Drug Pipeline Monthly Update

Critical updates in an ever changing environment

December 2018

New drug information

●● Temixys™ (lamivudine/tenofovir disoproxil fumarate): The Food and Drug Administration (FDA) approved Celltrion’s Temixys in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 35 kg, dosed once daily. Temixys is a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) in one tablet. Celltrion intends to sell Temixys at a discounted price compared to Gilead’s Truvada® (emtricitabine/tenofovir disoproxil fumarate).1 Celltrion plans to launch early 2019.1

●● Tolsura™ (itraconazole) capsules: Mayne Pharma received FDA approval for Tolsura for the treatment of systemic fungal infections in adult patients including certain forms of:

→→ blastomycosis,

→→ histoplasmosis, and

→→ aspergillosis Mayne notes that this is a Super-BioAvailable (SUBA) formulation of itraconazole that has been shown in clinical studies to have increased bioavailability and reduced variability when compared to other itraconazole formulations.2 Tolsura will launch in January 2019.2

●● Montegrity™ (prucalopride): The FDA approved Shire’s Montegrity, a once daily, oral medication for the treatment of adults with chronic idiopathic constipation (CIC). Montegrity will compete for market share in the CIC space with Allergan’s Linzess® (linaclotide), Takeda’s Amitiza® (lubiprostone), and Synergy’s Trulance® (plecanatide). Montegrity is anticipated to launch in 2019. continued

While the information in this newsletter is from sources we believe to be reliable, we do not warrant that the information in this document is free from error. Use it only as a guide. Statements regarding drugs or manufacturers are not intended as promotion; those statements should not be used to make assumptions about formulary status. Each trademarked drug name is the property of its respective owner. Drug Pipeline Monthly Update: December 2018 Page 2

Generic drug information

●● Fortesta® (testosterone transdermal gel pump): Actavis Pharma launched the first true generic of Endo Pharmaceuticals’ Fortesta gel pump. Fortesta is indicated in males for testosterone replacement therapy. Fortesta gel pump generated < $10 million in U.S. annual sales in 2017.

●● Harvoni® (edipasvir/sofosbuvir): Asegua Therapeutics/Gilead launched an authorized generic for Gilead Science’s Harvoni that is indicated for the treatment of:

→→ chronic hepatitis C virus (HCV) in adults with genotype 1, 4, 5, or 6 infections without cirrhosis or with compensated cirrhosis;

→→ adults with genotype 1 infection with decompensated cirrhosis, in combination with ribavirin;

→→ adults with genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, in combination with ribavirin; and

→→ pediatric patients 12 years of age and older or weighing at least 35 kg with genotype 1, 4, 5, or 6 without cirrhosis or with compensated cirrhosis. Harvoni generated $5,549 million in U.S. annual sales in 2017.

●● Epclusa® (sofosbuvir/velpatasvir): Asegua Therapeutics/Gilead launched an authorized generic of Gilead Science’s Epclusa for adult patients with chronic HCV genotype 1, 2, 3, 4, 5, or 6 infections:

→→ without cirrhosis or with compensated cirrhosis;

→→ with decompensated cirrhosis for use in combination with ribavirin. Epclusa is expected to be protected from additional generic competition until 2032. Epclusa generated $2,747 million in U.S. annual sales in 2017.

●● Zytiga® (abiraterone): Teva Pharmaceuticals, Hikma, and Mylan launched their generic versions of Janssen Biotech’s Zytiga 250 mg tablet which is indicated in combination with prednisone for the treatment of patients with:

→→ metastatic castration-resistant prostate cancer (CRPC); and

→→ metastatic high-risk castration-sensitive prostate cancer (CSPC). Teva, Hikma, and Mylan have shared 180-day exclusivity. Patriot launched an authorized generic version of Zytiga 250 mg. Zytiga 500 mg tablets are not available generically. Zytiga generated $1,224 million in U.S. in 2017.

●● Epipen® (epinephrine auto-injector): Teva Pharmaceuticals launched the first true generic version of Mylan Specialty’s Epipen 0.3 mg auto-injector indicated for the emergency treatment of allergic reactions (Type I) including anaphylaxis. Epipen had annual U.S. sales of $763 million in 2017.

