The Clinical InSight

March 2018

800.361.4542 | envisionrx.com

Recent FDA Approvals

New Medications

Trade Name Dosage Form Manufacturer Indication(s) Approval Date (generic name) Strength For use in combination with other antiretroviral(s) for the treatment of human immunodeficiency virus type 1 Trogarzo TaiMed Biologics Injection, (HIV-1) infection in heavily March 3, 2018 (ibalizumab-uiyk) USA 150 mg/mL treatment-experienced adults with multidrug resistant HIV-1 infection failing their current antiretroviral regimen. For the treatment of adults Ilumya with moderate-to-severe Merck Sharp & Injection, (tildrakizumab- plaque psoriasis who are March 20, 2018 Dohme 100 mg/mL asmn) candidates for systemic therapy or phototherapy.

New Combinations and Formulations

Trade Name Dosage Form Manufacturer Indication(s) Approval Date (generic name) Strength For use as a complete Symfi regimen for the treatment of (efavirenz; Tablet, human immunodeficiency lamivudine; Mylan Specialty 600 mg; 300 mg; virus type 1 (HIV-1) infection March 22, 2018 tenofovir L.P. 300 mg in adult and pediatric disoproxil patients weighing at least 40 fumarate) kg.

New Generics

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

Cinacalcet Cipla Ltd.; Aurobindo Sensipar Tablets March 8, 2018 Hydrochloride Pharma Limited

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 2 form or medium, without EnvisionRxOptions’ prior written consent.

Pipeline

New Medication Pipeline Anticipated Mechanism of Drug Name Generic Name Route Indication(s) Approval Action Date Jatenzo Testosterone Oral Androgens Hypogonadism 1Q 2018 Undecanoate Ryplazim Plasminogen Intravenous Enzyme Hypoplasminogenemia 04/14/2018 replacement therapy KRN23 Burosumab Subcutaneous Fibroblast growth Familial 04/17/2018 factor inhibitor hypophosphatemia Tavalisse Fostamatinib Oral Syk kinase inhibitor Immune 04/17/2018 thrombocytopenic purpura 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- Migraine 05/17/2018 related peptide (CGRP) inhibitor Avatrombopag Avatrombopag Oral Thrombopoietin Thrombocytopenia 05/21/2018 Receptor Agonists Methylene Methylene Blue Oral Imaging For diagnostic imaging 05/21/2018 Blue MMX of colorectal cancers BMN 165 Pegvaliase Subcutaneous Enzyme Phenylketonuria 05/25/2018 replacement 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

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 3 form or medium, without EnvisionRxOptions’ prior written consent.

Anticipated Mechanism of Drug Name Generic Name Route Indication(s) Approval Action Date Epidiolex Epidiolex Oral Cannabinoid Dravet syndrome; 06/27/2018 Lennox-Gastaut syndrome; Infantile spasms; Epilepsy Aripiprazole Aripiprazole Intramuscular Atypical Schizophrenia 06/30/2018 Lauroxil Lauroxil antipsychotic NanoCrystal Dispersion Binimetinib Binimetinib Oral MEK inhibitor BRAF-mutant 06/30/2018 melanoma LGX818 Encorafenib Oral B-RAF kinase BRAF-mutant 06/30/2018 inhibitor melanoma TEV-48125 Fremanezumab Subcutaneous Calcitonin gene- Migraine 06/2018 related peptide (CGRP) inhibitor Alicaforsen Alicaforsen Rectal Antisense Pouchitis 2Q 2018 oligonucleotide Elagolix Elagolix Oral Luteinizing Endometriosis 2Q 2018 hormone releasing hormone (LHRH) antagonist Lofexidine Lofexidine Oral Alpha adrenergic Symptoms associated 2Q 2018 agonist with acute opioid withdrawal Olumiant Baricitinib Oral Janus Kinase (JAK) Rheumatoid arthritis 2Q 2018 inhibitor 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 Tpoxx Tecovirimat Oral Orthopoxvirus Smallpox 08/08/2018 Intravenous egress inhibitor ALN-TTR02 Patisiran Intravenous Antisense Familial amyloid 08/11/2018 oligonucleotide polyneuropathy

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 4 form or medium, without EnvisionRxOptions’ prior written consent.

Anticipated Mechanism of Drug Name Generic Name Route Indication(s) Approval Action Date AG-120 Ivosidenib Oral Isocitrate Acute myeloid 08/21/2018 dehydrogenase 1 leukemia (IDH1) 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 in 08/26/2018 inhibitor hereditary angioedema Volanesorsen Volanesorsen Subcutaneous Antisense Familial 08/30/2018 apolipoprotein chylomicronemia inhibitor syndrome PF-06463922 Lorlatinib Oral Tyrosine kinase Non-small cell lung 08/2018 inhibitor cancer Tafenoquine Tafenoquine Oral Antimalarials Prophylaxis; treatment 08/2018; of malaria 4Q 2018 BAY 94-9027 Coagulation Intravenous Coagulation factor Hemophilia A 3Q 2018 Factor VIII VIII (recombinant) IDP-118 Halobetasol Topical Corticosteroid Moderate to severe 3Q 2018 Propionate; Retinoids chronic plaque Tazarotene psoriasis Symtuza Darunavir; Oral Protease inhibitor; HIV-1 infection 3Q 2018 Cobicistat; Nucleoside Emtricitabine; analogue reverse Tenofovir transcriptase Alafenamide inhibitor; Pharmacokinetic enhancer Baremsis Amisulpride Intravenous Atypical Postoperative nausea 10/05/2018 antipsychotic and vomiting

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 5 form or medium, without EnvisionRxOptions’ prior written consent.

Anticipated Mechanism of Drug Name Generic Name Route Indication(s) Approval Action Date DOR/3TC/TDF Doravirine; Oral Nucleoside HIV-1 infection 10/23/2018 Lamivudine; analogue reverse Tenofovir transcriptase Disoproxil inhibitor; Non- Fumarate nucleoside reverse transcriptase inhibitor MK-1439 Doravirine Oral Non-nucleoside HIV infection 10/23/2018 reverse transcriptase inhibitor LY2951742 Galcanezumab Subcutaneous Calcitonin gene- Migraine 10/2018 related peptide (CGRP) inhibitor TD-4208 Revefenacin Inhaled Long-acting Chronic obstructive 11/13/2018 muscarinic pulmonary disease antagonist Olinvo Oliceridine Intravenous Opioid agonist Acute pain 12/02/2018

JZP-110 Solriamfetol Oral CNS stimulant Narcolepsy; Daytime 12/20/2018 sleepiness in obstructive sleep apnea Resolor Prucalopride Oral 5-HT4 serotonin Chronic idiopathic 12/21/2018 receptor agonist constipation Calaspargase Calaspargase Intravenous Antineoplastic Acute lymphocytic 12/22/2018 pegol Pegol enzymes leukemia CL-108 Acetaminophen; Oral COX inhibitor; H1 Symptoms associated 4Q 2018 Hydrocodone; histamine receptor with acute opioid Promethazine antagonist; Opioid withdrawal agonist Galafold Migalastat Oral Chemical Fabry disease 4Q 2018 chaperone LOXO-101 Larotrectinib Oral Tropomyosin Solid tumors 4Q 2018 receptor kinases (TRK) inhibitor

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 6 form or medium, without EnvisionRxOptions’ prior written consent.

