Health Plan Insights

August 2020 Updates from July 2020

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Recent FDA Approvals New Medications TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE ByfavoTM Acacia Pharma, Injection, for IV use For the induction and maintenance of procedural July 2, 2020 (remimazolam) Inc. Eq 20 mg/vial sedation in adults undergoing procedures lasting 30 minutes or less. RukobiaTM ViiV Healthcare Extended-Release For use in combination with other antiretroviral(s), July 2, 2020 (fostemsavir) Tablets, for the treatment of HIV-1 infection in heavily 600 mg treatment-experienced adults with multidrug- resistant HIV-1 infection failing their current antiretroviral regimen due to resistance, intolerance, or safety considerations. QwoTM Endo Aesthetics Injection for SQ For the treatment of moderate to severe cellulite July 6, 2020 (collagenase LLC use, in the buttocks of adult women. clostridium 0.92 mg and 1.84 histolyticum-aaes) mg Hulio® Mylan Injection for SQ For the treatment of Rheumatoid Arthritis, July 6, 2020 (adalimumab-fkjp) Pharmaceuticals use, Juvenile Idiopathic Arthritis, Psoriatic Arthritis, Inc. 40 mg/0.8 mL and Ankylosing Spondylitis, Adult Crohn’s Disease, 20 mg/0.4 mL Ulcerative Colitis, and Plaque Psoriasis. Inqovi® Otsuka Tablets, For the treatment of adult patients with July 7, 2020 (decitabine and Pharmaceutical 35 mg/100 mg myelodysplastic syndromes (MDS), including cedazuridine) Company, Ltd. previously treated and untreated, de novo and secondary MDS with the following FrenchAmerican-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups. XywavTM Jazz Oral Solution, For the treatment of cataplexy or excessive July 21, 2020 (calcium, Pharmaceuticals, 0.5 mg/mL daytime sleepiness (EDS) in patients 7 years of magnesium, Inc. age and older with narcolepsy. potassium, and sodium oxybates)

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TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE XeglyzeTM Dr. Reddy’s Lotion, For the treatment of head lice infestation in July 24, 2020 (abametapir) Laboratories, SA 0.74% patients 6 months of age and older. XEGLYZE should be used in the context of an overall lice management program. Monjuvi® MorphoSys US Injection for IV use, For the treatment of adult patients with relapsed July 31, 2020 (tafasitamab-cxix) Inc. 200 mg per vial or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant (ASCT).

New Combinations and Formulations TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE TralementTM American Regent, Injection, for IV use, For use in adult and pediatric patients weighing July 2, 2020 (trace elements: Inc. Each mL contains at least 10 kg as a source of zinc, copper, zinc sulfate, cupric zinc 3 mg, copper 0.3 manganese, and selenium for parenteral sulfate, mg, manganese 55 nutrition when oral or enteral nutrition is not manganese sulfate mcg, and selenium possible, insufficient, or contraindicated. and selenious 60 mcg acid) Bendamustine Slayback Injection, For: (1) Chronic lymphocytic leukemia (CLL). July 2, 2020 Hydrochloride Pharmaceuticals 100 mg/m2 Efficacy relative to first line therapies other LLC than chlorambucil has not been established. (2) Indolent B-cell non-Hodgkin lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. UpneeqTM RVL Ophthalmic Solution, For the treatment of acquired blepharoptosis in July 8, 2020 (oxymetazoline Pharmaceuticals, 1% adults. hydrochloride) Inc. Carbon Dioxide, Nexair LLC Medical Gas For human and animal drug use. July 18, 2020 USP

Wynzora® MC2 Therapeutics, Topical Cream, For the topical treatment of plaque psoriasis in July 20, 2020 (calcipotriene and Inc. 0.005%/0.064% patients 18 years of age and older. betamethasone dipropionate)

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TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE Breztri AstraZeneca Inhalation Aerosol, For the maintenance treatment of patients with July 23, 2020 AerosphereTM Pharmaceuticals 160 mcg/9 mcg/4.8 chronic obstructive pulmonary disease (budesonide, LP mcg per inhalation (COPD). glycopyrrolate, and formoterol fumarate) Cyclophosphamide Ingenus Injection, for IV use For the treatment of Malignant Diseases: July 30, 2020 Pharmaceuticals malignant lymphomas: Hodgkin's disease, LLC lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt's lymphoma; multiple myeloma, leukemias, mycosis fungoides, neuroblastoma, adenocarcinoma of ovary, retinoblastoma, breast carcinoma.

New Generics APPROVAL GENERIC NAME TRADE NAME DOSAGE FORM MANUFACTURER(S) DATE Deferasirox Jadenu Sprinkle Oral Granules Alkem Laboratories Ltd. July 14, 2020 Metyrosine Demser Capsules Amneal Pharmaceuticals LLC July 24, 2020

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Pipeline New Medication Pipeline

MECHANISM OF ANTICIPATED DRUG NAME GENERIC NAME ROUTE INDICATION(S) ACTION APPROVAL DATE Botreso TBD Oral TBD Treatment of the 2Q 2020 signs and symptoms of benign prostatic hyperplasia Roctavian Valoctocogene Intravenous Gene therapy Hemophilia A 08/21/2020 Roxaparvovec TRC101 Veverimer Oral Acid binder Metabolic acidosis 08/22/2020

XaraColl Bupivacaine Implant Amide anesthetic Post-operative pain 08/26/2020

Winlevi Cortexolone 17a- Topical Antiandrogens Acne vulgaris 08/27/2020 Propionate SA237 Satralizumab Subcutaneous Interleukin 6 Neuromyelitis optica 08/2020 receptor (IL-6R) antagonist CC-486 Azacitidine Oral Antimetabolites Acute myeloid 09/03/2020 leukemia Lucassin Terlipressin Acetate Intravenous Vasopressin agonist Hepatorenal 09/12/2020 syndrome Ryoncil Remestemcel-L Intravenous Stem cell therapy Graft versus host 09/30/2020 disease Coronavirus disease 2019 (COVID-19) NETMedix Copper Cu-64 Intravenous Diagnostic For scintigraphic 09/2020 Dotatate radiopharmaceutical localization of neuroendocrine tumors GLPG0634 Filgotinib Oral Janus kinase (JAK) Rheumatoid arthritis 3Q 2020 inhibitor Ulcerative colitis Crohn's disease Ankylosing Spondylitis Psoriatic arthritis REGN-EB3 TBD Intravenous Antiviral antibodies Ebola virus disease 10/25/2020

