The Clinical InSight

April 2018

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Recent FDA Approvals

New Medications

Trade Name Dosage Form Manufacturer Indication(s) Approval Date (generic name) Strength For the treatment of thrombocytopenia in adult Rigel Tablets, patients with chronic immune Tavalise Pharmaceuticals, 100 mg and thrombocytopenia (ITP) who April 17, 2018 (fostamatinib) Inc. 150 mg have had an insufficient response to a previous treatment. For the treatment of X-linked Ultragenyx Crysvita Injection, hypophosphatemia (XLH) in Pharmaceutical April 17, 2018 (burosumab-twza) 10 mg/mL adult and pediatric patients 1 Inc. year of age and older. For use in combination with dexamethasone in adults for Akynzeo the prevention of acute and Helsinn Injection, (fosnetupitant; delayed nausea and vomiting Therapeutics 235 mg/0.25 April 19, 2018 palonosetron associated with initial and (U.S.), Inc. mg hydrochloride) repeat courses of highly emetogenic cancer chemotherapy.

New Combinations and Formulations

Trade Name Dosage Form Manufacturer Indication(s) Approval Date (generic name) Strength To slow kidney function Otsuka Immediate decline in adults at risk of Pharmaceutical Release Tablets, Jynarque rapidly progressing Development & 15 mg, 30 mg, April 23, 2018 (tolvaptan) autosomal dominant Commercializatio 45 mg, 60 mg, polycystic kidney disease n, Inc. and 90 mg (ADPKD).

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Trade Name Dosage Form Manufacturer Indication(s) Approval Date (generic name) Strength Hydrocodone For the symptomatic relief Bitartrate; ECI of cough and to loosen Guaifenesin Tablets, Pharmaceuticals, mucus associated with the April 25, 2018 (hydrocodone 5 mg/400 mg LLC common cold in patients bitartrate; 18 years of age and older. guaifenesin)

New Generics

Generic Name Trade Name Dosage Form Manufacturer(s) Approval Date

West-Ward Everolimus Zortress Tablets April 12, 2018 Pharmaceuticals Corp. Ertapenem Sodium Invanz Injection ACS Dobfar S.p.A. April 16, 2018 Amerigen Miglustat Zavesca Capsules April 17, 2018 Pharmaceuticals, Inc.

Pipeline

New Medication Pipeline Anticipated Drug Name Generic Name Route Mechanism of Action Indication(s) Approval Date AndexXa Andexanet Alfa Intravenous Antidote for oral Reversal of 05/04/2018 anticoagulants anticoagulation by FXa inhibitors Plenvu Polyethylene Oral Osmotic laxative Bowel cleansing 05/13/2018 Glycol Aimovig Erenumab Subcutaneous Calcitonin gene-related Migraine 05/17/2018 peptide (CGRP) inhibitor Avatrombopag Avatrombopag Oral Thrombopoietin Thrombocytopenia 05/21/2018 Receptor Agonists Methylene Blue Methylene Blue Oral Imaging For diagnostic 05/21/2018 MMX imaging of colorectal cancers

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Anticipated Drug Name Generic Name Route Mechanism of Action Indication(s) Approval Date BMN 165 Pegvaliase Subcutaneous Enzyme replacement Phenylketonuria 05/25/2018 therapy Yuvvexy Estradiol Other Estrogens Vaginal atrophy 05/29/2018

Evosyal Botulinum Toxin Injectable Neurotoxins Glabellar frown lines 05/2018 (Branded Type A Competitor of Botox (cosmetic), Xeomin, Dysport) KW-0761 Mogamulizumab Intravenous Anti-CCR4 antibody Cutaneous T-cell 06/04/2018 lymphoma ACHN-490 Plazomicin Intravenous Aminoglycoside Complicated UTI 06/25/2018 antibiotic caused by carbapenem-resistant Enterobacteriaceae Epidiolex Epidiolex Oral Cannabinoid Dravet syndrome; 06/27/2018 Lennox-Gastaut syndrome; Infantile spasms; Epilepsy Aripiprazole Aripiprazole Intramuscular Atypical antipsychotic Schizophrenia 06/30/2018 Lauroxil Lauroxil NanoCrystal Dispersion Binimetinib Binimetinib Oral MEK inhibitor BRAF-mutant 06/30/2018 melanoma LGX818 Encorafenib Oral B-RAF kinase inhibitor BRAF-mutant 06/30/2018 melanoma TEV-48125 Fremanezumab Subcutaneous Calcitonin gene-related Migraine 06/2018 peptide (CGRP) inhibitor Alicaforsen Alicaforsen Rectal Antisense Pouchitis 2Q 2018 oligonucleotide CL-108 Acetaminophen; Oral COX inhibitor, H1 Symptoms 2Q 2018 Hydrocodone; histamine receptor associated with acute Promethazine antagonist, Opioid opioid withdrawal; agonist Osteoarthritis LGX818 Encorafenib Oral B-RAF kinase inhibitor BRAF-mutant 06/30/2018 melanoma

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Anticipated Drug Name Generic Name Route Mechanism of Action Indication(s) Approval Date TEV-48125 Fremanezumab Subcutaneous Calcitonin gene-related Migraine 06/2018 peptide (CGRP) inhibitor Alicaforsen Alicaforsen Rectal Antisense Pouchitis 2Q 2018 oligonucleotide Lofexidine Lofexidine Oral Alpha adrenergic agonist Symptoms 2Q 2018 associated with acute opioid withdrawal Olumiant Baricitinib Oral Janus Kinase inhibitor Rheumatoid arthritis 2Q 2018

IONIS-TTRRx Inotersen Subcutaneous Protein synthesis Familial amyloid 07/06/2018 inhibitor polyneuropathy Azedra Ultratrace Injectable Electron transport Neuroendocrine 07/30/2018 Iobenguane I- inhibitor tumors; 131 Pheochromocytoma Tpoxx Tecovirimat Oral Orthopoxvirus egress Smallpox 08/08/2018 Intravenous inhibitor ALN-TTR02 Patisiran Intravenous Antisense Familial amyloid 08/11/2018 oligonucleotide polyneuropathy Galafold Migalastat Oral Chemical chaperone Fabry disease 08/13/2018

AG-120 Ivosidenib Oral Isocitrate Acute myeloid 08/21/2018 dehydrogenase 1 leukemia inhibitor Stannsoporfin Stannsoporfin Intramuscular Heme oxygenase Hyperbilirubinemia 08/22/2018 inhibitors S-888711 Lusutrombopag Oral Thrombopoietin Thrombocytopenia 08/26/2018 Receptor Agonists SHP643 Lanadelumab Subcutaneous Plasma kallikrein Prophylaxis against 08/26/2018 inhibitor angioedema attacks in hereditary angioedema Volanesorsen Volanesorsen Subcutaneous Antisense apolipoprotein Familial 08/30/2018 inhibitor chylomicronemia syndrome PF-06463922 Lorlatinib Oral Tyrosine kinase inhibitor Non-small cell lung 08/2018 cancer

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Anticipated Drug Name Generic Name Route Mechanism of Action Indication(s) Approval Date Tafenoquine Tafenoquine Oral Antimalarials Prophylaxis; 08/2018; Treatment of malaria 4Q 2018 Dacomitinib Dacomitinib Oral Tyrosine kinase inhibitor Non-small cell lung 09/2018 cancer BAY 94-9027 Coagulation Intravenous Coagulation factor VIII Hemophilia A 3Q 2018 Factor VIII (recombinant) CAT-8015 Moxetumomab Intravenous Cytotoxic agent Anti- Chronic lymphocytic 3Q 2018 Pasudotox CD22 antibody leukemia Duobri Halobetasol Topical Corticosteroid; retinoid Plaque psoriasis 3Q 2018 Propionate; Tazarotene Elagolix Elagolix Oral Luteinizing hormone Endometriosis 3Q 2018 releasing hormone Uterine fibroids antagonist Prograf (oral Tacrolimus Oral Immunosuppressant Prophylaxis of organ 3Q 2018 granules) rejection Symtuza Darunavir; Oral Protease inhibitor; HIV-1 infection 3Q 2018 Cobicistat; Nucleoside analogue Emtricitabine; reverse transcriptase Tenofovir inhibitor;Pharmacokinetic Alafenamide enhancer Baremsis Amisulpride Intravenous Atypical antipsychotic Postoperative nausea 10/05/2018 and vomiting Duvelisib Duvelisib Oral Phosphoinositide 3- Chronic lymphocytic 10/05/2018 kinaseinhibitor leukemia; Follicular lymphoma DOR/3TC/TDF Doravirine; Oral Nucleoside analogue HIV-1 infection 10/23/2018 Lamivudine; reverse transcriptase Tenofovir inhibitor; Non-nucleoside Disoproxil reverse transcriptase Fumarate inhibitor MK-1439 Doravirine Oral Non-nucleoside reverse HIV infection 10/23/2018 transcriptase inhibitor LY2951742 Galcanezumab Subcutaneous Calcitonin gene-related Migraine 10/2018 peptide (CGRP) inhibitor

