391-48-3

Tositumomab is another radioimmunotherapeutic antibody for the treatment of B-cell non-Hodgkin’s lymphoma. Treatment involves joint dosing of tositumomab and 131I-tositumomab and thus combines the tumor-targeting ability of the cytotoxic antibody with the therapeutic potential of radiation with patient-specific dosing.

Trabectedin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Yondelis Pharma Mar, Johnson & Johnson USA 2007 United Kingdom, Germany 114899-77-3

Trabectedin is a natural product derived from the marine tunicate Ecteinascidia turbinata. Trabectedin has been launched for the treatment of advanced soft tissue sarcoma after failure of first-line therapy with anthracyclines or ifosfamide or in patients who are otherwise intolerant to these agents.

Major Drug Introductions

81

Valrubicin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Valstar Anthra Pharm, Medeva USA 1999 USA 56124-62-0

Valrubicin possibly acts by blockade of SV40 large T-antigen helicase. It was launched for the treatment of bladder cancer by intravesical installation.

Vandetanib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Caprelsa AstraZeneca United Kingdom 2011 USA 443913-73-3

Vandetanib is a kinase inhibitor approved for the oral treatment of symptomatic or progressive medullary thyroid cancer in adults with unresectable locally advanced or metastatic disease. Vandetanib exhibits a 19 day elimination half-life and can prolong the QT interval.

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Major Drug Introductions

Vemurafenib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zelboraf Hoffman-La Roche, Plexxikon USA 2011 USA 918504-65-1

Vemurafenib was launched for the treatment of patients with metastatic melanoma with the BRAFV600E mutation but has low potency against wild-type BRAF. Vemurafenib is administered orally and twice daily.

Vorinostat Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zolinza Merck USA 2006 USA 149647-78-9

Vorinostat is a new in class anti-cancer agents that is an oral treatment launched for cutaneous manifestations in patients with cutaneous T cell lymphoma who have progressive, persistent, or recurrent disease on or following two systemic therapies. Vorinostat inhibit histone deacetylases.

Major Drug Introductions

83

Antineoplastic Drugs Abiraterone acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zytiga Janssen United Kingdom 2011 USA 154229-18-2

Abiraterone acetate inhibits 17 a-hydroxylase/CYP17, which is responsible for androgen biosynthesis. Abiraterone in combination with prednisone was launched for the oral treatment of metastatic castration-resistant prostate cancer for patients who were previously treated with a docetaxel containing regimen.

Amrubicin hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Calsed Sumitomo Japan 2002 Japan 92395-36-5

Amrubicin inhibits topoisomerase II. It was introduced for the treatment of non-small-cell and small-cell lung cancers.

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Major Drug Introductions

Anastrozole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Arimidex Zeneca United Kingdom 1995 United Kingdom 120511-73-1

Anastrozole is a potent and selective aromatase inhibitor that was introduced for the treatment of advanced breast cancer in postmenopausal women.

Azacitidine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vidaza Pharmion USA 2004 USA 320-67-2

Azacitidine is an antineoplastic agent launched for the treatment of five subtypes of myelodysplastic syndrome (MDS). Azacitidine is administered subcutaneously or intravenously and causes demethylation of DNA and direct cytotoxicity on hyperproliferating cells in bone marrow.

Major Drug Introductions

85

Bicalutamide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Casodex Zeneca United Kingdom 1995 United Kingdom 90357-06-5

Bicalutamide is a peripherally selective antiandrogen that was introduced for the treatment of advanced prostate cancer in combination with a luteinizing hormone-releasing hormone (LHRH) analog or surgical castration.

Capecitabine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Xeloda Roche Switzerland 1998 Switzerland 154661-50-9

Capecitabine is a prodrug of doxifluridine from which it is released at the target tumor site. It is marketed for the treatment of advanced neoplastic disease including refractory metastatic breast cancer.

Crizotinib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Xalkori Pfizer USA 2011 USA 877399-52-5

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Major Drug Introductions

Crizotinib was launched for the treatment of anaplastic lymphoma kinase (ALK) positive non-small-cell lung cancer (NSCLC). Crizotinib is an oral inhibitor of receptor tyrosine kinases, including ALK.

Dasatinib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sprycel BristolMyersSquibb USA 2006 USA 302962-49-8

Dasatinib is the second oral multi-tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia. Unlike imatinib, dasatinib binds to both active and inactive conformation of the ABL kinase protein and has shown activity against all imatinib-resistant mutants except the T315I mutant.

Decitabine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Dacogen SuperGen, MGI Pharma Netherlands 2006 USA 2353-33-5

Decitabine is a cytosine analog and inhibits the methylation of DNA and has been launched for the treatment of myelodysplastic syndromes (MDS). Decitabine is administered by continuous intravenous infusion over 3 h, every 8h, for 3 days.

Major Drug Introductions

87

Docetaxel Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Taxotere Rhone-Poulenc-Rorer France 1995 South Africa 114977-28-5

Docetaxel is a semisynthetic product from the taxoid family used for the treatment of ovarian, breast, and non-small-cell lung cancers.

Fadrozole hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Afema Ciba-Geigy Switzerland 1995 Japan 102676-31-3

The potent and specific aromatase activity of fadrozole led to its introduction for the treatment of postmenopausal breast cancer.

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Major Drug Introductions

Gemcitabine hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Gemzar Lilly USA 1995 Netherlands, Sweden 122111-03-9

Following phosphorylation in vivo, gemcitabine acts on non-small-cell-lung cancer and pancreatic cancer. It inhibits processes required for DNA synthesis and metabolism and shows an extraordinary array of self-potentiating mechanisms that increase the concentration and prolong the retention of its active nucleotides in tumor cells.

Gefitinib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Iressa AstraZeneca United Kingdom 2002 Japan 184475-35-2

Gefitinib was introduced as a daily oral monotherapy for the treatment of inoperable or recurrent non-small-cell lung cancers. It reversibly inhibits the activity of the epidermal growth factor receptor tyrosine kinase.

Imatinib mesilate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Gleevec, Glivec Novartis Switzerland 2001 USA 220127-57-1

Major Drug Introductions

89

Imatinib mesilate was launched for the treatment of chronic myelogenous leukemia (CML) in blast crisis, accelerated phase or chronic phase after interferon-alpha failure. It is the first agent to act specifically on a constitutively active tyrosine kinase that causes CML.

Irinotecan hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Campto, Topotecin Yakult Honsha Japan 1994 Japan 100286-90-6

Irinotecan hydrochloride is a water-soluble derivative of the anticancer agent campothecin that was marketed for the treatment of lung, ovarian, and cervical cancers. It inhibits topoisomerase I, the enzyme involved in maintaining the topographic structure of DNA during the process of translation, transcription, and mitosis.

Lenalidomide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Revlimid Celgene USA 2006 USA 191732-72-6

Lenalidomide is a chemical derivative of thalidomide. Lenalidomide inhibits TNF-alpha, pro-inflammatory cytokines secretion, angiogenic cytokines and stimulates the secretion of anti-inflammatory cytokines (eg. IL-10). Lenalidomide was launched for the treatment of multiple myeloma.

Nedaplatin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Aqulpa Shionogi Japan 1995 Japan 95734-82-0

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Major Drug Introductions

Nedaplatin is a novel, second-generation platinum complex that was marketed for the treatment of a variety of cancers including head and neck, small-cell and non-small-cell lung, osteophageal, prostatic, testicular, ovarian, cervical, bladder, and uterine cancers.

Nelarabine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Arranon GlaxoSmithKline USA 2006 USA 121032-29-9

Nelarabine is a purine nucleoside antimetabolite launched as an intravenous infusion for treating relapsed or refractory T cell acute lymphoblastic leukemia (T-ALL) and T cell lymphoblastic lymphoma (T-LBL).

Pegaspargase Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Oncaspar Enzon, Rhone-Poulenc Rorer USA 1994 USA 9015-68-3

Pegaspargase is a polyethylene glycol conjugate of L-asparaginase that was introduced for combination chemotherapy in acute lymphoblastic leukemia. The conjugation increases activity, prolongs half-life, and reduces immunogenicity.

Sipuleucel-T Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Provenge Dendreon USA 2010 USA 917381-47-6

Sipuleucel-T is a first in class therapeutic cancer vaccine. Sipuleucel-T was launched for the treatment of minimally symptomatic metastatic castration-resistant prostate cancer. Sipuleucel-T is an autologous vaccine that is generated from each individual patient’s own blood cells. The vaccine is composed of autologous peripheral blood mononuclear cells, including antigen presenting cells (APC), cultured with a fusion protein. Sipuleucel-T potency is determined by measuring the increased expression of the CD54

Major Drug Introductions

91

molecule on the surface of APCs after culture with prostatic acid phosphatase fused to granulocyte-macrophage colony-stimulating factor. Sipuleucel-T is given by three infusions given at two week intervals.

Sobuzoxane Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Perazolin Zenyaku Kogyo Japan 1994 Japan 98631-95-9

Sobuzoxane is a noncleavable complex-stabilizing topoisomerase II inhibitor that was introduced for the treatment of malignant lymphoma and adult T-cell leukemia/lymphoma that is resistant to chemotherapy and has a poor prognosis. It appears to significantly inhibit growth of human colon, lung, gastric, and breast cancers.

Temoporfin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Foscan Quanta Nova United Kingdom 2002 United Kingdom 122341-38-2

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Major Drug Introductions

Temoporfin is a second-generation photosensitizer for the photodynamic therapy of advanced head and neck cancers. It is extremely sensitive to wavelengths of light that penetrate tissues thus resulting in lower light/dose and irradiation time.

Vinflunine ditartrate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number 194468-36-5 [tartrate (1:2)] Structure

Javlor Pierre Fabre France 2009 United Kingdom 162652-95-1

Vinflunine ditartrate is a semisynthetic analog of natural vinca alkaloids vinblastine and vincristine. Vinflunine was launched for the intravenous treatment of adult patients with advanced or metastatic transitional cell carcinoma of the urothelial tract after failure of a prior platinum-containing regimen. Vinflunine exhibits the greatest tubulin-binding affinity compared to other vinca alkaloids.

Zinostatin stimalamer Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

SMANCS Yamanouchi Japan 1994 Japan 123760-07-6

Zinostatin stimalamer is a conjugate of poly(styrene-maleic acid) and neocarzinostatin that was launched for the treatment of hepatoma. Conjugation improves the in vivo stability, the effectiveness in reducing tumor size, and in prevention of the development of new tumors, decreases toxic side effects, and extends the half-life.

Major Drug Introductions

93

Antiemetic Agents Aprepitant Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Emend Merck USA 2003 USA 170729-80-3

Aprepitant is a substance P receptor antagonist used for the treatment of chemotherapy-induced nausea and vomiting. It is effective against both the acute and delayed phase of cisplatin-induced emesis.

Dolasetron mesylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Anzemet Hoechst Marion Roussel Germany 1998 Australia 115956-13-3

Dolasetron mesylate is a potent and very selective antagonist for 5HT3 receptors with potent antiemetic effects induced by cancer chemotherapy. Single doses of 10–50 mg prior to treatment with cisplatin effectively control emesis and nausea.

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Major Drug Introductions

Fosaprepitant dimeglumine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Emend Merck USA 2008 United Kingdom 265121-04-8

Fosaprepitant is an intravenous antiemetic launched for the treatment of chemotherapy-induced nausea and vomiting. Fosaprepitant is the prodrug of aprepitant which is a highly selective substance P neurokinin 1receptor antagonist. Is approved to be used in combination with antiemetic regimens consisting of 5HT3 antagonist plus a corticosteroid.

Indisetron Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sinseron Nisshin Kyorin Japan 2004 Japan 160472-97-9

Radiation and cytotoxic drugs produced an increase in 5-hydroxytrypramine (5-HT) in the brain stem and intestinal mucosa. The stimulation of the 5-HT3 receptors on vagal afferent nerves induces the vomiting reflex. Indisetron is a 5-HT3/5-HT4 antagonist launched for the treatment of nausea and vomiting associated with chemotherapy.

Nazasetron hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Serotone Yoshitomo, Japan Tobacco, Green Cross Japan 1994 Japan 123040-16-4

Nazasetron is a highly potent 5HT3 receptor antagonist that markedly reduces nausea and emesis following cancer chemotherapy and total body X-radiation.

Palonosetron Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Aloxi Syntex (Roche Bioscience), MGI Pharma, Helsinn USA 2003 USA 135729-62-3

Palonosetron is a 5HT3 receptor antagonist used as an injectable agent for the prevention of acute and delayed nausea and vomiting associated with cancer chemotherapy. Because of its long half-life, the therapeutic effect lasts for several days. The antiemetic effect acts against a number of agents including cisplatin, cyclophosphamide, and dacarbazine.

Ramosetron Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nasea Yamanouchi Japan 1996 Japan 132907-72-3

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Major Drug Introductions

Ramosetron is a 5HT3 receptor antagonist that is active against cisplatin-induced emesis.

Cytoprotective Agents Amifostine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ethyol US Bioscience, Schering Plough USA 1995 Germany 63717-27-1

Amifostine is used to reduce cisplatin-induced renal toxicity in patients with advanced ovarian cancer. It is also a radioprotective agent.

5a-Reductase Inhibitor Dutasteride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Avodart GlaxoSmithKline United Kingdom 2002 USA 164656-23-9

Dutasteride is marketed for the symptomatic treatment of benign prostatic hyperplasia. It is a dual inhibitor of type 1 and 2 isoforms of 5a-reductase and has a markedly prolonged half-life.

Major Drug Introductions

97

Chemotherapy-Induced Leukopenia Nartograstim Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Neu-Up Kyowa Hakka Japan 1994 Japan 134088-74-7

Nartograstim is a highly active mutein of the granulocyte colony-stimulating factor and is used in the treatment of chemotherapy-induced granulocytopenia, rhabdomyosarcoma, and anemia.

Anticancer Adjuvant Angiotensin II Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Delibert Toa Elyo, Yamanouchi Japan 1994 Japan 4474-91-3

Angiotensin II was introduced to improve the efficacy of systemic chemotherapy by controlling blood flow to tumor tissues.

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Major Drug Introductions

Hypercalcemia Zoledronate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zometa Novartis Switzerland 2000 Canada 165800-07-7

This bisphosphonate was introduced for the treatment of tumor-induced hypercalcemia.

Cardiovascular Agents This category includes 27 antihypertensives, 12 antithrombotics, nine hypocholesterolemics, seven antiarrhythmics, four agents for heart failure, three anticoagulants, three hematological agents, two anti-anginals, two cardiostimulants, two iron chelators, one agent with cardiotonic activity, one drug eluting stent, one fibrinolytic agent, one hemophilia agent, and a subarachnoid hemorrhage agent.

Antihypertensives Aliskiren Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tekturna Novartis Switzerland 2007 USA 173334-57-1

Aliskiren is a first-in-class, once daily, oral antihypertensive that exerts anti-hypertensive effects via direct renin inhibition. Aliskiren has been studied as monotherapy or in combination with other antihypertensive therapies.

Major Drug Introductions

99

Ambrisentan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Letairis Abbott, Gilead USA 2007 USA 177036-94-1

Ambrisentan is the 3rd selective, endothelin-A receptor antagonist introduced for the oral treatment of pulmonary arterial hypertension. Ambrisentan is selective for the ETA receptor and it is hypothesized that receptor selectivity may confer a greater clinical benefit.

Aranidipine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Bec, Sapresta Maruko Seiyaku, Taiho Japan 1996 Japan 86780-90-7

Aranidipine is a long-acting, potent antihypertensive agent that works by blocking Ca2þ entry into cells.

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Major Drug Introductions

Azelnidipine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Calblock Sankyo Japan 2003 Japan 116574-11-9

Azelnidipine is a blocker of L-type calcium channels and gives a sustained reduction in blood pressure in patients with mild to moderate hypertension.

Azilsartan medoxomil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Edarbi Takeda USA 2011 USA 863031-21-4

Azilsartan medoxomil is an angiotensin II receptor antagonist (ARB) launched for the oral, once daily treatment of hypertension in adults as monotherapy or in combination with other antihypertensive agents. Azilsartan medoxomil is a prodrug that is rapidly hydrolyzed to the active metabolite azilsartan. It is a potent and highly selective angiotensin II antagonist at the AT1 receptor.

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Bosentan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tracleer Roche, Actelion, Genentech Switzerland 2001 USA 147536-97-8

Bosentan was the first endothelin receptor antagonist to be launched and was introduced as a twice daily oral treatment for pulmonary arterial hypertension. It has demonstrated a beneficial selectivity for the pulmonary vasculature since it has no significant effect on mean aortic blood pressure and systolic vascular resistance.

Candesartan cilexetil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Atacand Takeda, Astra Japan 1997 Sweden 145040-37-5

Candesartan cilexetil is a potent antagonist of angiotensin II type 1 receptors and thus acts as an antihypertensive. It is long acting and is more potent than angiotensin-converting enzyme (ACE) inhibitors.

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Cilnidipine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cinalong/Siscard/Atelec Fujirebio, Boehringer Ingelheim, Roussel-Morishita Japan 1995 Japan 132203-70-4

Cilnidipine is dihydropyridine calcium antagonist intended for the treatment of essential and severe hypertension and hypertension associated with renopathy. Cilnidipine has slow onset and long duration with less cardiodepressant activity.

Clevidipine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cleviprex AstraZeneca United Kingdom 2008 USA 167221-71-8

Clevidipine is an injectable ultra-short-acting vasodilator of the dihydropyridine type calcium channel blocker class for the acute management of hypertension. Clevidipine is the 2nd intravenous calcium channel blocker to be launched for this indication. Clevidipine is an injectable emulsion that has a very quick onset and short duration of action allowing for rapid dose titration. Clevidipine is an arterial specific vasodilator that has little effect on the myocardium and venous system. It is administered via continuous intravenous infusion.

Major Drug Introductions

103

Efonidipine hydrochloride ethanol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Landel Nissan Chemical, Zeria Japan 1994 Japan 111011-76-8

Efonidipine hydrochloride ethanol is the 14th dihydropyridine calcium channel blocker to be launched. It was marketed for the treatment of essential severe and renal hypertension.

Eplerenone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Inspra Ciba-Geigy/Pfizer USA 2003 USA 107724-20-9

The antihypertensive effect of eplerenone is due to blockage of the binding of aldosterone at the mineralocorticoid receptor. It was approved for the oral treatment of hypertension but has been shown to also improve the survival of stable patients with left ventricular systolic dysfunction.