●● Rapaflo® (silodosin): Sandoz launched the first generic version of Allergan’s Rapaflo capsule for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Multiple manufacturers have since launched their generic versions of Rapaflo. Rapaflo brand generated $206 million in U.S. sales in 2017.

●● Amicar® (aminocaproic acid): Vitruvias Therapeutics launched the first true generic of Clover Pharmaceuticals’ Amicar tablet 1000 mg indicated to enhance hemostasis when fibrinolysis contributes to bleeding. Amicar generated $53 million in annual U.S. sales in 2017. Drug Pipeline Monthly Update: December 2018 Page 3

New molecular entity approvals in the past twelve months

Generic name Brand name Manufacturer Indication(s) Date approved* prucalopride Montegrity™ Shire CIC December 2018

rifamycin Aemcolo™ Cosmo Travelers’ diarrhea November 2018 Pharmaceuticals revefenacin Yupelri™ AcelRx COPD November 2018 Pharmaceuticals baloxavir marboxil Xofluza™ Shinogi & Co Influenza October 2018

omadacycline Nuzyra™ Paratek Pneumonia and skin infections October 2018 Pharmaceuticals sarecycline Seysara™ Allergan and Paratek Acne October 2018 Pharmaceuticals galcanezumab-gnlm Emgality™ Eli Lilly Prevention of migraine September 2018

fremanezumab-vfrm Ajovy™ Teva Prevention of migraine September 2018

doravirine Pifeltro™ Merck HIV September 2018

eravacycline Xerava™ Tetraphase Pharma Complicated intra-abdominal infections September 2018

segesterone acetate/ Annovera™ TherapeuticsMD Inc Pregnancy prevention August 2018 ethinyl estradiol elagolix Orilissa® AbbVie Pain with endometriosis July 2018

tafenoquine Krintafel® GSK Radical cure of P. vivax malaria July 2018

tecovirimat Tpoxx™ Siga Technologies Smallpox July 2018

glycopyrronium tosylate Qbrexa™ Dermina Excessive sweating July 2018

plazomicin Zemdri™ Achaogen Complicated urinary tract infections July 2018

moxidectin Moxidectin™ Medicines River blindness June 2018 Development for Global Health erenumab-aooe Aimovig® Amgen/Novartis Prevention of migraine May 2018

sodium zirconium cyclosilicate Lokelma™ AstraZeneca Hyperkalemia May 2018

lofexidine Lucemyra™ US WorldMeds Mitigation of opioid withdrawal symptoms May 2018

coagulation factor Xa Andexxa® Portola Factor Xa reversal agent May 2018 (recombinant), inactivated-zhza bictegravir/emtricitabine/ Biktarvy™ Gilead HIV February 2018 tenofovir alafenamide *Date indicates FDA approval date only. The product launch and marketing dates are determined by the approved product’s manufacturer.

continued Drug Pipeline Monthly Update: December 2018 Page 4

Other new product approvals in the past twelve months

Generic name Brand name Manufacturer Indication(s) Date approved* itraconazole capsule Tolsura™ Mayne Pharma Fungal infections December 2018

lamivudine/tenofovir disoproxil Temixys™ Celltrion HIV November 2018 fumarate sufentanil Dsuvia™ AcelRx Pain November 2018 Pharmaceuticals clobazam oral soluble film (OSF) Sympazan™ Aquestive Lennox-Gastaut syndrome November 2018 Therapeutics levoleucovorin Khapzory™ Spectrum Rescue after high-dose methotrexate October 2018 therapy halobetasol propionate lotion Bryhali™ Bausch Health Cos Plaque psoriasis October 2018 0.01% Inc (Valeant) meloxicam orally disintegrating Qmiiz ODT™ TerSera Pain and inflammation October 2018 tables estradiol and progesterone Bijuva™ TherapeuticsMD Vasomotor symptoms due to menopause October 2018

testosterone enanthate Xyosted™ Antares Testosterone replacement therapy October 2018