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Anticipated Drug Name Generic Name Route Mechanism of Action Indication(s) Approval Date PTK 0796 Omadacycline Oral Aminomethylcycline Acute Bacterial Skin 10/2018 Intravenous antibiotic and Skin Structure Infections; Community-acquired bacterial pneumonia TD-4208 Revefenacin Inhaled Long-acting muscarinic Chronic obstructive 11/13/2018 antagonist pulmonary disease Olinvo Oliceridine Intravenous Opioid agonist Acute pain 12/02/2018

JZP-110 Solriamfetol Oral CNS stimulant Excessive sleepiness 12/20/2018 in narcolepsy/ obstructive sleep apnea Resolor Prucalopride Oral 5-HT4 serotonin receptor Chronic idiopathic 12/21/2018 agonist constipation Calaspargase Calaspargase Intravenous Antineoplastic enzymes Acute lymphocytic 12/22/2018 pegol Pegol leukemia LOXO-101 Larotrectinib Oral Tropomyosin receptor Solid tumors 4Q 2018 kinases (TRK) inhibitor Hematological malignancies VivaGel BV Astodrimer Intravaginal Anti-infective Bacterial vaginosis 4Q 2018 Sodium Seysara Sarecycline Oral Tetracycline antibiotic Acne vulgaris 2H 2018

ALKS 5461 Buprenorphine; Oral Opioid antagonist; Major depressive 01/31/2019 Samidorphan Opioid partial agonist disorder Arikayce Liposomal Inhaled Aminoglycoside Nontuberculous 1Q 2019 amikacin antibiotic mycobacteria lung infections ASP2215 Gilteritinib Oral Receptor tyrosine Acute myeloid 1Q 2019 kinase inhibitor leukemia Eravacycline Eravacycline Oral Fluorocycline antibiotic Complicated intra- 1Q 2019 Intravenous abdominal infections; Complicated UTI Firdapse Amifampridine Oral Potassium Channel Lambert-Eaton 1Q 2019 Phosphate Inhibitor myasthenic syndrome

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Anticipated Drug Name Generic Name Route Mechanism of Action Indication(s) Approval Date N8-GP Coagulation Intravenous Coagulation factor VIII Hemophilia A 1Q 2019 Factor VIII (recombinant) (Recombinant) NI-0501 Emapalumab Intravenous Type II interferon Hemophagocytic 1Q 2019 inhibitor lymphohistiocytosis Rekynda Bremelanotide Injectable Peptide melanocortin Female sexual 1Q 2019 receptor agonist dysfunction Zemcolo Rifamycin-SV Oral Rifamycin antibacterial Diarrhea caused by 1Q 2019 certain organisms BI 655066 Risankizumab Subcutaneous Interleukin 23 (IL-23) Plaque psoriasis; 2Q 2019 antagonist Crohn's disease SAGE-547 Brexanolone Intravenous GABA Modulators Postpartum 2Q 2019 depression SL-401 TBD Injectable Antineoplastics Blastic plasmacytoid 2Q 2019 dendritic cell neoplasm

2018 New Generic Pipeline

Anticipated Brand 2016 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 04/08/2018 NUVARING Ethinyl Estradiol; Organon; Merck & Contraception $773M Etonogestrel Co 05/22/2018 ADCIRCA Tadalafil Eli Lilly; United Pulmonary Arterial $372M Therapeutics Hypertension Net sales 06/01/2018 ONEXTON Benzoyl Peroxide; Dow Pharmaceutical Acne $134M Clindamycin Sciences; Valeant Phosphate 06/12/2018 EMSAM Selegiline Somerset Depression $42M Pharmaceuticals; Mylan 06/26/2018 REMODULIN Treprostinil United Therapeutics Pulmonary Arterial $602M Hypertension Net sales 06/26/2018 SOLTAMOX Tamoxifen Citrate DARA BioSciences; Breast Cancer $1M Midatech

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Anticipated Brand 2016 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 06/2018 ABSTRAL Fentanyl Citrate Sentynl; Orexo Acute breakthrough $17M cancer pain 2Q 2018 DELZICOL Mesalamine Allergan Inflammatory Bowel $173M Disease; Ulcerative colitis 2Q 2018 RESTASIS Cyclosporine Allergan Dry eye $1,812M

2Q 2018 SENSIPAR Cinacalcet Amgen Thyroid Cancer; $1,523M Hydrochloride Hypercalcemia in parathyroid carcinoma 1H 2018 GANIRELIX Ganirelix Acetate Organon; Merck & Female infertility $54M ACETATE Co INJECTION 1H 2018 MAKENA (vial) Hydroxyprogesterone Lumara Health; Prevention of pre-term $219M Caproate AMAG birth Pharmaceuticals 07/01/2018 ACANYA Benzoyl Peroxide; Dow Pharmaceutical Acne $74M Clindamycin Sciences; Valeant Phosphate 07/2018 LETAIRIS Ambrisentan Gilead Pulmonary Arterial TBD Hypertension 09/24/2018 MOVIPREP Ascorbic Acid; Salix; Valeant Constipation or Bowel $50M Polyethylene Glycol Cleansers 3350; Potassium Chloride; Sodium Ascorbate; Sodium Chloride; Sodium Sulfate 09/27/2018 CIALIS Tadalafil Eli Lilly Benign Prostatic $1,954M Hyperplasia; Erectile Dysfunction 09/30/2018 ZYPREXA Olanzapine Pamoate Eli Lilly Schizophrenia $11M RELPREVV 3Q 2018 LEVITRA (5, 10, Vardenafil Bayer Erectile Dysfunction $164M 20 mg) Hydrochloride

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Anticipated Brand 2016 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 3Q 2018 ZORTRESS Everolimus Novartis Complications of $110M Transplanted Organs and Tissues: Prophylaxis of organ rejection 10/21/2018 ONFI (oral Clobazam H. Lundbeck A/S Epilepsy: Lennox- $147M suspension) Gastaut syndrome 10/21/2018 ONFI (tablets) Clobazam H. Lundbeck A/S Epilepsy: Lennox- $420M Gastaut syndrome 10/22/2018 VIVLODEX Meloxicam Iroko; iCeutica Osteoarthritis $27M

10/31/2018 STAXYN Vardenafil Bayer Erectile Dysfunction TBD Hydrochloride 11/18/2018 FINACEA GEL Azelaic Acid Bayer Rosacea: $83M

12/15/2018 CANASA Mesalamine Forest; Allergan Inflammatory Bowel $237M Disease; Ulcerative colitis 12/27/2018 ELIDEL Pimecrolimus Valeant Atopic dermatitis $211M

4Q 2018 PROAIR HFA Albuterol Sulfate Teva Asthma; Exercise- $1,365M induced bronchospasm 4Q 2018 PYLERA Bismuth Subcitrate Aptalis; Allergan Gastrointestinal Ulcers: $29M Potassium; Eradication of Metronidazole; Heliobacter pylori Tetracycline 4Q 2018 RAPAFLO Silodosin Allergan Benign Prostatic $230M Hyperplasia 2H 2018 AMPYRA Dalfampridine Acorda Multiple Sclerosis TBD

2H 2018 FLECTOR Diclofenac Epolamine IBSA Institut Acute pain $136M Biochemique; Pfizer 2018 ANDROGEL Testosterone AbbVie Hypogonadism $78M (1.62% packets) 2018 ANDROGEL Testosterone AbbVie Hypogonadism $946M (1.62% pump)

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Anticipated Brand 2016 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 2018 ASTAGRAF XL Tacrolimus Astellas Complications of $14M Transplanted Organs and Tissues: Prophylaxis of organ rejection 2018 BYETTA Exenatide Synthetic AstraZeneca Diabetes Mellitus $277M

2018 CUPRIMINE (250 Penicillamine Aton; Valeant Genitourinary System $172M mg) Diseases 2018 INVANZ Ertapenem Sodium Merck & Co Infections $364M