Anticipated Mechanism of Drug Name Generic Name Route Indication(s) Approval Action Date VivaGel BV Astodrimer Intravaginal Anti-infective Bacterial vaginosis 4Q 2018 Sodium Seysara Sarecycline Oral Tetracycline Acne vulgaris 2H 2018 antibiotic ALKS 5461 Buprenorphine; Oral Opioid antagonist; Major depressive 1Q 2019 Samidorphan Opioid partial disorder agonist Arikayce Liposomal Inhaled Aminoglycoside Nontuberculous 1Q 2019 amikacin antibiotic mycobacteria lung infections Eravacycline Eravacycline Oral Fluorocycline Complicated intra- 1Q 2019 Intravenous antibiotic abdominal infections Firdapse Amifampridine Oral Potassium Channel Lambert-Eaton 1Q 2019 Phosphate Inhibitor myasthenic syndrome N8-GP Coagulation Intravenous Coagulation factor Hemophilia A 1Q 2019 Factor VIII VIII (recombinant) (Recombinant) PTK 0796 Omadacycline Oral Aminomethylcycline Acute Bacterial Skin 1Q 2019 Intravenous antibiotic and Skin Structure Infections; Community-acquired bacterial pneumonia Rekynda Bremelanotide Injectable Peptide Female sexual 1Q 2019 melanocortin dysfunction receptor agonist Zemcolo Rifamycin-SV Oral Rifamycin Diarrhea caused by 1Q 2019 antibacterial certain organisms

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 7 form or medium, without EnvisionRxOptions’ prior written consent.

2018 New Generic Pipeline

Anticipated Brand 2016 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 1Q 2018 ISTODAX Romidepsin Celgene Non-Hodgkin's $65M Lymphoma (2015) 04/08/2018 NUVARING Ethinyl Estradiol; Organon; Merck & Contraception $773M Etonogestrel Co 05/18/2018 INVEGA Paliperidone Janssen Schizophrenia $256M TRINZA Palmitate 05/22/2018 ADCIRCA Tadalafil Eli Lilly; United Pulmonary Arterial $372M Therapeutics Hypertension Net sales 06/01/2018 ONEXTON Benzoyl Peroxide; Dow Acne $134M Clindamycin Pharmaceutical Phosphate Sciences; Valeant 06/12/2018 EMSAM Selegiline Somerset Depression $42M Pharmaceuticals; Mylan 06/26/2018 REMODULIN Treprostinil United Pulmonary Arterial $602M Therapeutics Hypertension Net sales 06/26/2018 SOLTAMOX Tamoxifen Citrate DARA Breast Cancer $1M BioSciences; Midatech 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

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 8 form or medium, without EnvisionRxOptions’ prior written consent.

Anticipated Brand 2016 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 1H 2018 ZORTRESS Everolimus Novartis Complications of $110M Transplanted Organs and Tissues: Prophylaxis of organ rejection 07/01/2018 ACANYA Benzoyl Peroxide; Dow Acne $74M Clindamycin Pharmaceutical Phosphate Sciences; Valeant 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 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

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 9 form or medium, without EnvisionRxOptions’ prior written consent.

Anticipated Brand 2016 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 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 IBSA Institut Acute pain $136M Epolamine Biochemique; Pfizer 2018 ANDROGEL Testosterone AbbVie Hypogonadism $78M (1.62% packets) 2018 ANDROGEL Testosterone AbbVie Hypogonadism $946M (1.62% pump) 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 Penicillamine Aton; Valeant Genitourinary System $172M (250 mg) Diseases 2018 INVANZ Ertapenem Sodium Merck & Co Infections $364M

2018 KALETRA Lopinavir; Ritonavir AbbVie HIV-1 infection $134M (tablets) 2018 LOTEMAX (gel) Loteprednol Bausch + Lomb; Post-operative $115M Etabonate Valeant inflammation and pain following ocular surgery

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 10 form or medium, without EnvisionRxOptions’ prior written consent.

Anticipated Brand 2016 U.S. Brand Name Generic Name Indication(s) Launch Date Manufacturer(s) Sales 2018 NEXIUM (20 mg Esomeprazole AstraZeneca Gastroesophageal $49M and 40 mg Magnesium Reflux Disease packets for oral suspension) 2018 PROVENTIL- Albuterol Sulfate 3M Health Care; Asthma: Exercise- $254M HFA Merck & Co induced bronchospasm 2018 TRACLEER Bosentan Actelion; Janssen Pulmonary Arterial $53M (film-coated Hypertension tablet) 2018 TRISENOX Arsenic Trioxide Cephalon; Teva Leukemia $4M

2018 ZAVESCA Miglustat Actelion; Janssen Metabolic, Endocrine $3M And Nutritional Diseases: Gaucher disease, Type 1 2018-2019 ADVAIR Fluticasone GSK Asthma; Chronic $4,765M DISKUS Propionate; Obstructive Pulmonary Salmeterol Xinafoate Disease

Medication with Significant Label Changes

Trade Name Summary of Label Changes (generic name) Adectris 5 Warnings and Precautions 5.1 Peripheral Neuropathy (brentuximab vedotin) (additions underlined) In a study of ADCETRIS as combination therapy (Study 5, ECHELON-1) 67% of patients treated with ADCETRIS + AVD experienced any grade of neuropathy. The median time to onset of any grade was 8 weeks (range, 0–29), of Grade 2 was 14 weeks (range, 0–28) and of Grade 3 was 16 weeks (range, 1– 29). The median time from onset to resolution or improvement of any grade was 10 weeks (range, 0–139), of Grade 2 was 12 weeks (range, 0–123), and of Grade 3 was 17 weeks (range, 0–139). Of these patients, 43% had complete resolution, 24% had partial improvement (a decrease in severity by one or more grade from worst grade) and 33% had no improvement at the time of their last evaluation. Of the patients with residual neuropathy at the time of their last evaluation (57%), patients reported Grade 1 (36%), Grade 2 (16%), Grade 3 (4%), or Grade 4 (1 patient) neuropathy. Median time of overall study follow-up was 84.3 weeks (range, 0–194). Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain, or weakness. Patients experiencing new or worsening peripheral neuropathy may require a delay, change in dose, or discontinuation of ADCETRIS. 5.3 Hematologic Toxicities (additions underlined)