latanoprost Xelpros™ Sun Pharma Open-angle glaucoma September 2018

buprenorphine/naloxone SL film Cassipa™ Teva Opioid dependence September 2018

doravirine, lamivudine and Delstrigo™ Merck HIV September 2018 tenofovir disoproxil fumarate loteprednol etabonate Inveltys™ Kala Pharmaceuticals Post-operative inflammation and pain September 2018 following ocular surgery tretinoin Altreno™ Ortho Dermatologic Acne September 2018

methylphenidate Jornay PM™ Ironshore ADHD August 2018 Pharmaceuticals cyclosporine Cequa™ Sun Pharma Dry eye disease August 2018

tafenoquine Arakoda™ 60 Degrees Prevention of malaria August 2018 Pharmaceuticals risperidone injectable Perseris™ Indivior Schizophrenia August 2018

pimavanserin, 34 mg capsule, Nuplaxid® Acadia Parkinson’s disease psychosis July 2018 10 mg tablet Pharmaceutical darunavir, cobicistat, Symtuza® Janssen HIV July 2018 emtricitabine, tenofovir alafenamide aripiprazole lauroxil Aristada Initio™ Alkermes Schizophrenia July 2018

desmopressin Nocdurna™ Ferring Nocturia July 2018 Pharmaceuticals celecoxib/amlodipine Consensi™ Kitov Pharma Osteoarthritis pain/hypertension May 2018

vaginal estradiol Imvexxy™ TherapeuticsMD Menopause symptoms May 2018

polyethylene glycol 3350, sodium Plenvu® Norgine Osmotic laxative May 2018 ascorbate, sodium sulfate, ascorbic acid, sodium chloride and potassium chloride for oral solution

continued Drug Pipeline Monthly Update: December 2018 Page 5

Other new product approvals in the past 12 months (continued)

Generic name Brand name Manufacturer Indication(s) Date approved* efavirenz, lamivudine, tenofovir Symfi™ Mylan HIV April 2018 disoproxil fumarate efavirenz, lamivudine, tenofovir Symfi Lo™ Mylan HIV March 2018 disoproxil fumarate lamivudine, tenofovir disoproxil Cimduo™ Mylan HIV March 2018 fumarate lidocaine topical system 1.8% ZTlido™ Sorrento Pain associated with post-herpetic March 2018 Therapeutics neuralgia (PHN) benzhydrocodone/ Apadaz™ KemPharm Pain March 2018 acetaminophen amantadine extended release Osmolex ER™ Osmotica Parkinson’s disease and drug-induced February 2018 Pharmaceutical extrapyramidal symptoms *Date indicates FDA approval date only. The product launch and marketing dates are determined by the approved product’s manufacturer. Drug Pipeline Monthly Update: December 2018 Page 6

Pipeline watch Anticipated FDA Generic Name Brand Name Manufacturer Indication(s) Decision Date solriamfetol N/A Jazz Pharmaceuticals Excessive sleepiness with narcolepsy or December 2018 obstructive sleep apnea tegaserod Zelnorm™ Sloan Pharma Irritable bowel syndrome — constipation December 2018

buprenorphine FluidCrystal N/A Braeburn Opioid dependence December 2018 injection depot (CAM2038) Pharmaceuticals astodrimer sodium VivaGel BV™ StarPharma Bacterial vaginosis December 2018

levetiracetam extended- release Elepsia XR™ Sun Pharma Seizures January 2019

samidorphan/ buprenorphine N/A Alkermes Major depressive disorder January 2019

prabotulinumtoxinA Evosyal™ Evolus and Daewoong Frown lines February 2019

iclaprim N/A Motif Bio Bacterial infections February 2019

sumatriptan nasal spray (DFN-02) N/A Promius Pharma/ Migraine February 2019 Aegis Therapeutics loteprednol etabonate N/A Bausch + Lomb Post-operative pain February 2019

halobetasol propionate and Duobrii™ Ortho Dermatologics Plaque psoriasis February 2019 tazarotene (Valeant) netarsudil/latanoprost Roclatan™ Aerie Glaucoma March 2019