2018 KALETRA Lopinavir; Ritonavir AbbVie HIV-1 infection $134M (tablets) 2018 LOTEMAX (gel) Loteprednol Etabonate Bausch + Lomb; Post-operative $115M Valeant inflammation and pain following ocular surgery 2018 NEXIUM (20 mg Esomeprazole AstraZeneca Gastroesophageal Reflux $49M and 40 mg Magnesium Disease packets for oral suspension) 2018 PROVENTIL-HFA Albuterol Sulfate 3M Health Care; Asthma: Exercise- $254M Merck & Co induced bronchospasm 2018 TRACLEER (film- Bosentan Actelion; Janssen Pulmonary Arterial $53M coated tablet) Hypertension 2018 TRISENOX Arsenic Trioxide Cephalon; Teva Leukemia $4M

2018 ZAVESCA Miglustat Actelion; Janssen Gaucher disease, $3M Type 1 2018-2019 ADVAIR DISKUS Fluticasone GSK Asthma; Chronic $4,765M Propionate; Salmeterol Obstructive Pulmonary Xinafoate Disease 2018-2019 AZASITE Azithromycin Akorn Conjunctivitis $20M

2018-2019 DUREZOL Difluprednate Alcon; Novartis Eye And Adnexa TBD Diseases; Uveitis 2018-2019 FENTORA Fentanyl Citrate Cephalon; Teva Acute Pain: $139M Breakthrough cancer pain

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Anticipated Brand 2016 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 2018-2019 MOXEZA Moxifloxacin Alcon; Novartis Conjunctivitis $21M Hydrochloride 2018-2019 PRESTALIA Amlodipine Besylate; Symplmed; Marina Hypertension: $1M Perindopril Arginine Biotech 2018-2019 QUILLIVANT XR Methylphenidate NextWave Attention Deficit $188M Hydrochloride Pharmaceuticals; Hyperactivity Disorder Pfizer 2018-2019 SAMSCA Tolvaptan Otsuka Hypervolemic and $99M euvolemic hyponatremia 2018-2019 TORISEL Temsirolimus Wyeth; Pfizer Kidney Cancer $40M

2018-2019 ZYTIGA Abiraterone Acetate Janssen Prostate Cancer: $1,154M (250,500 mg) Prostate cancer

Medication with Significant Label Changes

Trade Name Summary of Label Changes (generic name) Afinitor, Afinitor 4 Contraindications Additions and/or revisions underlined: Disperz AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to (everolimus) everolimus or to other rapamycin derivatives. 5 Warnings and Precautions Additions and/or revisions underlined: 5.1 Non-infectious Pneumonitis Addition of /AFINITOR DISPERZ to wherever the word AFINITOR is throughout the W&P section. … Continue AFINITOR/AFINITOR DISPERZ without dose alteration in patients who develop radiological changes … For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity. Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose. 5.2 Infections … Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. The incidence of serious infections was reported at a higher frequency in patients less than 6 years of age. Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity of infection. Administer prophylaxis for PJP … 5.3 Severe Hypersensitivity Reactions Newly added subsection:

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Trade Name Summary of Label Changes (generic name) Hypersensitivity reactions to AFINITOR/AFINITOR DISPERZ have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue AFINITOR/AFINITOR DISPERZ for the development of clinically significant hypersensitivity. Additions and/or revisions underlined: 5.4 Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ … was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue AFINITOR/AFINITOR DISPERZ for angioedema. 5.5 Stomatitis … as they may exacerbate the condition. Do not administer antifungal agents, unless fungal infection has been diagnosed. 5.6 Renal Failure Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR/AFINITOR DISPERZ. The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure. 5.9 Metabolic Disorders Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR/AFINITOR DISPERZ at an incidence up to 75%, 86%, and 73%, respectively. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively. In non- diabetic patients, monitor fasting serum glucose prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting AFINITOR/AFINITOR DISPERZ. For Grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity. 5.10 Myelosuppression Newly added subsection: Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR/AFINITOR DISPERZ. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively. Monitor complete blood count prior to starting AFINITOR/AFINITOR DISPERZ every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity. Additions and/or revisions underlined: 5.11 Risk of Infection or Reduced Immune Response with Vaccination The safety of immunization with live vaccines during AFINITOR/AFINITOR DISPERZ therapy has not been studied. Due to the potential increased risk of infection, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with AFINITOR/AFINITOR DISPERZ. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations …

Besivance 5 Warnings and Precautions 5.1 Not for Injection into the Eye (besifloxacin (Newly added subsection) hydrochloride) 5.1 Not for Injection into the Eye

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Trade Name Summary of Label Changes (generic name) Carnitor, 5 Warnings and Precautions WARNINGS Carnitor SF (additions underlined) (levocarnitine) Hypersensitivity Reactions Serious hypersensitivity reactions, including rash, urticarial, and facial edema have been reported with oral CARNITOR. Other serious hypersensitivity reactions, including anaphylaxis, laryngeal edema, and bronchospasm have been reported following intravenous levocarnitine administration, mostly in patients with end stage renal disease undergoing dialysis. Discontinue use of CARNITOR and instruct patients to seek medical attention if they experience symptoms suggestive of a hypersensitivity reaction.

Celestone 5 Warnings and Precautions WARNINGS Soluspan Additions and/or revisions underlined: (betamethasone General Rare instances of anaphylactoid/anaphylactic reactions with a possibility of shock have occurred in acetate; patients receiving parenteral corticosteroid therapy. Use caution in patients who have a history of allergic betamethasone reactions to corticosteroids. Ophthalmic Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular sodium pressure, glaucoma with possible damage to the optic nerves, and may enhance the establishment of phosphate) secondary ocular infections due to bacteria, fungi, or viruses. Consider referral to an ophthalmologist for patients who develop ocular symptoms or use corticosteroid-containing products for more than 6 weeks. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should not be used in active ocular herpes simplex.

Decadron 5 Warnings and Precautions WARNINGS (dexamethasone) Infections General (Additions and/or revisions are underlined) Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Consider referral to an ophthalmologist for patients who develop ocular symptoms or use corticosteroid-containing products for more than 6 weeks…

E.E.S., Eryped 4 Contraindications (Additions and/or revisions are underlined) (erythromycin Do not use erythromycin concomitantly with HMG CoA reductase inhibitors (statins) that are extensively ethylsuccinate) metabolized by CYP 3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis. 5 Warnings and Precautions PRECAUTIONS (Additions and/or revisions are underlined) When indicated, incision and drainage or other surgical procedures should be performed in conjunction with antibiotic therapy. Observational studies in humans have reported cardiovascular malformations after exposure to drug products containing erythromycin during early pregnancy.

Eryc 4 Contraindications (Additions and/or revisions are underlined)

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Trade Name Summary of Label Changes (generic name) (erythromycin) Do not use erythromycin concomitantly with HMG CoA reductase inhibitors (statins) that are extensively metabolized by CYP 3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis.

Erythrocin 4 Contraindications (Additions and/or revisions are underlined) (erythromycin Do not use erythromycin concomitantly with 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase lactobionate) inhibitors (statins) that are extensively metabolized by cytochrome P450 isoform 3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis.

Evotaz 4 Contraindications (additions to Table 1, please refer to label) (atazanavir 5 Warnings and Precautions sulfate; 5.5 Chronic Kidney Disease cobicistat) (new subsection added) Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to EVOTAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with EVOTAZ and continued during treatment with EVOTAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking EVOTAZ. In patients with progressive kidney disease, discontinuation of EVOTAZ may be considered.

Exparel 5 Warnings and Precautions 5.2 Warnings and Precautions Specific for EXPAREL (bupivacaine) (Additions and/or revisions are underlined) Avoid additional use of local anesthetics within 96 hours following administration of EXPAREL. EXPAREL has not been evaluated for the following uses and, therefore, is not recommended for these types of analgesia or routes of administration.  Epidural  Intrathecal  regional nerve blocks other than interscalene brachial plexus nerve block  intravascular or intra-articular use EXPAREL has not been evaluated for use in the following patient population and, therefore, is not recommended for administration to these groups.  patients younger than 18 years old  pregnant patients The potential sensory and/or motor loss with EXPAREL is temporary and varies in degree and duration depending on the site of injection and dosage administered and may last for up to 5 days as seen in clinical trials.