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 11 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) Fatal and serious cases of febrile neutropenia have been reported with ADCETRIS. Prolonged (?1 week) severe neutropenia and Grade 3 or Grade 4 thrombocytopenia or anemia can occur with ADCETRIS. Start primary prophylaxis with G-CSF beginning with Cycle 1 for previously untreated patients who receive ADCETRIS in combination with chemotherapy for Stage III or IV. Monitor complete blood counts prior to each dose of ADCETRIS. Monitor more frequently for patients with Grade 3 or 4 neutropenia. Monitor patients for fever. If Grade 3 or 4 neutropenia develops, consider dose delays, reductions, discontinuation, or G-CSF prophylaxis with subsequent ADCETRIS doses.

Agrylin 5 Warnings and Precautions 5.2 Pulmonary Hypertension (anagrelide (new subsection added) hudrochloride) Cases of pulmonary hypertension have been reported in patients treated with anagrelide. Evaluate patients for signs and symptoms of underlying cardiopulmonary disease prior to initiating and during anagrelide therapy.

Aquamephyton Boxed Warning Additions and/or revisions underlined: (phytonadione) WARNING – HYPERSENSITIVITY REACTIONS WITH INTRAVENOUS AND INTRAMUSCULAR USE Fatal hypersensitivity reactions, including anaphylaxis, have occurred during and immediately after INTRAVENOUS and INTRAMUSCULAR injection of AquaMEPHYTON. Reactions have occurred despite dilution to avoid rapid infusion and upon first dose. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified. 4 Contraindications Additions and/or revisions underlined: Hypersensitivity to phytonadione or any other component of this medication. 5 Warnings and Precautions Addition of the following subsection: 5.1 Hypersensitivity Reactions Fatal and severe hypersensitivity reactions, including anaphylaxis, have occurred with intravenous or intramuscular administration of AquaMEPHYTON. Reactions have occurred despite dilution to avoid rapid intravenous infusion and upon first dose. These reactions have included shock, cardiorespiratory arrest, flushing, diaphoresis, chest pain, tachycardia, cyanosis, weakness, and dyspnea. Administer AquaMEPHYTON subcutaneously whenever feasible. Avoid the intravenous and intramuscular routes of administration unless the subcutaneous route is not feasible and the serious risk is justified. Additions and/or revisions underlined: 5.2 Risk of Serious Adverse Reaction in Infants due to Benzyl Alcohol Preservative Use benzyl alcohol-free formulations in neonates and infants, if available … When prescribing AquaMEPHYTON in infants, consider the combined daily metabolic … 5.3 Cutaneous Reactions Parenteral administration of vitamin K replacements (including AquaMEPHYTON) may cause cutaneous reactions. Reactions have included eczematous reactions, scleroderma-like patches, urticaria, and delayed-type hypersensitivity reactions. Time of onset ranged from 1 day to a year after parenteral administration. Discontinue AquaMEPHYTON for skin reactions and institute medical management.

Asclera 5 Warnings and Precautions Newly added subsections: (polidocanol) 5.2 Venous Thrombosis and Pulmonary Embolism

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 12 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) Asclera can cause venous thrombosis and subsequent pulmonary embolism or other thrombotic events. Follow administration instructions closely and monitor for signs of venous thrombosis after treatment. Patients with reduced mobility, history of deep vein thrombosis or pulmonary embolism, or recent (within 3 months) major surgery, prolonged hospitalization or pregnancy are at increased risk for developing thrombosis. 5.3 Arterial Embolism Stroke, transient ischemic attack, myocardial infarction, and impaired cardiac function have been reported in close temporal relationship with polidocanol administration. These events may be caused by air embolism when using the product foamed with room air (high nitrogen concentration) or thromboembolism. The safety and efficacy of polidocanol foamed with room air has not been established and its use should be avoided. 5.4 Tissue Ischemia and Necrosis Intra-arterial injection or extravasation of polidocanol can cause severe necrosis, ischemia or gangrene. Care should be taken in intravenous needle placement and the smallest effective volume at each injection site should be used. After the injection session is completed, apply compression with a stocking or bandage and have patients walk for 15-20 minutes. If intra-arterial injection of polidocanol occurs, consult a vascular surgeon immediately.

Asmanex HFA 5 Warnings and Precautions 5.7 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors (mometasone (Additions and/or revisions are underlined) furoate) Caution should be exercised when considering the coadministration of ASMANEX HFA with ketoconazole, and other known strong cytochrome P450 (CYP) isoenzyme 3A4 (CYP3A4) inhibitors (e.g., ritonavir, cobicistat-containing products… 5.11 Glaucoma and Cataracts (Additions and/or revisions are underlined) Glaucoma, increased intraocular pressure, and cataracts have been reported following the use of long- term administration of inhaled corticosteroids, including mometasone furoate. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use ASMANEX HFA long term.

Asmanex 5 Warnings and Precautions 5.11 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors TwistHaler (Newly Added Subsection) (mometasone Caution should be exercised when considering the coadministration of ASMANEX TWISTHALER with furoate) ketoconazole, and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) because adverse effects related to increased systemic exposure to mometasone furoate may occur. 5.9 Glaucoma and Cataracts (Additions and/or revisions are underlined) In clinical trials, glaucoma, increased intraocular pressure, and cataracts have been reported in 8 of 3007 patients following the administration of ASMANEX TWISTHALER. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use ASMANEX TWISTHALER long term.

Depakote Boxed Warning (additions underlined) (divalproex sodium) Fetal Risk

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 13 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. 4 Contraindications (additions underlined)  Depakote is contraindicated for use in prophylaxis of migraine headaches in pregnant women. 5 Warnings and Precautions 5.3 Decreased IQ Following in utero Exposure (additions underlined) Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks.