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Eprosartan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Teveten SmithKlineBeecham United Kingdom 1997 Germany 133040-01-4

Eprosartan is a potent, highly selective competitive antagonist of the AT1 receptor that was marketed for the treatment of hypertension.

Fenoldopam mesylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Neurex SmithKlineBeecham USA 1998 USA 67227-57-0

Fenoldopam is a potent dopamine D1 receptor agonist acting peripherally to produce systemic vasodilation. It is unable to cross the blood–brain barrier and thus has no central effects. In addition, it interacts with 5HT1c and 5HT2 receptors. Fenoldopam is fast acting and maintains a long-lasting antihypertensive effect.

Major Drug Introductions

105

Irbesartan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Aprovel/Avapro Sanofi France 1997 United Kingdom 138402-11-6

Irbesartan is an angiotensin II receptor antagonist that is noncompetitive and selective for AT1 subtypes and has no AT2 activity at postsynaptic receptors compared to presynaptic receptors. It was marketed as an antihypertensive.

Lercanidipine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lerdip Recordati, Byk Gulden Italy 1997 Neatherlands 100427-26-7

Lercanidipine is an antagonist of L-type calcium channels with no activity in smooth muscle cells, and has gradual onset with a long duration of activity as an antihypertensive agent.

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Major Drug Introductions

Losartan Potassium

Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cozaar DuPont, Merck USA 1994 Sweden 124750-99-8

Losartan was the first potent and selective nonpeptide angiotensin II AT1 receptor antagonist to be marketed. It acts as a potent and long-lasting once daily orally dosed antihypertensive.

Mibefradil Hydrochloride

Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Posicor Roche Switzerland 1997 USA 116666-63-8

Mibefradil is a calcium channel blocker with selectivity for the T-type and is marketed for the treatment of mild to moderate hypertension.

Major Drug Introductions

107

Moexipril hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Univase Warner-Lambert USA 1995 USA 82586-52-5

Moexipril is an ACE inhibitor that is marketed as a treatment for hypertension as a monotherapy and as a second-line therapy in combination with diuretics or calcium antagonists.

Nebivolol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nebilet Johnson & Johnson USA 1997 Germany 99200-09-6

Nebivolol is a selective b1-adrenergic receptor antagonist and is 50 times less potent at b2-receptors. It is marketed as an antihypertensive agent and has vasodilating activity via the nitric oxide pathway. It causes an immediate fall in blood pressure and improves both left ventricular systolic and diastolic function and lowers peripheral blood resistance.

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Major Drug Introductions

Olmesartan medoxomil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Benicar Sankyo, Forest Japan 2002 USA 144689-63-4

Spirapril is an orally active ACE inhibitor marketed for the treatment of hypertension.

Sitaxsentan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Thelin Encysive USA 2006 United Kingdom 184036-34-8

Sitaxsentan is a selective endothelin-A receptor antagonist launched for the treatment of pulmonary arterial hypertension. Sitaxsentan has been discontinued worldwide due to cases of liver toxicity.

Major Drug Introductions

109

Spirapril hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Renpress, Renormax Schering-Plough, Sandoz USA 1995 Finland 94841-17-5

Spirapril is an orally active ACE inhibitor marketed for the treatment of hypertension.

Telmisartan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Micardis Boehringer Ingelheim Germany 1999 USA 144701-48-4

Telmisartan blocks the activity of angiotensin II and is an angiotensin receptor blocker. It shows effective and sustained blood pressure lowering effects with a single daily oral dosage.

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Major Drug Introductions

Temocapril hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Acecol Sankyo, Nippon Boehringer Ingelheim Japan 1994 Japan 110221-44-8

Temocapril is an ACE inhibitor that is marketed for the treatment of hypertension. It is orally active and has a long duration of action. Because it is largely eliminated through the biliary route it is useful for the treatment of hypertensive patients with renal dysfunction.

Treprostinil sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Remodulin Pharmacia, GlaxoSmithKline USA 2002 USA 289840-64-4

Treprostinil sodium, which appears to act at the prostacyclin receptor, was launched for the treatment of pulmonary hypertension. In patients with primary pulmonary hypertension, treprostinil causes a 22% improvement in cardiac output, a 24% significant decrease in peripheral vascular resistance, a decrease in mean pulmonary arterial pressure, and an improvement in New York Heart Association (NYHA) functional class.

Major Drug Introductions

111

Valsartan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Diovan Novartis Switzerland 1996 Germany 137862-53-4

Valsartan is a highly specific antagonist of the AT1 receptor that is potent and orally active.

Zofenopril calcium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zantipres Bristol-Meyers USA 2000 Italy 81872-10-8

Zofenopril calcium was introduced as a second-generation ACE inhibitor for the treatment of acute myocardial infarction. It is a prodrug with the S-benzoyl group being rapidly hydrolyzed by cardiac esterase. It may also possess antioxidant effects, which could account for some of its strong anti-ischemic effects.

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Major Drug Introductions

Antithrombotic Agents Apixaban Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Eliquis Bristol-Myers Squibb, Pfizer USA 2011 European Union 503612-47-3

Apixaban is the 3rd direct inhibitor of factor Xa introduced to market. Apixaban was launched for the prevention of venous thromboembolic events in adults who have undergone elective hip or knee replacement surgery. Inhibition of factor Xa inhibits the formation of thrombin, halting the formation of a cross-linked fibrin rich clot. The effects of apixaban like other direct factor Xa inhibitors are not immediately reversible.

Major Drug Introductions

113

Bivalirudin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Angiomax Biogen, The Medicines Company USA 2000 New Zealand 128270-60-0

Bivalirudin was introduced as an intravenous treatment of patients with unstable angina undergoing percutaneous transluminal coronary angioplasty. It is a possible alternative to heparin treatment.

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Major Drug Introductions

Clopidogrel hydrogen sulfate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Plavix, Iscover Sanofi, Bristol-Meyers Squibb France 1998 USA 113665-84-2

Clopidogrel is an adenosine diphosphate antagonist acting on the purinergic P2y receptor and was launched as a potent inhibitor of platelet aggregation for the preventative management of secondary ischemic events including myocardial infarction (MI), stroke, and vascular deaths.

Dabigatran etexilate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Pradaxa Boehringer Ingelheim Germany 2008 United Kingdom 211915-06-9

Dabigatran etexilate is an oral a prodrug of dabigatran which is a direct thrombin inhibitor. Dabigatran is the second oral direct thrombin inhibitor to reach the market (following the withdrawal of ximelagatran). Dabigatran was launched for thromboprophylaxis in patients after undergoing hip and knee replacement surgeries. Dabigatran etexilate is taken twice daily.

Major Drug Introductions

115

Edoxaban Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lixiana Daiichi Sankyo Japan 2011 Japan 480448-29-1

Edoxaban is the 2nd oral direct Factor Xa inhibitor introduced to market and was launched for the prevention of venous thromboembolic events (VTE) in adult patients who have undergone elective hip or knee replacement surgery. Edoxaban is approved for once daily dosing and is eliminated renally.

Eptifibatide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Integrilin Cor Therapeutics, Schering-Plough USA 1999 USA 188627-80-7

Eptifibatide was introduced for the treatment of acute coronary syndrome, in particular for patients at risk of abrupt vessel closure during or after coronary angioplasty.

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Major Drug Introductions

Fondaparinux sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Arixtra Sanofi-Synthelabo, Akzo Nobel France 2002 USA 114870-03-0

Fondaparinux sodium was introduced for prophylaxis of deep vein thrombosis, which sometimes leads to pulmonary embolism, following major orthopedic surgery.

Prasugrel Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Effient Daiichi Sankyo & Eli Lilly Japan 2009 United Kingdom 150322-43-3

Prasugrel is a third-generation thienopyridine introduced to market. Prasugrel was launched for the prevention of atherothrombotic events in patients with acute coronary syndrome following percutaneous coronary intervention. Prasugrel is more rapidly converted to its active metabolite and has more consistent absorption in comparison to previous generations of thienopyridines.

Major Drug Introductions

117

Rivaroxaban Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Xarelto Bayer, Ortho-McNeil Germany 2008 Canada 366789-02-8

Rivaroxaban is the first oral anticoagulant that selectively and potently inhibits coagulation factor Xa. Rivaroxaban was launched for prophylaxis of deep vein thrombosis in patients undergoing elective knee or hip replacement surgery. Presently the anticoagulant effect of rivaroxaban cannot be monitored with standard laboratory testing and is not easily reversed.

Ticagrelor Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Brilique, Possia AstraZeneca United Kingdom 2010 USA 274693-27-5

Ticagrelor is an oral platelet P2Y12 adenosine-5’-diphosphate (ADP) receptor antagonist that inhibits platelet aggregation. Ticagrelor was launched for the treatment of acute coronary syndrome (ACS). ACS symptoms range from unstable angina, to non-Q wave infarctions and Q-wave myocardial infarctions. In clinical trials it has been shown to reduce the rate of a combined endpoint of cardiovascular death, myocardial infarction, or stroke compared to clopidogrel. Ticagrelor does not require hepatic activation and also has a reversible effect on platelets.

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Major Drug Introductions

Tirofiban hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Aggrastat Merck USA 1998 Switzerland, USA 142373-60-2

Tirofiban hydrochloride is a highly potent antiplatelet agent that inhibits the interaction of fibrinogen with GPIIb/IIIa. It was introduced for the treatment of patients with unstable angina or non-Q wave myocardial infarction to prevent cardiac ischemic events.

Ximelgatran Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Exanta AstraZeneca Germany 2004 Germany 192939-46-1

Ximelgatran is an oral direct thrombin inhibitor launched for prophylaxis of venous thrombolic events in patients undergoing elective hip or knee replacement surgery. Hepatotoxicity and elevations in alanine aminotransferase three times the upper limit of normal has been observed in the first four months of therapy.

Major Drug Introductions

119

Hypocholesterolemic Agents Atorvastatin calcium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lipitor Parke-Davis USA 1997 United Kingdom 134523-03-8

Atorvastatin calcium is a liver-selective reversible competitive inhibitor of HMG-CoA reductase that was introduced as an orally active hypocholesterolemic agent. It became the first pharmaceutical product ever to make over US $1billion in sales in its first year.

Cerivastatin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lipobay Bayer Germany 1997 United Kingdom 143201-11-0

Lipobay is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor with a high liver selectivity that was launched for the treatment of primary hypercholesterolemia.

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Major Drug Introductions

Choline fenofibrate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

TriLipix Abbott, Solvay USA 2008 USA 856676-23-8

Choline fenofibrate is a salt formulation of fenofibric acid. It was launched for use in combination with a statin to reduce triglycerides and high-density lipoprotein cholesterol in patients with mixed dyslipidemia and coronary heart disease. Also choline fenofibrate can be used as monotherapy in patients with severe hypertriglyceridemia.

Colesevelam hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Welchol GelTex, Sankyo, Pfizer USA 2000 USA 182815-44-7

Colesevelam is a nonabsorbable, water-insoluble polymer of a hexanamium chloride with N-(2-propenyl) decanamine, 2-propene-1-amine hydrochloride, and chloromethyloxirane. It is used for the reduction of elevated levels of serum low-density lipoprotein (LDL) cholesterol. It can either be used as a monotherapy or as a dual therapy with statins.

Colestimide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cholebine Mitsubishi, Tokyo Tanabe, Yamanouchi Japan 1999 Japan 95522-45-5

Colestimide is a methyl imidazole-epichlorin copolymer used as a bile acid sequestrant that leads to the enhancement of the rate of LDL removal. It can be used in monotherapy or coadministered with HMG-CoA reductase inhibitors.

Ezetimibe Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ezetrol Schering-Plough, Merck USA 2002 Germany 163222-33-1

Ezetimibe is a once a day orally active cholesterol absorption inhibitor that is marketed as a hypolipidemic agent. When coadministred with statins it is more effective at reducing blood cholesterol levels.

Fluvastatin sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lescol Sandoz Switzerland 1994 United Kingdom 93957-55-2

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Major Drug Introductions

Fluvastatin sodium was the fourth HMG-CoA reductase inhibitor to be marketed for lowering total and LDL cholesterol.

Pitavastatin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Livalo Nissan, Sankyo, Kowa Japan 2003 Japan 147526-32-7

This is a second-generation statin that was introduced for the treatment of hypercholesterolemia. It is an inhibitor of HMG-CoA reductase. It is well absorbed, undergoes little metabolism, and is excreted via the bile.

Rosuvastatin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Crestor Shionogi/AstraZeneca Japan 2003 Netherlands 147098-20-2

Major Drug Introductions

123

Rosuvastatin is a second-generation statin with high hepatoselectivity and more potent inhibitory effects on HMG-CoA reductase than the previously marketed statins. It is rapidly absorbed following oral dosing, minimally metabolized, and excreted via the bile. The length of action permits once daily dosing.

Antiarrhythmic Dofetilide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tikosyn Pfizer USA 2000 USA 115256-11-6

Dofetilide was launched for the treatment of cardiac patients with highly symptomatic atrial fibrillation. It potently and selectively inhibits a single potassium channel, lkr, the rapidly acting component of the delayed rectifier potassium current. By blocking the open state of lkr, dofetilide is able to prolong the effective refractory period in both atrial and ventricular myocardium and the monophasic action potential duration. Because it targets only one cardiac ion channel, it does not produce any effects on the sinus node, cardiac conduction system, and other extracardiac organs.

Dronedarone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Multaq Sanofi-Aventis USA 2009 USA 141626-30-0

Dronedarone is a twice-daily, oral antiarrhythmic and a close analog of amiodarone. It is less lipophilic, has lower tissue accumulation, and has a much shorter serum half-life compared with amiodarone. Dronedarone was launched to reduce the risk of

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Major Drug Introductions

cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. Dronedarone is contraindicated in patients who are NYHA Class IV.

Ibutilide fumarate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Corvert Pharmacia & Upjohn United Kingdom 1996 USA 122647-32-9

Ibutilide fumarate activates slow inward sodium channels and thus is able to prolong the action potential duration and lengthen the refractory period of myocardial tissue. It was launched for the treatment of atrial fibrillation and flutter.

Landiolol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Onoact Ono Pharmaceutical Japan 2002 Japan 133242-30-3

Landiolol is an ultra-short-acting b1-adrenergic blocker that was launched for the treatment of tachyarrhythmia during surgery.

Major Drug Introductions

125

Nifekalant hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Shinbit Mitsui Japan 1999 Japan 130656-51-8

Nifekalant is a nonselective blocker of myocardial repolarizing potassium currents and is completely devoid of any b-adrenergic effects. It was launched for the treatment of serious ventricular arrhythmias.

Pirmenol hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Pimenol Warner-Lambert USA 1994 Japan 61477-94-9

Pirmenol hydrochloride is a long-acting class Ia antiarrhythmic agent acting against atrial and ventricular arrhythmias of diverse etiology. It is highly active when given by both the oral and intravenous routes.

Vernakalant Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Brinavess Merck, Cardiome Pharma Corp. Canada 2010 European Union 794466-70-9

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Major Drug Introductions

Vernakalant is a potassium channel blocker launched for the acute, intravenous, treatment of atrial fibrillation. Vernakalant has activity for cardiac Naþ, K þ and atrial-selective Kv1.5 channels. Was launched for rapid conversion of recent onset atrial fibrillation to normal sinus rhythm in adults, for non-surgery patients with atrial fibrillation of 7 days or less and for postcardiac surgery patients with atrial fibrillation of 3 days or less.

Heart Failure Carperitide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Hanp Suntory/Zeria Japan 1995 Japan 89213-87-6

Carperitide is the a-human atrial natriuretic peptide and is used for the treatment of congestive heart failure.

Levosimendan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Simdax Orion Finland 2000 Sweden 141505-33-1

Levosimendan is a myofilament calcium sensitizer that increases myocardial contractility by selectively binding to the N-terminus of troponin C and by stabilizing the Ca2þ-bound conformation of this contractile protein. It was introduced as an intravenous infusion for the treatment of acute heart failure or refractory symptoms of chronic heart failure in cases where conventional treatment is not sufficient.

Nesiritide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Natrecor Scios, GlaxoSmithKline USA 2001 USA 124584-08-3

Nesiritide is a recombinant form of the human vasodilatory B-type natriuretic peptide that was introduced for the treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.

Major Drug Introductions

127

Pimobendan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Acardi Boehringer Ingelheim Germany 1994 Japan 74150-27-9

Pimobendan is a phosphodiesterase III (PDE III) inhibitor that is able to enhance sensitization of myocardial contractile regulatory protein to calcium ions. It was introduced for the treatment of mild to moderate chronic heart failure.

Anticoagulants Duteplase Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Solclot Sumitomo Japan 1995 Japan 120608-46-0

Duteplase is a recombinant tissue-type plasminogen activator that acts by converting the proenzyme plasminogen to the active enzyme plasmin. It was launched for the treatment of acute myocardial infarction.

Lepirudin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Refludan Hoechst Marion Roussel Germany 1997 Germany 8001-27-2

Refludan is an almost irreversible inhibitor of thrombin and was launched for the treatment of heparin-associated thrombocytopenia. It is used for myocardial infarcts, unstable angina, and cardiovascular events.

Thrombomodulin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant human glycoprotein; 62 kDa

Recomodulin AsahiKasei Pharma Japan 2008 Japan 112414-64-9

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Major Drug Introductions

Thrombomodulin is an anticoagulant launched for the intravenous treatment of disseminated intravascular coagulation (DIC). DIC usually occurs as a complication of malignant tumors and infections leading to blockages of capillaries and tissue damage. Thrombomodulin neutralizes thrombin and accelerates activation of protein C.

Hematological Anagrelide hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Agrylin Roberts USA 1997 USA 58579-51-4

Anagrelide hydrochloride was launched for the treatment of thrombocytosis. It has anti-cAMP phosphodiesterase activity and was initially tested as a platelet aggregation inhibitor. Its actual mechanism of action is not fully understood. It does not shorten platelet survival but it does it appear to interfere with the maturation of megakaryocytes.