Flagyl, Flagyl 5 Warnings and Precautions WARNINGS ER (Newly added subsection) (metronidazole) …

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Trade Name Summary of Label Changes (generic name) Risk of Hepatotoxicity and Death in Patients with Cockayne Syndrome Cases of severe hepatotoxicity/acute hepatic failure, including cases with a fatal outcome with very rapid onset after treatment initiation in patients with Cockayne syndrome have been reported with products containing metronidazole for systemic use. In this population, metronidazole should therefore be used after careful benefit-risk assessment and only if no alternative treatment is available. Obtain liver function tests prior to the start of therapy, within the first 2-3 days after initiation of therapy, frequently during therapy and after end of treatment. Discontinue metronidazole if elevation of liver function tests occurs, and monitor liver function tests until the baseline values are reached. Advise patients with Cockayne syndrome to stop taking metronidazole immediately if they experience any symptoms of potential liver injury, such as abdominal pain, nausea, change in stool color or jaundice, and to contact their healthcare provider.

Hibistat 5 Warnings and Precautions DRUG FACTS (chlorhexidine WARNINGS gluconate) (additions underlined) For external use only. Flammable: Keep away from fire or flame Allergy alert: This product may cause a severe allergic reaction. Symptoms may include:  wheezing/diffi ulty breathing  shock  facial swelling  hives  rash If an allergic reaction occurs, stop use and seek medical help right away.

Kisqali Femara 4 Contraindications (Additions and/or revisions are underlined) Co-pack Known hypersensitivity to the active substance (letrozole), or to any of the excipients of FEMARA. Refer to (Copackaged) FEMARA Prescribing Information. (letrozole; ribociclib succinate) Levulan 5 Warnings and Precautions 5.1 Transient Amnestic Episodes (aminolevulinic (new subsection added) acid Transient amnestic episodes have been reported during postmarketing use of Levulan Kerastick in hydrochloride) combination with BLU-U Blue Light Photodynamic Therapy Illuminator. Inform patients and their caregivers that Levulan Kerastick in combination with PDT may cause transient amnestic episodes. Advise them to contact the healthcare provider if the patient develops amnesia after treatment.

Lincocin 5 Warnings and Precautions Warnings (lincomycin (Additions and/or revisions are underlined) hydrochloride) ….Hypersensitivity

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Trade Name Summary of Label Changes (generic name) Severe hypersensitivity reactions, including anaphylactic reactions and severe cutaneous adverse reactions (SCAR) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and erythema multiforme (EM) have been reported in patients receiving LINCOCIN therapy. If an anaphylactic reaction or severe skin reaction occurs, LINCOCIN should be discontinued and appropriate therapy should be initiated. …..Skin and subcutaneous tissue disorders Toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis, dermatitis bullous, dermatitis exfoliative, erythema multiforme, rash, urticaria, pruritus.

Lopid 4 Contraindications (Additions and/or revisions are underlined) (gemfibrozil) 4. Combination therapy of gemfibrozil with simvastatin. 5. Combination therapy of gemfibrozil with repaglinide. 6. Combination therapy of gemfibrozil with dasabuvir. 7. Combination therapy of gemfibrozil with selexipag. 5 Warnings and Precautions WARNINGS (Additions and/or revisions are underlined) 7. CYP2C8 substrates - Gemfibrozil, a strong inhibitor of CYP2C8, may increase exposure of CYP2C8 substrates when administered concomitantly. 8. OATP1B1 substrates – Gemfibrozil is an inhibitor of organic anion-transporter polyprotein (OATP) 1B1 and may increase exposure of drugs that are substrates of OATP1B1 (e.g., atrasentan, atorvastatin, bosentan, ezetimibe, fluvastatin, glyburide, SN-38 [active metabolite of irinotecan], rosuvastatin, pitavastatin, pravastatin, rifampin, valsartan, olmesartan). Therefore, dosing reductions of drugs that are substrates of OATP1B1 may be required when gemfibrozil is used concomitantly. Combination therapy of gemfibrozil with simvastatin or with repaglinide, which are OATP1B1 substrates, is contraindicated.

Lupron Depot 5 Warnings and Precautions (PLR conversion; subsections created as below, please see label for more information) (leuprolide 5.1 Loss of Bone Mineral Density Pregnancy Risk acetate) 5.2 Pregnancy Risk 5.3 Serious Allergic Reactions 5.4 Initial Flare of Symptoms 5.5 Convulsions 5.6 Clinical Depression

Olux 5 Warnings and Precautions 5.2 Ophthalmic Adverse Reactions (clobetasol (Newly Added Subsection) propionate) Use of topical corticosteroids, including OLUX Foam, may increase the risks of glaucoma and posterior subcapsular cataract. Glaucoma and cataracts have been reported in postmarketing experience with the use of topical corticosteroid products, including topical clobetasol products. Avoid contact of OLUX Foam with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

Opdivo 5 Warnings and Precautions 5.1 Immune-Mediated Pneumonitis

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Trade Name Summary of Label Changes (generic name) (nivolumab) (additions underlined) … OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 6% (25/407) of patients. The median time to onset of immune- mediated pneumonitis was 1.6 months (range: 24 days to 10.1 months). Immune-mediated pneumonitis led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 2.2% and 3.7% of patients, respectively. Approximately 84% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 30 days (range: 5 days to 11.8 months). Complete resolution occurred in 68% of patients. Approximately 13% of patients had recurrence of pneumonitis after re-initiation of OPDIVO with ipilimumab. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, immune- mediated pneumonitis occurred in 4.4% (24/547) of patients. The median time to onset of immune- mediated pneumonitis was 2.6 months (range: 8 days to 9.2 months). Immune-mediated pneumonitis led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 2.0% and 1.6% of patients, respectively. Approximately 92% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 19 days (range: 4 days to 3.2 months). Approximately 8% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 79% of patients without recurrence of pneumonitis after re-initiation of OPDIVO with ipilimumab. 5.2 Immune-Mediated Colitis (additions underlined) … OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, immune- mediated colitis occurred in 26% (107/407) of patients including three fatal cases. The median time to onset of immune- mediated colitis was 1.6 months (range: 3 days to 15.2 months). Immune- mediated colitis led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 16% and 7% of patients, respectively. Approximately 96% of patients with colitis received high- dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1.1 month (range: 1 day to 12 months). Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 75% of patients. Approximately 28% of patients had recurrence of colitis after re-initiation of OPDIVO with ipilimumab. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, immune- mediated colitis occurred in 10% (52/547) of patients. The median time to onset of immune- mediated colitis was 1.7 months (range: 2 days to 19.2 months). Immune-mediated colitis led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 3.5% and 4.2% of patients, respectively. Approximately 83% of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 27 months). Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 89% of patients. Two patients had recurrence of colitis after re-initiation of OPDIVO with ipilimumab. 5.3 Immune-Mediated Hepatitis (additions underlined) …

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Trade Name Summary of Label Changes (generic name) OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, immune- mediated hepatitis occurred in 13% (51/407) of patients; the median time to onset was 2.1 months (range: 15 days to 11 months). Immune-mediated hepatitis led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 6% and 5% of patients, respectively. Approximately 92% of patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1.1 month (range: 1 day to 13.2 months). Complete resolution occurred in 75% of patients. Approximately 11% of patients had recurrence of hepatitis after re-initiation of OPDIVO with ipilimumab. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg

In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, immune- mediated hepatitis occurred in 7% (38/547) of patients; the median time to onset was 2 months (range: 14 days to 26.8 months). Immune-mediated hepatitis led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 3.7% and 3.1% of patients, respectively. Approximately 92% of patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1.0 month (range: 1 day to 4.0 months). Complete resolution occurred in 87% of patients without recurrence of hepatitis after re-initiation of OPDIVO with ipilimumab. 5.4 Immune-Mediated Endocrinopathies Hypophysitis (additions underlined) … OPDIVO as a Single Agent In patients receiving OPDIVO as a single agent, hypophysitis occurred in 0.6% (12/1994) of patients; the median time to onset was 4.9 months (range: 1.4 to 11 months). Hypophysitis led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.2% of patients. Approximately 67% of patients with hypophysitis received hormone replacement therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 5 to 26 days). OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, hypophysitis occurred in 9% (36/407) of patients; the median time to onset was 2.7 months (range: 27 days to 5.5 months). Hypophysitis led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 1.0% and 3.9% of patients, respectively. Approximately 75% of patients with hypophysitis received hormone replacement therapy and 56% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 19 days (range: 1 day to 2.0 months). OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, hypophysitis occurred in 4.6% (25/547) of patients; the median time to onset was 2.8 months (range: 1.3 months to 7.3 months). Hypophysitis led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 1.3% and 2.6% of patients, respectively. Approximately 72% of patients with hypophysitis received hormone replacement therapy and 60% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 10 days (range: 1 day to 1.6 months). Adrenal Insufficiency … OPDIVO as a Single Agent