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MECHANISM OF ANTICIPATED DRUG NAME GENERIC NAME ROUTE INDICATION(S) ACTION APPROVAL DATE Bronchitol Mannitol Inhaled Mucolytic Cystic fibrosis 11/01/2020 Bronchiectasis SPN-812 Viloxazine Oral Norepinephrine Attention deficit 11/08/2020 Hydrochloride reuptake inhibitor hyperactivity disorder ALKS 3831 Olanzapine; Oral Opioid antagonist Schizophrenia 11/15/2020 Samidorphan Atypical Bipolar disorder I or antipsychotic II AR19 Amphetamine Oral CNS stimulant Attention deficit 11/15/2020 hyperactivity disorder JCAR017 Lisocabtagene Intravenous Chimeric antigen B-cell lymphoma 11/16/2020 Maraleucel receptor T-cell (CAR-T) immunotherapy Cellular immunotherapy Zokinvy Lonafarnib Oral Farnesyltransferase Progeria Hepatitis D 11/20/2020 inhibitor BLU-667 Pralsetinib Oral RET inhibitor Non-small cell lung 11/23/2020 cancer Xofluza (oral Baloxavir marboxil Oral Endonuclease Acute uncomplicated 11/23/2020 suspension) inhibitor influenza/ Prophylaxis of influenza RM-493 Setmelanotide Subcutaneous Peptide Obesity 11/27/2020 melanocortin receptor agonist Danyelza Naxitamab Injectable Anti-GD2 antibody Neuroendocrine 11/30/2020 tumors Hetlioz (liquid) Tasimelteon TBD Melatonin receptor Sleep disorders 12/01/2020 agonist associated with Smith-Magenis syndrome ALN-GO1 Lumasiran Subcutaneous Antisense Primary 12/03/2020 oligonucleotide hyperoxaluria BCX7353 Berotralstat Oral Plasma kallikrein Prophylaxis against 12/03/2020 inhibitor angioedema attacks in hereditary angioedema

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MECHANISM OF ANTICIPATED DRUG NAME GENERIC NAME ROUTE INDICATION(S) ACTION APPROVAL DATE FG-4592 Roxadustat Oral Hypoxia-inducible Anemia due to 12/20/2020 factor (HIF) kidney disease stabilizer Relugolix Relugolix Oral Gonadotropin- Prostate cancer 12/20/2020 releasing hormone Uterine fibroids (GnRH) antagonist RVT-901 Vibegron Oral Beta adrenergic Overactive bladder 12/26/2020 agonist symptoms Ontinua ER Arbaclofen Oral GABA receptor Spasticity in multiple 12/29/2020 agonist sclerosis KX2-391 Tirbanibulin Topical Tubulin inhibitor Actinic keratosis 12/30/2020

Tanezumab Tanezumab Subcutaneous Anti-NGF antibody Osteoarthritis 12/2020

Inclisiran Inclisiran Subcutaneous PCSK9 inhibitor Atherosclerotic 4Q 2020 vascular disease risk NS-065 Viltolarsen Injectable Antisense Duchenne muscular 4Q 2020 oligonucleotide dystrophy Remune HIV Vaccine Intramuscular HIV vaccine HIV infection 4Q 2020

MK-1242 Vericiguat Oral Guanylate cyclase Heart failure 01/20/2021 stimulants LY03005 Ansofaxine Oral Norepinephrine- Major depressive 01/2021 Hydrochloride dopamine reuptake disorder inhibitor (NDRI) Serotonin- norepinephrine reuptake inhibitor (SNRI) StrataGraft TBD Other Organ replacement Burns 02/02/2021

BIIB037 Aducanumab Intravenous Amyloid beta Alzheimer's disease 03/07/2021 protein inhibitor ZP4207 Dasiglucagon Subcutaneous Glucagon analog Improve glycemic 03/27/2021 control in type 1 and/or type 2 diabetes Tivozanib Tivozanib Oral Vascular endothelial Kidney cancer 03/31/2021 growth factor 800.361.4542 | envisionrx.com 7

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MECHANISM OF ANTICIPATED DRUG NAME GENERIC NAME ROUTE INDICATION(S) ACTION APPROVAL DATE receptor (VEGFR) inhibitor ACT-128800 Ponesimod Oral Sphingosine 1- Relapsing multiple 1Q 2021 phosphate (S1P) sclerosis receptor modulators Estelle Drospirenone; Oral Estrogens Pregnancy 2Q 2021 Estetrol Progestins prevention Evinacumab Evinacumab Intravenous Anti-angiopoietin- Homozygous familial 2Q 2021 like protein 3 hypercholesterolemia (ANGPTL3) antibody NexoBrid TBD Topical Proteolytic enzymes Wound debridement 2Q 2021

Orelvo Voclosporin Oral Immunosuppressant Lupus nephritis 2Q 2021

SRP-4045 Casimersen Intravenous Antisense Duchenne muscular 2Q 2021 oligonucleotide dystrophy TGR-1202 Umbralisib Oral Phosphoinositide 3- Follicular lymphoma 2Q 2021 kinase (PI3K) inhibitor Tralokinumab Tralokinumab Subcutaneous Interleukin 13 (IL- Atopic dermatitis 2Q 2021 13) antagonist TransCon hGH Lonapegsomatropin Subcutaneous Growth hormone Pediatric growth 2Q 2021 hormone deficiency Ygalo Melflufen Intravenous Alkylating agent Multiple myeloma 2Q 2021

2020 New Generic Pipeline ANTICIPATED BRAND US BRAND NAME GENERIC NAME INDICATION(S) LAUNCH DATE MANUFACTURER SALES 09/29/2020 TYKERB Lapatinib Novartis Breast Cancer: HER2-positive $66M Ditosylate breast cancer 09/30/2020 ATRIPLA Efavirenz; Gilead HIV or AIDS $731M Emtricitabine; (2019) Tenofovir Disoproxil Fumarate

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ANTICIPATED BRAND US BRAND NAME GENERIC NAME INDICATION(S) LAUNCH DATE MANUFACTURER SALES 09/30/2020 TRUVADA Emtricitabine; Gilead HIV or AIDS: HIV-1 infection; HIV $3,401M (200 mg/300 Tenofovir or AIDS: Prophylaxis to reduce risk (2019) mg) Disoproxil of sexually acquired HIV-1; HIV or Fumarate AIDS: Prophylaxis to reduce risk of sexually acquired HIV-1 3Q 2020 TIROSINT Levothyroxine IBSA Institut Thyroid Cancer: Differentiated $96M Sodium Biochemique thyroid cancer (2019) 10/01/2020 KUVAN Sapropterin BioMarin Hyperphenylalaninemia due to $19M (500 mg Dihydrochloride tetrahydrobiopterin‑ (BH4‑) powder) responsive Phenylketonuria 10/01/2020 KUVAN Sapropterin BioMarin Hyperphenylalaninemia due to $25M (tablet) Dihydrochloride tetrahydrobiopterin‑ (BH4‑) responsive Phenylketonuria 12/27/2020 ABSORICA Isotretinoin Ranbaxy; Cipher Acne Vulgaris $308M Pharmaceuticals; Sun 4Q 2020 CHANTIX Varenicline Pfizer Aid to smoking cessation $1,221M Tartrate (2019) 2H 2020 ENTEREG Alvimopan Cubist Postsurgical recovery $108M Pharmaceuticals; (2019) Merck & Co 2H 2020 KORLYM Mifepristone Corcept Hyperglycemia secondary to $2M hypercortisolism in patients with (2019) endogenous Cushing's syndrome 2020 ADRENALIN Epinephrine Par; Endo Anaphylactic reactions $168M (2019) 2020 BYETTA Exenatide AstraZeneca Diabetes Mellitus $187M Synthetic 2020 KALETRA Lopinavir; AbbVie HIV or AIDS: HIV-1 infection $64M (tablets) Ritonavir 2020 MOVIPREP Ascorbic Acid; Salix; Bausch Constipation or Bowel Cleansers: $34M Polyethylene Health; Valeant Bowel cleansing Glycol 3350; Potassium Chloride; Sodium Ascorbate; Sodium Chloride; Sodium Sulfate