Eltrombopag Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Promacta GlaxoSmithKline USA 2009 USA 496775-61-2

Eltrombopag is an oral non-peptide thrombopoietin receptor agonist launched for the treatment of thrombocytopenia in patients with idiopathic thrombocytopenic purpura (ITP). ITP is characterized by low platelet counts (less than 20 000 ml1) and increases risk of bleeding and intracranial hemorrhage. Eltrombopag is a non-peptide thrombopoietin (TPO) receptor agonist. Eltrombopag interacts with the TPO receptor to cause proliferation and differentiation of megakaryocytes from bone marrow progenitor cells to increase platelet production.

Major Drug Introductions

129

Romiplostim Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant fusion protein; molecular weight 60 kDa

Nplate Amgen USA 2008 USA 267639-76-9

Romiplostim is an injectable that stimulates platelet production produced by stimulating the thrombopoietin (TPO) receptor. Romiplostim was launched for the treatment of idiopathic thrombocytopenia and to restore platelet levels. Romiplostim is produced by recombinant DNA technology and is recombinant fusion protein consisting of two identical TPO-binding domains.

Anti-Anginals Ivabradine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Procoralan Servier France 2006 United Kingdom 148849-67-6

Ivabradine was launched for the treatment of chronic stable angina. Ivabradine interacts directly with the pacemaking cells of the sinoatrial node, and provides a viable alternative to patients with a contraindication or intolerance of beta-blockers or calcium channel blockers.

Ranolazine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ranexa Roche, CV Therapeutics USA 2006 USA 95635-55-5

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Major Drug Introductions

Ranolazine is an oral treatment for chronic angina in patients who have failed prior therapies for chronic refractory chronic angina. Ranolazine is a racemic mixture and improved diastolic function, decreases oxygen demand and increases coronary blood supply.

Cardiostimulants Docarpamine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tanadopa Tanabe Seiyaku Japan 1994 Japan 74639-40-0

Docarpamine is an orally effective peripheral dopamine prodrug that was launched as a cardiostimulant with diuretic activity for the treatment of circulatory insufficiency.

Loprinone hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Coatec Eisai Japan 1996 Japan 119615-63-3

Loprinone is a potent and selective inhibitor of PDE III and a long-lasting, orally active positive inotropic agent. It is used for acute cardiac insufficiency in cases resistant to other treatments.

Major Drug Introductions

131

Iron Chelation Deferasirox Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Exjade Novartis Switzerland 2005 USA 201530-41-8

Deferasirox is a first in class, tridentate, oral, iron-chelating agents used in the treatment of chronic iron overload due to transfusional iron overload and non-transfusion dependent thalassemia syndromes. Deferasirox is the second oral iron chelator.

Deferiprone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Kelfer Cipla India 1995 India 30652-11-0

Deferiprone is the first oral iron chelator; it was marketed for the management of thalassemia. It appears also to act as a chelator for aluminum.

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Major Drug Introductions

Cardiotonic Colforsin daropate hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Adele, Adehi Nippon Kayaku Japan 1999 Japan 138605-00-2

Colforsin daropate is a water-soluble and orally active prodrug of forskolin that was launched as a treatment for acute heart failure. It directly stimulates adenylate cyclase and increases the intracellular concentration of cAMP and inhibits calcium mobilization. Thus, it induces significant vasodilation and provides a moderate positive inotropic and chronotropic effect.

Drug-eluting Stent Biolimus drug-eluting stent Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Biomatrix Biosensors USA 2008 European Union 851536-75-9

Major Drug Introductions

133

Coronary stents have improved outcomes in interventional cardiology, however, the long-term success of coronary stenting is hampered by a high rate of restenosis. The biolimus drug-eluting stent contains biolimus in a matrix of biodegradable PLA which is released over time. Biolimus is an analog of sirolimus and inhibits cell proliferation resulting in a reduced rate of restenosis.

Fibrinolytic Reteplase Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 39.5 kDa

Retevase Boehringer Mannheim Germany 1996 USA 133652-38-7

Reteplase is a single-chain recombinant form of tissue plasminogen activator that was launched for the treatment of acute myocardial infarction.

Hemophilia Factor vIIa Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant human factor VIIa

NovoSeven Novo Nordisk Denmark 1996 Denmark 151821-07-7

Factor VIIa was launched for the treatment of hemophila A and B. In vivo, it has inhibitor bypassing activity and thus can circulate throughout the body with no effect until it comes into contact with tissue factor at a site of injury where activation occurs.

Subarachnoid Hemorrhage Tirilazad mesylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Freedox Pharmacia & Upjohn Sweden, USA 1995 Austria 110101-67-2

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Major Drug Introductions

Tirilazad was marketed for the intravenous treatment of subarachnoid hemorrhage in male patients. It localizes into the cell membrane and is a potent inhibitor of lipid peroxidation induced by oxygen free radicals.

Nervous System (Both Central and Peripheral) This section contains 10 compounds for depression, 10 antiepileptics, 10 neuroleptics, nine for Parkinson’s disease, seven for migraine, five for multiple sclerosis, four antihistamines, three for inducing sleep, three for muscle relaxation, three for neuroprotection, two for Alzheimer’s disease, two for attention deficit hyperactivity, two for local anesthesia, two for narcolepsy, and one each for dependence, psychostimulation, diagnosis of CNS disorders, sedation, anxiety, muscle relaxation reversal and stimulation.

Antidepressants Desvenlafaxine succinate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Pristiq Wyeth USA 2008 USA 93413-62-8

Desvenlafaxine succinate is an oral, extended-release, once-daily antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. Desvenlafaxine is the major active metabolite of venlafaxine and was launched for the treatment of major depressive disorder in adults. Similar to venlafaxine, desvenlafaxine is a more potent inhibitor of serotonin and norepinephrine reuptake.

Duloxetine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cymbalta Eli Lilly, Boehringer-Ingelheim USA 2004 USA 136434-34-9

Major Drug Introductions

135

Duloxetine is a Selective Serotonin-Norepinephrine Reuptake Inhibitor (SSNRI) and is often referred to as a ’dual’ inhibitor. Duloxetine is approved for the treatment of major depressive disorder and is the second SSNRI brought to market. Additionally, duloxetine is the first drug approved for the treatment of neuropathic pain associated with diabetic neuropathy.

Escitalopram oxalate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cipralex Lundbeck Denmark 2002 Switzerland, United Kingdom, Sweden 219861-08-2

Escitalopram oxalate is the S-enantiomer of the selective serotonin reuptake inhibitor citalopram and was launched for the treatment of depression and panic disorder. It has a fast onset of action and long half-life (27–32 h).

Milnacipran Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ixel Pierre Fabre France 1997 France 92623-85-3

Milnacipran is a specific serotonin and noradrenaline reuptake inhibitor. It has as short (7 h) half-life, no active metabolites, and is not metabolized by cytochrome P450. It was launched for the treatment of severe depression.

136

Major Drug Introductions

Mirtazapine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Remeron Organon Netherlands 1994 Netherlands 61337-67-5

Mirtazapine is a potent antagonist of presynaptic a2-receptors and a moderately potent 5HT antagonist. In the clinic, it demonstrated antidepressant activity with low anticholinergic action and gastrointestinal side effects and low cardiovascular toxicity.

Nefazodone hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Serzone Bristol-Meyers Squibb USA 1994 Canada 82752-99-6

Nefazodone hydrochloride acts as both a potent 5HT2 receptor antagonist and as a serotonin reuptake blocker. The very selective serotonergic effects are accompanied by few side effects from cholinergic, histamine, and adrenergic systems.

Major Drug Introductions

137

Pivagabine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tonerg Angelini Italy 1997 Italy 69542-93-4

Pivagabine was launched for the treatment of acute stress, posttraumatic stress syndrome, and ‘burnout’ syndrome. It inhibits the release of corticotropin-releasing factor from the hypothalamus.

Reboxetine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Edronax Pharmacia & Upjohn Sweden 1997 United Kingdom 71620-98-8

Reboxetine is a selective noradrenaline reuptake blocker that was shown to be effective in both the short and long term in the treatment of severe depression.

138

Major Drug Introductions

Venlafaxine hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Effexor Wyeth-Ayerst USA 1994 USA 93413-69-5

Venlafaxine is the first in the class of second-generation antidepressants with dual serotonin/norepinephrine reuptake inhibitory activity. It appears to have a rapid onset of action.

Vilazodone hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Viibryd Forest Germany 2011 USA 163521-12-8

Vilazodone hydrochloride is a first-in-class, oral, dual-mechanism antidepressant. Vilazodone was launched for the treatment of major depressive disorder. Vilazodone is both a potent serotonin reuptake inhibitor with high affinity for 5-HT1A receptors and is a partial 5-HT1A receptor agonist.

Major Drug Introductions

139

Antiepileptics Eslicarbazepine acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zebinix, Exalief, Stedesa Eisai Spain 2009 United Kingdom 236395-14-5

Eslicarbazepine acetate is a member of the carbamazepine family, and is a third generation antiepileptic drug launched for the treatment of partial-onset seizures with or without secondary generalization. Eslicarbazepine acetate is the prodrug of eslicarbazepine and also the active metabolite of oxcarbazepine.

Fosphenytoin sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cerebyx Warner-Lambert USA 1996 USA 93390-81-9

Fosphenytoin sodium is a prodrug that is rapidly converted by phosphatases to phenytoin. It was launched for the treatment of status epilepticus and for neurosurgery-derived seizures.

140

Major Drug Introductions

Gabapentin enacarbil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Horizant GlaxoSmithKline USA 2011 USA 478296-72-9

Gabapentin enacarbil is a novel, extended-release, oral, prodrug of gabapentin and has a more predictable bioavailability. Gabapentin enacarbil was launched for the treatment of moderate-to-severe restless legs syndrome. Gabapentin enacarbil is a substrate for monocarboxylate transporter type 1 and sodium-dependent multivitamin transporter.

Lacosamide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vimpat SchwarzPharma USA 2008 Germany 175481-36-4

Lacosamide (formerly known as harkoseride and erlosamide), a functionalized amino acid, and launched as an anticonvulsant indicated for the adjuvant treatment of partial seizures. Psychological dependence may be possible as euphoria-type reactions similar to the benzodiazepine alprazolam.

Major Drug Introductions

141

Levetiracetam Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Keppra UCB USA 2000 USA 102767-28-2

Levetiracetam is a second-generation analog of piracetam whose precise mode of action is not well established. However, it has been shown that it reversibly binds to a specific site predominantly present in the membranes of the brain. It was introduced as an adjunctive therapy in the treatment of partial onset seizures in adults with epilepsy.

Rufinamide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Inovelon Novartis, Eisai USA 2007 Germany 106308-44-5

Rufinamide is an anticonvulsant launched as adjunctive therapy for Lennox–Gastaut syndrome, a debilitating childhood-onset epilepsy. Rufinamide is approved for use in children at least 4 years of age.

Pregabalin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lyrica Pfizer USA 2004 United Kingdom 148553-50-8

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Major Drug Introductions

Pregabalin is a compound that is chemically and structurally similar to gabapentin, however, unlike gabapentin, pregabalin does not interact with g-aminobutyric acid (GABA) -A or GABA-B receptors or influence GABA uptake. Pregabalin was initially approved for the treatment of epilepsy and neuropathic pain.

Retigabine, ezogabine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Trobalt, Potiga Valeant, GlaxoSmithKline Germany 2011 European Union 150812-12-7

Retigabine (as known in the European Union) or ezogabine (as known in the United States) was launched for the adjunctive oral treatment of partial-onset seizures in adults with epilepsy. Ezogabine is a potassium channel opener with additional pharmacologic actions mediated through GABA. Retigabine or ezogabine may be given with 1 to 3 adjuvant anticonvulsants and is dosed three times daily.

Tiagabine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Gabatril Novo Nordisk Denmark 1996 Denmark 115103-54-3

Tiagabine was launched as an add-on therapy in patients refractory to other epilepsy therapies and appears to work by potent and selective inhibition of GABA synaptosomal uptake. It is selective for the GAT-1 GABA transporter in neurons and glia, thus enhancing inhibitory GABAergic transmission.

Major Drug Introductions

143

Topiramate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Topamax Johnson & Johnson USA 1995 United Kingdom 97240-79-4

Topiramate was introduced as an adjunct therapy for use in partial seizures with or without secondary generalized seizures in adult patients inadequately controlled on conventional antiepileptics. It appears to act by blocking voltagesensitive sodium channels.

Neuroleptics Aripiprazole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Abilify Otsuka/Bristol-Meyers Squibb Japan 2002 USA 129722-12-9

Aripiprazole is a partial D2 receptor agonist that was launched for the treatment of psychoses including schizophrenia.

144

Major Drug Introductions

Asenapine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Saphris Merck, Schering-Plough USA 2009 USA 65576-45-6

Asenapine is the 7th atypical antipsychotic introduced to the market. Asenapine is a dual antagonist of dopamine D2 and serotonin 5-HT2 receptors and has high affinity for subsets of these receptors. Asenapine was launched as an adjuvant to lithium or valproate for the treatment of schizophrenia, mania, or mixed episodes associated with bipolar disorder.

Blonanserin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lonasen Sumitomo Japan 2008 Japan 132810-10-7

Blonanserin is a dual dopamine D2 and serotonin 5-HT2 receptor antagonist and considered an atypical antipsychotic. Blonanserin was launched for the oral treatment of psychosis and schizophrenia.

Major Drug Introductions

145

Lurasidone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Latuda Dainippon Sumitomo Pharma Japan 2010 USA 367514-87-2

Lurasidone is an atypical antipsychotic launched for the treatment of schizophrenia. Lurasidone is a potent antagonist at potent affinity for D2 and 5-HT2A, a partial agonist for 5-HT1A receptor, and unlike other atypical antipsychotics is a potent antagonist at the 5-HT7 receptor. Lurasidone has a lack of affinity fro receptors H1 and 5-HT2C, which are associated with weight gain.

Olanzapine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zyprexa Lilly USA 1996 United Kingdom 132539-06-1

Olanzapine is a potent 5HT2/D2 antagonist with anticholinergic activity that was launched as an antipsychotic agent.

146

Major Drug Introductions

Paliperidone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Invega Johnson & Johnson USA 2007 USA 144598-75-4

Paliperidone is the 5th second generation, or atypical antipsychotic to be launched for the treatment of schizophrenia. Atypical antipsychotics, including paliperidone, antagonize both the mesolimbic pathway dopamine D2 receptors and the serotonin 5-HT2A receptors in the prefrontal cortex. Paliperidone is taken orally once daily and has been shown to improve positive and negative symptoms of schizophrenia.

Perospirone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lullan Sumitomo Pharm Japan 2001 Japan 150915-41-6

Perospirone was launched as a new treatment of schizophrenia and other psychoses. It seems to have a significantly lower propensity for the development of extrapyramidal symptoms and tardive schizophrenia.

Major Drug Introductions

147

Quetiapine fumarate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Seroquel Zeneca United Kingdom 1997 United Kingdom 111974-72-2

Quetiapine fumarate is selective for the limbic region with activity as a moderate dopamine receptor antagonist with greater affinity for D2 over D1 and D4 receptors and a greater affinity for 5HT2A than for D2 receptors. It was launched for the treatment of schizophrenia.

Sertindole

Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Serdolect Lundbeck Denmark 1996 United Kingdom 106516-24-9

Sertindole is selective for the limbic areas of the brain and has a high affinity for the serotonin 5HT2 receptor where it acts as an antagonist. It was launched for the treatment of acute and chronic schizophrenia and schizoaffective psychoses.

Ziprasidone hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zeldox Pfizer USA 2000 Sweden 122883-93-6

Ziprasidone was launched as the sixth atypical antipsychotic for the treatment of schizophrenia and agitated psychoses.

Antiparkinsonian Agents Budipine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Parkinsan Byk Gulden/Promonta Lundbeck Germany 1997 Germany 57982-78-2

Budipine is effective for the treatment of parkinsonian tremors. It exhibits use-dependent, open channel, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist activity and interacts with sigma-binding sites in the frontal cortex.

CHF-1301 Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Levomet Chiesi Farmaceutici SPA Italy 1999 Italy 7101-51-1

Major Drug Introductions

149

Levomet was introduced as an injection for patients with Parkinson’s disease who experienced complications in their chronic treatment with levodopa.

Entacapone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Comtess Orion Pharma Finland 1998 Finland, Germany, Sweden 130929-57-6

Entacapone is a peripherally selective, reversible, orally active catechol O-methyltransferase inhibitor intended to be used as an adjuvant to levodopa therapy for Parkinson’s disease.

Pramipexole hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Mirapex Boehringer Ingelheim, Pharmacia & Upjohn Germany 1997 USA 104632-25-9

Pramipexole is a presynaptic dopamine D2 autoreceptor agonist that also activates D3 receptors.

Rasagiline Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Azilect Teva, Eisai, Lundbeck Israel 2005 Israel 136236-51-6161735-79-1 (mesylate salt)

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Major Drug Introductions

Rasagiline is a second-generation, irreversible monoamine oxidase type B (MAO-B) inhibitor that indicated for the treatment of the signs and symptoms of Parkinson’s disease as initial monotherapy in early disease, and as adjunct therapy in later disease. Rasagiline inhibits MAO-B which prevents the degradation of dopamine leading to prolonged action of dopamine to reduce the effects of dopaminergic neuronal deficit. Its major metabolite, 1(R)-aminoindane does not possess MAO-B inhibitory activity, but has been implicated in the neuroprotective, anti-apoptotic properties of rasagiline.

Ropinirole hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

ReQuip SmithKlineBeecham United Kingdom 1996 United Kingdom 91374-20-8

Ropinirole is a nonergot postsynaptic dopamine D2 agonist with activity in the extrapyramidal system. It was introduced as a monotherapy or for use in combination with low-dose levodopa for the treatment of early stage idiopathic Parkinson’s disease.

Rotigotine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Neupro Schwarz Pharma USA 2006 Germany 99755-59-6

Rotigotine hydrochloride is a transdermal non-ergoline dopamine agonist used for the treatment of Parkinson’s disease (PD). Rotigotine binds to D2 dopamine receptors within the caudate-putamen in the brain and also is an agonist at D3 and D1 dopamine receptors.

Major Drug Introductions

151

Talipexole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Domin Boehringer Ingelheim Germany 1996 Japan 101626-70-4

Talipexole is a selective agonist for presynaptic dopamine D2 receptors with no D1 receptor activity.

Tolcapone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tasmar Roche Switzerland 1997 Germany 134308-13-7

Tolcapone is a peripherally selective, reversible, orally active catechol O-methyltransferase inhibitor that was introduced as an adjuvant to levodopa therapy for Parkinson’s disease.