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Trade Name Summary of Label Changes (generic name) In patients receiving OPDIVO as a single agent, adrenal insufficiency occurred in 1% (20/1994) of patients and the median time to onset was 4.3 months (range: 15 days to 21 months). Adrenal insufficiency led to permanent discontinuation of OPDIVO in 0.1% and withholding of OPDIVO in 0.5% of patients. Approximately 85% of patients with adrenal insufficiency received hormone replacement therapy and 25% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 11 days (range: 1 day to 1 month). OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, adrenal insufficiency occurred in 5% (21/407) of patients and the median time to onset was 3.0 months (range: 21 days to 9.4 months). Adrenal insufficiency led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 0.5% and 1.7% of patients, respectively. Approximately 57% of patients with adrenal insufficiency received hormone replacement therapy and 33% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 9 days (range: 1 day to 2.7 months). OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, adrenal insufficiency occurred in 7% (41/547) of patients and the median time to onset was 3.4 months (range: 2.0 months to 22.3 months). Adrenal insufficiency led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 1.3% and 2.0% of patients, respectively Approximately 93% of patients with adrenal insufficiency received hormone replacement therapy and 18% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 12 days (range: 1 day to 5.6 months). Hypothyroidism and Hyperthyroidism … OPDIVO as a Single Agent In patients receiving OPDIVO as a single agent, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 9% (171/1994) of patients; the median time to onset was 2.9 months (range: 1 day to 16.6 months). Approximately 79% of patients with hypothyroidism received levothyroxine and 4% also required corticosteroids. Resolution occurred in 35% of patients. Hyperthyroidism occurred in 2.7% (54/1994) of patients receiving OPDIVO as a single agent; the median time to onset was 1.5 months (range: 1 day to 14.2 months). Approximately 26% of patients with hyperthyroidism received methimazole, 9% received carbimazole, 4% received propylthiouracil, and 9% received corticosteroids. Resolution occurred in 76% of patients. OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (89/407) of patients; the median time to onset was 2.1 months (range: 1 day to 10.1 months). Approximately 73% of patients with hypothyroidism or thyroiditis received levothyroxine. Resolution occurred in 45% of patients. Hyperthyroidism occurred in 8% (34/407) of patients receiving OPDIVO with ipilimumab: the median time to onset was 23 days (range: 3 days to 3.7 months). Approximately 29% of patients with hyperthyroidism received methimazole and 24% received carbimazole. Resolution occurred in 94% of patients. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients; the median time to onset was 2.2 months (range: 1 day to 21.4 months). Approximately 76% of patients with hypothyroidism or thyroiditis received levothyroxine. Resolution occurred in 31% of patients.

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Trade Name Summary of Label Changes (generic name) Hyperthyroidism occurred in 12% (66/547) of patients receiving OPDIVO with ipilimumab: the median time to onset was 1.4 months (range: 6 days to 14.2 months). Approximately 14% of patients with hyperthyroidism received methimazole and 3% received carbimazole. Resolution occurred in 85% of patients.

Type 1 Diabetes Mellitus … OPDIVO as a Single Agent In patients receiving OPDIVO as a single agent, diabetes occurred in 0.9% (17/1994) of patients including two cases of diabetic ketoacidosis. The median time to onset was 4.4 months (range: 15 days to 22 months). OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, diabetes occurred in 1.5% (6/407) of patients; the median time to onset was 2.5 months (range: 1.3 to 4.4 months). OPDIVO with ipilimumab was withheld in a patient and permanently discontinued in a second patient who developed diabetes. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, diabetes occurred in 2.7% (15/547) of patients; the median time to onset was 3.2 months (range: 19 days to 16.8 months). OPDIVO with ipilimumab was withheld in 33% of patients and permanently discontinued in 20% of patients who developed diabetes. 5.5 Immune-Mediated Nephritis and Renal Dysfunction (additions underlined) … OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, immune- mediated nephritis and renal dysfunction occurred in 2.2% (9/407) of patients; the median time to onset was 2.7 months (range: 9 days to 7.9 months). Immune-mediated nephritis and renal dysfunction led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 0.7% and .05 % of patients, respectively. Approximately 67% of patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 13.5 days (range: 1 day to 1.1 months). Complete resolution occurred in all patients. Two patients resumed OPDIVO with ipilimumab without recurrence of nephritis or renal dysfunction. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, immune- mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients; the median time to onset was 2.5 months (range: 1 day to 13.2 months). Immune-mediated nephritis and renal dysfunction led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 1.1% and 2.7% of patients, respectively. Approximately 76% of patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 15 days (range: 1 day to 5.9 months). Complete resolution occurred in 64% of patients. One patient had recurrence of nephritis or renal dysfunction after re-initiation of OPDIVO with ipilimumab. 5.6 Immune-Mediated Skin Adverse Reactions (additions underlined) … OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, immune- mediated rash occurred in 22.6% (92/407) of patients; the median time to onset was 18 days (range: 1 day to 9.7 months).

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Trade Name Summary of Label Changes (generic name) Immune-mediated rash led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 0.5% and 3.9% of patients, respectively. Approximately 17% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 14 days (range: 2 days to 4.7 months). Complete resolution occurred in 47% of patients. Approximately 6% of patients who resumed OPDIVO and ipilimumab after resolution had recurrence of rash. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, immune- mediated rash occurred in 16.6% (91/547) of patients; the median time to onset was 1.5 months (range: 1 day to 20.9 months). Immune-mediated rash led to permanent discontinuation or withholding of OPDIVO with ipilimumab in 0.5% and 2.9% of patients, respectively. Approximately 19% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 25 days (range: 1 day to 23.1 months). Complete resolution occurred in 64% of patients. Approximately 3.6% of patients who resumed OPDIVO and ipilimumab after resolution had recurrence of rash. 5.7 Immune-Mediated Encephalitis (additions underlined) … OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg Encephalitis occurred in one patient (0.2%) receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks after 1.7 months of exposure. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg Encephalitis occurred in one patient receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks (0.2%) after approximately 4 months of exposure. 5.8 Other Immune-Mediated Adverse Reactions (additions underlined) … Across clinical trials of OPDIVO administered as a single agent or in combination with ipilimumab, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in less than 1.0% of patients receiving OPDIVO: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome. … 5.9 Infusion Reactions (additions underlined) … OPDIVO with Ipilimumab OPDIVO 1 mg/kg with Ipilimumab 3 mg/kg In patients receiving OPDIVO 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. OPDIVO 3 mg/kg with Ipilimumab 1 mg/kg In patients receiving OPDIVO 3 mg/kg with ipilimumab 1 mg/kg every 3 weeks, infusion-related reactions occurred in 5.1% (28/547) of patients.

PCE 4 Contraindications (Additions and/or revisions are underlined) (erythromycin)

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Trade Name Summary of Label Changes (generic name) Do not use erythromycin concomitantly with HMG CoA reductase inhibitors (statins) that are extensively metabolized by CYP 3A4 (lovastatin or simvastatin), due to the increased risk of myopathy, including rhabdomyolysis.

Plan B 5 Warnings and Precautions Warnings (levonorgestrel) (Additions and/or revisions are underlined) Ask a doctor or pharmacist before use if you are taking efavirenz (HIV medication) or rifampin (tuberculosis treatment) or medication for seizures (epilepsy). These medications may reduce the effectiveness of levonorgestrel.

Reyataz 4 Contraindications (additions to Table 6, please refer to label) (atazanavir sulfate) Rituxan 5 Warnings and Precautions 5.11 Embryo-Fetal Toxicity (rituximab) (Newly added subsection) Based on human data, RITUXAN can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the risk to a fetus. Females of childbearing potential should use effective contraception while receiving RITUXAN and for 12 months following the last dose of RITUXAN. 5.6 Infections (Additions and/or revisions are underlined) … RITUXAN is not recommended for use in patients with severe, active infections. 5.7 Cardiovascular Adverse Reactions (Additions and/or revisions are underlined) Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving RITUXAN. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RITUXAN for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.