Dextrose 20% in 4 Contraindications PLR conversion Plastic Container, The use of Dextrose Injection is contraindicated in patients: Dextrose 30% in  Who are severely dehydrated as hypertonic dextrose solution can worsen the patient’s hyperosmolar state Plastic Container,  Known hypersensitivity to dextrose Dextrose 40% in 5 Warnings and Precautions PLR conversion: subsections created as below; see label for complete information Plastic Container, 5.1 Pulmonary Embolish due to Pulmonary Vascular Precipitates Dextrose 50% in 5.2 Hyperglycemia and Hyperosmolar Hyperglycemic State Plastic Container, 5.3 Hypersensitivity Reactions Dextrose 60% in 5.4 Risk of Infections 5.5 Refeeding Syndrome Plastic Container, 5.6 Vein Damage and Thrombosis Dextrose 70% in 5.7 Hepatobiliary Disorders Plastic Container 5.8 Aluminum Toxicity 5.9 Risk of Parenteral Nutrition Associated Liver Disease 5.10 Electrolyte Imbalance and Fluid Overload

Diflucan 5 Warnings and Precautions PRECAUTIONS (fluconazole) Additions and/or revisions underlined: Drug Interactions Cisapride: … A controlled study found that concomitant treatment with fluconazole 200 mg once daily … Pregnancy Teratogenic Effects Potential for Fetal Harm: Use in pregnancy should be avoided except in patients with severe or potentially life-threatening fungal infections in whom fluconazole may be used if the anticipated benefit outweighs the possible risk to the fetus. These reported anomalies are similar to those seen in animal studies. Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with DIFLUCAN 400-800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half- lives) after the final dose. If DIFLUCAN is used during pregnancy … informed of the potential hazard to the

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 14 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) fetus. Spontaneous abortions and congenital abnormalities have been suggested as potential risks associated with 150 mg of fluconazole as a single or repeated dose in the first trimester of pregnancy based on retrospective epidemiological studies. There are no adequate and well-controlled studies … Human Data Case reports describe a distinctive and rare pattern … These effects are similar to those seen in animal studies. Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials. WARNINGS Additions and/or revisions underlined: (4) Potential for Fetal Harm There are no adequate and well-controlled clinical trials of DIFLUCAN in pregnant women … These reported anomalies are similar to those seen in animal studies. If DIFLUCAN is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed of the potential hazard to the fetus. Effective contraceptive measures should be considered in women of child-bearing potential who are being treated with DIFLUCAN 400 to 800 mg/day and should continue throughout the treatment period and for approximately 1 week (5 to 6 half-lives) after the final dose. Epidemiological studies suggest a potential risk of spontaneous abortion and congenital abnormalities in infants whose mothers were treated with 150 mg of fluconazole as a single or repeated dose in the first trimester, but these epidemiological studies have limitations and these findings have not been confirmed in controlled clinical trials.

Diprolene, 5 Warnings and Precautions 5.2 Visual Disturbance Diprolene AF (Newly Added Subsection) (betamethasone Use of topical corticosteroids, including DIPROLENE Ointment, may increase the risk of posterior dipropionate) subcapsular cataracts and glaucoma. Cataracts and glaucoma have been reported postmarketing with the use of topical corticosteroid products, including DIPROLENE Ointment. Avoid contact of DIPROLENE Ointment with eyes. Advise patients to report any visual symptoms and consider referral to an ophthalmologist for evaluation.

Dulera 5 Warnings and Precautions 5.8 Drug Interactions with Strong Cytochrome P450 3A4 Inhibitors (formoterol fumarate; Additions and/or revisions underlined: mometasone furoate) … (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin … 5.14 Glaucoma and Cataracts Additions and/or revisions underlined: … including mometasone furoate, a component of DULERA. Consider referral to an ophthalmologist in patients who develop ocular symptoms or use DULERA long term.

Emend 5 Warnings and Precautions 5.3 Infusion Site Reactions (fosaprepitant (Newly Added Subsection) dimeglumine) Infusion site reactions (ISRs) have been reported with the use of EMEND for injection. The majority of severe ISRs, including thrombophlebitis and vasculitis, were reported with concomitant vesicant

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 15 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) (anthracycline-based) chemotherapy administration, particularly when associated with extravasation. Necrosis was also reported in some patients with concomitant vesicant chemotherapy. Most ISRs occurred with the first, second or third exposure to single doses of EMEND for injection and in some cases, reactions persisted for two weeks or longer. Treatment of severe ISRs consisted of medical, and in some cases surgical, intervention. Avoid infusion of EMEND for injection into small veins or through a butterfly catheter. If a severe ISR develops during infusion, discontinue the infusion and administer appropriate medical treatment.

Heparin Lock Flush 5 Warnings and Precautions PRECAUTIONS (heparin sodium) (Additions and/or revisions are underlined) General Thrombocytopenia, Heparin-induced Thrombocytopenia (HIT) (With or Without Thrombosis) and Delayed Onset of HIT (With or Without Thrombosis) Other Interactions Intravenous nitroglycerin administered to heparinized patients may result in a decrease of the partial thromboplastin time with subsequent rebound effect upon discontinuation of nitroglycerin. Careful monitoring of partial thromboplastin time and adjustment of heparin dosage are recommended during coadministration of heparin and intravenous nitroglycerin.

Invirase 4 Contraindications (additions underlined) (saquinavir mesylate) INVIRASE/ritonavir is contraindicated in patients receiving the following co-administered drugs; however, it should be noted that this list is not intended to be exhaustive.  Alpha 1-adrenoreceptor antagonist: alfuzonsin  Antiarrhythmics: amiodarone, bepridil, deofeilide, flecainide, lidocaine (systemic), propafenone, quinidine  Antidepressant: trazodone  Anti-infectives: clarithromycin, erythromycin, halofantrine, pentamidine  Antimycobacterial Agents: rifampin  Antipsychotics: lurasidone, clozapine, haloperidol, pimozide, sertindole, ziprasidone, phenothiazines (e.g. chlorpromazine, mesoridazine, thioridazine).  Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine  HIV-1 Protease Inhibitor: atazanavir  HMG-CoA Reductase Inhibitors: lovastatin, simvastatin  Immunosuppressant: tacrolimus  Non-nucleoside reverse transcriptase inhibitor (NNRTI): rilpivirine (concomitant use and switching from rilpivirine to INVIRASE/ritonavir without a washout period of at least 2 weeks is contraindicated)  PDE5 Inhibitors: sildenafil (Revatio®)[for treatment of pulmonary arterial hypertension]  Sedative/Hypnotics: triazolam, and orally administered midazolam  Tyrosine kinase inhibitors: dasatinib, sunatinib  Other drugs that are CYP3A substrates: disopyramide, quinine 5 Warnings and Precautions 5.1 Importance of Co-administration with Ritonavir (new subsection header added) INVIRASE must be used in combination with ritonavir. Please refer to the ritonavir full prescribing information for additional precautionary measures. INVIRASE is not recommended for use in combination with cobicistat. Dosing recommendations for this combination have not been established. Cobicistat is also not recommended in combination with