152

Major Drug Introductions

Antimigraine Agents Almotriptan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Almogran Almirall Prodesfarma Spain 2000 Spain 154323-57-6

Almotriptan acts as a dual 5HT1D/1B agonist with a 35- to 51-fold selectivity versus 5HT1A and 5HT7 receptors, respectively, as well as having insignificant affinity for the most relevant nonserotonic receptors.

Eletriptan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Relpax Pfizer USA 2001 Switzerland 143322-58-1

Eletriptan is a 5HT receptor agonist that binds to 5HT1B, 5HT1D, and 5HT1F receptors with high potency. It was found to be more potent than other triptans as an agonist at the 5HT1D receptor. It acts more rapidly and effectively against migraine attacks than other triptans.

Major Drug Introductions

153

Frovatriptan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Frova GlaxoSmithKline/Vernalis United Kingdom 2002 USA 158930-09-7

Frovatriptan was launched as an oral treatment for acute migraine attacks with or without aura in adults. It is the eighth member of the triptan class to be launched. It shows a very long half-life and a remarkably low level of headache recurrence rate.

Lomerizine hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Teranas, Migsis Akzo Nobel, Kanebo Netherlands 1999 Japan 101477-54-7

Lomerizine hydrochloride was the first in its class of dual sodium and calcium channel blockers to be marketed for migraine. It has demonstrated effectiveness in migraine treatment but it may also have utility in other neurological diseases such as cerebrovascular ischemia or cerebral infarction.

154

Major Drug Introductions

Naratriptan hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Naramig Glaxo Wellcome United Kingdom 1997 United Kingdom 1433388-64-1

Naratriptan is a serotonin 5HT1B/1D receptor antagonist with modest affinity for 5HT1a and very weak affinity for 5HT3 receptors. It mediates vasoconstriction in cerebral vasculature, reduces neurogenic inflammation, and inhibits responses mediated by the trigeminal nerves. Naratriptan has no clinical effects on blood pressure or heart rate, and has a long duration of action with very good tolerability and a high oral bioavailability.

Rizatriptan benzoate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Maxalt Merck USA 1998 Mexico 145202-66-0

Rizatriptan is a full 5HT1B/1D receptor agonist retaining a significant affinity at 5HT1A sites with low affinity for non-5HT sites. In humans, it shows craniovascular selectivity for isolated middle meningeal arteries over coronary arteries.

Major Drug Introductions

155

Zolmitriptan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zomig Zeneca United Kingdom 1997 United Kingdom 139264-17-8

Zolmitriptan is a serotonin 5HT1B/1D receptor agonist with modest affinity for 5HT1A and 5HT1F receptors. It acts centrally on the trigeminal nucleus caudalis and peripherally on the trigeminovascular system.

Multiple Sclerosis Dalfampridine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ampyra Acorda Therapeutics Inc. USA 2010 USA 504-24-5

Dalfampridine is a first-in-class, oral, extended-release, once daily dosed, potassium channel blocker launched to increase walking distance in patients with multiple sclerosis (MS). In MS patients nerve conduction is slowed down due to damage to myelinated fibers. Dalfampridine is a voltage-gated potassium channel blocker that penetrates the CNS and increases the conduction and duration of action potential across nerve fibers resulting in enhanced functionality as observed by increased walking ability of MS patients.

Interferon b-1a Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 20 025 Da

Avonex Biogen USA 1996 USA 145258-61-3

156

Major Drug Introductions

Interferon b-1a was launched for the treatment of relapsing forms of multiple sclerosis.

Fingolimod hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Gilenya Novartis, Mitsubishi Tanabe Pharma USA 2010 Russia 162359-56-0

Fingolimod hydrochloride is a sphingosine 1-phosphate receptor modulator and is the first oral medication launched for the treatment of relapsing-remitting multiple sclerosis. Fingolimod binds to the sphingosine 1-phosphate receptors 1, 3, 4, and 5 to reduce the influx of lymphocytes into peripheral blood. This reduces the frequency of clinical exacerbations and to delay the accumulation of physical disability.

Glatiramer acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 14–23 kDa

Copaxone Yeda Israel 1997 USA 28704-27-0

Glatiramer acetate was launched for the treatment of relapsing-remitting multiple sclerosis.

Natalizumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – monoclonal antibody; molecular weight 149 kDa

Tysabri Elan, Biogen Idec United Kingdom 2004 USA 189261-10-7

Natalizumab is a humanized monoclonal antibody and is in a class of agents known as selective adhesion molecule inhibitors. Inhibition of the alpha-4 integrin on leukocytes is a viable approach in disrupting the inflammatory cascade. Natalizumab was initially launched for the treatment of multiple sclerosis, but is also under investigation for use in other chronic inflammatory diseases.

Major Drug Introductions

157

Antihistamines Desloratadine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Clarinex Sepracor, Schering-Plough USA 2001 United Kingdom 100643-71-8

Desloratadine was launched for the treatment of nasal and non-nasal symptoms of seasonal allergic rhinitis. It is a nonsedating competitive histamine H1-receptor antagonist with increased potency and improved safety.

Bilastine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Bilaxten FAES FARMA, S.A., Menarini, Pierre Fabre Spain 2010 European Union 202189-78-4

Bilastine is a selective histamine H1 receptor agonist and was launched for the once-daily, oral treatment of allergic rhinoconjunctivitis and urticaria.

158

Major Drug Introductions

Mizolastine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Mizollen Synthelabo, Galderma France 1998 Germany, Switzerland 108612-45-9

Mizolastine is a long-acting, orally active antihistamine that was introduced for the symptomatic relief of seasonal and perennial allergic rhinoconjuctivitis and urticaria. It selectively blocks peripheral H1 receptors with little effect on brain receptors.

Levocetirizine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Xusak Sepracor/UCB USA 2001 Germany 130018-77-8

Levocetrizine is the R-isomer of the second-generation antihistamine cetirizine. It was launched for the treatment of seasonal allergic rhinitis, perennial allergic rhinitis, and chronic idiopathic urticaria.

Major Drug Introductions

159

Hypnotic Eszopiclone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lunesta Sanofi-Aventis France 2005 USA 138729-47-2

Eszopiclone is the third non-benzodiazepine hypnotic agent that reduces sleep latency and improves the quality of sleep in patients with chronic insomnia. Unlike zolpidem and zaleplon, eszopiclone is not restricted to short-term treatment of insomnia and studies with use up to 6-months have shown no development of tolerance.

Ramelteon Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Rozerem Takeda Japan 2005 USA 196597-26-9

Ramelteon is a highly selective, potent melatonin receptor agonist indicated for the treatment of insomnia due to prolonged sleep onset. Ramelteon has high selectivity for the MT1 and MT2 receptor subtypes, which have been implicated in the maintenance of circadian rhythms. It lacks affinity for GABA, dopaminerigic, opiate, and benzodiazepine receptors and does not have an abuse potential of hypnotic drugs that target these receptors. As such, ramelteon is the first approved hypnotic that is not classified as a controlled substance.

160

Major Drug Introductions

Zaleplon Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sonata American Home Products USA 1999 Sweden, Denmark 15319-34-5

Zaleplon is a nonbenzodiazepine that reduces sleep latency and improves the quality of sleep in patients with chronic insomnia.

Muscle Relaxation Cisatracurium besylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nimbex Glaxo Wellcome United Kingdom 1995 USA 96946-42-8

Cisatracurium besylate is a nondepolarizing muscle relaxant of intermediate duration that was launched for intubation and maintenance of muscle relaxation during surgery and intensive care.

Major Drug Introductions

161

Rapacuronium bromide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Raplon Akzo Nobel Netherlands 1999 USA 156137-99-4

Rapacuronium bromide was introduced as a parenterally administered adjunct to general anesthesia during surgical procedures. It is a nondepolarizing neuromuscular blocking drug with a rapid onset and short duration of action.

Rocuronium bromide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zemuron, Esmeron Organo Netherlands 1994 USA, United Kingdom 119302-91-9

Rocuronium bromide is a short-acting, nondepolarizing steroidal neuromuscular blocker that was introduced for use as an adjunct to general anesthesia to facilitate endotracheal intubation and to provide skeletal muscle relaxation during surgery or mechanical ventilation.

162

Major Drug Introductions

Neuroprotective Agents Edaravone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Radicut Mitsubishi Pharma Japan 2001 Japan 89-25-8

Edaravone was marketed for improving the neurologic recovery following acute brain infarction. It is an antioxidant with free radical scavenging activity.

Fasudil hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Eril Asahi Chemical Japan 1995 Japan 105628-07-7

Fasudil is a calcium antagonist vasodilator that was marketed for the treatment of cerebral vasospasm following subarachnoid hemorrhage. It is also a potent inhibitor of myosin light chain kinase and protein kinase C.

Riluzole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Rilutek Rhone-Poulenc Rorer France 1996 USA 1744-22-5

Major Drug Introductions

163

Riluzole was launched for the treatment of amyotrophic lateral sclerosis. It antagonizes excitatory amino acids and blocks presynaptic release of glutamate and quisqualate-induced increases in cGMP.

Anti-Alzheimer’s Disease Donepezil hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Aricept Eisai, Pfizer Japan 1997 USA 120011-70-3

Donepezil is a reversible, noncompetitive inhibitor of acetylcholinesterase that was introduced for the treatment of mild to moderate Alzheimer’s disease and dementia.

Rivastigmine tartrate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Exelin Novartis Switzerland 1997 Switzerland 129101-54-8

Rivastigmine is a centrally selective and long-lasting drug with anticholinesterase activity that facilitates cholinergic transmission in the cortex and hippocampus. It was launched for the treatment of mild to moderate Alzheimer’s disease.

164

Major Drug Introductions

Attention Deficit Hyperactivity Atomoxetine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Strattera Lilly USA 2003 USA 082248-59-7

Atomoxetine is the first non-stimulant to be marketed for this condition. It is a potent and selective norepinephrine uptake inhibitor and does not bind to monoamine receptors. It is about 63% orally bioavailable, is highly protein bound, and has a halflife of around 5.2 h.

Lisdexamfetamine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vyvanse Shire USA 2007 USA 608137-33-3

Lisdexamfetamine was launched for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. Lisdexamfetamine is an L-lysine prodrug of D-amphetamine is hydrolyzed to the active drug following oral absorption. Additionally, due to the prodrug formulation of lisdexamfetamine the possibility of amphetamine reaching eliciting euphoria if inhaled or injected is reduced. Lastly, the prodrug establishes an extended-release benefit.

Major Drug Introductions

165

Local Anesthesia Levobupivacaine hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Chirocaine Chiroscience, Purdue Pharma United Kingdom 2000 USA 27262-48-2

Levobupivacaine is the S-enantiomer of bupivacaine. It was launched for the production of local anesthesia in surgery and obstetrics and for postoperative pain management.

Ropivacaine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Naropin Astra Sweden 1996 Australia 84057-95-4

Ropivacaine is a sodium channel blocker that has a specific effect on the nerves involved in transmission of pain but has no effect on the nerve fibers responsible for motor function. It was launched as a local anesthetic.

166

Major Drug Introductions

Narcolepsy Armodafinil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nuvigil Cephalon USA 2009 USA 112111-43-0

Armodafinil is the R-enantiomer of the racemic compound modafinil. Armodafinil is a once daily, oral a1-adrenoceptor agonist. Armodafinil was launched last year for the treatment of excessive sleepiness associated with narcolepsy, shift work sleep disorder, and obstructive sleep apnea.

Modafinil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Modiodal, Provigil Lafon France 1994 France 68693-11-8

Modafinil is a centrally active a1-adrenergic agonist that was marketed as a psychostimulant for the treatment of narcolepsy and idiopathic hypersomnia including Gelineau’s syndrome.

Major Drug Introductions

167

Anxiolytic Tandospirone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sediel Sumitomo Japan 1996 Japan 87760-53-0

Tandospirone is a partial agonist of the postsynaptic 5HT1A receptor. It was launched as an anxiolytic, which is as effective as the benzodiazepines but without the side effects.

Central Nervous System Diagnosis Ioflupane Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

DatSCAN Research Biochemicals Int/Nycomed Amersham United Kingdom 2000 United Kingdom 155798-07-5

Ioflupane was introduced as an imaging agent for the investigation of the dopaminergic neurons and the early diagnosis of Parkinson’s disease and related syndromes. The radioactive label is detected using single-photon emission computed tomography.

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Major Drug Introductions

Central Nervous System Stimulants Taltirelin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ceredist Tanabe Seiyaku Japan 2000 Japan 103300-74-9

Taltirelin was launched as the first orally active drug for the treatment of neurodegenerative diseases, in particular the improvement of ataxia due to spinocerebellar degeneration.

Dependence Treatment Nalmefene hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Revex IVAX, Ohmeda USA 1995 USA 58895-64-0

Nalmefene is an opioid antagonist that was introduced for opioid reversal following surgery and in the treatment of opioid overdoses and epidurally administered narcotics.

Major Drug Introductions

169

Muscle Relaxation Reversal Sugammadex Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Bridion Schering-Plough Netherlands 2008 Sweden 343306-71-8

Sugammadex is a novel selective relaxant binding agent and functions to reverse the effects of neuromuscular blocking agents. Sugammadex encapsulates non-depolarizing neuromuscular blocking agents (eg. rocuronium, vecuronium) and immediately reduces the free aminosteroid-relaxant plasma concentration, which results in a rapid migration of the relaxant away from the synaptic cleft back into the circulation.

170

Major Drug Introductions

Psychostimulants Dexmethylphenidate hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Focalin Celgene, Norvartins USA 2002 USA 19262-68-1

Dexmethylphenidate is the pharmacologically effective enantiomer of D,L-methyl phenidate. It was introduced as an improved treatment for children with attention deficit hyperactivity disorder.

Sedative Dexmedetomidine hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Precedex Orion, Abbott Finland 2000 USA 145108-58-3

Dexmedetomidine was launched as an intravenous infusion for the sedation of initially intubated and mechanically ventilated patients during treatment in an intensive care unit. It is a full agonist of a2-adrenoreceptors and has the unique property of being able to provide sedation, analgesia, and anxiolysis, yet allows patients to be easily awakened.

Gastrointestinal Tract Related This category includes 10 antiulcerative agents, three for irritable bowel syndrome, two for ulcerative colitis, one for constipation/ irritable bowel, one for Crohn’s disease, and one with gastroprokinetic effects.

Major Drug Introductions

171

Antiulcerative Agents Dexlansoprazole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Kapidex Takeda Japan 2009 USA 138530-94-6

Dexlansoprazole is a proton pump inhibitor (PPI) that functions by irreversibly binding to the hydrogen/potassium adenosine triphosphate enzyme system of the gastric parietal cell, which results in increased gastric pH. Dexlansoprazole is the 5th PPI to be marketed and is the R-enantiomer of the racemic lansoprazole. Dexlansoprazole drug release is optimized through different pH-dependent granules, there is an initial release in the proximal small intestine followed by a subsequent release at distal regions of the small intestine. This unique drug release system provides a longer duration of action.

Dosmalfate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Diotul Faes Spain 2000 Spain 122312-55-4

172

Major Drug Introductions

Dosmalfate was launched for the prevention and treatment of gastroduodenal lesions caused by prolonged treatment with nonsteroidal anti-inflammatory agents. Its mode of action does not appear to be defined.

Ebrotidine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ebrocit Ferrer Spain 1997 Spain 100981-43-9

Ebrotidine was launched as a gastroprotective agent that is able to antagonize histamine H2 receptors. It causes enhanced mucosal blood flow and has activity against Helicobacter pylori.

Egualen Sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Azuloxa Kotobuki Seiyaku Japan 2000 Japan 97683-31-3

Egualen is a water-soluble sulfonate analog of guaiazulene, a natural azulene with antiulcer activity. Its mechanism of action does not appear to be well defined.

Major Drug Introductions

173

Esomeprazole magnesium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nexium AstraZeneca United Kingdom 2000 Sweden 119141-88-7

Esomeprazole magnesium was launched as a treatment for acid-related diseases such as gastroesophageal reflux disease including peptic ulcer disease and reflux esophagitis. It is the active S-enantiomer of omeprazole and irreversibly inhibits the gastric Hþ/Kþ adenosine triphosphatase.

Lafutidine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Stogar, Protecadin Fujirebio, UCB, Taiho Japan 2000 Japan 118288-08-7

Lafutidine is a potent and long-acting H2-receptor antagonist marketed for the treatment of gastritis, reflux esophagitis, and peptic ulcers.

Pantoprazole sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Pantozol, Rufin Byk Gulden, Schwarz Pharm Germany 1994 Germany 102625-70-7

174

Major Drug Introductions

Pantoprazole is an irreversible proton pump inhibitor that was marketed for acute treatment of gastric and duodenal ulcers and gastroesophageal reflux disease.

Polaprezinc Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Promac Hamari Chemicals Japan 1994 Japan 107667-60-7

It appears that this compound combines the cytoprotective properties of zinc with the ulcer healing properties of L-carnosine. It is effective in promoting the healing of gastric ulcers in addition to preventing ulcer relapse.

Rabeprazole sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Aciphex, Pariet Eisai Japan 1998 Japan 117976-90-6

Rabeprazole is an inhibitor of gastric Hþ/Kþ adenosine triphosphatase and also has antibacterial activity against H. pylori. It has a fast onset of action but a relatively short duration of activity.

Major Drug Introductions

175

Ranitidine bismuth citrate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Pylorid Glaxo Wellcome United Kingdom 1995 United Kingdom 128345-62-0

Ranitidine bismuth citrate is a novel salt formed between ranitidine and bismuth citrate complex. It was launched for the treatment of duodenal and benign gastric ulcers, for the eradication of H. pylori, and for the prevention of relapse of duodenal ulcer when administered in combination with an antibiotic such as clarithromycin or amoxicillin.

Irritable Bowel Syndrome Alosetron hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lotronex Glaxo Wellcome United Kingdom 2000 USA 132414-02-9

Alosetron is a potent and selective 5HT3 antagonist although its precise mechanism of action in the treatment of diarrheapredominant irritable bowel syndrome in women for which it was launched is unclear.

Tegaserod maleate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zelmag Novartis Switzerland 2001 Mexico 189188-57-6

Tegaserod is a selective partial agonist of the excitatory 5HT4 receptor. It was launched for the treatment of constipation- or diarrhea-predominant irritable bowel syndrome.