Rubraca 5 Warnings and Precautions 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia (rucaparib (Additions and/or revisions are underlined) camsylayte) Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML) occur uncommonly in patients treated with Rubraca, and are potentially fatal adverse reactions. In approximately 1100 treated patients, MDS/AML occurred in 12 patients (1.1%), including those in long term follow-up. Of these, 5 occurred during treatment or during the 28 day safety follow- up (0.5%). The duration of Rubraca treatment prior to the diagnosis of MDS/AML ranged from 1 month to approximately 28 months. The cases were typical of secondary MDS/cancer therapy-related AML; in all cases, patients had received previous platinum-containing chemotherapy regimens and/or other DNA damaging agents. Do not start Rubraca until patients have recovered from hematological toxicity caused by previous chemotherapy (less than or equal to Grade 1). Monitor complete blood counts for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities (greater than 4 weeks), interrupt Rubraca or reduce dose according to Table 1 and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks or if MDS/AML is

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Trade Name Summary of Label Changes (generic name) suspected, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue Rubraca. 5.2 Embryo-Fetal Toxicity (Additions and/or revisions are underlined) Rubraca can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of rucaparib to pregnant rats during the period of organogenesis resulted in embryo-fetal death at exposures that were 0.04 times the AUC0-24h in patients receiving the recommended human dose of 600 mg twice daily. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months following the last dose of Rubraca.

Samsca Boxed Warning (Additions and/or revisions are underlined) (tolvaptan) WARNING: NOT FOR USE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD) Because of the risk of hepatoxicity, tolvaptan should not be used for ADPKD outside of the FDA-approved REMS. 4 Contraindications 4.1 Use in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) outside of FDA approved REMS (Newly Added Subsection) Tolvaptan can cause serious and potentially fatal liver injury. Tolvaptan should not be prescribed or used outside of the FDA-approved Risk Evaluation and Mitigation Strategy (REMS) for ADPKD patients. 5 Warnings and Precautions 5.1 Liver Injury (Additions and/or revisions are underlined) Tolvaptan can cause serious and potentially fatal liver injury. In placebo-controlled studies and an open label extension study of chronically administered tolvaptan in patients with ADPKD, cases of serious liver injury attributed to tolvaptan, generally occuring during the first 18 months of therapy, were observed. In postmarketing experience with tolvaptan in ADPKD, acute injury resulting in liver failure requiring liver transplantation has been reported. Tolvaptan should not be used to treat ADPKD outside of the FDA- approved risk evaluation and mitigation strategy (REMS) for ADPKD patients.

Tagrisso 5 Warnings and Precautions 5.1 Interstitial Lung Disease/Pneumonitis (osimertinib (additions and revisions underlined) mesylate) Interstitial lung disease (ILD)/pneumonitis occurred in 3. 9% of the 1142 TAGRISSO-treated patients; 0. 4% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (e.g., dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed. 5.2 QTc Interval Prolongation (additions and revisions underlined) Heart rate-corrected QT (QTc) interval prolongation occurs in patients treated with TAGRISSO. Of the 1142 patients treated with TAGRISSO in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. No QTc-related arrhythmias were reported. … 5.3 Cardiomyopathy (additions and revisions underlined)

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Trade Name Summary of Label Changes (generic name) Across clinical trials, cardiomyopathy (defined as cardiac failure, chronic cardiac failure, congestive heart failure, pulmonary edema or decreased ejection fraction) occurred in 2.6% of the 1142 TAGRISSO- treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) greater than or equal to 10% from baseline and to less than 50% LVEF occurred in 3.9% of 908 patients who had baseline and at least one follow-up LVEF assessment. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO. 5.4 Keratitis (revision underlined) Keratitis was reported in 0.7% of 1142 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist. 5.5 Embryo-Fetal Toxicity (additions underlined) Based on data from animal studies and its mechanism of action, TAGRISSO can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, osimertinib caused post-implantation fetal loss when administered during early development at a dose exposure 1.5 times the exposure at the recommended clinical dose. When males were treated prior to mating with untreated females, there was an increase in preimplantation embryonic loss at plasma exposures of approximately 0.5 times those observed at the recommended dose of 80 mg once daily. Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose.

Tazorac 4 Contraindications (PRL conversion) (tazarotene) TAZORAC Gel is contraindicated in:  Pregnancy. Retinoids may cause fetal harm when administered to a pregnant female.  Individuals who have known hypersensitivity to any of its components. 5 Warnings and Precautions (PLR conversion: subsections created as below, see label for complete information) 5.1 Embryofetal Toxicit 5.2 Local Irritation and Hypersensitivity Reaction 5.3 Photosensitivity and Risk for Sunburn

Trelegy Ellipta 5 Warnings and Precautions 5.1 Serious Asthma-Related Events – Hospitalizations, Intubations, Death (fluticasone (Additions and/or revisions are underlined) furoate; Use of long-acting beta2-adrenergic agonists (LABA) as monotherapy [without inhaled corticosteroid (ICS)] umeclidinium for asthma is associated with an increased risk of asthma-related death. Available data from controlled bromide; clinical trials also suggest that use of LABA as monotherapy increases the risk of asthma-related hospitalization in pediatric and adolescent patients. These findings are considered a class effect of LABA vilanterol monotherapy. When LABA are used in fixed-dose combination with ICS, data from large clinical trials do not trifenatate) show a significant increase in the risk of serious asthma-related events (hospitalizations, intubations, death) compared with ICS alone.

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Trade Name Summary of Label Changes (generic name) Available data from clinical trials in subjects with COPD do not suggest an increased risk of death with use of LABA in patients with COPD. 5.12 Cardiovascular Effects (Additions and/or revisions are underlined) In a 52-week trial of subjects with COPD, the exposure-adjusted rates for any on-treatment major adverse cardiac event, including non-fatal central nervous system hemorrhages and cerebrovascular conditions, non- fatal myocardial infarction (MI), non-fatal acute MI, and adjudicated on-treatment death due to cardiovascular events, was 2.2 per 100 patient-years for TRELEGY ELLIPTA (n = 4,151), 1.9 per 100 patient-years for fluticasone furoate/vilanterol 100 mcg/25 mcg (n = 4,134), and 2.2 per 100 patient-years for umeclidinium/vilanterol 62.5 mcg/25 mcg (n = 2,070). Adjudicated on-treatment deaths due to cardiovascular events occurred in 20 of 4,151 patients (0.54 per 100 patient-years) receiving TRELEGY ELLIPTA, 27 of 4,134 patients (0.78 per 100 patient-years) receiving fluticasone furoate/vilanterol, and 16 of 2,070 patients (0.94 per 100 patient-years) receiving umeclidinium/vilanterol. 5.5 Pneumonia (Additions and/or revisions are underlined) In a 52-week trial of subjects with COPD (N = 10,355), the incidence of pneumonia was 8% for TRELEGY ELLIPTA (n = 4,151), 7% for fluticasone furoate/vilanterol 100 mcg/25 mcg (n = 4,134), and 5% for umeclidinium/vilanterol 62.5 mcg/25 mcg (n = 2,070). Fatal pneumonia occurred in 12 of 4,151 patients (0.35 per 100 patient-years) receiving TRELEGY ELLIPTA, 5 of 4,134 patients (0.17 per 100 patient-years) receiving fluticasone furoate/vilanterol, and 5 of 2,070 patients (0.29 per 100 patient-years) receiving umeclidinium/vilanterol.