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ANTICIPATED BRAND US BRAND NAME GENERIC NAME INDICATION(S) LAUNCH DATE MANUFACTURER SALES 2020 NEXIUM Esomeprazole AstraZeneca; Gastroesophageal Reflux Disease $12M 24HR (tablet) Magnesium Pfizer (2019) 2020 NOXAFIL Posaconazole Merck & Co Prophylaxis of $23M (suspension) invasive Aspergillus and Candida in (2019) fections 2020 PREPOPIK Citric Acid; Ferring Constipation or Bowel Cleansers $12M Magnesium Oxide; Sodium Picosulfate 2020 VIVLODEX Meloxicam Egalet; iCeutica; Osteoarthritis: Osteoarthritis pain $14M Zyla (2019) 2020-2021 DALIRESP Roflumilast AstraZeneca Chronic Obstructive Pulmonary $231M Disease (2019) 2020-2021 EPIDUO Adapalene; Galderma Acne Vulgaris $301M FORTE Benzoyl Peroxide 2020-2021 NARCAN Naloxone Adapt Pharma; Opioid overdose $359M (nasal spray) Hydrochloride Emergent (2019) BioSolutions; Opiant 2020-2021 PROTONIX Pantoprazole Wyeth; Pfizer Gastroesophageal Reflux Disease $47M (granules) Sodium (2019) 2020-2021 TECFIDERA Dimethyl Biogen Relapsing multiple sclerosis $3,990M Fumarate (2019) 2020-2021 THALOMID Thalidomide Celgene; Bristol- Multiple Myeloma $29M Myers Squibb

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Medication with Significant Label Changes TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Arthrotec Boxed Warning (Box Warning in supplement 33 has been revised; see underlined text) (diclofenac sodium; ARTHROTEC CONTAINS DICLOFENAC SODIUM AND MISOPROSTOL. ADMINISTRATION OF misoprostol) MISOPROSTOL TO WOMEN WHO ARE PREGNANT CAN CAUSE ABORTION, PREMATURE BIRTH, BIRTH DEFECTS, OR UTERINE RUPTURE. UTERINE RUPTURE HAS BEEN REPORTED WHEN MISOPROSTOL WAS ADMINISTERED IN PREGNANT WOMEN TO INDUCE LABOR OR TO INDUCE ABORTION. THE RISK OF UTERINE RUPTURE INCREASES WITH ADVANCING GESTATIONAL AGES AND WITH PRIOR UTERINE SURGERY, INCLUDING CESAREAN DELIVERY. ARTHROTEC SHOULD NOT BE TAKEN BY PREGNANT WOMEN (4, 5.10, 8.1). PATIENTS MUST BE ADVISED OF THE ABORTIFACIENT PROPERTY AND WARNED NOT TO GIVE THE DRUG TO OTHERS. ARTHROTEC should not be used in women of childbearing potential unless the patient requires nonsteroidal anti-inflammatory drug (NSAID) therapy and is at high risk of developing gastric or duodenal ulceration or for developing complications from gastric or duodenal ulcers associated with the use of the NSAID. In such patients, ARTHROTEC may be prescribed if the patient:  has had a negative serum pregnancy test within 2 weeks prior to beginning therapy (8.3).  is capable of complying with effective contraceptive measures.  has received both oral and written warnings of the hazards of misoprostol, the risk of possible contraception failure, and the danger to other women of childbearing potential should the drug be taken by mistake.  will begin ARTHROTEC only on the second or third day of the next normal menstrual period. Cardiovascular Thrombotic Events Risk  Nonsteroidal anti-inflammatory drugs (NSAIDs) cause an increased risk of serious cardiovascular thrombotic events, including myocardial infarction and stroke, which can be fatal. This risk may occur early in treatment and may increase with duration of use (5.1).  ARTHROTEC is contraindicated in the setting of coronary artery bypass graft (CABG) surgery (4, 5.1). Gastrointestinal Bleeding, Ulceration, and Perforation Risk  NSAIDs cause an increased risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients and patients with a prior history of peptic ulcer disease and/or GI bleeding are at greater risk for serious GI events (5.2).

Cervidil 5 Warnings and Precautions (PLR conversion; subsections as below) (dinoprostone) 5.1 For Hospital Use Only CERVIDIL should be administered in a hospital setting with an obstetrical care facility. 5.2 Disseminate d Intravascular Coagulation CERVIDIL should be used with caution in women at high risk of postpartum disseminated intravascular coagulation (DIC). Physiologic or pharmacologic induction of labor, including the use of CERVIDIL, is associated with an increased risk of DIC during the postpartum period. Women aged 30 years or older, those with complications during pregnancy and those with a gestational age over 40 weeks have an increased risk of DIC during the postpartum period. As soon as possible, assess for an evolving fibrinolysis in the immediate post-partum period. Therapy consisting of prompt removal of the source of procoagulant material, replacement of depleted clotting factors and, in some cases, anti-coagulation with heparin should be instituted promptly. 5.3 Amniotic Fluid Embolism Syndrome

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) The use of dinoprostone-conta ining products, including CERVIDIL, can result in inadvertent disruption and subsequent embolization of antigenic tissue causing the development of Amniotic Fluid Embolism Syndrome, a rare and often fatal obstetric condition. Carefully monitor patients for clinical signs of Amniotic Fluid Embolism Syndrome including hypotension, hypoxemia and respiratory failure, DIC, coma or seizures and provide supportive care as needed. 5.4 Uterine Tachysystole and Uterine Hypersystole/Hypertonicity The use of CERVIDIL may cause uterine tachysystole with or without fetal heart rate changes (see Table 1). While using CERVIDIL, carefully monitor uterine activity, fetal status and the progression of cervical dilatation and effacement. Remove CERVIDIL with any evidence of uterine tachysystole, uterine hypersystole/hypertonic ity, fetal distress, or if labor commences. CERVIDIL is contraindicated when prolonged contraction of the uterus is detrimental to fetal safety or uterine integrity, such as previous cesarean section or major uterine surgery, because of the risk of uterine rupture and obstetrical complications (e.g., need for hysterectomy and the occurrence of fetal or neonatal death). Prostaglandins, including CERVIDIL, may potentiate the effect of oxytocin [see Drug Interactions (7)]. Remove CERVIDIL at least 30 minutes before administration of an oxytocic agent is initiated and continue to carefully monitor uterine activity. Remove CERVIDIL prior to amniotomy or following rupture of membranes because the higher vaginal pH that occurs with rupture of membranes may result in higher release rate of dinoprostone. 5.5 Glaucoma Prostaglandins, including CERVIDIL, can lead to raised intraocular pressure and constriction of pupils. Consider non-prostaglandin cervical ripening procedures in patients with Glaucoma.