Itopride hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ganaton Hokuirku Japan 1995 Japan 122892-31-3

Itopride is a dopamine D2-receptor antagonist that stimulates the release of acetylcholine on the postganglionic cholinergic neurons. It was launched for the relief of gastrointestinal symptoms in patients with chronic gastritis.

Ulcerative Colitis Balsalazide disodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Colazide Biorex, Astra United Kingdom 1997 United Kingdom 80573-04-2

Major Drug Introductions

177

Balsalazide has cytoprotective and anti-inflammatory properties. It was launched for mild to moderate acute attacks of ulcerative colitis.

Silodosin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Urief, Rapaflo Kissei Japan 2006 Japan 160970-54-7

Silodosin is a highly selective, oral alpha-1 blocker launched for the treatment of dysuria associated with benign prostatic hyperplasia.

Constipation/Irritable Bowel Syndrome Lubiprostone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Amitiza Sucampo, Takeda USA 2006 USA 333963-40-9

Lubiprostone is a bicyclic fatty acid, prostaglandin E1 (PGE 1) derivative for the treatment of chronic idiopathic constipation. Lubiprostone increases intestinal fluid secretion by activating intestinal chloride ion channels in the luminal cells of the intestinal epithelium.

178

Major Drug Introductions

Crohn’s Disease Certolizumab pegol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; 91 kDa

Cimzia UCB United Kingdom 2008 Switzerland 428863-50-7

Certolizumab pegol is the third TNF-a blocker launched for the treatment of moderate-to-severe Crohn’s disease. Certolizumab pegol is a recombinant humanized antibody Fab’ fragment linked to a polyethylene glycol unit. The Fab fragment is a neutralizer of circulating TNF-a and results in a reduction in inflammation.

Gastroprokinetic Agents Mosapride citrate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Gasmotin Dainippon Japan 1998 Japan 112885-41-3

Mosapride was launched for the treatment of gastrointestinal symptoms in patients with chronic gastritis, gastrooesophageal reflux, dyspepsia, and postsurgery complications.

Genitourinary Related This category contains four agents for urinary incontinence, and two agents for dysuria.

Major Drug Introductions

179

Urinary Incontinence Fesoterodine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Toviaz SchwarzPharma, Pfizer Germany 2008 United Kingdom 286930-02-7

Fesoterodine is a muscarinic receptor antagonist was launched for the treatment of overactive bladder with symptoms of urge incontinence, urgency, and frequency. Fesoterodine is an orally active pro-drug that is converted to the active metabolite 5-HMT, which is also the active metabolite of tolterodine. 5-HMT is non-specific and has equivalent affinity for M1, M2, M3, M4, and M5 receptors.

Imidafenacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Staybla Kyorin, Ono Japan 2007 Japan 170105-16-5

Imidafenacin is the 6th muscarinic antagonist introduced for the oral treatment of overactive bladder. Imidafenacin antagonizes and shows equal activity for both the M1 and M3 muscarinic receptors and 10-fold less active at M2 receptors.

180

Major Drug Introductions

Mirabegron Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Betanis Astellas Japan 2011 Japan 223673-61-8 (free base)

Mirabegron is first in class a beta-3 adrenergic receptor agonist indicated for the oral treatment of patients with overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Mirabegron relaxes the detrusor muscle via beta-3 AR activation, which allows for increase in bladder capacity during the storage fill.

Solifenacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vesicare Yamanouchi Japan 2004 United Kingdom 242478-38-2

Solifenacin succinate is a once daily oral competitive selective M3 muscarinic antagonist indicated for the treatment of overactive bladder (OAB) and the associated symptoms of OAB. Additionally, solifenacin has affinity for M2 receptors on the detrusor muscle of the bladder. Muscarinic specificity results in a more favorable adverse reaction profile when compared to non-selective muscarinic antagonists.

Major Drug Introductions

181

Dysuria Naftopidil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Avishot, Flivas Boehringer Mannheim, Kanebo, Asahi Germany 1999 Japan 57149-07-2

Naftopidil is a potent postsynaptic-selective alpha-1-antagonist that was launched for the treatment of dysuria associated with benign prostatic hypertrophy.

Darifenacin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Enablex; Emselex Pfizer, Novartis USA 2005 Germany 133099-04-04

Darifenacin is a once-daily oral muscarinic M3 selective antagonist for the treatment of urinary incontinence and overactive bladder. Darifenacin is significantly more selective for the M3 receptor than other muscarinics such as tolterodine, oxybutynin, and trospium, which are all essentially equipotent against M1, M2, and M3 receptors.

Lung Related (Including Antiallergics) Twenty-seven compounds are described in this category, including 10 antiallergics, seven antiasthmatics, four bronchodilators, two expectorants, and one of following: a treatment for cystic fibrosis, treatment for idiopathic pulmonary fibrosis, one lung surfactant, and a mucopolysaccharide.

182

Major Drug Introductions

Antiallergics Betotastine besilate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Talion UBE, Tanabe Seiyaku Japan 2000 Japan 190786-44-8

Betotastine besilate is a nonsedating histamine H1-receptor antagonist that was marketed for the treatment of allergic rhinitis.

Epinastine hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Alesion Boehringer Ingelheim, Sankyo Germany 1994 Japan 80012-43-7

Epinastine is a peripherally acting histamine H1-receptor antagonist that was launched for the oral treatment of bronchial asthma, allergic rhinitis, urticaria, eczema, dermatitis, and psoriasis vulgaris. It is without sedative activity.

Major Drug Introductions

183

Fexofenadine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Allegra Sepracor, Hoechst Marion Roussel USA 1996 USA 138452-21-8

Fexofenadine is a metabolite of terfenadine and is a histamine H1 receptor antagonist with fewer side effects. It is used for the treatment of seasonal allergies.

Fluticasone furoate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Veramyst GlaxoSmithKline USA 2007 USA 397864-44-7

Fluticasone furoate is a corticosteroid derivative nasal spray for once daily use launched for the treatment of seasonal and perennial allergic rhinitis in adults and in children. Fluticasone furoate exhibits minimal systemic exposure and a long duration of action.

184

Major Drug Introductions

Loteprednol etabonate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lotemax, Ali Pharmos, Bausch & Lomb USA 1998 USA 082034-46-6

Loteprednol etabonate was introduced for the treatment of steroid responsive inflammatory conditions of the palpebral and bulbar cojunctiva, cornea, and anterior segment of the ocular globe.

Olopatadine hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Patanol Kyowa Hakko Japan 1997 USA 140462-76-6

Olopatadine combines the ability to prevent human conjunctival mast cell mediator release with selective H1-receptor antagonist activity to give potent activity in allergic conjunctivitis.

Omalizumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Xolair Genentech USA 2003 USA 242138-07-04

Major Drug Introductions

185

Omalizumab is a recombinant humanized construct of murine IgG1k monoclonal antibody that was introduced for the treatment of allergic asthma. It forms complexes with circulating IgE, thus inhibiting the binding of IgE to the high affinity IgE receptor on the surface of mast cells and basophils. Omalizumab is administered subcutaneously every 2–4 weeks. It is well tolerated and can replace steroidal treatment for asthma.

Ramatroban Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Baynas Bayer Germany 2000 Japan 116649-85-5

Ramatroban is a potent antagonist of prostaglandin receptors and thromboxane receptors that was marketed for the treatment of allergic rhinitis.

Rupatadine fumarate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Rupafin Uriach Spain 2003 Spain 182349-12-8

186

Major Drug Introductions

Rupatadine fumarate is an oral treatment for perennial and seasonal rhinitis. It acts as a nonsedating histamine H1-receptor antagonist and platelet-activating factor antagonist.

Suplatast tosylate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

IPD Taiho Japan 1995 Japan 94055-76-2

Suplatast is a potent inhibitor of IgE synthesis without affecting IgM and IgG. It was launched for the treatment of bronchial asthma, atopic dermatitis, and allergic rhinitis.

Antiasthmatic Agents Ciclesonide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Alvesco Recordati Espana, Altana, Aventis, Teijin Spain 2005 United Kingdom 126544-47-6

Ciclesonide is a once daily inhaled corticosteroid is indicated for the prophylactic treatment of persistent asthma. Ciclesonide is an isobutyryl ester prodrug. It is cleaved by the endogenous esterases in the lung to des-isobutyryl ciclesonide, then undergoes reversible lipid conjugation to form oleate and palmitate ester conjugates, which act as a slow-release pool for the drug and increase the pulmonary residence time.

Major Drug Introductions

187

Levalbuterol hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Xopenex Sepracor USA 1999 USA 34391-04-3

Levalbuterol is the single R-enantiomer of salbutamol. It was marketed for the treatment or prevention of bronchospasm in patients with reversible obstructive airway disease.

Montelukast sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Singulair Merck USA 1998 Finland, Mexico 151767-02-1

Montelukast is a potent, selective, and orally active antagonist of the leukotriene D4 (LTD4) receptor. It is marketed for the management of mild to moderate asthma that has been inadequately controlled by inhaled corticosteroids and short-acting b2-agonists.

188

Major Drug Introductions

Pranlukast Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Onon Ono Japan 1995 Japan 103177-37-3

Pranlukast is a highly potent, selective, and competitive antagonist of peptidoleukotrienes with high affinity for the LTD4 receptor. It was introduced for the treatment of bronchial asthma and allergic diseases.

Seratrodast Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Bronica Takeda Japan 1995 Japan 112665-43-7

Seratrodast is a thromboxane A2 receptor antagonist that was marketed for the treatment of bronchospastic disorders such as asthma.

Major Drug Introductions

189

Zafirlukast Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Accolate Zeneca United Kingdom 1996 USA 107753-87-6

Zafirlukast is an LTD4 antagonist that was launched for the treatment of asthma.

Zileuton Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zyflo Abbott USA 1997 USA 111406-87-2

Zileuton is an orally active, reversible direct inhibitor of 5-lipoxygenase that was marketed for chronic asthma. The bronchodilatory effect occurs within 2 h of administration.

190

Major Drug Introductions

Bronchodilator Arformoterol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Brovana Sepracor USA 2007 USA 067346-49-0

Arformoterol is a selective long-acting b2-agonist, and is the active (R,R)-enantiomer of formoterol. Arformoterol was launched as an inhalation solution for treatment of bronchoconstriction associated with chronic obstructive pulmonary disorder. It is administered twice daily via nebulizer.

Indacaterol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Onbrez Breezehaler, Arcapta Neohaler Novartis, Skye Pharma United Kingdom 2009 Germany 312753-06-3

Indacaterol is an ultra-long-acting b2 adrenoceptor agonist and is the first agent this class of agents approved for once-daily use. Indacaterol was launched for the maintenance treatment of chronic obstructive pulmonary disorder. Indacaterol is supplied as an aerosol formulation and is administered via a dry powder inhaler device.

Major Drug Introductions

191

Roflumilast Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Daxas, Daliresp Nycomed Germany 2010 Germany 162401-32-3

Roflumilast is the first-in-class phosphodiesterase-4 (PDE4) inhibitor. The PDE4 enzyme is expressed in pro-inflammatory cells and inhibition results in down-regulation of inflammation. Roflumilast was launched for the oral management of chronic obstructive pulmonary disorder. Roflumilast is a prodrug and undergoes hepatic metabolism to its active metabolite.

Tiotropium bromide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Spiriva Boehringer Ingelheim, Pfizer Germany 2002 Netherlands, Philippines 136310-93-5

Tiotropium bromide is a long-acting inhaled muscarinic antagonist that was developed for the treatment of chronic obstructive pulmonary disease.

Expectorants Erdosteine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Edirel, Vectrine Refarmed, Pierre Fabre, Negma Switzerland 1995 France 84611-23-4

192

Major Drug Introductions

Erdosteine has mucomodulator, mucolytic, mucokinetic, and free radical scavenging properties and was launched for the treatment of chronic bronchitis. It is also reported to possess local anti-inflammatory and antielastase activities, and enhances the penetration of antibiotics into bronchial mucus.

Fudosteine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cleanal SS Pharmaceutical/Mitsubishi Pharma Japan 2001 Japan 13189-98-5

Fudosteine was introduced for the treatment of bronchitis and respiratory congestion. It is able to significantly reduce mucus glycoprotein hypersecretion and inhibit infiltration of airway mucosa by lymphocytes and inflammatory cells in bronchitic rats.

Cystic Fibrosis Dornase alfa Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant human deoxyribonuclease

Pulmozyme Genetech USA 1994 USA

Dornase alfa, the first new drug treatment for cystic fibrosis for 30 years, is effective in liquefying secretions from the lungs of cystic fibrosis patients. It achieves this by cleaving the extracellular DNA in purulent sputum, thereby reducing the viscoelasticity of the secretion.

Major Drug Introductions

193

Idiopathic Pulmonary Fibrosis Pirfenidone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Pirespa Shinogi USA 2008 Japan 53179-13-8

Idiopathic pulmonary fibrosis is characterized by dyspnea followed by abnormalities in lung function tests, and conformational distortion of lung architecture. Pirfenidone has fibrinolytic activity derived from inhibition of p38 MAP kinase which inhibits downstream collagen synthesis. Pirfenidone also reduces inflammation by inhibiting TNF- a, IL-1, and ICAM-1.

Lung Surfactant Pumactant Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – mixture of dipalmitoylphosphatidylcholine and phosphatidylglycerol

ALEC Britannia United Kingdom 1994 United Kingdom Not applicable

dipalmitoylphosphatidylcholine

phosphatidylglycerol

This is a mixture of dipalmitoylphosphatidylcholine and phosphatidylglycerol in a 7:3 ratio, used for the treatment of respiratory distress syndrome in premature infants.

194

Major Drug Introductions

Mucopolysaccharides Laronidase Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant human a-L-iduronidase

Aldurazyme BioMarin USA 2003 USA 210589-09-6

Mucopolysaccharidosis I is a genetic disorder caused by a deficiency of a-L-iduronidase, an enzyme required for the catabolism of dermatan sulfate and heparin sulfate. Sulfate laronidase is a recombinant form of this enzyme produced in Chinese hamster ovary cell lines. It is administered weekly as an intravenous infusion.

Joints and Bones Fourty-one new therapies have been included in this category including 14 antiarthritic/rheumatic drugs including the cyclooxygenase-2 (COX-2) inhibitors, nine for the treatment of osteoporosis, seven anti-inflammatory agents, five vitamin D analogs, three analgesics, one osteoinductor, and one hypocalcemic agent.

Antirheumatic Agents Abatacept Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 92 kDa

Orencia BristolMyersSquibb USA 2006 USA 332348-12-6

Abatacept is a fully human recombinant fusion protein categorized as a second-signal blocker of T cell activation introduced for the treatment of rheumatoid arthritis. Abatacept is a recombinant fusion protein of the extracellular domain of human cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and the modified heavy chain constant segment of human immunoglobulin G1. Abatacept reduces inflammation by inhibiting the engagement of CD28 with CD80 and CD86, and CTLA4-Ig prevents the delivery of the second costimulatory signal that is required for optimal T cell activation, which decreases T cell proliferation and cytokine production including TNF-alpha.

Actarit Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Orcl, Mover Nippon Shinyaku, Mitsubishi, Kesei Japan 1994 Japan 18699-02-0

Major Drug Introductions

195

While the structure of actarit might suggest nonsteroidal anti-inflammatory activity, it actually has no effect on models of acute inflammation. It appears to work by the modulation of production and serum levels of interleukin-2, which enhances the production of suppressor T cells by the immune system.

Adalimumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant humanized antibody; molecular weight 148 kDa

Humira Cambridge Antibody Technology, Abbott USA 2003 USA 331731-18-1

Adalimumab was the first fully human neutralizing IgG1 monoclonal antibody specific for tumor necrosis factor alpha (TNF-a). Blockade of TNF binding to p55 and p75 cell surface TNFreceptors decreases leukocyte migration and acute phase reactants. Adalimumab is administered subcutaneously once every 2 weeks; in combination with methotrexate it results in improved American College of Rheumatology (ACR) scores and reduced joint space narrowing.

Anakinra Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein molecular weight 17.3 kDa

Kinret Amgen, University of Colorado USA 2001 USA 143090-092-0

Anakinra is a recombinant nonglycosylated human interleukin-1 receptor antagonist that was introduced as a daily subcutaneous injection therapy for the reduction of signs and symptoms of moderate to severe rheumatoid arthritis in adults who have failed to respond to one or more disease-modifying antirheumatic drugs.

Celecoxib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Celebrex Searle, Pfizer USA 1999 USA 169590-42-5

Celecoxib is a potent and highly selective inhibitor of COX-2, the inducible form of cyclooxygenase expressed during the inflammatory process. It does not block COX-1 thus suppressing the gastric and intestinal toxicity of most nonselective

196

Major Drug Introductions

nonsteroidal anti-inflammatory drugs (NSAIDs). It was launched for the treatment of rheumatoid arthritis and osteoarthritis but has also been approved for use in patients with familial adenomatous polyposis.

Etoricoxib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Arcoxia Merck USA 2002 Mexico 202409-33-4

Etoricoxib was introduced as a follow-up to rofecoxib for the treatment of osteoarthritis, rheumatoid arthritis, dysmenorrhea, gout, ankylosing spondylitis, and pain. It is the most-selective COX-2 so far marketed.

Golimumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant monoclonal antibody; molecular weight 150 kDa

Simponi Centocor Ortho USA 2009 USA, Canada 476181-74-5

Golimumab is a fully humanized monoclonal antibody that binds to both soluble and transmembrane forms of tumor necrosis factor (TNF)-a, a primary mediator of articular inflammation. Golimumab is the first once-monthly subcutaneous biologic launched for the treatment of rheumatoid arthritis in combination with methotrexate, and as monotherapy or in combination with methotrexate for the treatment of psoriatic arthritis and ankylosing spondylitis.

Major Drug Introductions

197

Iguratimod Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Iremod Simcere Pharmaceutical Japan 2011 China 123663-49-0

Iguratimod is a disease modifying anti-rheumatic drug (DMARD) launched for the oral treatment of rheumatoid arthritis. Studies suggest that iguratimod inhibits PGE2 production and COX-2 m-RNA expression in fibroblasts.