olopatadine/mometasone Ryaltris™ Glenmark Seasonal allergic rhinitis March 2019 Pharmaceuticals sotagliflozin Zynquista™ Sanofi/Lexicon Type 1 diabetes March 2019

bremelanotide Rekynda™ AMAG/Palatin Hypoactive sexual desire disorder in women March 2019

aclidinium/formoterol Duaklir™ Circassia/ COPD March 2019 AstraZeneca brexanolone Zulresso™ Sage Therapeutics Postpartum depression March 2019

nasal glucagon N/A Lilly/Locemia Severe hypoglycemia March 2019 solutions metoclopramide nasal spray Gimoti™ Evoke Pharma Women with diabetic gastroparesis April 2019

dolutegravir/lamivudine N/A Viiv Healthcare HIV April 2019

loxicodegol (formerly known as N/A Nektar Therapeutics Chronic low back pain May 2019 NK TR-181) glucagon rescue pen G-Pen™ Xeris Pharmaceuticals Severe hypoglycemia June 2019

tiopronin Thiola® Mission Pharmcal Cystinuria June 2019 and Retrophin *Date usually indicates FDA approval date. The product’s launch date is determined by the manufacturer. Generic approvals that do not come to market within three months of approval are listed and dated when they enter the market. Drug Pipeline Monthly Update: December 2018 Page 7

First generic approvals of top selling brand name drugs in the past twelve months

Generic name Brand name Manufacturer Indication(s) Date approved* epinephrine auto-injector, 0.3 mg Epipen® Mylan Specialty The emergency treatment of allergic reactions December 2018

ledipasvir/sofosbuvir Harvoni® (authorized Gilead Sciences Hepatitis C virus (HCV) November 2018 generic-AG) sofosbuvir/velpatasvir Epclusa (AG) Gilead Sciences HCV November 2018

clobazam tablet Onfi® Lundbeck Lennox-Gastaut syndrome November 2018

testosterone Androgel® 1.62% Abbvie Testosterone replacement therapy (TRT) October 2018 pump tadalafil Cialis® Lilly Benign prostatic hyperplasia (BPH) and October 2018 erectile dysfunction (ED) tadalafil Adcirca® Lilly Pulmonary arterial hypertension (PAH) August 2018

mesalamine DR Asacol HD® Allergan Ulcerative colitis August 2018

buprenorphine/naloxone Suboxone® Indivior Opioid dependence June 2018 sublingual film, 8– 2 mg colesevelam hydrochloride Welchol® Sankyo High cholesterol and type 2 DM May 2018

memantine ER Namenda® XR Allergan Alzheimer’s disease March 2018

estradiol vaginal cream Estrace® Allergan Menopause symptoms January 2018

*Date usually indicates FDA approval date. The product’s launch date is determined by the manufacturer. Generic approvals that do not come to market within three months of approval are listed and dated when they enter the market.