Copaxone 5 Warnings and Precautions 5.5 Hepatic Injury (glatiramer acetate) (Newly added section) Cases of hepatic injury, some severe, including liver failure and hepatitis with jaundice, have been reported with COPAXONE. Hepatic injury has occurred from days to years after initiating treatment with COPAXONE. If signs or symptoms of liver dysfunction occur, consider discontinuation of COPAXONE.

Docetaxel 5 Warnings and Precautions (Extensive changes; please refer to label) (docetaxel)

Emflaza Boxed Warning PATIENT COUNSELING INFORMATION (delfazacort) (Additions underlined) …  EMFLAZA may be taken with or without food. Do not take EMFLAZA with grapefruit juice. …  The EMFLAZA Oral Suspension dose may be placed in 3-4 ounces of juice (except grapefruit juice) or milk, mixed thoroughly, and immediately administered.

Epidiolex 5 Warnings and Precautions 5.2 Somnolence and Sedation (cannabidiol) Additions and/or revisions underlined: EPIDIOLEX can cause somnolence and sedation. In controlled studies for LGS and DS (10 and 20 mg/kg/day dosages), the incidence of somnolence and sedation (including lethargy) was 32% in EPIDIOLEX-treated patients (27% and 34% of patients taking EPIDIOLEX 10 or 20 mg/kg/day, respectively), compared with 11% in patients on placebo and was generally dose-related. The rate was higher in patients on concomitant clobazam (46% in EPIDIOLEX-treated patients taking clobazam compared with 16% in EPIDIOLEX-treated

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) patients not on clobazam). In the controlled study for TSC, the incidence of somnolence and sedation (including lethargy) was 19% in EPIDIOLEX-treated patients (25 mg/kg/day), compared with 17% in patients on placebo. The rate was higher in patients on concomitant clobazam (33% in EPIDIOLEX-treated patients taking clobazam compared with 14% in EPIDIOLEX-treated patients not on clobazam). In general, these effects were more common … 5.4 Hypersensitivity Reactions Additions and/or revisions underlined: EPIDIOLEX can cause hypersensitivity reactions. Some subjects in the EPIDIOLEX clinical trials had pruritus, erythema, and angioedema requiring treatment, including corticosteroids and antihistamines. Additions and/or revisions underlined: 5.1 Hepatocellular Injury EPIDIOLEX can cause dose-related elevations of liver transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase [AST]). In controlled studies for LGS and DS (10 and 20 mg/kg/day dosages) and TSC (25 mg/kg/day), the incidence of ALT elevations above 3 times the upper limit of normal (ULN) was 13% (10 and 20 mg/kg/day dosages) and 12% (25 mg/kg/day dosage) in EPIDIOLEX-treated patients compared with 1% in patients on placebo … … Risk Factors for Transaminase Elevation Concomitant Valproate and Clobazam The majority of ALT elevations occurred in patients taking concomitant valproate [see Drug Interactions (7.3)]. Concomitant use of clobazam also increased the incidence of transaminase elevations, although to a lesser extent than valproate [see Drug Interactions (7.2)]. In EPIDIOLEX-treated patients with LGS or DS (10 and 20 mg/kg/day dosages), the incidence of ALT elevations greater than 3 times the ULN was 30% in patients taking both concomitant valproate and clobazam, 21% in patients taking concomitant valproate (without clobazam), 4% in patients taking concomitant clobazam (without valproate), and 3% in patients taking neither drug. In EPIDIOLEX-treated patients with TSC (25 mg/kg/day), the incidence of ALT elevations greater than 3 times the ULN was 20% in patients taking both concomitant valproate and clobazam, 25% in patients taking concomitant valproate (without clobazam), 0% in patients taking concomitant clobazam (without valproate), and 6% in patients taking neither drug. Consider discontinuation or dose adjustment of valproate or clobazam if liver enzyme elevations occur. Dose Transaminase elevations are generally dose-related. In patients with DS or LGS (10 and 20 mg/kg/day) or TSC (25 mg/kg/day), ALT elevations greater than 3 times the ULN were reported in 17% and 12% of patients taking EPIDIOLEX 20 or 25 mg/kg/day, respectively, compared with 1% in patients taking EPIDIOLEX 10 mg/kg/day. The risk of ALT elevations was higher (25%) in patients with TSC receiving a dosage above the recommended maintenance dosage of 25 mg/kg/day in Study 4. Baseline Transaminase Elevations Patients with baseline transaminase levels above the ULN had higher rates of transaminase elevations when taking EPIDIOLEX. In the DS and LGS controlled trials (Studies 1, 2, and 3) in patients taking EPIDIOLEX 20 mg/kg/day … No patients taking EPIDIOLEX 10 mg/kg/day experienced ALT elevations greater than 3 times the ULN when ALT was above the ULN at baseline, compared with 2% of patients in whom ALT was within the normal range at baseline. In the TSC controlled trial (Study 4) in patients taking EPIDIOLEX 25 mg/kg/day, the frequency of treatment-emergent ALT elevations greater than 3 and 5 times the ULN were both 11% when ALT was above the ULN at baseline, compared to 12% and 6%, respectively, when ALT was within the normal range at baseline.

Erivedge 5 Warnings and Precautions Newly added subsection: (vismodegib) 5.2 Severe Cutaneous Adverse Reactions

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), which can be life- threatening or fatal, have been reported during treatment with ERIVEDGE [see Adverse Reactions (6.2)]. Permanently discontinue ERIVEDGE in patients with these reactions [see Dosage and Administration (2.3)].