Leflunomide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Arava Hoechst Marion Roussel Germany 1998 USA 75706-12-6

Leflunomide is the first and only drug to be indicated to slow down structural joint damage in rheumatoid arthritis. It is a prodrug with a metabolic ring opening giving the active agent, which inhibits the enzyme dihydroorotate dehydrogenase involved in the biosynthesis of pyrimidine nucleosides. It is an orally available disease-modifying antirheumatic drug.

198

Major Drug Introductions

Lumiracoxib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Prexige Novartis AG Switzerland 2005 Brazil 220991-20-8

Lumiracoxib is a second-generation, selective, orally-active cyclooxygenase (COX-2) inhibitor indicated for the treatment of rheumatoid arthritis and osteoarthritis. Lumiracoxib bindings to COX-2 differently than other selective COX-2 inhibitors; the carboxylic acid forms hydrogen bonds with Tyr-385 and Ser-530 in the catalytic site rather than interacting within the larger hydrophobic side pocket. No significant difference in cardiovascular events, such as myocardial infarction, stroke, or cardiovascular death, was found between lumiracoxib and the combined comparator non-steroidal anti-inflammatory drugs, although, liver function abnormalities are more frequent.

Meloxicam Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Mobec, Mobic Boehringer Ingelheim Germany 1996 United Kingdom 71125-38-7

Meloxicam was launched as an NSAID for the treatment of osteo- and rheumatoid arthritis.

Major Drug Introductions

199

Parecoxib sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Dynastat Pharmacia (Searle) USA 2002 United Kingdom 197502-82-1

Parecoxib sodium is a prodrug of parecoxib that was launched as an injectable COX-2 inhibitor for the treatment of inflammation and acute pain, particularly postoperative pain.

Rofecoxib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vioxx Merck USA 1999 Mexico 162011-90-7

Rofecoxib was launched for the management of acute pain and the treatment of osteoarthritis and primary dysmenorrhea. It is a selective inhibitor of COX-2. Unanticipated circulatory problems have led to the withdrawal of Vioxx from the market.

200

Major Drug Introductions

Valdecoxib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Bextra Pharmacia (Searle) USA 2002 USA 181695-72-7

Valdecoxib was launched as a second-generation COX-2 inhibitor for the treatment of osteoarthritis, adult rheumatoid arthritis, and menstrual pain. It combines good activity against osteoarthritis, rheumatoid arthritis, and dysmenorrhea with lower levels of abdominal pain, dyspepsia, and constipation than seen with the traditional NSAIDs.

Osteoporosis Eldecalcitol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Edirol Taisho Pharmaceuticals, Chugai Pharmaceuticals Japan 2011 USA 104121-92-8

Eldecalcitol was approved for the treatment of osteoporosis. Eldecalcitol is an analog of the active form of vitamin D, calcitriol, however, eldecalcitol binds to the vitamin D receptor 2.7-fold more potently than calcitol and is administered once daily.

Major Drug Introductions

201

Ibandronic acid Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Bondronat Boehringer Mannheim Germany 1996 Germany 114084-78-5

Ibandronic acid was introduced for the treatment of bone disorders such hypercalcemia in malignancy and osteolysis, Paget’s disease, and osteoporosis. While the precise mode of action is unclear, it is known to be an inhibitor of osteoclastmediated bone resorption and binds to hydroxyapatite crystals with a half-life in the skeleton of several years.

Incandronic acid Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Bisphonal Yamanouchi Japan 1997 Japan 124351-85-5

The mechanism of action of incandronic acid is not well understood but it is known to bind tightly to the calcified bone matrix and inhibit bone resorption. It was launched for the treatment of osteoporosis.

202

Major Drug Introductions

Minodronic acid Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Recalbon, Bonoteo Ono, Astellas Japan 2009 Japan 180064-38-4

Minodronic acid is a 3rd generation bisphosphonate, and was launched for the oral, once-daily treatment of osteoporosis.

Raloxifene hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Evista Lilly USA 1998 USA 82640-04-8

Raloxifene is a selective estrogen receptor modulator with estrogenic activity on bone metabolism. It was launched for the treatment of postmenopausal osteoporosis.

Major Drug Introductions

203

Risedronate sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Actonel Procter Gamble, HMR USA 1998 USA 115436-72-1

Risedronate is an orally active bisphosphonate with potent bone resorption properties. It was launched for the treatment of Paget’s disease, a chronic disease of the elderly characterized by alteration of bone tissue, especially in the spine, shoulder, and pelvis.

Strontium ranelate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Protelos Servier, Fujisawa Japan 2004 United Kingdom 135459-87-9

Strontium enhances pre-osteoblastic cell replication, and suppresses osteoclasts. Due to physiochemical properties, ranelate was chosen as an ideal carrier for strontium. Strontium ranelate is taken orally and was initially launched for the treatment of osteoporosis. Upon ingestion ranelate dissociates from strontium and absorption is negligible.

204

Major Drug Introductions

Tiludronate disodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Skelid Sanofi France 1995 Switzerland 149845-07-8

Tiludronate was introduced to treat Paget’s disease. It is suggested to be a specific inhibitor of functioning osteoclasts through selective incorporation into the polarized osteoclast-like multinucleated cells and direct interference with the maintenance of the cytoskeletal structure.

Trimegestone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Totelle Sekvens, Ondeva Aventis, Wyeth Pharmaceuticals France 2001 Sweden 074513-62-5

Trimegestone exhibits high specificity and affinity for the progesterone receptor with no affinity for the estrogen receptor and only weak binding to the androgen, glucocorticoid, and mineralocorticoid receptors. It was introduced in combination with 17-b-estradiol as hormone replacement therapy for, inter alia, the treatment of osteoporosis.

Major Drug Introductions

205

Anti-Inflammatory Agents Ampiroxicam Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nacyl, Flucam Pfizer Japan 1994 Japan 99464-64-9

Ampiroxicam is a prodrug of piroxicam that was introduced as a once daily NSAID.

Betamethasone butyrate propionate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Antebate, Antevate Mitsubishi Kasai, Torii Japan 1994 Japan 5534-02-1

Betamethasone butyrate propionate was introduced as a topical anti-inflammatory agent. It has potent effects at the site of application with little or no topical or systemic side effects.

206

Major Drug Introductions

Bromfenac sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Senju American Home Products, Senju USA 1997 USA 120638-55-3

Bromfenac is a cyclooxygenase inhibitor that was launched as a potent, orally active, long-lasting peripheral analgesic with antiinflammatory properties.

Dexibuprofen Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Seractil Gebro Broschek Austria 1994 Austria 51146-56-6

Dexibuprofen is the S-(þ)-isomer of the widely used NSAID ibuprofen. It was launched for the treatment of rheumatoid arthritis.

Lornoxicam Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Xefo Nycomed Amersham Norway 1997 Denmark 70374-39-9

Major Drug Introductions

207

Lornoxicam was launched as an NSAID for mild to moderate pain and inflammation.

Rimexolone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vexol Akzo, Alcon Netherlands 1995 USA 49697-38-3

Rimexolone has a high corticoid receptor affinity and is a potent local anti-inflammatory agent with minimal systemic effects. It was launched for the treatment of postoperative inflammation following ocular surgery and anterior uveitis. It has also been approved for the treatment of rheumatoid arthritis.

Sivelestat Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Elaspol Ono Pharmaceutical Japan 2002 Japan 201677-61-4

Sivelestat is an inhibitor of neutrophil elastase that was developed as an injectable formulation for the treatment of acute lung injury associated with systemic inflammatory response syndrome.

208

Major Drug Introductions

Vitamin D Cinacalcet Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Sensipar Amgen USA 2004 USA 364782-34-3

Cinacalcet is a novel oral calcimimetic agent launched for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease on dialysis, and in patients with parathyroid carcinoma who are unable to undergo parathyroidectomy. Cinacalcet mimics calcium and interacts with the calcium-sensing receptor chief cell of the parathyroid gland and increases the sensitivity of this calcium-sensing receptor, and parathyroid hormone (PTH) secretion is reduced. The reduction in PTH is associated with a concomitant decrease in serum calcium levels and eventually slows the progression of bone disease and the systemic consequences of deranged mineral metabolism.

Doxercalciferol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Hectorol Bone Care Int. USA 1999 USA 54573-75-0

Doxercalciferol is an orally active, synthetic vitamin D2 analog that was introduced for the treatment of secondary hyperparathyroidism in patients with end-stage renal failure.

Major Drug Introductions

209

Falecalcitriol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Hornel, Fulstan University of Wisconsin, Kissei, Sumitomo, Taisho USA 2001 Japan 83805-11-2

Falecalcitriol regulates the proliferation of parathyroid cells and parathyroid hormone synthesis possibly via binding to a nuclear receptor for vitamin D (VDR). It was launched for the treatment of secondary hyperthyroidism.

Maxacalcitol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Prezios, Oxarol Chugai Japan 2000 Japan 103909-75-7

Maxacalcitol is a synthetic vitamin D analog that was introduced for the treatment of secondary hyperparathyroidism.

210

Major Drug Introductions

Paricalcitol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zemplar Abbott USA 1998 USA 131918-61-1

Paricalcitol is a synthetic vitamin D2 analog that was launched for the treatment of secondary hyperthyroidism associated with chronic renal failure.

Analgesia Mofezolac Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Disopain Pasteur Merieux, Taiho France 1994 Japan 78967-07-4

Mofezolac is an NSAID, which probably acts via the cyclooxygenase enzyme. It also has potent inhibitory activity on the algesic responses induced by the mechanical stimulus of the inflamed tissue. It was introduced for the treatment of postoperative and posttraumatic pain, acute upper respiratory tract pain, osteoarthritis, and lumbago.

Major Drug Introductions

211

Remifentanil hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ultiva Glaxo Wellcome United Kingdom 1996 Germany 132539-07-2

Remifentanil is a specific m-opioid agonist with rapid onset of action and rapid offset independent of duration of administration. It was launched for use in general anesthesia and immediate postoperative pain management.

Zucapsaicin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Civanex Winston, Merck Germany 2010 Canada 25775-90-0

Zucapsaicin is a topical analgesic launched for use in conjunction with oral COX-2 inhibitors or NSAIDs to relieve severe pain in adults with osteoarthritis of the knee. Zucapsaicin is the cis-isomer of capsaicin. In comparison to capsaicin, zucapsaicin causes less local irritation.

212

Major Drug Introductions

Antihyperuricemic Febuxostat Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Uloric, Adenuric Takeda, Teijin, Ipsen Japan 2009 USA 144060-53-7

Febuxostat is an oral, non-purine selective xanthine oxidase inhibitor that was launched last year for the management of hyperuricemia in patients with gout. Febuxostat is the first oral treatment approved for gout since the 1960’s. Febuxostat reduces serum uric acid levels by impeding the transformation of hypoxanthine to xanthine and xanthine to uric acid. During initiation of febuxostat patients are at risk for gout flares.

Osteoinductor OP-1 Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 36 kDa

Novos Curis, Stryker Biotech USA 2001 Australia Not applicable

The OP-1 implant was introduced as an alternative to autograft in recalcitrant long bone nonunion fractures where the use of autograft is unfeasible and alternative treatments have failed. It is a mix of human recombinant osteogenic protein and a bovinederived collagen carrier.

Hypocalcemic Neridronic acid Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nerixia Instituto Gentili Italy 2002 Italy 79778-41-9

Major Drug Introductions

213

Neridronic acid was launched for the treatment of osteogenesis imperfecta, a disease in which the bones are characterized by extreme fragility. Clinical trials remarkably increased bone mass in patients, especially young growing individuals. It is a bisphosphonate, a class known to be potent inhibitors of bone resorption and to increase bone mineral density.

Immunology (Including Vaccines) This category contains eight immunosuppressants and two vaccines.

Immunosuppressants Belatacept Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Nulojix Bristol-Myers Squibb USA 2011 USA 706808-37-9

Belatacept is an immunosuppressive formulated as a lyophilized powder for intravenous infusion launched for prophylactic prevention of rejection in kidney transplant recipients. its primary mechanism is blockade of CD28-mediated T cell activation. Belatacept is used in combination with basiliximab induction, mycophenolate mofetil, and corticosteroids and is only indicated for use in Epstein-Barr virus (EBV) seropositive patients.

Belimumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant monoclonal antibody; molecular weight 147 kDa

Benlysta Human Genome Sciences USA 2011 USA 356547-88-1

Belimumab is a human monoclonal antibody launched for the treatment of autoantibody-positive, systemic lupus erythematosus (SLE). Prior to the introduction of belimumab no new treatments for SLE have been approved in the last 50 years. Belimumab binds to human B lymphocyte stimulator protein which is overexpressed in patients with SLE, reducing the survival of B cells and reducing the quantity of immunoglobulin-producing plasma cells.

214

Major Drug Introductions

Everolimus Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Certican Novartis Switzerland 2004 Germany 159251-69-6

Everolimus is a macrolide immunosuppressant and analog of sirolimus and a derivative of rapamycin. Everolimus inhibits antigenic and interleukin (IL-2 and IL-15) stimulated activation and proliferation of T and B lymphocytes. Everolimus was initially launched for kidney transplant and liver transplant rejection prophylaxis.

Gusperimus trihydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Spanidin Nippon Kayaku Japan 1994 Japan 104317-84-2

Gusperimus is a synthetic derivative of the antitumor antibiotic spergualin. It was introduced as a treatment for accelerated and acute rejection reactions after kidney transplants. In combination with cyclosporin it has been reported that gusperimus exhibits exceptional activity in the prevention of transplant rejection and in inducing long-term tolerance. It appears to work by inhibition of the differentiation and proliferation of effector cells, including cytotoxic T cells and antibody-producing B cells.

Major Drug Introductions

215

Mycophenolate mofetil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cellcept Roche Switzerland 1995 USA 128794-94-5

Mycophenolate mofetil is a prodrug of mycophenolic acid, a selective, reversible, noncompetitive inhibitor of inosinate dehydrogenase and guanylate synthetase. Mycophenolate mofetil has improved oral absorption and bioavailability and was introduced to prevent acute kidney transplant rejection in combination with other immunosuppressive therapy and to treat refractory acute kidney graft rejection.

Mycophenolate sodium Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Myfortic Novartis Switzerland 2003 Switzerland 37415-62-6

Mycophenolate sodium is formulated as an enteric coated tablet, which is absorbed in the upper intestine thus protecting the upper gastrointestinal (GI) tract from the side effects of mycophenolic acid. It was introduced as an oral treatment in combination with other immunosuppressants to prevent acute rejection in adult patients receiving allogeneic renal transplantation.

216

Major Drug Introductions

Pimecrolimus Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Elidel Novartis USA 2002 USA 137071-32-0

Pimecrolimus is a derivative of the immunosuppressant FK520. It was introduced as a topical formulation for the treatment of mild to moderate atopic dermatitis for patients of age 2 and over in whom the use of conventional therapies is inadvisable. It is an inflammatory cytokine inhibitor that works by selectively targeting Tcells in the skin.

GMDP Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Likopid Peptech Australia 1996 Russia 18194-24-6

Major Drug Introductions

217

GMDP is an enzymatic degradation product of a bacterial peptidoglycan that was introduced for hospital-related infections, psoriasis, cervical precancerous lesions, and ophthalmic keratitis caused by herpes.

Vaccines Influenza virus (live) Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – attenuated whole influenza virus

FluMist Medimmune, Wyeth USA 2003 USA Not applicable

This is a live attenuated influenza virus vaccine. It is a cold-adapted trivalent formulation that is administered nasally to provide active immunity against select influenza A and B strains in healthy people aged 5–49 years.

Lyme disease vaccine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 30 kDa

LYMErix Yale University, SmithKlineBeecham USA 1999 USA 147519-65-1

This vaccine was introduced for protection against Lyme disease, a tick-borne disease caused by infection with the spirochete Borrelia burgdorferi.

Hormone Related Twenty-two new therapies have been included in this category including 18 antidiabetic agents including dipeptidyl peptidase-4 (DPP-4) inhibitors, two for the treatment of acromegaly, and two growth hormones.

218

Major Drug Introductions

Antidiabetic Alogliptin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number 850649-62-6 (benzoate) Structure

Nesina Takeda, Furiex Japan 2010 Japan 850649-61-5

Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor, and is the 4th oral DPP4 inhibitor launched for the treatment of type 2 diabetes mellitus. Alogliptin potentiates the effects of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, by inhibiting their breakdown by DPP-4, thereby, lowering blood glucose levels. Alogliptin is approved for once daily dosing and can be used in combination with other blood glucose lowering therapies.

Exenatide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Byetta Amylin, Eli Lilly USA 2005 USA 141758-74-9

Exenatide is the first drug in a new class of anti-diabetics known as the incretin mimetics, and it is indicated as adjunctive therapy to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus inadequately controlled on metformin. Glucagon-Like Peptide-1 (GLP-1) is naturally released from cells in the GI tract in response to food intake and acts on its receptor on beta-cells to potentiate glucose-stimulated insulin secretion. Exenatide is a long-acting agonist at the GLP-1 receptor. It is a synthetic version of a 39-amino acid peptide found in the salivary secretions of the Gila monster lizard. Exenatide has a 53% amino acid similarity to naturally occurring GLP1, however it is less susceptible to degradation and has an in vivo half-life of 2.4 h

Major Drug Introductions

219

Glimepiride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Amaryl Hoechst Marion Roussel Germany 1995 Sweden 93479-97-1

Glimepiride was claimed as a new generation sulfonylurea drug and was launched to reduce blood sugar levels in type 2 diabetic patients. Such agents function by direct stimulation of insulin release from glucose-insensitive pancreatic b-cells and glucose transporter (GLUT) translocation in insulin-resistant fat and muscle cells.

Insulin lispro Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 5.8 kDa

Humalog Lilly USA 1996 USA 133107-64-9

Humalog, a recombinant protein, is a form of human insulin in which amino acids 28 and 29 have been inverted. This reduces the tendency of the protein to dimerize and further aggregate to hexamers. Thus, it has a faster rate of absorption and shorter duration of action, and this has advantages in controlling blood glucose levels after meals.

220

Major Drug Introductions

Linagliptin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tradjenta Boehringer Ingelheim, Eli Lilly USA 2011 USA 668270-12-0

Linagliptin is the 5th inhibitor of dipeptidyl peptidase-4 (DPP-4) that was approved for the once daily, oral treatment of type two diabetes mellitus. Linagliptin potentiates the effects of the incretin hormones, glucagon-like peptide-1 (GLP-1) and glucosedependent insulinotropic peptide (GIP), by inhibiting their breakdown by DPP-IV.