continued Drug Pipeline Monthly Update: December 2018 Page 8

Other first generic launches in the past twelve months

Generic name Brand name Manufacturer Indication(s) Date approved* aminocaproic acid, 1000 mg Amicar® Clover Pharmaceuticals Hemostasis December 2018 silodosin Rapaflo® Allergan BPH December 2018 abiraterone tab, 250 mg Zytiga® Janssen Biotech Cancer chemotherapy November 2018 testosterone transdermal gel pump Fortesta® Endo Pharmaceuticals TRT November 2018 estradiol patch Minivelle® Noven Therapeutics Menopause November 2018 glycopyrrolate tablet Glycate® Carwin Pharmaceutical Peptic ulcer disease (PUD) November 2018 Associates itraconazole oral solution Sporanox® Janssen Fungal infections September 2018 dalfampridine ER Ampyra® Acorda Therapeutics Multiple sclerosis September 2018 carmustine BiCNU® Heritage Cancer chemotherapy September 2018 nevirapine Viramune® Boehringer Ingelheim HIV September 2018 dorzolamide/timolol Cosopt PF ® Merck Sharp & Dohme Glaucoma August 2018 dexamethasone Dexpak® Valeant Inflammation/allergic reactions/ August 2018 autoimmune diseases crotamiton Eurax® Ranbaxy Scabies and itchy skin August 2018 desoximetasone Topicort® Taro Plaque psoriasis August 2018 Topical Spray colesevelam oral suspension Welchol® Sankyo High cholesterol/diabetes July 2018 budesonide Uceris® Valeant Ulcerative colitis July 2018 doxycycline hyclate Targadox® Journey Medical Bacterial infection May 2018 praziquantel Biltricide® Bayer Healthcare Infection May 2018 miglustat Zavesca® Actelion Gaucher disease May 2018 clozapine orally disintegrating Fazaclo® ODT Teva Schizophrenia April 2018 tablet (ODT) cyclophosphamide Cyclophos- Amerigen Malignant diseases April 2018 phamide® drospirenone/ethinyl estradiol/ Safyral® West-Ward HIV April 2018 levomefolate ritonavir tablets Norvir® AbbVie HIV April 2018 tiagabine 12 mg, 16 mg Gabitril® Cephalon Seizures March 2018 methylphenidate, 10 mg capsule Ritalin LA® Novartis ADHD March 2018 minocycline ER Solodyn® Valeant Acne March 2018 sumatriptan/naproxen 85 mg – Treximet® Aurobindo Pharma Migraine February 2018 500 mg hydrocortisone butyrate Locoid® Lotion Valeant Atopic dermatitis February 2018 trientine Syprine® Valeant Wilson’s disease February 2018 efavirenz 600 mg Sustiva® BMS HIV February 2018

continued Drug Pipeline Monthly Update: December 2018 Page 9

Other first generic launches in the past twelve months (continued)

Generic name Brand name Manufacturer Indication(s) Date approved* atazanavir Reyataz® BMS HIV January 2018

carbinoxamine maleate Palgic® Alfasigma USA Allergies and cold January 2018

efavirenz, 50 mg and 200 mg Sustiva® BMS HIV January 2018

Generics of top selling brand drugs potentially available soon

Generic name Brand name Manufacturer Indication(s) To market date* cinacalcet Sensipar® Amgen Hyperparathyroidism 2018

cyclosporine Restasis® Allergan Dry eye 2018

treprostinil Remodulin® United Therapeutics PAH 2018

ambrisentan Letairis® Gilead PAH 2018

ascorbic acid; PEG; potassium Moviprep® Salix Valeant Osmotic laxative 2018 chloride; sodium ascorbate; sodium chloride; sodium sulfate mesalamine Canasa® Forest/Allergan Ulcerative colitis 2018

pimecrolimus Elidel® Valeant Atopic dermatitis 2018

loteprednol Lotemax® Bausch + Lomb/ Valeant Eye inflammation 2018

difluprednate Durezol® Alcon/Novartis Eye inflammation 2018 – 2019

albuterol sulfate Proventil® HFA/ Merck/Teva Asthma/COPD 2018 – 2019 ProAir® HFA fluticasone/ salmeterol Advair® Diskus GSK Asthma/COPD 2018 – 2019

ethinyl estradiol/etonogestrel NuvaRing® Organon/Merck & Co Pregnancy prevention 1H2019

exenatide Byetta® AstraZeneca Diabetes 2019

tolvaptan Samsca® Otsuka Pharmaceutical Hyponatremia 2019

ranolazine Ranexa® Gilead Sciences Angina February 2019

aliskiren Tekturna® Noden Pharma Hypertension March 2019

erlotinib Tarceva® Genentech Cancer 2Q2019

solifenacin Vesicare® Astellas Over active bladder April 2019

* Expected to market dates are predictions made by Prime based on industry information.

References 1. https://www.poz.com/article/fda-approves-truvadalike-hiv-tablet-temixys. 2. https://www.prnewswire.com/news-releases/mayne-pharma-receives-fda-approval-of-tolsura-suba-itraconazole-capsules-for-the-treatment-of-certain-fungal-infections-300763882.html.

All brand names are property of their respective owners.