Tysabri 5 Warnings and Precautions 5.1 Progressive Multifocal Leukoencephalopathy (natalizumab) (additions underlined) … Retrospective analyses of postmarketing data from various sources, including observational studies and spontaneous reports obtained worldwide, suggest that the risk of developing PML may be associated with relative levels of serum anti-JCV antibody compared to a calibrator as measured by ELISA (often described as an anti-JCV antibody index value). … MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. … 5.6 Immunosuppression/Infections (additions underlined) … In a long-term safety study of patients treated with TYSABRI for multiple sclerosis, opportunistic infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia) have been observed in <1% of TYSABRI-treated patients. … Varubi 4 Contraindications Additions and/or revisions underlined: (rolapitant hydrochloride)

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Trade Name Summary of Label Changes (generic name) VARUBI is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index, such as thioridazine and pimozide. VARUBI can significantly increase the plasma concentrations of thioridazine and pimozide, which may result in QT prolongation and Torsades de Pointes. 5 Warnings and Precautions 5.1 Interaction with CYP2D6 Substrates Additions and/or revisions underlined: Rolapitant is a moderate inhibitor of CYP2D6. Exposure to dextromethorphan, a CYP2D6 substrate, following a single dose of rolapitant increased about 3-fold on Days 8 and Day 22. The inhibition of CYP2D6 persisted on Day 28 with a 2.3-fold increase in dextromethorphan concentrations, the last time point measured. The inhibitory effect of rolapitant on CYP2D6 is expected to persist beyond 28 days for an unknown duration following administration of VARUBI. Narrow Therapeutic Index Drugs (Thioridazine and Pimozide) VARUBI is contraindicated in patients taking CYP2D6 substrates with a narrow therapeutic index such as thioridazine and pimozide. Increased plasma concentrations of thioridazine and pimozide are associated with serious and/or life-threatening events of QT prolongation and Torsades de Pointes. Before starting treatment with VARUBI, consider whether patients require treatment with thioridazine or pimozide. If patients require these drugs, use an alternative antiemetic to VARUBI or an alternative to thioridazine or pimozide that is not metabolized by CYP2D6. Other Drugs VARUBI can also increase plasma concentrations of other CYP2D6 substrates for at least 28 days following administration of VARUBI and may result in adverse reactions. Before starting treatment with VARUBI, consult the prescribing information for CYP2D6 substrates to obtain additional information about interactions with CYP2D6 inhibitors.

Viberzi 5 Warnings and Precautions 5.4 Constipation (eluxadoline) Newly added subsection: Constipation, sometimes requiring hospitalization, has been reported following VIBERZI administration. In postmarketing experience, severe cases with development of intestinal obstruction, intestinal perforation, and fecal impaction, requiring intervention, have also been reported. Instruct patients to stop VIBERZI and immediately contact their healthcare provider if they experience severe constipation. Avoid use with other drugs that may cause constipation.

Yervoy 5 Warnings and Precautions 5.1 Immune-Mediated Enterocolitis/Colitis (ipilimumab) (additions underlined) … YERVOY as a Single Agent Metastatic Melanoma In patients receiving YERVOY 3 mg/kg in MDX010-20 (NCT00094653), severe, life-threatening, or fatal (diarrhea of 7 or more stools above baseline, fever, ileus, peritoneal signs; Grade 3 to 5) immune-mediated enterocolitis occurred in 34 YERVOY-treated patients (7%), and moderate (diarrhea with up to 6 stools above baseline, abdominal pain, mucus or blood in stool; Grade 2) enterocolitis occurred in 28 YERVOY- treated patients (5%). Across all YERVOY-treated patients (n=511), 5 patients (1%) developed intestinal perforation, 4 patients (0.8%) died as a result of complications, and 26 patients (5%) were hospitalized for severe enterocolitis. … Adjuvant Treatment of Melanoma

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Trade Name Summary of Label Changes (generic name) In patients receiving YERVOY 10 mg/kg in CA184-029 (NCT00636168), Grade 3 to 5 immune- mediated enterocolitis occurred in 76 patients (16%) and Grade 2 enterocolitis occurred in 68patients (14%). Seven patients (1.5%) developed intestinal perforation and 3 patients (0.6%) died as a result of complications. … Nivolumab with YERVOY Nivolumab 3 mg/kg with YERVOY 1 mg/kg Renal Cell Carcinoma Immune-mediated colitis occurred in 10% (52/547) of patients. Median time to onset was 1.7 months (range: 2 days to 19.2 months). Immune-mediated colitis led to permanent discontinuation or withholding of nivolumab with YERVOY in 3.5% and 4.2% of patients, respectively. Approximately 83% of patients with colitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 21 days (range: 1 day to 27 months). Approximately 23% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 89% of patients. Two patients had recurrence of colitis after re- initiation of nivolumab with YERVOY. 5.10 Other Immune-Mediated Adverse Reactions, Including Ocular Manifestations (additions underlined) YERVOY as a Single Agent Permanently discontinue YERVOY for clinically significant or severe immune-mediated adverse reactions. Initiate systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent for severe immune- mediated adverse reactions. … Metastatic Melanoma In MDX010-20, the following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients: cytopenias, nephritis, pneumonitis, meningitis, pericarditis, uveitis, and iritis. Adjuvant Treatment of Melanoma In CA184-029, the following clinically significant immune-mediated adverse reactions were seen in less than 1% of YERVOY-treated patients unless specified: cytopenias, eosinophilia (2.1%), pancreatitis (1.3%), meningitis, pneumonitis, sarcoidosis, pericarditis, uveitis, and fatal myocarditis. … Nivolumab with YERVOY Nivolumab 3 mg/kg with YERVOY 1 mg/kg Renal Cell Carcinoma Nivolumab in combination with YERVOY can cause other clinically significant and potentially fatal immune- mediated adverse reactions. Immune-mediated adverse reactions may occur after discontinuation of YERVOY therapy. For any suspected immune-mediated adverse reactions, exclude other causes. Based on the severity of the adverse reaction, permanently discontinue or withhold YERVOY, administer high-dose corticosteroids, and if appropriate, initiate hormone- replacement therapy. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider restarting YERVOY after completion of corticosteroid taper based on the severity of the event. Across clinical trials of nivolumab administered as a single agent or in combination with YERVOY, the following clinically significant immune-mediated adverse reactions, some with fatal outcome, occurred in less than 1.0% of patients: myocarditis, rhabdomyolysis, myositis, uveitis, iritis, pancreatitis, facial and abducens nerve paresis, demyelination, polymyalgia rheumatica, autoimmune neuropathy, Guillain-Barré syndrome, hypopituitarism, systemic inflammatory response syndrome, gastritis, duodenitis, sarcoidosis, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), motor dysfunction, vasculitis, aplastic anemia, pericarditis, and myasthenic syndrome. 5.2 Immune-Mediated Hepatitis

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Trade Name Summary of Label Changes (generic name) (additions underlined) … YERVOY as a Single Agent Metastatic Melanoma In patients receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or fatal hepatotoxicity. … Adjuvant Treatment of Melanoma In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3 to 4 immune-mediated hepatitis occurred in 51 patients (11%) and moderate Grade 2 immune-mediated hepatitis occurred in 22 patients (5%). Liver biopsy performed in 6 patients with Grade 3 to 4 hepatitis showed evidence of toxic or autoimmune hepatitis. … Nivolumab with YERVOY Nivolumab 3 mg/kg with YERVOY 1 mg/kg Renal Cell Carcinoma Immune-mediated hepatitis occurred in 7% (38/547) of patients. Median time to onset was 2 months (range: 14 days to 26.8 months). Immune-mediated hepatitis led to permanent discontinuation or withholding of nivolumab with YERVOY in 3.7% and 3.1% of patients, respectively. Approximately 92% of patients with hepatitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 1.0 month (range: 1 day to 4.0 months). Complete resolution occurred in 87% of patients without recurrence of hepatitis after re-initiation of nivolumab with YERVOY. 5.3 Immune-Mediated Dermatitis/Skin Adverse Reactions (additions underlined) … YERVOY as a Single Agent Metastatic Melanoma In patients receiving YERVOY 3 mg/kg in MDX010-20, severe, life-threatening, or fatal immune- mediated dermatitis (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash… Adjuvant Treatment of Melanoma In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3 to 4 immune-mediated dermatitis occurred in 19 patients (4%). There were 99 patients (21%) with moderate (Grade 2) dermatitis. The median time to onset for Grade 3 to 4 dermatitis was 14 days (range: 5 days to 11.3 months) and for Grade 2 dermatitis was 11 days (range: 1 day to 16.6 months). … Nivolumab with YERVOY Nivolumab 3 mg/kg with YERVOY 1 mg/kg Renal Cell Carcinoma Immune-mediated rash occurred in 16.6% (91/547) of patients. Median time to onset was 1.5 months (range: 1 day to 20.9 months). Immune-mediated rash led to permanent discontinuation orwithholding of nivolumab with YERVOY in 0.5% and 2.9% of patients, respectively. Approximately 19% of patients with rash received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 25 days (range: 1 day to 23.1 months). Complete resolution occurred in 64% of patients. Approximately 3.6% of patients who resumed nivolumab and YERVOY after resolution had recurrence of rash. 5.4 Immune-Mediated Neuropathies (additions underlined) … YERVOY as a Single Agent Metastatic Melanoma