Liraglutide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Victoza Novo Nordisk USA 2009 United Kingdom, Germany, Denmark 204656-20-2

Liraglutide is the 2nd synthetic glucagon-like peptide (GLP)-1 receptor agonist to enter the market. Liraglutide was launched for the management of type-2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control. Liraglutide is 97% homologous to endogenous GLP-1, has a 12 to 13 hour half-life which allows for once daily subcutaneous administration

Major Drug Introductions

221

Miglitol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Diastabol Bayer, Sanofi Germany 1998 Germany 72432-03-2

Miglitol is an a-D-glucosidase inhibitor that was marketed as an auxiliary treatment for type 2 diabetes mellitus.

Mitiglinide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Glufast Kissei Japan 2004 Japan 145525-41-3

Mitiglinide is a non-sulfonylurea drug that was initially approved for the treatment of type-2 diabetes. Similar to other sulfonylureas, mitiglinide binds to sulfonylurea receptors on the pancreatic b -cells resulting in stimulation of insulin secretion.

Nateglinide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Fastic, Starsis Ajinomoto, Yamanouchi, Roussel Japan 1999 Japan 105816-04-4

222

Major Drug Introductions

Nateglinide specifically blocks the ATP-sensitive Kþ channel in pancreatic b-cells, thus resulting in an increase in intracellular calcium concentrations, which causes an increase in insulin secretion. Hence, nateglinide was marketed as an insulinotropic agent for the treatment of type 2 diabetes mellitus.

Pioglitazone hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Actos Takeda, Lilly Japan 1999 USA 112529-15-4

Pioglitzone is an orally active treatment for type 2 diabetes mellitus. It binds to peroxisome proliferator-activated receptor gamma, thus activating this nuclear receptor, which then influences carbohydrate metabolism.

Pramlintide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Symlin Amylin USA 2005 USA 151126-32-8

Pramlintide is a novel synthetic analog of amylin, a hormone co-secreted with insulin from pancreatic beta cells, and is indicated as an adjunct to insulin therapy in patients with type 1 and type 2 diabetes mellitus. Pramlintide slows gastric emptying, reduces postprandial glucagon secretion, and modulates appetite leading to decreased caloric intake. Unlike insulin pramlintide does not require constant adjustments and patients remain on a consistent dose.

Major Drug Introductions

223

Repaglinide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Prandin Boehringer Ingelheim Germany 1998 USA 135062-02-1

Repaglinide has an insulin-releasing effect mediated by pancreatic b-cells. It was marketed as an orally active hypoglycemic agent in patients with type 2 diabetes mellitus. The mechanism of action appears to be similar to that of nateglinide.

Rosiglitazone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Avandia SmithKlineBeecham USA 1999 USA, Mexico 155141-29-0

Rosiglitazone is a potent agonist of peroxisome proliferator-activated receptor gamma, a nuclear receptor involved in the differentiation of adipose tissue, without activating liver PPAR-alpha receptors. This could in turn mediate the downregulation of leptin gene expression. Rosiglitazone has been shown to normalize glucose metabolism and reduce the exogenous dose of insulin needed to achieve glycemic control.

224

Major Drug Introductions

Saxagliptin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number 945667-22-1 (monohydrate) Structure

Onglyza Bristol-Myers-Squibb, AstraZeneca USA 2009 USA 361442-04-8

Saxagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is the 3rd oral DPP4 launched for the treatment of type 2 diabetes mellitus. Saxagliptin potentiates the effects of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, by inhibiting their breakdown by DPP-4, thereby, lowering blood glucose levels. Saxagliptin has 10-fold greater potency than previous generations.

Sitagliptin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Januvia Merck USA 2006 Mexico 486460-32-6

Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a first-in-class oral drug launched for the treatment of type 2 diabetes. Sitagliptin potentiates the effects of the incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, by inhibiting their breakdown by DPP-4, thereby, lowering blood glucose levels.

Major Drug Introductions

225

Troglitazone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Rezulin Sankyo Japan 1997 Japan 97322-87-7

Troglitazone was introduced for the treatment of type 2 diabetes and apparently reduces glucose concentrations without affecting insulin secretion. Troglitazone binds to peroxisome proliferator-activated receptor gamma thus activating this nuclear receptor, which then influences carbohydrate metabolism. Unfortunately, liver toxicity problems have led to this drug being withdrawn from the market.

Vildagliptin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Galvus Novartis USA 2007 Brazil 274901-16-5

Vildagliptin is the 2nd dipeptidyl-peptidase-IV (DPP-4) inhibitor launched for the once-daily oral treatment of type 2 diabetes mellitus. It is approved as an add-on therapy with a sulfonylurea, metformin or a thiazolidinedione. Vildagliptin increases the concentration and duration of active incretin levels, which in a glucose-dependent manner results in increased insulin release and decreased glucagon levels.

226

Major Drug Introductions

Voglibose Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Basen Takeda Japan 1994 Japan 83480-29-9

Voglibose is an orally active a-D-glucosidase inhibitor that was launched for the treatment of postprandial hyperglycemia in diabetic patients. It acts by decreasing the release of glucose from carbohydrates ingested in food.

Acromegaly Lanreotide acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Somatuline LP Beaufour-Ipsen France 1995 France 127984-74-1

Lanreotide is an octapeptide somatostatin analog that was marketed for the treatment of acromegaly in cases where surgery or radiotherapy have failed to restore normal growth hormone secretion. It is a selective inhibitor of growth hormone and also reduces the secretion of growth hormone, thyrotropin, motilin, and pancreatic polypeptide. It is also being evaluated for the treatment of neuroendocrine tumors and hormone-responsive prostate cancer.

Major Drug Introductions

227

Pegvisomant Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 40–50 kDa

Somavert Sensus, Pfizer USA 2003 USA 218620-50-9

Acromegaly is a debilitating endocrine disease caused by the excessive secretion of growth hormone and increased production of insulin-like growth factor-I in middle-aged adults. Pegvisomant is a modified form of human growth hormone that acts as a highly selective growth hormone antagonist acting on cell surfaces where it blocks the binding of growth hormone.

Growth Hormone Somatomedin-1 Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 76.5 kDa

Igef Biogen, Pharmacia USA 1994 Sweden 67763-96-6

Somatomedin-1 is an insulin-like growth factor-I that was launched for the treatment of children with growth disorders caused by growth hormone insensitivity. It is also a potent hypoglycemic agent that resembles insulin in some respects and its use in diabetes is also being investigated.

Somatotropin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 22 kDa

Nutropin Genentech USA 1994 USA 12629-01-5

Somatotropin is a second-generation and methionine-free human growth hormone that was launched for the treatment of growth failure in children due to chronic renal insufficiency before transplantation and for the long-term treatment of short stature in children with a lack of endogenous growth hormone secretion.

228

Major Drug Introductions

Reproduction and Fertility Fertility Enhancer Cetrorelix Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cetrotide Asta Medica Germany 1999 Germany 120287-85-6; 130289-71-3

Cetrorelix is a structurally modified decapeptidic analog of luteinizing hormone-releasing hormone. It is an extremely potent and long-lasting gonadotropin releasing hormone antagonist, which blocks gonadotropins and sex steroid secretion immediately after administration.

Corifollitropin alfa Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein, molecular weight 47 kDa

Elonva Merck, N.V. Organon Netherlands 2010 European Union 195962-23-3

Corifollitropin is a first-in-class, injectable follicle-stimulating hormone (FSH) receptor agonist launched for the treatment of infertility in women. Corifollitropin binds to the FSH receptor to increase follicle development in women. Corifollitropin is approved for use in women in an assisted reproductive technology program in combination with a gonadotropin-releasing hormone agonist.

Follitropin alpha Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Gonal-F Genzyme, Serono Switzerland 1996 Austria 9002-68-0

Major Drug Introductions

229

Follitropin alpha is a recombinant form of human follical-stimulating hormone that was introduced for the treatment of infertility.

Follitropin beta Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Puregon Organon Netherlands 1996 Denmark 9002-68-0

Follitropin beta is another recombinant form of human follicle-stimulating hormone that was introduced for the induction of ovulation in clomiphene-resistant anovulation and for controlled ovarian hyperstimulation. It appears to be more active than follitropin alpha in that a greater pregnancy rate is achieved.

Ganirelix acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Orgalutran Roche Bioscience USA 2000 Germany 129311-55-3

Ganirelix acetate is another decapeptide analog of luteinizing hormone-releasing hormone but is more water soluble than cetrorelix. It is highly bioavailable and immediately blocks the endogenous release of luteinizing hormone and follicle-stimulating hormone. It was launched as prefilled syringes for subcutaneous injections that inhibit premature luteinizing hormone surges in women undergoing controlled ovarian hyperstimulation.

230

Major Drug Introductions

Contraceptive Drospirenone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Yasmin Schering AG Germany 2000 Germany 067392-87-4

Drospirenone was launched in combination with ethinylestradiol as a novel oral contraceptive. Its receptor binding profile for steroid receptors is very similar to that of progesterone and thus it mimics the progestogen’s agonistic activity as well as the antiandrogenic and antimineralocorticoid activity of the endogenous hormone.

Norelgestromin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Ortho Evra Johnson & Johnson USA 2002 USA 53016-31-2

Norelgestromin is one of the components, along with ethinylestradiol, in the first birth control transdermal patch. This patch is changed weekly for 3 weeks, followed by a treatment-free week. Following application, norelgestromin rapidly appears in the serum and reaches a plateau after 48 h; this level is maintained during the patch-wearing period.

Major Drug Introductions

231

Ulipristal acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

ellaOne HRA Pharma USA 2009 USA 126784-99-4

Ulipristal acetate is the 2nd orally administered, single-dose, post-coital contraceptive to be introduced to the market. Ulipristal is a synthetic steroid derived from 19-nor-progesterone and is a potent progesterone receptor antagonist. Ulipristal acetate is efficacious up to 120 hours following unprotected intercourse.

Hyperprolactinemia Quinagolide hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Norprolac Sandoz Switzerland 1994 Netherlands 94424-50-7

Quinagolide is a potent and specific nonergot dopamine D2 agonist that was launched for the treatment of hyperprolactinemia. It is effective in inhibiting prolactin secretion by human pituitary tumors and can also provide relief from associated effects such as, inter alia, infertility.

232

Major Drug Introductions

Preterm Labor Atosiban Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Tractocile, Antocin Ferring AG Sweden 2000 United Kingdom 090779-69-4

Atosiban is a peptidic oxytocin analog that acts as an antagonist of the vasopressin V1a receptor and of the oxytocin receptor. It was introduced as an injectable inhibitor of preterm labor.

Skin Related Antipsoriasis Alefacept Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein; molecular weight 91.4 kDa

Amevive Biogen USA 2003 USA 222535-22-0

Alefacept is a dimeric fusion protein consisting of the leukocyte function antigen-3 protein and Fc portion of human IgG1 that blocks the T-cell CD2 receptor thus preventing T-cell proliferation, a key mechanism in psoriasis.

Efalizumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant antibody; molecular weight 150 kDa

Raptiva Xoma, Genentech USA 2003 USA 214745-43-4

Major Drug Introductions

233

Efalizumab is a humanized monoclonal antibody that was marketed for the treatment of psoriasis. It is full-length IgG1 antibody developed through a murine antihuman CD11a mAb, where CD11a is the alpha-chain leukocyte function associate antigen that is expressed on the surface of T lymphocytes. CD11a also binds to the intercellular cell adhesion molecules ICAM-1, ICAM-2, and ICAM3, on endothelial cells, monocytes, keratinocytes, fibroblasts, and activated lymphocytes. Psoriasis is a disease that is mediated through inflammatory cells, primarily T cells expressing CD4 or CD8 markers and keratinocytes. Thus, by blocking binding, the ability of T cells to adhere, migrate, and be activated is blunted.

Tazarotene Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zorac Allergan USA 1997 Germany 118292-40-3

Tazarotene normalizes abnormal keratinocyte differentiation and proliferation and reduces the expression of inflammatory markers. It is a prodrug that is hydrolyzed in vivo to the acid, which has selectivity for retinoid acid receptors. Tazarotene was introduced for the treatment of psoriasis and acne.

Ustekinumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – humanized monoclonal antibody; molecular weight 149 kDa

Stelara Janssen-Ortho USA 2009 Canada 815610-63-0

Ustekinumab was launched for the treatment of plaque psoriasis. Ustekinumab is a human IgG1k monoclonal antibody that binds the p40 protein subunit utilized by both IL-12 and IL-23 which reduces inflammation and immune responses. Ustekinumab is administered by subcutaneous injection every 12 weeks in the maintenance phase of therapy.

Wound Healing Acemannan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – carbohydrate-derived polymer; molecular weight 1–2 million Da

Acemannan hydrogel Carrington Laboratories USA 2001 USA 110042-95-0

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Major Drug Introductions

Acemannan is a complex water-soluble polymanno-galacto acetate derived from Aloe vera that was marketed as a wound healing agent for the care of ulcers, burns, and postsurgical incisions.

Prezatide copper acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Iamin gel ProCyte USA 1996 USA 130120-57-9

Prezatide copper acetate is a tripeptide–copper acetate complex where the sequence GHK is an endogenous growth factor that stimulates collagen synthesis and angiogenesis. The gel was launched for the treatment of chronic and acute wounds.

Dermatological Kinetin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Kinerase Senetek United Kingdom 1999 USA 525-79-1

Major Drug Introductions

235

Kinetin is a synthetic cytokinin (a plant growth factor) that was introduced for the treatment of age-related photodamage of skin.

Photosenstization Verteporfin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Visudyne QLT Canada 2000 Switzerland 129497-78-5

Verteporfin was launched as a photosensitizer for photodynamic therapy of wet age-related macular degeneration in patients with subfoveal choroidal neovascularization. It is injected intravenously as a liposomal formulation.

Eye Related Antiglaucoma Bimatoprost Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lumigan Allergan USA 2001 USA, Brazil 155206-00-1

236

Major Drug Introductions

Bimatoprost is a PGF2a-analog that was introduced for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

Brimonidine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Alphagan Allergan USA 1996 USA 59803-98-4

Brimonidine is a potent and relatively selective a2a-adrenergic agonist with low affinity for the imidazoline I1 receptor. It was introduced as a topical treatment for open-angle glaucoma and ocular hypertension.

Brinzolamide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Azopt Alcon USA 1998 USA 138890-62-7

Brinzolamide is a potent inhibitor of the human carbonic anhydrase introduced for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.

Major Drug Introductions

237

Dorzolamide hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Trusopt Merck USA 1995 USA 130693-82-2

Dorzolamide is a carbonic anhydrase inhibitor that lowers intraocular pressure on topical administration. It was launched for the treatment of open-angle glaucoma and ocular hypertension.

Latanoprost Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Xalatan Pharmacia & Upjohn United Kingdom 1996 United Kingdom 130209-82-4

Latanoprost is a PGF2a-analog with greater lipophilicity and therefore greater corneal penetration, which reduces intraocular pressure. It was launched for the treatment of glaucoma.

238

Major Drug Introductions

Tafluprost Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Taflotan Santen, AsahiGlass Japan 2008 Denmark 209860-87-7

Tafluprost is the 5th ophthalmic prostaglandin to come to market. Tafluprost, like other prostaglandin it was launched to reduce elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension analogs via stimulation of the fluoroprostaglandin (FP) receptor which is believed to reduce intraocular pressure by increasing uveoscleral outflow. In comparison to latanoprost, tafluprost has a 10-fold greater affinity for the FP receptor.

Travoprost Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Travatan Alcon USA 2001 USA 157283-68-6

Travoprost is a PGF2a analog that was launched as an ophthalmic solution administered topically for the treatment of elevated intraocular hypertension as a result of open-angle glaucoma, a common optic neuropathy, and a leading cause of blindness.

Major Drug Introductions

239

Unoprostone isopropyl ester Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Rescula Ueno, Fujisawa Japan 1994 Japan 120373-24-2

Unoprostone is a prostaglandin derivative launched for the treatment of glaucoma and ocular hypertension. It is suggested that it acts by increasing uveoscleral outflow or by decreasing episcleral venous pressure.

Antiangiogenic Aflibercept Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant fusion protein; molecular weight 115 kDa

Eylea Regeneron Pharmaceuticals USA 2011 USA 862111-32-8

Aflibercept is a recombinant fusion protein administered via intravitreal injection. It binds vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PIGF). Aflibercept was launched for the treatment of neovascular age-related macular degeneration administered every other month or monthly. Aflibercept is also undergoing evaluation for use as an anticancer agent.

240

Major Drug Introductions

Pegaptanib Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Macugen Eyetech, Pfizer USA 2005 USA 222716-86-1

Pegaptanib is the first anti-angiogenic agent launched for the treatment of neovascular (wet) age-related macular degeneration (AMD). Pegaptanib is an RNA aptamer, a pegylated modified oligonucleotide, which is a selective vascular endothelial growth factor (VEGF) antagonist. Pegaptanib is administered by intravitreal injection given every 6 weeks for up to two years. The role of pegaptanib is to maintain current vision status or to slow the progression of vision loss. Pegaptanib is not indicated to restore vision in cases where the photoreceptors are damaged and degenerated.

Ranibizumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant humanized monoclonal antibody; molecular weight 48 kDa

Lucentis Genentech, Novartis USA 2006 USA 347396-82-1

Ranibizumab, is derived from bevacizumab, and is a recombinant, humanized, IgG1 monoclonal antibody fab fragment that binds all active isoforms of vascular endothelial growth factor A, and it is indicated for the treatment of neovascular age-related macular degeneration. Ranibizumab is administered via intraocular injection.

Major Drug Introductions

241

Antihistamines Alcaftadine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Lastacaft Vistakon Pharmaceuticals, LLC USA 2010 USA 147084-10-4

Alcaftadine is a histamine H1/H2/H4 receptor agonist. Alcaftadine is a long-acting, topical ophthalmic solution launched for the treatment of allergic conjunctivitis. Histamine’s actions on H1 and H2 receptors result in the redness of the conjunctiva while the effects of eosinophils have been ascribed to H4 receptor stimulation. Alcaftadine has a 16 hour half-life which allows for once daily instillation.