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 16 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) regimens containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A. Please refer to the cobicistat full prescribing information for additional precautionary measures. 5.2 Risk of Serious Adverse Reactions Due to Drug Interactions (additions underlined) If a serious or severe toxicity occurs during treatment with INVIRASE/ritonavir, discontinue INVIRASE/ritonavir. For concomitantly used drugs including antiretroviral agents used in combination with INVIRASE/ritonavir, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug-associated adverse reactions. 5.3 PR Interval Prolongation (additions underlined) INVIRASE/ritonavir prolongs the PR interval in a dose-dependent fashion. Cases of second or third degree atrioventricular block have been reported rarely. Patients with underlying structural heart disease, pre- existing conduction system abnormalities, cardiomyopathies and ischemic heart disease may be at increased risk for developing cardiac conduction abnormalities. ECG monitoring is recommended in these patients. Discontinue INVIRASE/ritonavir if significant arrhythmias, QT or PR prolongation occur. The impact on the PR interval of coadministration of INVIRASE/ritonavir with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, coadministration of INVIRASE/ritonavir with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A, and clinical monitoring is recommended. For concomitantly used drugs, including antiretroviral agents used in combination with INVIRASE/ritonavir, physicians should refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug- associated adverse reactions. 5.4 QT Interval Prolongation (additions underline) For concomitantly used drugs including antiretroviral agents used in combination with INVIRASE/ritonavir, refer to the complete product information for these drugs for dose adjustment recommendations and for information regarding drug- associated adverse reactions.Discontinue INVIRASE/ritonavir if significant arrhythmias, QT or PR prolongation occurs. Patients initiating therapy with INVIRASE/ritonavir: An ECG should be performed prior to initiation of treatment. Patients with a QT interval ? 450 msec should not initiate treatment with INVIRASE/ritonavir. Treatment-naïve patients initiating treatment with INVIRASE/ritonavir should receive a reduced starting dose of INVIRASE 500 mg twice daily with ritonavir 100 mg twice daily for the first 7 days of treatment followed by INVIRASE/ritonavir 1000/100 mg twice daily due to potential for an increased risk of PR and QT interval prolongation with the standard 1000/100 mg twice daily dose. For patients with a baseline QT interval < 450 msec, an on-treatment ECG is recommended after approximately 10 days of therapy. Discontinue INVIRASE/ritonavir in patients with a QT interval prolongation > 20 msec over pre-treatment. 5.6 Hepatotoxicity (additions underlined) In patients with underlying hepatitis B or C, cirrhosis, chronic alcoholism or other underlying liver abnormalities, there have been reports of worsening of the underlying liver disease and development of portal hypertension after starting INVIRASE/ritonavir. Jaundice and exacerbation of chronic liver disease with grade 4 elevated liver function tests were also observed. No dosage adjustment is necessary for patients with mild or moderate hepatic impairment based on limited data. INVIRASE/ritonavir is contraindicated in patients with severe hepatic impairment. If a serious or severe toxicity occurs during treatment with INVIRASE/ritonavir, discontinue INVIRASE/ritonavir.

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 17 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name)

Kinevac 4 Contraindications (additions underlined) (sincalide) The preparation is contraindicated in patients with: . a history of hypersensitivity to sincalide. Serious hypersensitivity reactions have included anaphylaxis and anaphylactic shock. . intestinal obstruction. 5 Warnings and Precautions WARNINGS (additions underlined) Anaphylaxis, Anaphylactic Shock and Other Hypersensitivity Reactions In postmarketing experience, anaphylaxis, anaphylactic shock and other serious hypersensitivity reactions have been reported during and within one hour following administration of Kinevac (see ADVERSE REACTIONS). Due to the potential for anaphylaxis, appropriate medical support should be readily available when Kinevac is administered. If anaphylaxis or other hypersensitivity reactions occur, immediately discontinue the infusion and initiate appropriate medical treatment. Observe patients closely during and after the infusion. Do not reinitiate Kinevac in patients who have experienced symptoms of hypersensitivity. (see CONTRAINDICATIONS). Preterm Labor or Spontaneous Abortion Because of Kinevac’s effect on smooth muscle, pregnant patients should be advised that spontaneous abortion or premature induction of labor may occur (see Pregnancy Category B).

Kyleena 5 Warnings and Precautions 5.5 Perforation (levonorgestrel) Additions and/or revisions underlined: … Delay Kyleena insertion a minimum of six weeks or until involution is complete following a delivery or a second trimester abortion. Clinical trials with Kyleena excluded breast-feeding women. A large postmarketing safety study conducted in Europe over a 1-year observational period reported that lactation at the time of insertion of an IUD/IUS was associated with an increased risk of perforation. For users of another LNG-releasing IUS, the incidence of uterine perforation was reported as 6.3 per 1,000 insertions for lactating women, compared to 1.0 per 1,000 insertions for non-lactating women. 5.6 Expulsion Delay Kyleena insertion a minimum of six weeks or until uterine involution is complete following a delivery or a second trimester abortion. Remove a partially expelled Kyleena. If expulsion has occurred, a new Kyleena can be inserted any time the provider can be reasonably certain the woman is not pregnant.

Latuda 5 Warnings and Precautions 5.11 Seizures (lurasidone (additions underlined) hydrochloride) Bipolar Depression Monotherapy In the adult and pediatric 6-week, flexible-dose, placebo-controlled monotherapy bipolar depression studies, no patients experienced seizures/convulsions. 5.12 Potential for Cognitive and Motor Impairment (additions underlined) Bipolar Depression

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 18 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) Adults Monotherapy Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, somnolence was reported by 11.4% (20/175) of patients treated with LATUDA 20 to 80 mg/day compared to 5.8% (10/172) of placebo treated patients. 5.14 Activation of Mania/Hypomania (addition underlined) Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes. In the adult bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the LATUDA and placebo groups developed manic or hypomanic episodes. 5.4 Neuroleptic Malignant Syndrome (additions underlined) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue LATUDA and provide intensive symptomatic treatment and monitoring. 5.5 Tardive Dyskinesia (additions underlined) The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. 5.6 Metabolic Changes Bipolar Depression Adults Monotherapy Pediatric Patients (10 to 17 years) In studies of pediatric patients 10 to 17 years and adults with bipolar depression, changes in fasting glucose were similar. In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dL for LATUDA 20 to 80 mg/day (n=145) and -0.5 mg/dL for placebo (n=145). Bipolar Depression Adults Monotherapy Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dL for LATUDA 20 to 80 mg/day (n=144) and - 1.4 mg/dL for placebo (n=145), and mean change in fasting triglyceride was -7.6 mg/dL for LATUDA 20 to 80 mg/day (n=144) and +5.9 mg/dL for placebo (n=145). 5.7 Hyperprolactinemia (additions underlined) Adjunctive Therapy with Lithium or Valproate Pediatric Patients (10 to 17 years)