Evotaz 5 Warnings and Precautions 5.1 Cardia Conduction Abnormalities (atazanavir sulfate; Additions and/or revisions underlined: cobicistate) Atazanavir prolongs the PR interval of the electrocardiogram in some patients. In healthy subjects and in subjects with HIV-1 infection treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.1) and Overdosage (10)]. In clinical trials of atazanavir in subjects with HIV-1 infection that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of subjects treated with atazanavir (n=920) and 5% of subjects (n=118) treated with atazanavir coadministered with ritonavir. 5.11 Immune Reconstitution Syndrome … Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution …

Exjade 5 Warnings and Precautions 5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity (deferasirox) Including Fanconi Syndrome (Newly added information) Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated. 5.6 Overchelation (Additions and/or revisions underlined) For patients with transfusional iron overload, measure serum ferritin monthly to assess the patient’s response to therapy and minimize the risk of overchelation

Heparin Sodium, 4 Contraindications Additions and/or revisions underlined: Heparin Sodium The use of heparin sodium is contraindicated in patients: in Sodium  With history of heparin-induced thrombocytopenia (HIT) (With or Without Thrombosis) [see Warnings and Chloride Precautions (5.3)] (heparin sodium)  With a known hypersensitivity to heparin or pork products (e.g., anaphylactoid reactions) [see Adverse Reactions (6.1)]  In whom suitable blood coagulation tests — e.g., the whole blood clotting time, partial thromboplastin time, etc., — cannot be performed at appropriate intervals (this contraindication refers to full-dose heparin; there is usually no need to monitor coagulation parameters in patients receiving low-dose heparin) [see Warnings and Precautions (5.5)]  With an uncontrollable active bleeding state [see Warnings and Precautions (5.5)], except when treating disseminated intravascular coagulation. 5 Warnings and Precautions 5.1 Fatal Medication Errors Additions and/or revisions underlined:

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Do not use Heparin Sodium Injection as a “catheter lock flush” product. Heparin Sodium Injection is supplied in vials containing various strengths of heparin, including vials that contain a highly concentrated solution of 10,000 units in 1 mL … Newly added subsection: 5.4 Risk of Serious Adverse Reactions in Infants Due to Benzyl Alcohol Preservative Serious and fatal adverse reactions including “gasping syndrome” can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including Heparin Sodium Injection multiple-dose vials. The “gasping syndrome” is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. When prescribing Heparin Sodium Injection multiple-dose vials in infants consider the combined daily metabolic load of benzyl alcohol from all sources including Heparin Sodium Injection multiple-dose vials and other drugs containing benzyl alcohol. The minimum amount of benzyl alcohol at which toxicity may occur is not known [see Use in Specific Populations (8.4)]. 5.5 Coagulation Testing and Monitoring When heparin sodium is administered in therapeutic amounts, its dosage should be monitored by frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, heparin sodium should be discontinued promptly [see Overdosage (10)]. Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy [see Dosage and Administration (2.2)]. Additions and/or revisions underlined: 5.6 Coagulation Testing and Monitoring Additions and/or revisions underlined: When using a full dose heparin regimen, adjust the heparin dose based on frequent blood coagulation tests. If the coagulation test is unduly prolonged or if hemorrhage occurs, discontinue heparin promptly [see Overdosage (10)]. Periodically monitor platelet counts, hematocrit, and occult blood in stool during the entire course of heparin therapy, regardless of the route of administration [see Dosage and Administration (2.2)]. 5.7 Hypersensitivity Reactions Patients with documented hypersensitivity to heparin should be given the drug only in clearly life-threatening situations [see Adverse Reactions (6.1)]. Because heparin sodium is derived from animal tissue, monitor for signs and symptoms of hypersensitivity when it is used in patients with a history of allergy.

Jadenu 5 Warnings and Precautions 5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis and Renal Tubular Toxicity (deferasirox) Including Fanconi Syndrome (Newly added information) Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated. 5.6 Overchelation (Additions and/or revisions underlined) For patients with transfusional iron overload, measure serum ferritin monthly to assess the patient’s response to therapy and minimize the risk of overchelation

Jandenu Sprinkle 5 Warnings and Precautions 5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity (deferasirox) Including Fanconi Syndrome (Newly added information)

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated. 5.10 Auditory and Ocular Abnormalities (Additions and/or revisions underlined) The frequency of auditory adverse reactions was increased among pediatric patients, who received Exjade doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day JADENU when serum ferritin was less than 1,000 mcg/L [see Warnings and Precautions (5.6)]. 5.2 Hepatic Toxicity and Failure (Additions and/or revisions underlined) Acute liver injury and failure, including fatal outcomes, have occurred in pediatric deferasirox-treated patients. 5.5 Age-Related Risk of Toxicity Pediatric Patients (Additions and/or revisions underlined) JADENU has been associated with serious and fatal adverse reactions in pediatric patients in the postmarketing setting. These events were frequently associated with volume depletion or with continued Exjade doses in the 20-40 mg/kg/day range equivalent to 14-28 mg/kg/day JADENU when body iron burden was approaching or in the normal range. 5.6 Overchelation (Additions and/or revisions underlined) For patients with transfusional iron overload, measure serum ferritin monthly to assess the patient’s response to therapy and minimize the risk of overchelation. An analysis of pediatric patients treated with Exjade in pooled clinical trials (n = 158), found a higher rate of renal adverse reactions among patients receiving doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day JADENU while their serum ferritin values were less than 1,000 mcg/L. 5.8 Severe Skin Reactions (Newly added information) If any severe skin reactions are suspected, discontinue JADENU immediately and do not reintroduce JADENU therapy.

Juluca 4 Contraindications (Additions and/or revisions underlined) (dolutegravir JULUCA is contraindicated in patients: sodium; rilpivirine  with previous hypersensitivity reaction to dolutegravir or rilpivirine. hcl)  receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events.  receiving other coadministered drugs in Table 1 that significantly decrease rilpivirine plasma concentrations.

Kisqali 5 Warnings and Precautions 5.2 Severe Cutaneous Adverse Reactions (ribociclib (New subsection added) succinate) Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson Syndrome (SJS), toxic epidermal Kisqali Femara necrolysis (TEN), and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and Co-Pack systemic symptoms (DRESS) can occur in patients treated with KISQALI [see Adverse Reactions (6.2)]. If signs or symptoms of severe cutaneous reactions occur, interrupt KISQALI until the etiology of the reaction (letrozole; ribociclib has been determined [see Dosage and Administration (2.2)]. Early consultation with a dermatologist is succinate) recommended to ensure greater diagnostic accuracy and appropriate management.

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) If SJS, TEN, or DiHS/DRESS is confirmed, permanently discontinue KISQALI. Do not reintroduce KISQALI in patients who have experienced SCARs or other life threatening cutaneous reactions during KISQALI treatment.

Natpara 5 Warnings and Precautions 5.2 NATPARA REMS Program (parathyroid Additions and/or revisions underlined: hormone) Further information is available at www.NATPARAREMS.com or by telephone at 1-855-NATPARA (1-855- 628-7272).