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Trade Name Summary of Label Changes (generic name) In patients receiving YERVOY 3 mg/kg in MDX010-20, 1 case of fatal Guillain-Barré syndrome and 1 case of severe (Grade 3) peripheral motor neuropathy were reported. Across the clinical development program of YERVOY, myasthenia gravis and additional cases of Guillain-Barré syndrome have been reported. Adjuvant Treatment of Melanoma In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3 to 5 immune-mediated neuropathy occurred in 8 patients (2%); the sole fatality was due to complications of Guillain- Barré syndrome. Moderate Grade 2 immune-mediated neuropathy occurred in 1 patient (0.2%). … 5.5 Immune-Mediated Endocrinopathies (additions underlined) … YERVOY as a Single Agent Metastatic Melanoma In patients receiving YERVOY 3 mg/kg in MDX010-20, severe to life-threatening immune- mediated endocrinopathies... Adjuvant Treatment of Melanoma In patients receiving YERVOY 10 mg/kg in CA184-029, Grade 3 to 4 immune- mediated endocrinopathies occurred… Nivolumab with YERVOY Nivolumab 3 mg/kg with YERVOY 1 mg/kg Renal Cell Carcinoma Hypophysitis. Hypophysitis occurred in 4.6% (25/547) of patients. Median time to onset was 2.8 months (range: 1.3 months to 7.3 months). Hypophysitis led to permanent discontinuation or withholding of nivolumab with YERVOY in 1.3% and 2.6% of patients, respectively. Approximately 72% of patients with hypophysitis received hormone replacement therapy and 60% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 10 days (range: 1 day to 1.6 months). Adrenal Insufficiency. Adrenal insufficiency occurred in 7% (41/547) of patients. Median time to onset was 3.4 months (range: 2.0 months to 22.3 months). Adrenal insufficiency led to permanent discontinuation or withholding of nivolumab with YERVOY in 1.3% and 2.0% of patients, respectively. Approximately 93% of patients with adrenal insufficiency received hormone replacement therapy and 18% received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 12 days (range: 1 day to 5.6 months). Hypothyroidism and Hyperthyroidism. Hypothyroidism or thyroiditis resulting in hypothyroidism occurred in 22% (119/547) of patients. Median time to onset was 2.2 months (range: 1 day to 21.4 months). Approximately 76% of patients with hypothyroidism or thyroiditis received levothyroxine. Resolution occurred in 31% of patients. Hyperthyroidism occurred in 12% (66/547) of patients. Median time to onset was 1.4 months (range: 6 days to 14.2 months). Approximately 14% of patients with hyperthyroidism received methimazole and 3% received carbimazole. Resolution occurred in 85% of patients. Type 1 Diabetes Mellitus. Diabetes occurred in 2.7% (15/547) of patients. Median time to onset was 3.2 months (range: 19 days to 16.8 months). Nivolumab with YERVOY was withheld in 33% of patients and permanently discontinued in 20% of patients who developed diabetes. 5.6 Immune-Mediated Pneumonitis (new subsection added) Immune-mediated pneumonitis, including fatal cases, can occur with nivolumab with YERVOY. Monitor patients for signs with radiographic imaging and for symptoms of pneumonitis. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for moderate (Grade 2) or more severe (Grade 3-4)

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Trade Name Summary of Label Changes (generic name) pneumonitis, followed by corticosteroid taper. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY for life-threatening (Grade 4) pneumonitis. Nivolumab with YERVOY Nivolumab 3 mg/kg with YERVOY 1 mg/kg Renal Cell Carcinoma Immune-mediated pneumonitis occurred in 4.4% (24/547) of patients. Median time to onset was 2.6 months (range: 8 days to 9.2 months). Immune-mediated pneumonitis led to permanent discontinuation or withholding of nivolumab with YERVOY in 2.0% and 1.6% of patients, respectively. Approximately 92% of patients with pneumonitis received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 19 days (range: 4 days to 3.2 months). Approximately 8% of patients required addition of infliximab to high-dose corticosteroids. Complete resolution occurred in 79% of patients without recurrence of pneumonitis after re-initiation of nivolumab with YERVOY. 5.7 Immune-Mediated Nephritis and Renal Dysfunction (new subsection added) Immune-mediated nephritis can occur with nivolumab with YERVOY. Monitor patients for elevated serum creatinine prior to and periodically during treatment. Administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents followed by corticosteroid taper for life-threatening (Grade 4) increased serum creatinine. Administer corticosteroids at a dose of 0.5 to 1 mg/kg/day prednisone equivalents for moderate (Grade 2) or severe (Grade 3) increased serum creatinine, if worsening or no improvement occurs, increase dose of corticosteroids to 1 to 2 mg/kg/day prednisone equivalents. Withhold YERVOY dosing in patients with moderate to severe signs and symptoms. Permanently discontinue YERVOY for life-threatening (Grade 4) increased serum creatinine. Nivolumab with YERVOY Nivolumab 3 mg/kg with YERVOY 1 mg/kg Renal Cell Carcinoma Immune-mediated nephritis and renal dysfunction occurred in 4.6% (25/547) of patients. Median time to onset was 2.5 months (range: 1 day to 13.2 months). Immune-mediated nephritis and renal dysfunction led to permanent discontinuation or withholding of nivolumab with YERVOY in 1.1% and 2.7% of patients, respectively. Approximately 76% of patients received high-dose corticosteroids (at least 40 mg prednisone equivalents per day) for a median duration of 15 days (range: 1 day to 5.9 months). Complete resolution occurred in 64% of patients. One patient had recurrence of nephritis or renal dysfunction after re-initiation of nivolumab with YERVOY. 5.8 Immune-Mediated Encephalitis (new subsection added) Immune-mediated encephalitis can occur with nivolumab with YERVOY. Evaluation of patients with neurologic symptoms may include, but not be limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Withhold YERVOY in patients with new-onset moderate to severe neurologic signs or symptoms and evaluate to rule out infectious or other causes of moderate to severe neurologic deterioration. If other etiologies are ruled out, administer corticosteroids at a dose of 1 to 2 mg/kg/day prednisone equivalents for patients with immune-mediated encephalitis, followed by corticosteroid taper. Permanently discontinue YERVOY for immune-mediated encephalitis. Nivolumab with YERVOY Nivolumab 3 mg/kg with YERVOY 1 mg/kg Renal Cell Carcinoma Immune-mediated encephalitis occurred in one patient (0.2%) after approximately 4 months of exposure. 5.9 Infusion Reactions (new subsection added)

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Trade Name Summary of Label Changes (generic name) Severe infusion reactions can occur with nivolumab with YERVOY. Discontinue YERVOY in patients with severe or life-threatening infusion reactions. Interrupt or slow the rate of infusion in patients with mild or moderate infusion reactions. Nivolumab with YERVOY Nivolumab 3 mg/kg with YERVOY 1 mg/kg Renal Cell Carcinoma Infusion-related reactions occurred in 5.1% (28/547) of patients. (additions underlined) YERVOY can result in severe and fatal immune-mediated reactions [see Boxed Warning]. When YERVOY is administered in combination with nivolumab, review the nivolumab Full Prescribing Information for information on the serious risks of nivolumab administered after completion of YERVOY with nivolumab.

Treatment Guideline Updates

Title Citation/Link Practice guideline recommendations Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, summary: Disease-modifying Haboubi M et al. Practice guideline recommendations summary: Disease- therapies for adults with multiple modifying therapies for adults with multiple sclerosis. Neurology. 2018; 90 sclerosis (17): 777-788.

DOI: https://doi.org/10.1212/WNL.0000000000005347 Medical cannabis and the treatment of Ramar K, Rosen IM, Kirsch DB, Chervin RD, Carden KA, Aurora RN, Kristo obstructive sleep apnea: an American DA, Malhotra RK, Martin JL, Olson EJ, Rosen CL, Rowley JA; American Academy of Sleep Medicine position Academy of Sleep Medicine Board of Directors. Medical cannabis and the statement treatment of obstructive sleep apnea: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2018;14(4):679–681.

http://jcsm.aasm.org/ViewAbstract.aspx?pid=31249 Evaluation and management of "American Urological Association - Evaluation And Management Of testosterone deficiency: AUA Testosterone Deficiency". Auanet.Org, 2018, Guidlienes https://www.auanet.org/guidelines/evaluation-and-management-of- testosterone-deficiency. Accessed 30 April 2018.

https://www.auanet.org/guidelines/evaluation-and-management-of- testosterone-deficiency

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