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 19 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +1.10 ng/mL and was +0.50 ng/mL for placebo-treated patients. For LATUDA-treated patients, the median change from baseline to endpoint for males was +0.85 ng/mL and for females was +2.50 ng/mL. Median changes for prolactin are shown in Table 18. (please refer to label to view Table 8) The proportion of patients with prolactin elevations greater than or equal to 5x ULN was 0% for LATUDA- treated patients and 0.6% for placebo-treated patients. The proportion of female patients with prolactin elevations greater than or equal to 5x ULN was 0% for LATUDA-treated patients and 1.3% for placebo- treated female patients. No male patients in the placebo or LATUDA treatment groups had prolactin elevations greater than or equal to 5x ULN. 5.9 Orthostatic Hypotension and Syncope (additions underlined) Bipolar Depression Adults Monotherapy Pediatric Patients (10 to 17 years) In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, there were no reported adverse events of orthostatic hypotension or syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 80 mg/day, compared to 0.6% with placebo.

Levulan 5 Warnings and Precautions 5.1 Photosensitivity (aminolevulinic acid (additions underlined) hydrochloride) After LEVULAN KERASTICK topical solution has been applied, the treatment site will become photosensitive and patients should avoid exposure of the photosensitive treatment sites to sunlight or bright indoor light (e.g., examination lamps, operating room lamps, tanning beds, or lights at close proximity) for 40 hours. Exposure may result in a stinging and/or burning sensation and may cause erythema and/or edema of the lesions. Therefore, before exposure to sunlight, patients should protect treated lesions from the sun by wearing a wide- brimmed hat or similar head covering of light-opaque material, and/or a long-sleeved shirt and/or gloves. Sunscreens will not protect against photosensitivity reactions caused by visible light. It has not been determined if perspiration can spread the LEVULAN KERASTICK topical solution outside the treatment site to the eye or surrounding skin. of LEVULAN KERASTICK topical solution to perilesional areas of photodamaged skin of the face, scalp or upper extremities may result in photosensitization. Upon exposure to activating light from the BLU-U, such photosensitized skin may produce a stinging and/or burning sensation and may become erythematous and/or edematous in a manner similar to that of actinic keratoses treated with LEVULAN KERASTICK Photodynamic Therapy. Because of the potential for skin to become photosensitized, the LEVULAN KERASTICK topical solution should be used by a qualified health professional to apply drug to no more than 5mm of perilesional skin surrounding the target actinic keratosis lesions. ... 5.2 Irritation (additions underlined) The LEVULAN KERASTICK topical solution contains alcohol and is intended for topical use only. Irritation may be experienced if this product is applied to eyes or mucus membranes. Do not apply to the eyes or to

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 20 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) mucous membranes. Excessive irritation may be experienced if this product is applied under occlusion longer than 3 hours.

Methotrexate 5 Warnings and Precautions PRECAUTIONS Sodium, Drug Interactions Methotrexate LPF, (additions underlined) Methotrexate … Preservative Free, The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways, resulting in the potential for increased toxicity such as stomatitis, myelosuppression, and Methotrexate neurotoxicity. Avoid concomitantnitrous oxide anesthesia in patients receiving methotrexate. Use caution Sodium when administering methotrexate after a recent history of nitrous oxide administration. Preservative Free (methotrexate sodium) Opdivo 5 Warnings and Precautions 5.8 Other Immune-Mediated Adverse Reactions (nivolumab) (additions underlined) … If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt- Koyanagi-Harada-like syndrome, which has been observed in patients receiving OPDIVO or OPDIVO in combination with ipilimumab and may require treatment with systemic steroids to reduce the risk of permanent vision loss.

Orbactiv 5 Warnings and Precautions 5.3 Infusion Related Reactions (oritavancin (additions underlined) diphosphate) ORBACTIV is administered via intravenous infusion, using a total infusion time of 3 hours to minimize the risk of infusion-related reactions. Infusion related reactions have been reported with the glycopeptide class of antimicrobial agents, including ORBACTIV, that resemble “Red- man Syndrome”, including flushing of the upper body, urticaria, pruritus and/or rash. Stopping or slowing the infusion may result in cessation of these reactions.

Pomalyst 5 Warnings and Precautions 5.1 Embryo-Fetal Toxicity (pomalidomide) (additions underlined) Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning POMALYST therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. 5.7 Severe Cutaneous Reactions Including Hypersensitivity Reactions (additions underlined) Angioedema and severe cutaneous reactions including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis,

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 21 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) pneumonitis, myocarditis, and/or pericarditis. Discontinue POMALYST for angioedema, skin exfoliation, bullae, or any other severe cutaneous reactions such as SJS, TEN or DRESS, and do not resume therapy

Qsymia 5 Warnings and Precautions 5.8 Elevation in Creatinine (phentermine Additions and/or revisions underlined: hydrochloride; Qsymia can cause an increase in serum creatinine that reflects a decrease in renal function (glomerular topiramate) filtration rate). In phase 3 trials, peak increases in serum creatinine were observed after 4 to 8 weeks of treatment. On average, serum creatinine gradually declined but remained elevated over baseline creatinine values. The changes in serum creatinine (and measured GFR) with short-term Qsymia treatment appear reversible with treatment discontinuation, but the effect of chronic treatment on renal function is not known. Therefore, measurement of …

Signifor Lar 5 Warnings and Precautions 5.2 Bradycardia and QT Prolongation (pasireotide pamoate) OT Prolongation In cardiac electrophysiology studies (i.e., thorough QT studies) with pasireotide via subcutaneous route, QT prolongation occurred …

Skelaxin 5 Warnings and Precautions WARNINGS (metaxalone) (new subsections added) Serotonin Syndrome Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of serotonergic drugs with SKELAXIN used within the recommended dosage range (see PRECAUTIONS: Drug Interactions) and with SKELAXIN as a single agent taken at doses higher than the recommended dose (see OVERDOSAGE). Serotonergic drugs include selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, opioids (particularly fentanyl, meperidine, and methadone), drugs that affect the serotonergic neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and drugs that impair metabolism of serotonin (including monoamine oxidase (MAO) inhibitors, both those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue). Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The onset of symptoms generally occurs within several hours to a few days, but may occur later than that. Discontinue SKELAXIN if serotonin syndrome is suspected. Risks from Concomitant Use with Alcohol or other CNS Depressants The sedative effects of SKELAXIN and other CNS depressants (e.g., alcohol, benzodiazepines, opioids, tricyclic antidepressants (TCAs)) may be additive. Exercise caution with patients who take more than one of these CNS depressants simultaneously. Follow patients closely for signs and symptoms of respiratory depression and sedation.