Nerlynx 5 Warnings and Precautions 5.1 Diarrhea (neratinib maleate) (Additions and/or revisions underlined) … Diarrhea was reported in 83% of NERLYNX plus capecitabine treated patients in NALA, a randomized placebo-controlled trial in the metastatic breast cancer setting who were required to receive anti-diarrheal prophylaxis in the first 21-day cycle. The majority of patients (70%) had diarrhea in the first 21 days of treatment, the median time to first onset of Grade greater than or equal to 3 diarrhea was 11 days (range, 2– 728) and the median cumulative duration of Grade greater than or equal to 3 diarrhea was 3 days (range, 1– 21). In the NERLYNX plus capecitabine arm, Grade 3 diarrhea occurred in 24% of patients [see Adverse Reactions (6.1)].

Nexavar 5 Warnings and Precautions 5.2 Hemorrhage (sorafenib tosylate) (Additions and revisions underlined) An increased risk of bleeding may occur following NEXAVAR administration. In the SHARP (HCC) study, an excess of bleeding regardless of causality was not apparent and the rate of bleeding from esophageal varices was 2.4% in NEXAVAR-treated patients and 4% in placebo-treated patients. Bleeding with a fatal outcome from any site was reported in 2.4% of NEXAVAR-treated patients and 4% in placebo-treated patients. In the TARGET (RCC) study, bleeding regardless of causality was reported in 15.3% of patients in the NEXAVAR- treated group and 8.2% of patients in the placebo-treated group. The incidence of CTCAE Grade 3 and 4 bleeding was 2% and 0%, respectively, in NEXAVAR-treated patients, and 1.3% and 0.2%, respectively, in placebo-treated patients. There was one fatal hemorrhage in each treatment group in the TARGET (RCC) study. In the DECISION (DTC) study, bleeding was reported in 17.4% of NEXAVAR-treated patients and 9.6% of placebo-treated patients; however the incidence of CTCAE Grade 3 bleeding was 1% in NEXAVAR- treated patients and 1.4% in placebo- treated patients. There was no Grade 4 bleeding reported and there was one fatal hemorrhage in a placebo-treated patient. … 5.5 Gastrointestinal Perforation (Additions underlined) Gastrointestinal perforation is an uncommon adverse reaction and has been reported in less than 1% of patients taking NEXAVAR. In some cases this was not associated with apparent intra-abdominal tumor. In the event of a gastrointestinal perforation, permanently discontinue NEXAVAR. 5.7 Risk of Impaired Wound Healing (Newly added subsection) Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, NEXAVAR has the potential to adversely affect wound healing.

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Withhold NEXAVAR for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of NEXAVAR after resolution of wound healing complications has not been established. 5.11 Embryo-Fetal Toxicity (Additions underlined) … Verify the pregnancy status of females of reproductive potential prior to initiation of NEXAVAR.

Olumiant 5 Warnings and Precautions 5.7 Hypersensitivity (baricitinib) (New subsection added) Reactions such as angioedema, urticaria, and rash that may reflect drug hypersensitivity have been observed in patients receiving OLUMIANT, including serious reactions. If a serious hypersensitivity reaction occurs, promptly discontinue OLUMIANT while evaluating the potential causes of the reaction [see Adverse Reactions (6.2)].

Pazeo 5 Warnings and Precautions Warnings (olopatadine hcl) (Newly added section) For external use only Do not use  if solution changes color or becomes cloudy  if you are sensitive to any ingredient in this product  to treat contact lens related irritation When using this product  do not touch tip of container to any surface to avoid contamination  remove contact lenses before use  wait at least 10 minutes before reinserting contact lenses after use  do not wear a contact lens if your eye is red Stop use and ask a doctor if you experience:  eye pain  changes in vision  increased redness of the eye  itching worsens or lasts for more than 72 hours Keep out of reach of children. If swallowed, get medical help or contact a Poison Control Center right away.

Potassium Chloride 4 Contraindications (Additions underlined) in Dextrose Potassium Chloride in Dextrose Injection is contraindicated in patients with:  known hypersensitivity to potassium chloride and/or dextrose [see Warnings and Precautions 5.1)]  clinically significant hyperkalemia [see Warnings and Precautions (5.2)]  clinically significant hyperglycemia [see Warnings and Precautions (5.3)] 5 Warnings and Precautions (PLR conversion; subsections as below, please refer to label for complete information) 5.1 Hypersensitivity Reactions 5.2 Hyperkalemia 5.3 Hyperglycemia and Hyperosmolar Hyperglycemic State 5.4 Hyponatremia 5.5 Hypokalemia

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) 5.6 Fluid Overload 5.7 Refeeding syndrome (new subsection added) Refeeding severely undernourished patients may result in the refeeding syndrome that is characterized by the shift of potassium, phosphorus, and magnesium intracellularly as the patient becomes anabolic. Thiamine deficiency and fluid retention may also develop. To prevent these complications, monitor severely undernourished patients and slowly increasing nutrient intake.

Qutenza 5 Warnings and Precautions 5.4 Sensory Function (capsaicin) (Newly added subsection) Reductions in sensory function have been reported following administration of QUTENZA. Decreases in sensory functions are generally minor and temporary (including to thermal and other harmful stimuli). All patients with pre-existing sensory deficits should be clinically assessed for signs of sensory deterioration or loss prior to each application of QUTENZA. If sensory deterioration or loss is detected or pre-existing sensory deficit worsens, continued use of QUTENZA treatment should be reconsidered.

Signifor Lar Kit 5 Warnings and Precautions 5.1 Hyperglycemia, Diabetes, and Ketoacidosis (pasireotide (additions and revisions underlined) pamoate) SIGNIFOR LAR can cause increases in blood glucose levels which are sometimes severe. There have been postmarketing cases of ketoacidosis with SIGNIFOR LAR in patients with history of diabetes and in patients without history of diabetes. In the acromegalic patient study, 5 patients naïve to drug therapy treated with SIGNIFOR LAR (2 of whom were normoglycemic at baseline) and none in the active comparator group were hospitalized for hyperglycemia (blood glucose range 359-506 mg/dL). Two additional patients who had received active comparator in the main trial and were switched to SIGNIFOR LAR in the extension trial, were hospitalized for elevated glucose levels while on SIGNIFOR LAR; one of those patients developed diabetic ketoacidosis. In the Cushing’s disease study, 2 patients were hospitalized for elevated blood glucose. … Patients with poor baseline glycemic control are at higher risk of developing severe hyperglycemia. Assess FPG and HbA1c prior to starting treatment with SIGNIFOR LAR [see Dosage and Administration (2.1)]. In patients with poorly controlled diabetes mellitus, optimize anti-diabetic treatment before SIGNIFOR LAR initiation. … the dose of SIGNIFOR LAR or discontinue SIGNIFOR LAR. Assess FPG and HbA1c after SIGNIFOR LAR discontinuation, if indicated. Patients receiving anti-diabetic treatment may require more frequent blood glucose monitoring and dose adjustment to their anti-diabetic drug therapy to mitigate the risk of hypoglycemia after discontinuing SIGNIFOR LAR. Patients who present with signs and symptoms consistent with severe metabolic acidosis should be assessed for ketoacidosis regardless of diabetes history. In some reported post-marketing cases of ketoacidosis in patients taking SIGNIFOR LAR, factors predisposing to ketoacidosis such as acute illness, infection, pancreatic disorders (e.g. pancreatic malignancy or pancreatic surgery), and alcohol abuse were present. If ketoacidosis is suspected, discontinue SIGNIFOR LAR and promptly evaluate and treat the patient.