Anti-Inflammatory Nepafenac Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nevanac Alcon USA 2005 USA 78281-72-8

Nepafenac is a topical ophthalmic medication indicated for the treatment of ocular pain and inflammation associated with cataract surgery. Nepafenac is a prodrug and mediated by ocular tissue hydrolases is converted to amfenac, which is a non-selective inhibitor of COX-1 and COX-2. Nepafenac is found to have a 4- to 28-fold greater ocular penetration than other NSAIDs such as diclofenac, bromfenac, and ketorolac. Additionally, Nepafenac has been shown to inhibit prostaglandin synthesis in the iris and ciliary body by 85% to 95% for more than 6 h.

242

Major Drug Introductions

Moistening Agents Diquafosol Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Diquas Santen, Inspire Pharmaceuticals USA 2010 Japan 211427-08-6

Diquafosol is a first-in-class agent for ocular use. Diquafosol was launched for the treatment of dry eye disease characterized by a lack of tear volume, improper tear composition, and damage to the ocular surface. Diquafosol stimulates the P2Y2 receptor on the ocular surface to stimulate water, lipid, and mucin secretion.

Miscellaneous Male Sexual Dysfunction Avanafil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zepeed JW Choongwae, Vivus, Mitsubishi Pharma Japan 2011 South Korea 330784-47-9

Avanafil is the 5th orally administered selective 5 phosphodiesterase (PDE5) inhibitor was launched for the treatment of erectile dysfunction. Avanafil is highly selective and is reported to be the most selective PDE5 inhibitor on the market.

Major Drug Introductions

243

Dapoxetine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Priligy Lilly, Janssen-Cilag USA 2009 Finland, Sweden 119356-77-3 (free base)

Dapoxetine is a SSRI launched for the treatment of premature ejaculation. Dapoxetine actively blocks presynaptic membranes of 5-HT transporters, resulting in greater serotonin levels which binds to 5-HT2c and 5-HT1a receptors to delay ejaculation. In clinical trials IELT increased from 0.9 min to 1 min to 2.78 min to 4.2 min by week 12.

Sildenafil citrate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Viagra Pfizer United Kingdom 1998 USA 139755-83-2

Sildenafil is a potent and selective inhibitor of type V cGMP phosphatase that was launched for the treatment of organic and/or psychological male erectile dysfunction.

244

Major Drug Introductions

Tadalafil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Cialis Lilly, ICOS USA 2003 United Kingdom, Germany 171596-29-5

Tadalafil is a phosphodiesterase-5 (PDE5) inhibitor that was launched for the oral treatment of male erectile dysfunction.

Udenafil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zydena Dong-A South Korea 2005 South Korea 268203-93-6

Udenafil was released in South Korea and is the 4th in a class of drugs targeting the inhibition of the enzyme phosphodiesterase 5 (PDE5) and is indicated for the treatment of erectile dysfunction.

Major Drug Introductions

245

Vardenafil Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Levitra Bayer AG, GlaxoSmithKline Germany 2003 Germany 224785-90-4

Vardenafil is another PDE5 inhibitor that was marketed for the treatment of male erectile dysfunction.

Antiobesity Dexfenfluramine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Redux Servier France 1997 France 3239-45-0

Dexfenfluramine is the (þ)-isomer of fenfluramine; it has with a greater anorectic effect because of a greater selectivity for the serotonin system as a 5HTagonist with no dopaminergic or noradrenergic activity. It was launched for the treatment of obesity but was withdrawn due to side effects of primary pulmonary hypertension, brain serotonin neurotoxicity, and valvular heart disease.

246

Major Drug Introductions

Orlistat Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Xenical Roche Switzerland 1998 New Zealand 096829-58-2

Orlistat is a potent inhibitor of gastrointestinal lipases required for the lypolysis and digestion of dietary fat; thus, it inhibits the absorption of about a third of the fat in food. It was introduced for the long-term treatment of obesity in conjunction with a moderately reduced calorie diet.

Rimonabant Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Acomplia Sanofi-Aventis France 2006 United Kingdom 168273-06-1

Rimonabant is a first-in-class drug launched last year as an oral treatment for obesity as an adjuvant to diet and exercise. Rimonabant functions by selective antagonism of central and peripheral cannabinoid type 1 receptors. The most common adverse reactions associated with rimonabant treatment included nausea and upper respiratory tract infection.

Major Drug Introductions

247

Sibutramine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Meridia, Reductil Knoll Germany 1998 USA 125494-59-9

Sibutramine is a serotonin and noradrenaline reuptake inhibitor that reduces energy intake by creating a satiated feeling and increases energy expenditure by enhancing thermogenesis.

Antidote Antidigoxin polyclonal antibody Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – polyclonal antibody; molecular weight 46 kDa

DigiFab Protherics, Savage Laboratories United Kingdom 2002 USA 339086-83-8

Digoxin is widely used for the treatment of cardiac conditions such as atrial arrhythmias and congestive heart failure, but has a narrow therapeutic range. Intravenous infusion of antidigoxin polyclonal antibody was introduced to overcome digoxin poisoning.

Crotalidae polyvalent immune fab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – Antibody fragment

CroFab Protherics, Savage Laboratories United Kingdom 2001 USA Not applicable

Crotalidae was launched for the treatment of North American crotalid snake envenomation.

Fomepizole Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Antizol Orphan Medical/Cambridge USA 1998 USA 7554-65-6

Fomepizole was introduced as an antidote for the treatment of ethylene glycol poisoning.

Hyponatremia Conivaptan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vaprisol Astellas, Yamanouchi Japan 2006 USA 168626-94-6

Conivaptan is a non-peptide dual V1a and V2 vasopressin receptor antagonist. Conivaptan is given intravenously and was initially approved for the treatment of potentially life threatening euvolemic or hypervolemic hyponatremia due to heart failure, cirrhosis, and nephrotic syndrome. Conivaptan increases serum sodium concentrations and increases free water clearance

Mozavaptan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Physuline Otsuka Japan 2006 Japan 137975-06-5

Major Drug Introductions

249

Mozavaptan is an oral vasopressin selective V2 antagonist that has been launched for the treatment of inappropriate antidiuretic hormone secretion syndrome (IADHS) and is the second therapy approved for this use.

Tolvaptan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Samsca Otsuka Pharmaceutical USA 2009 USA 150638-30-0

Tolvaptan is a nonpeptide, selective V2-renal receptor antagonist. Stimulation of the V2-renal receptor promotes excretion of free water without impacting electrolyte balance. Tolvaptan has been launched for the once-daily oral treatment of hypervolemic and euvolemic hyponatremia.

Analgesics Tapentadol hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Nucynta Ortho-McNeil-Janssen Germany 2009 USA 175591-09-0

Tapentadol hydrochloride is an oral, immediate release, and is both a m-opioid-receptor agonist and norepinephrine reuptake inhibitor. Tapentadol is 50-fold less potent for the m-opioid-receptor however, because of the dual mechanism it is efficacious for both acute and chronic pain conditions with fewer side effects than conventional m-opioid-receptor agonists. Tapentadol was launched for the treatment of acute and chronic pain that is moderate to severe in intensity.

250

Major Drug Introductions

Ziconotide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Prialt Elan USA 2005 USA 107452-89-1

Ziconotide is an intrathecally infused synthetic equivalent of omega-conopeptide MVIIA derived from the venom of the marine snail, Conus magus, and was launched as a novel non-opioid treatment for severe chronic pain. Ziconotide is a calcium channel blocker specific to the neuronal calcium channels that regulate synaptic transmission in nociceptive neurons. Intrathecal administration is necessary to bypasses the blood-brain barrier since ziconotide membrane permeability is poor due to hydrophilicity and large molecular size. Since ziconotide has no affinity for opioid receptors, it is devoid of tolerance issues associated with opioid therapy and has shown efficacy in opioid refractory patients.

Cryopyrin-Associated Periodic Syndromes (CAPS) Canakinumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant monoclonal antibody; molecular weight 150 kDa

Ilaris Novartis USA 2009 USA 914613-48-2

Canakinumab was launched for the treatment of CAPS including familial cold autoinflammatory syndrome and Muckle-Wells syndrome. CAPS is a genetic disease that causes excessive IL-1b production and signaling which results in autoinflammatory symptoms. Canakinumab is an injectable monoclonal antibody that inhibits IL-1b which reduces inflammation.

Rilonacept Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Arcalyst Regeneron USA 2008 USA 501081-76-1

Rilonacept is the first approved treatment for cryopyrin-associated periodic syndromes (CAPS) including familial cold autoinflammatory syndrome and Muckle-Wells syndrome. CAPS causes excessive IL-1b signaling which results in autoinflammatory symptoms. Rilonacept is an injectable dimeric IL-1b inhibitor that serves to reduce inflammation.

Major Drug Introductions

251

Heredity Angioedema Ecallantide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Kalbitor Dyax Corp USA 2009 USA 460738-38-9

Ecallantide is a 60-amino acid recombinant protein, administered subcutaneously launched for the treatment of hereditary angioedema (HAE). HAE is an autosomal dominant disorder that causes subcutaneous and submucosal edema that can affect the face, extremities, genitals, gastrointestinal tract and can be potentially life-threatening when swelling manifests itself within the upper airways. Ecallantide is a potent and selective inhibition of plasma kallikrein which results in reduction of HAE symptoms and the frequency and duration of HAE attacks.

Icatibant Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Firazyr Jerini Germany 2008 United Kingdom, Germany 138614-30-9

Heredity angioedema (HAE) is an autosomal dominant disorder that causes subcutaneous and submucosal edema that can affect the face, extremities, genitals, gastrointestinal tract and can be potentially life-threatening when swelling manifests itself within the upper airways. Icatibant is a selective bradykinin B2 receptor antagonist administered subcutaneously to treat acute attacks of HAE.

252

Major Drug Introductions

Type 1 Gaucher’s Disease Imiglucerase Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Cerezyme Genzyme USA 1994 USA 154248-97-2

This is a mannose-terminated form of human placental glucocerebrosidase that catalyzes the hydrolysis of glucocerebroside and thus prevents the accumulation of this lipid in organs and tissues. It was launched for the treatment of type I Gaucher’s disease.

Miglustat Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Zavesca G.D. Searle, Actelion USA 2003 United Kingdom 72599-27-0

Miglustat is an inhibitor of glucosylceramide synthase that was launched as an oral treatment for mild to moderate type I Gaucher’s disease in adult patients for whom enzyme replacement therapy is not a therapeutic option.

Antixerostomia Cevimeline hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Evoxac Israel Institute for Biological Research, Snow Brand, Daiichi Pharmaceutical Israel 2000 USA 153504-70-2

Major Drug Introductions

253

Cevimeline was originally developed as a cognition enhancer but was launched for the treatment of dry mouth symptoms in patients with Sjogren’s syndrome. This action is due to stimulation of M3 receptors in salivary and lacrimal glands.

Antityrosinemia Nitisinone Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Orfadin AstraZeneca, Rare Disease Therapeutics United Kingdom 2002 USA 104206-65-7

Nitisinone was introduced as an adjunct to dietary restriction of tyrosine and phenylalanine for the treatment of hereditary tyrosinemia type 1, an inborn error of metabolism. It acts as an inhibitor of the 4-hydroxyphenylpyruvate dioxygenase and prevents the formation of toxic metabolites such as succinylacetoacetate in the liver.

Fabry’s Disease Agalsidase alfa Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Replagal Transkaryotic Therapies USA 2001 Sweden 104138-64-9

Fabry’s disease is a genetic disorder of fat metabolism caused by a deficiency of the enzyme a-galactosidase A, which is involved in the biodegradation of lipids. Agalsidase alfa is a recombinant form of this enzyme that was launched as a twice-weekly intravenous infusion for the long-term treatment of Fabry’s disease. Treatment for 6–12 months greatly reduces the accumulation of microvascular endothelial deposits of globotriaosylceramide in the kidneys, heart, and skin.

Hematological Thrombin alfa Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant human protein; molecular weight 33.8 kDa

Recothrom ZymoGenetics USA 2008 USA 869858-13-9

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Major Drug Introductions

Thrombin alfa is a recombinant human thrombin with an identical amino acid sequence to that of endogenous thrombin. Thrombin alfa was launched as a topical hemostat to that may be used with a gelatin sponge during surgical procedures.

Hepatoprotectant Mivotilate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Not applicable Yuhan Corp South Korea 1999 South Korea 130112-42-4

Mivotilate was launched as an orally active hepatoprotective agent for the treatment of liver cirrhosis and hepatitis B infection. The mode of action appears to involve inactivation of Kupffer cells.

HIV Lipodystrophy Tesamorelin acetate Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Egrifta Thera Technologies Canada 2010 USA 804475-66-9

Tesamorelin acetate is an analog of growth hormone-releasing hormone. It is a first-in-class, subcutaneous treatment launched for reducing excess abdominal fat reduction in HIV-infected patients with lipodystrophy.

Major Drug Introductions

255

Magnetic Resonance Imaging (MRI) Contrast Agent Gadoversetamide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

OptiMARK Mallinckrodt USA 2000 USA 131069-91-5

Gadoversetamide is a gadolinium(III) complex that was launched for intravenous injection prior to MRI in patients with anomalous blood–brain barrier or anomalous vascularity in the CNS or liver.

Mucopolysaccharidosis II (Hunter Syndrome) Idursulfase Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Elaprase Shire, Transkaryotic Therapies United Kingdom 2006 USA 50936-59-9

Idursulfase is a purified form of human iduronate-2-sulfatase and is the first treatment available for Mucopolysaccharidosis II (Hunter Syndrome). Hunter syndrome is a lysosomal storage disorder characterized by a deficiency in iduronate-2-sulfatase enzyme responsible for the hydrolysis of glycosaminoglycans dermatan sulfate and heparin sulfate in lysosomes of cells.

Mucopolysaccharidosis VI Galsulfase Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Naglazyme BioMarin USA 2005 USA 55354-43-3

256

Major Drug Introductions

Mucopolysaccharidosis VI is characterized by the absence or marked reduction in N-acetylgalactosamine 4-sulfatase which results in the accumulation of the glycosaminoglycan (GAG) substrate, dermatan sulfate, throughout the body. The accumulation leads to widespread cellular, tissue, and organ dysfunction. Galsulfase glycoprotein is a variant of N-acetylgalactosamine 4-sulfatase and is the first treatment indicated for the treatment of mucopolysaccharidosis VI. Galsulfase is a polymorphic human enzyme and is produced by recombinant DNA technology in a Chinese hamster ovary cell expression system. Galsulfase replaces the enzyme N-acetylgalactosamine 4-sulfatase and has been shown to increase the catabolism of and reduce the urinary excretion of GAGs chondroitin 4-sulfate and dermatan sulfate.

Opioid Induced Constipation Methylnaltrexone bromide Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Relistor Wyeth, Progenics USA 2008 Canada 073232-52-7

Methylnaltrexone bromide is an injectable opioid antagonist launched to reduce opioid-induced bowel dysfunction. It is a peripherally-acting m-opioid receptor antagonist. Methylnaltrexone bromide does not cross the blood brain barrier, thus having a reduced potential to reverse analgesia or precipitate opioid withdrawal symptoms.

Paroxysmal Nocturnal Hemoglobinuria Eculizumab Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure –monoclonal antibody; molecular weight 148 kDa

Soliris Alexion USA 2007 USA 219685-50-4

Eculizumab is a fully humanized anti-C5 monoclonal antibody. It was launched for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis and is the first therapy to be approved for this indication. Eculizumab has been shown to reduce the need for red blood cell transfusions. It is given as a 35 minutes intravenous infusion.

Major Drug Introductions

257

Pompe Disease Alglucosidase alfa Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant human protein; molecular weight 110 kDa

Myozyme Genzyme General USA 2006 USA 420784-05-0

Alglucosidase alfa is an enzyme replacement therapy for endogenous acid alpha-glucosidase launched for the treatment of Pompe disease. Pompe disease is a lysosomal storage disorder that is characterized by a deficiency in the acid alpha-glucosidase enzyme which facilitates the conversion of glycogen to glucose, this results in accumulation of glycogen lysosomes in cardiac, hepatic, and skeletal muscles.

Postoperative Ileus Prophylaxis Alvimopan Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Entereg GlaxoSmithKline USA 2008 USA 156053-89-3

Alvimopan is the first oral, gastrointestinal specific peripherally restricted antagonist of the m-opioid receptor. It was launched for the oral treatment of postoperative ileus following bowel resection surgery. Alvimopan accelerates the time to gastrointestinal recovery following bowel resection surgery.

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Major Drug Introductions

Pruritus Nalfurafine hydrochloride Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Remitch Toray, Japan Tobacco Japan 2009 Japan 152657-84-6 (free base)

Pruritus is a common symptom seen in of uremic patients. Nalfurafine hydrochloride is an k-opioid receptor agonist, which inhibits MOR pathway signaling which is thought to be a contributor to pruritus. Nalfurafine hydrochloride was launched for the once-daily oral treatment refractory pruritus in hemodialysis patients. It was found to inhibit scratching behavior in a dose dependent manner.

Smoking Cessation Varenicline Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Chantix Pfizer USA 2006 USA 249296-44-4

Varenicline is a first in class treatment launched to aid in smoking cessation. Varenicline is a partial agonist of the alpha a 4b2 nicotinic receptor which results in decreased craving and withdrawal symptoms, and by decreases reinforcement associated with smoking.

Major Drug Introductions

259

Stomatitis Palifermin Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure – recombinant protein

Kepivance Amgen USA 2005 USA 162394-19-6

Palifermin is a human keratinocyte growth factor produced by recombinant DNA technology and is indicated for reducing the incidence and duration of oral mucositis (stomatitis) in patients with hematologic malignancies receiving chemotherapy and/or radio therapy. Palifermin provides protection from the damaging effects of chemotherapy and radiation by selectively promoting epithelial cell proliferation, leading to an increased rate of healing.

Transthyretin Familial Amyloid Polyneuropathy Tafamidis meglumine Trade name Manufacturer Country of origin Year of introduction Country in which first launched CAS registry number Structure

Vyndaqel Pfizer USA 2011 European Union 951395-08-7

Tafamidis meglumine is the first treatment that was launched for the treatment of transthyretin familial amyloid polyneuropathy (TTR-FAP) in adults with stage 1 symptomatic polyneuropathy. TTR-FAP is estimated to affect 8000 to 10 000 people worldwide and is a progressive and fatal disorder which presents as neuropathy, cardiomyopathy, renal failure, and blindness.

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