Skyla 4 Contraindications Additions and/or revisions underlined: (levonorgestrel) The use of Skyla is contraindicated when one or more of the following conditions exist:  Congenital or acquired uterine anomaly including fibroids, that distorts the uterine cavity

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 22 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) 5 Warnings and Precautions Additions and/or revisions underlined: 5.1 Risk of Ectopic Pregnancy Menses replaces periods in this subsection. 5.2 Risks with Intrauterine Pregnancy IUS replaces IUD in this subsection. 5.4 Pelvic Infection Additions and/or revisions are underlined: Pelvic Inflammatory Disease (PID) Skyla is contraindicated in the presence of known or suspected PID or in women with a history of PID unless there has been a subsequent intrauterine pregnancy. IUDs have been associated with an increased risk of PID, most likely due to organisms being introduced into the uterus during insertion. In clinical trials, PID was observed in 0.4% of women … 5.6 Expulsion … If expulsion has occurred, a new Skyla can be inserted any time the provider can be reasonably certain the woman is not pregnant. 5.7 Ovarian Cysts … Ovarian cysts (reported as adverse reactions if they were abnormal, non-functional cysts and/or had a diameter greater than 3 cm on ultrasound examination) were reported at least once over the course of clinical trials in 13.2% of women using Skyla, and 0.3% of subjects discontinued because of an ovarian cyst. Most ovarian cysts are asymptomatic … 5.8 Bleeding Pattern Alterations Thereafter, the number of bleeding and spotting days usually decreases but bleeding may remain irregular. In Skyla clinical trials, amenorrhea developed by the end of the first year of use in approximately 6% of Skyla users. A total of 77 subjects out of 1,672 (4.6%) discontinued due to uterine bleeding complaints. Table 2 shows the bleeding patterns as documented in the Skyla clinical trials based on 90-day reference periods. Table 3 shows the number of bleeding and spotting days based on 28-day cycle equivalents. Table 2: Bleeding Patterns Reported with Skyla in Contraception Studies (by 90-day reference periods) Table inserted here; please refer to label for complete information. Table 3: Mean number of Bleeding and Spotting Days per 28-day Cycle Equivalent Table inserted here; please refer to label for complete information. … If a significant change in bleeding develops during prolonged use, take appropriate diagnostic measures to rule out endometrial pathology. Consider the possibility of pregnancy if menstruation does not occur within six weeks of the onset of a previous menstruation. Once pregnancy has been excluded, repeated pregnancy tests … 5.11 Magnetic Resonance Imaging (MRI) Safety Information Non-clinical testing has demonstrated that Skyla is MR Conditional. A patient with Skyla can be safely scanned in an MR system meeting the following conditions:  Static magnetic field of 3.0 T or less  Maximum spatial field gradient of 36,000 gauss/cm (360 T/m)  Maximum MR system reported, whole body averaged specific absorption rate (SAR) of 4W/kg (First Level Controlled Operating Mode) Under the scan conditions defined above, the Skyla IUS is expected to produce a maximum temperature rise of less than 2°C after 15 minutes of continuous scanning. In non-clinical testing, the image artifact caused by the IUS extended up to 5 mm from the IUS when imaged with a gradient echo pulse sequence and a 3.0 T MRI system.

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 23 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) Solu-Medrol 4 Contraindications (Additions and/or revisions are underlined) (methylprednisolone SOLU-MEDROL Sterile Powder is contraindicated: sodium succinate)  in systemic fungal infections and patients with known hypersensitivity to the product and its constituents. The SOLU-MEDROL 40 mg presentation includes lactose monohydrate produced from cow’s milk. This presentation is therefore contraindicated in patients with a known or suspected hypersensitivity to cow’s milk or its components or other dairy products because it may contain trace amounts of milk ingredients. 5 Warnings and Precautions WARNINGS General (Additions and/or revisions are underlined) In patients receiving the 40 mg presentation of SOLU-MEDROL during the treatment for acute allergic conditions and where these symptoms worsen or any new allergic symptoms occur, consideration should be given to the potential for hypersensitivity reactions to cow’s milk ingredients. If appropriate, administration of SOLU-MEDROL should be stopped, and the patient’s condition should be treated accordingly. Alternative treatments, including the use of corticosteroid formulations that do not contain ingredients produced from cow’s milk, should be considered for acute allergy management, where appropriate.

Tasigna 5 Warnings and Precautions 5.14 Effects on Growth and Development in Pediatric Patients (nilotinib (new subsection added) hydrochloride Adverse reactions associated with growth and development can occur in pediatric patients receiving BCR- monohydrate) ABL tyrosine kinase inhibitors. The long-term effect of prolonged treatment with BCR-ABL tyrosine kinase inhibitors on growth and development in pediatric patients are unknown. Therefore, monitor growth and development in pediatric patients receiving BCR-ABL tyrosine kinase inhibitor treatment. 5.6 Hepatotoxicity (additions underlined) Tasigna may result in hepatotoxicity as measured by elevations in bilirubin, AST, ALT, and alkaline phosphatase. Grade 3-4 elevations of bilirubin, AST, and ALT were reported at a higher frequency in pediatric than in adult patients. Monitor hepatic function tests monthly or as clinically indicated.

Tecentriq 5 Warnings and Precautions 5.5 Other Immune-Related Adverse Reactions (atezolizumab) Additions and/or revisions underlined: … Guillain-Barré, ocular inflammatory toxicity, pancreatitis, including increases in serum amylase and lipase levels, and myocarditis have occurred in less than or equal to 1.0% of patients treated with TECENTRIQ. Myocarditis Monitor patients for signs and symptoms of myocarditis. Withhold TECENTRIQ for Grade 2 myocarditis. Permanently discontinue TECENTRIQ for Grade 3 or 4 myocarditis. Consider initiation of treatment with systemic corticosteroids.