Spravato 5 Warnings and Precautions 5.1 Sedation (esketamine) Additions and/or revisions underlined:

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) In clinical trials, 48% to 61% of SPRAVATO-treated patients developed sedation based on the Modified Observer’s Assessment of Alertness/Sedation scale (MOAA/S) [see Adverse Reactions (6.1)], and 0.3% to 0.4% of SPRAVATO-treated patients experienced loss of consciousness (MOAA/S score of 0). 5.2 Dissociation Additions and/or revisions underlined: The most common psychological effects of SPRAVATO were dissociative or perceptual changes (including distortion of time, space and illusions), derealization and depersonalization (61% to 84% of SPRAVATO- treated patients developed dissociative or perceptual changes based on the Clinician-Administered Dissociative States Scale) [see Adverse Reactions (6.1)] … 5.1 SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) Additions and/or revisions underlined: … Important requirements of the SPRAVATO REMS include the following:  Healthcare settings must be certified in the program and ensure that SPRAVATO is:  Only dispensed and administered in healthcare settings.  Patients treated in outpatient settings (e.g. medical offices and clinics) must be enrolled in the program. 5.6 Increase in Blood Pressure Additions and/or revisions underlined: … Approximately 8% to 19% of SPRAVATO-treated patients and 1% to 4% of placebo-treated patients experienced an increase of greater than or equal to 40 mmHg in systolic BP and/or 25 mmHg in diastolic BP in the first 1.5 hours after administration at least once during the first 4 weeks of treatment …

Stelara 5 Warnings and Precautions 5.8 Concomitant Therapies (ustekinumab) (Additions and/or revisions underlined) In clinical studies of psoriasis the safety of STELARA® in combination with other biologic immunosuppressive agents or phototherapy was not evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL- 12 and IL-23 or IL-12 alone [see Concomitant Therapies (7.1), Nonclinical Toxicology (13.1)].

Sumavel Dosepro 5 Warnings and Precautions 5.4 Cerebrovascular Events (sumatriptan Additions and/or revisions underlined: succinate) Before treating headaches in patients not previously diagnosed with migraine or cluster headache or in patients who present with atypical symptoms, exclude other potentially serious neurological conditions. Sumavel DosePro is contraindicated in patients with a history of stroke or TIA.

Tecentriq 5 Warnings and Precautions 5.1 Immune-Mediated Pneumonitis (atezolizumab) Newly added information to the bottom of the subsection: In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], immune-mediated pneumonitis occurred in 13% of patients, including Grades 3-4 in 1.3% of patients. 5.2 Immune-Mediated Hepatitis Newly added information to the bottom of the subsection: In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Reactions (6.1)], immune-mediated hepatitis occurred in 53% of patients, including Grades 3-4 in 22%, and Grade 5 in <1% of patients. 5.3 Immune-Mediated Colitis Newly added information to the bottom of the subsection: In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], diarrhea or colitis occurred in 50% of patients, including Grades 3-4 in 3% of patients. 5.4 Immune-Mediated Endocrinopathies Additions and/or revisions underlined: In clinical studies enrolling 2616 patients who received TECENTRIQ as a single-agent [see Adverse Reactions (6.1)], hypothyroidism occurred in 4.6% of patients, and 3.8% of patients required the use of hormone replacement therapy. Hyperthyroidism occurred in 1.6% of patients. One patient experienced acute thyroiditis. In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], hypothyroidism occurred in 26% of patients. In clinical studies enrolling 2421 patients with NSCLC and SCLC who received TECENTRIQ in combination with platinum-based chemotherapy [see Adverse Reactions (6.1)], hypothyroidism occurred in 11% of patients … In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], hyperthyroidism occurred in 19% of patients, including Grades 3-4 in 0.9% of patients. 5.6 Infections Newly added information to the bottom of the subsection: In a clinical study enrolling 230 patients with unresectable or metastatic BRAF V600 mutation- positive melanoma who received TECENTRIQ in combination with cobimetinib and vemurafenib [see Adverse Reactions (6.1)], infections occurred in 60% of patients, including Grade 3-4 in 9%, and Grade 5 in 1.7% of patients. The most common infection was upper respiratory tract infection.

Tigecycline 5 Warnings and Precautions Newly added subsection: (tigecycline) 5.6 Monitoring of Blood Coagulation Parameters Hypofibrinogenemia has been reported in patients treated with Tigecycline [see Adverse Reactions (6.2)]. Obtain baseline blood coagulation parameters, including fibrinogen, and continue to monitor regularly during treatment with Tigecycline.

Tobi Podhaler 5 Warnings and Precautions 5.5 Embryo-Fetal Toxicity (tobramycin) (Additions and/or revisions underlined) Aminoglycosides can cause fetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in pediatric patients exposed in utero. However, systemic absorption of tobramycin following inhaled administration is expected to be minimal. Patients who use TOBI Podhaler during pregnancy, or become pregnant while taking TOBI Podhaler should be apprised of the potential hazard to the fetus. 5.6 Concomitant Use of Systemic Aminoglycosides (Newly added subsection)

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Patients receiving concomitant TOBI and parenteral aminoglycoside therapy should be monitored as clinically appropriate for toxicities associated with aminoglycosides as a class. Serum tobramycin levels should be monitored.

Tranexamic Acid 5 Warnings and Precautions 5.2 Seizures (tranexamic acid) (Additions and/or revisions underlined) Tranexamic acid may cause seizures, including focal and generalized seizures. The most common setting for tranexamic acid-induced seizures has been during cardiovascular surgery (a setting in which Tranexamic Acid in Sodium Chloride Injection is not FDA approved and which uses doses of up to ten-fold higher than the recommended human dose and in patients inadvertently given tranexamic acid into the neuraxial system). Tranexamic Acid in Sodium Chloride Injection is not approved and not recommended for neuraxial administration. Consider dose reduction during surgery and dose adjustments for patients with clinical conditions such as renal dysfunction. Closely monitor the patient during surgery. Consider electroencephalogram (EEG) monitoring for patients with history of seizures or who experience myoclonic movements, twitching, or show evidence of focal seizures. Discontinue Tranexamic Acid in Sodium Chloride Injection if seizures occur. 5.4 Visual Disturbances (Additions and/or revisions underlined) Although not seen in humans, focal areas of retinal degeneration have been observed in cats and dogs following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (1.6 to 22 times the recommended usual human dose based on body surface area) from 6 days to 1 year. No retinal changes have been observed in eye examinations of patients treated with tranexamic acid for up to 8 years. Patients expected to be treated for greater than 3 months may consider ophthalmic monitoring including visual acuity and optical coherence tomography at regular intervals. Discontinue Tranexamic Acid in Sodium Chloride Injection if changes in ophthalmological examination occurs.