Tegretol, Tegretol Boxed Warning (additions underlined) XR …ALTHOUGH REPORTS OF TRANSIENT OR PERSISTENT DECREASED PLATELET OR WHITE (carbamazepine) BLOOD CELL COUNTS ARE NOT UNCOMMON IN ASSOCIATION WITH THE USE OF TEGRETOL,

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 24 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) DATA ARE NOT AVAILABLE TO ESTIMATE ACCURATELY THEIR INCIDENCE OR OUTCOME. HOWEVER, THE VAST MAJORITY OF THE CASES OF LEUKOPENIA HAVE NOT PROGRESSED TO THE MORE SERIOUS CONDITIONS OF APLASTIC ANEMIA OR AGRANULOCYTOSIS. BECAUSE OF THE VERY LOW INCIDENCE OF AGRANULOCYTOSIS AND APLASTIC ANEMIA, THE VAST MAJORITY OF MINOR HEMATOLOGIC CHANGES OBSERVED IN MONITORING OF PATIENTS ON TEGRETOL ARE UNLIKELY TO SIGNAL THE OCCURRENCE OF EITHER ABNORMALITY. NONETHELESS, COMPLETE PRETREATMENT HEMATOLOGICAL TESTING SHOULD BE OBTAINED AS A BASELINE. IF A PATIENT IN THE COURSE OF TREATMENT EXHIBITS LOW OR DECREASED WHITE BLOOD CELL OR PLATELET COUNTS, THE PATIENT SHOULD BE MONITORED CLOSELY. DISCONTINUATION OF THE DRUG SHOULD BE CONSIDERED IF ANY EVIDENCE OF SIGNIFICANT BONE MARROW DEPRESSION DEVELOPS. 5 Warnings and Precautions PRECAUTIONS (additions underlined) …Information for Patients …Patients should be advised that anaphylactic reactions and angioedema may occur during treatment with Tegretol (see WARNINGS). Advise patients to immediately report signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, or tongue, or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their healthcare provider. WARNINGS (additions underlined) …Anaphylaxis and Angioedema Rare cases of anaphylaxis and angioedema involving the larynx, glottis, lips, and eyelids have been reported in patients after taking the first or subsequent doses of Tegretol. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with Tegretol, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug.

Torisel 5 Warnings and Precautions 5.11 Proteinuria and Nephrotic Syndrome (temsirolimus) Newly added subsections: Proteinuria (including cases of nephrotic syndrome) has occurred in patients treated with TORISEL. Monitor urine protein prior to the start of TORISEL therapy and periodically thereafter. Discontinue TORISEL in patients who develop nephrotic syndrome. 5.15 Embryo-Fetal Toxicity Additions and/or revisions underlined: Based on findings in animal studies and its mechanism of action, TORISEL can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, daily oral administration of temsirolimus to pregnant animals during organogenesis caused adverse embryo-fetal effects in rats and rabbits at approximately 0.04 and 0.12 times the AUC in patients at the recommended human dose, respectively. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TORISEL and for 3 months after the last dose.

Toujeo SoloStar 5 Warnings and Precautions 5.4 Medication Errors (Additions and/or revisions are underlined)

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 25 form or medium, without EnvisionRxOptions’ prior written consent.

Trade Name Summary of Label Changes (generic name) (insulin glargine To avoid dosing errors and potential overdose, never use a syringe to remove TOUJEO from the TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen into a syringe. recombinant)

Tresiba 5 Warnings and Precautions 5.4 Hypoglycemia Due to Medication Errors (insulin degludec) (Additions and/or revisions are underlined) To avoid dosing errors and potential overdose, never use a syringe to remove TRESIBA from the TRESIBA pen into a syringe.

Tyzeka 5 Warnings and Precautions 5.2 Lactic Acidosis (telbivudine) (Additions and/or revisions are underlined) Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues. Postmarketing cases of lactic acidosis have been reported with TYZEKA. Cases were often associated with other serious conditions (e.g. rhabdomyolysis) and/or associated with muscle-related events (e.g. myopathy, myositis). Some cases were also associated with pancreatitis, liver failure/hepatic steatosis and renal failure. 5.3 Myopathy and Rhabdomyolysis (Additions and/or revisions are underlined) Cases of myopathy/myositis have been reported with TYZEKA use, several weeks to months after starting therapy. Myopathy has also been reported with some other drugs in this class. Rhabdomyolysis, including fatal cases, has been reported during postmarketing use of TYZEKA. Some of the muscle related events (e.g., myopathy, myositis, and rhabdomyolysis) reported with TYZEKA were associated with lactic acidosis.

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 26 form or medium, without EnvisionRxOptions’ prior written consent.

Treatment Guideline Updates

Title Citation/Link Stachler RJ, Francis DO, Schwartz SR, et al. Clinical Practice Clinical Practice Guideline: Guideline: Hoarseness (Dysphonia) (Update). Otolaryngol Head Neck Hoarseness (Dysphonia) (Update) Surg. 2018 Mar;158(1 suppl): S1-S42. http://journals.sagepub.com/doi/full/10.1177/0194599817751030 Martin KA, Anderson RR, Chang RJ, et al. Evaluation and Treatment of Evaluation and Treatment of Hirsutism in Premenopausal Women: An Endocrine Society Clinical Hirsutism in Premenopausal Practice Guideline. J Clin Endocrinol Metab. 2018 Mar 7. Women: An Endocrine Society https://academic.oup.com/jcem/advance-article/doi/10.1210/jc.2018- Clinical Practice Guideline 00241/4924418 Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Testosterone Therapy in Men With Men With Hypogonadism: An Endocrine Society Clinical Practice Hypogonadism: An Endocrine Guideline. J Clin Endocrinol Metab. 2018 Mar 17. Society Clinical Practice Guideline. https://www.ncbi.nlm.nih.gov/pubmed/29562364 NCCN Guidelines Insights: Hoppe RT, Advani RH, AI WZ, et al. NCCN Guidelines Insights: Hodgkin Lymphoma, Version Hodgkin Lymphoma, Version 1.2018. J Natl Compr Canc Netw. 2018 1.2018 Mar;16(3):245-254. http://www.jnccn.org/content/16/3/245.long Radiation therapy for the whole Smith BD, Bellon JR, Blitzblau R, et al. Radiation therapy for the whole breast: Executive summary of an breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Pract Radiat Oncol. American Society for Radiation 2018 mar 12. Oncology (ASTRO) evidence- https://www.ncbi.nlm.nih.gov/pubmed/?term=guideline+2018+mar+wbi based guideline +american+society+for+radiation+oncology American Gastroenterological Crockett SD, Wani S, Gardner TB, et al. American Gastroenterological Association Institute Guideline Association Institute Guideline on Initial Management of Acute on Initial Management of Acute Pancreatitis. Gastroenterology. 2018 Mar;154(4):1090-1101. Pancreatitis http://www.gastrojournal.org/article/S0016-5085(18)30076-3/fulltext

Confidential - Document has confidential information and may not be copied, published or distributed, in whole or in part, in any 800.361.4542 | envisionrx.com 27 form or medium, without EnvisionRxOptions’ prior written consent.