Tremfya 5 Warnings and Precautions 5.1 Hypersensitivity Reactions (guselkumab) (Additions and/or revisions underlined) Serious hypersensitivity reactions, including anaphylaxis, have been reported with postmarket use of TREMFYA. Some cases required hospitalization. If a serious hypersensitivity reaction occurs, discontinue TREMFYA and initiate appropriate therapy. 5.2 Infections (Additions and/or revisions underlined) TREMFYA may increase the risk of infection. In clinical trials in subjects with plaque psoriasis, infections occurred in 23% of subjects in the TREMFYA group versus 21% of subjects in the placebo group through 16 weeks of treatment. Upper respiratory tract infections, gastroenteritis, tinea infections, and herpes simplex infections occurred more frequently in the TREMFYA group than in the placebo group. The rate of serious infections for the TREMFYA group and the placebo group was less than or equal to 0.2%. A similar risk of infection was seen in placebo-controlled trials in subjects with psoriatic arthritis. Treatment with TREMFYA should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. In patients with a chronic infection or a history of recurrent infection, consider the risks and benefits prior to prescribing TREMFYA. Instruct patients to seek medical help if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a clinically important or serious infection or is not responding to standard therapy, monitor the patient closely and discontinue TREMFYA until the infection resolves.

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) 5.3 Pre-treatment Evaluation for Tuberculosis (Additions and/or revisions underlined) Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with TREMFYA. Initiate treatment of latent TB prior to administering TREMFYA. In clinical trials, 105 subjects with plaque psoriasis and 71 subjects with psoriatic arthritis with latent TB who were concurrently treated with TREMFYA and appropriate TB prophylaxis did not develop active TB. Monitor patients for signs and symptoms of active TB during and after TREMFYA treatment.

Vectical 5 Warnings and Precautions 5.1 Effects on Calcium Metabolism (calcitriol) (Additions and/or revisions underlined) In controlled clinical trials hypercalcemia was observed in subjects exposed to VECTICAL Ointment. If aberrations in parameters of calcium metabolism occur, treatment should be discontinued until these parameters have normalized. The effects of VECTICAL Ointment on calcium metabolism following treatment durations greater than 52 weeks have not been evaluated. Increased absorption may occur with occlusive use. VECTICAL Ointment should be used with caution in patients receiving medications known to increase the serum calcium level, such as thiazide diuretics, and in patients receiving calcium supplements or high doses of vitamin D.

Versacloz 5 Warnings and Precautions 5.6 Myocarditis, Cardiomyopathy and Mitral Valve Incompetence (clozapine) (Subsection title revised; Additions and/or revisions underlined) Myocarditis and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue VERSACLOZ and obtain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy. Generally, patients with a history of clozapine-associated myocarditis or cardiomyopathy should not be rechallenged with VERSACLOZ. However, if the benefit of VERSACLOZ treatment is judged to outweigh the potential risks of recurrent myocarditis or cardiomyopathy, the clinician may consider rechallenge with VERSACLOZ in consultation with a cardiologist, after a complete cardiac evaluation, and under close monitoring. Consider the possibility of myocarditis or cardiomyopathy in patients receiving VERSACLOZ who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression). Myocarditis most frequently presents within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis and cardiomyopathy can occur at any period during treatment with VERSACLOZ. It is common for nonspecific flu- like symptoms such as malaise, myalgia, pleuritic chest pain, and low-grade fevers to precede more overt signs of heart failure. Typical laboratory findings include elevated troponin I or T, elevated creatinine kinase- MB, peripheral eosinophilia, and elevated C-reactive protein (CRP). Chest roentgenogram may demonstrate cardiac silhouette enlargement, and cardiac imaging (echocardiogram, radionucleotide studies, or cardiac catheterization) may reveal evidence of left ventricular dysfunction. In patients who are diagnosed with cardiomyopathy while taking clozapine mitral valve incompetence has been reported. These cases reported either mild or moderate mitral regurgitation on two-dimensional echocardiography. In patients with suspected cardiomyopathy, consider a 2D-echo Doppler examination to identify mitral valve incompetence.

Xyrem 4 Contraindications (Additions and/or revisions underlined)

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) (sodium oxybate) Xyrem is contraindicated for use in:  combination with sedative hypnotics [see Warnings and Precautions (5.1)].  combination with alcohol [see Warnings and Precautions (5.1)].  patients with succinic semialdehyde dehydrogenase deficiency [see Clinical Pharmacology (12.3)]. 5 Warnings and Precautions 5.1 Central Nervous System Depression (Additions and/or revisions underlined) Xyrem is contraindicated in combination with alcohol and sedative hypnotics. 5.3 XYWAV and XYREM REMS (Section title revised) (Additions and/or revisions underlined) Xyrem is available only through a restricted distribution program called the XYWAV and XYREM REMS because of the risks of central nervous system depression and abuse and misuse [see Warnings and Precautions (5.1, 5.2)]. Notable requirements of the XYWAV and XYREM REMS include the following: . Healthcare Providers who prescribe Xyrem are specially certified . Xyrem will be dispensed only by the central pharmacy that is specially certified . Xyrem will be dispensed and shipped only to patients who are enrolled in the XYWAV and XYREM REMS with documentation of safe use Further information is available at www.XYWAVXYREMREMS.com or 1-866-997-3688. 5.4 Respiratory Depression and Sleep-Disordered Breathing (Additions and/or revisions underlined) Prescribers should be aware that sleep-related breathing disorders tend to be more prevalent in obese patients, in men, in postmenopausal women not on hormone replacement therapy and among patients with narcolepsy. 5.7 Parasomnias (Additions and/or revisions underlined) It is unclear if some or all of the reported sleepwalking episodes correspond to true somnambulism, which is a parasomnia occurring during non-REM sleep, or to any other specific medical disorder. Five instances of sleepwalking with potential injury or significant injury were reported during a clinical trial of Xyrem in patients with narcolepsy.

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Treatment Guideline Updates

TITLE CITATION / LINK

Human papillomavirus vaccination 2020 guideline Saslow, D., Andrews, K., Manassaram‑Baptiste, D., Smith, R., & Fontham, E. update: American Cancer Society guideline (2020). Human papillomavirus vaccination 2020 guideline update: American Cancer Society guideline adaptation. CA: A Cancer Journal For Clinicians, 70(4), 274-280. adaptation https://doi.org/10.3322/caac.21616

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