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Health Plan Insights

December 2019 Updates from November 2019

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Recent FDA Approvals New TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE Ziextenzo Sandoz, Inc. Injection, To decrease the incidence of infection, as November 4, (pegfilgrastim- 6 mg/0.6 mL manifested by febrile neutropenia, in patients 2019 bmez) with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. ExEm (air Giskit B.V. Intrauterine Foam For sonohysterosalpingography to assess November 7, polymer-type A) fallopian tube patency in women with known or 2019 Intrauterine Foam suspected infertility. Reblozyl Celgene Injection, For the treatment of anemia in adult patients with November 8, (luspatercept- Corporation 25 mg/vial and 75 beta thalassemia who require regular red blood 2019 aamt) Injection mg/vial cell (RBC) transfusions. Brukinsa Beigene USA, Inc. Capsules, For the treatment of adult patients with mantle November 14, (zanubrutinib) 80 mg cell lymphoma (MCL) who have received at least 2019 one prior therapy. Fetroja Shionogi Inc. Intravenous For the treatment of patients 18 years of age and November 14, (cefiderocol) Injection, older with complicated urinary tract infections 2019 1 gm/vial (cUTI), including kidney infections caused by susceptible Gram-negative microorganisms, who have limited or no alternative treatment options. Abrilada Pfizer Inc. Injection, Biosimilar to Humira. For the treatment of November 15, (adalimumab- 40 mg/0.8 mL, 20 rheumatoid arthritis, juvenile idiopathic arthritis, 2019 afzb) mg/0.4 mL, and 10 psoriatic arthritis, ankylosing spondylitis, adult mg/0.2 mL Crohn’s disease, ulcerative colitis, and plaque psoriasis Adakveo Novartis Injection, To reduce the frequency of vasoocclusive crises November 15, (crizanlizumab- Pharmaceuticals 100 mg/10 mL in adults and pediatric patients aged 16 years 2019 tmca) Corporation and older with sickle cell disease Givlaari Alnylam Injection, For the treatment of adults with acute hepatic November 20, (givosiran) Pharmaceuticals 189 mg/ mL porphyria. 2019 Inc. Xcopri SK Life Science Tablet, For the treatment of partial-onset seizures in November 21, (cenobamate) Inc. 12.5 mg, 25 mg, adult patients. 2019 50 mg, 100 mg, 150 mg, and 200 mg

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TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE Oxbryta Global Blood Tablet, For the treatment of sickle cell disease in adults November 25, (voxelotor) Therapeutics, Inc. 500 mg and pediatric patients 12 years of age and older. 2019

New Combinations and Formulations TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE Ibrance Pfizer Inc. Tablets, For the treatment of adult patients with hormone November 1, (palbociclib) 75 mg, 100 mg, receptor (HR)-positive, human epidermal growth 2019 and 125 mg factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with: (1) an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or in men; or (2) fulvestrant in patients with disease progression following endocrine therapy. Talicia Rehill Delayed-Release For the treatment of Helicobacter pylori infection November 1, (omeprazole Biopharmaceuticals, Capsules, in adults. 2019 magnesium, LTD 10 mg; 250 mg, amoxicillin and 12.5 mg rifabutin) Epinephrine Hospira Inc. Injection, For increasing mean arterial blood pressure in November 5, (epinephrine) 1 mg/10 mL adult patients with hypotension associated with 2019 septic shock. Absorica LD Sun Capsules, For the treatment of severe recalcitrant nodular November 5, (isotretinoin) Pharmaceuticals 8 mg, 16 mg, 20 acne in non-pregnant patients 12 years of age 2019 Industries Ltd. mg, 24 mg, 28 and older with multiple inflammatory nodules with mg, and 32 mg a diameter of 5 mm or greater. Because of significant adverse reactions associated with its use, ABSORICA and ABSORICA LD are reserved for patients with severe nodular acne who are unresponsive to conventional therapy, including systemic antibiotics. Exservan Aquestive Oral Film, For the treatment of amyotrophic lateral November 22, (riluzole) Therapeutics 50 mg sclerosis. 2019

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TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE Potassium Fresenius Kabi, Injection, A source of phosphorus: (1) in intravenous fluids November 26, Phosphates USA 3 mmol/mL; 4.4 to correct hypophosphatemia in adults and 2019 (potassium meq/mL pediatric patients when oral or enteral phosphates) replacement is not possible, insufficient or contraindicated; (2) for parenteral nutrition in adults and pediatric patients when oral or enteral nutrition is not possible, insufficient or contraindicated. Reditrex Cumberland Injection, For: (1) the management of patients with severe, November 27, (methotrexate) Pharmaceuticals 7.5 mg, 10 mg, active rheumatoid arthritis (RA) and polyarticular 2019 12.5 mg, 15 mg, juvenile idiopathic arthritis (pJIA), who are 17.5 mg, 20 mg, intolerant of or had an inadequate response to 22.5 mg, and 25 first-line therapy; and (2) symptomatic control of mg severe, recalcitrant, disabling psoriasis in adults who are not adequately responsive to other forms of therapy.

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Pipeline New Pipeline MECHANISM OF ANTICIPATED DRUG NAME GENERIC NAME ROUTE INDICATION(S) ACTION APPROVAL DATE

Brinavess Vernakalant Intravenous Antiarrhythmic agents Atrial fibrillation 12/24/2019 receptor E2006 Oral antagonist 12/27/2019 5-HT2A serotonin and dopamine D2 receptor , serotonin reuptake ITI-007 Lumateperone Oral inhibitor Schizophrenia 12/27/2019 Non-nucleoside reverse transcriptase inhibitor, integrase Cabotegravir; strand transfer CAB LA + RPV LA Rilpivirine Intramuscular inhibitor HIV-1 infection 12/29/2019 Integrase strand GSK1265744 (oral) Cabotegravir Oral transfer inhibitor HIV-1 infection 12/29/2019 Tissue-based Primary RVT-802 TBD Soft Tissue regenerative therapy immunodeficiency 12/2019 gene- related Ubrogepant Oral inhibitor 12/2019 Calcitonin gene- related peptide BHV-3000 Oral inhibitor Migraine 4Q 2019 Sodium Chemotherapy-induced Pedmark Thiosulfate Intravenous Chelating agent ototoxicity 2H 2019

Tazemetostat Tazemetostat Oral EZH2 inhibitor Soft tissue sarcoma 01/23/2020 Dificid (oral Narrow-spectrum Clostridium difficile suspension) Fidaxomicin Oral macrocyclic antibiotic associated diarrhea 01/24/2020 Allergen Palforzia TBD Oral immunotherapy Allergy to peanuts 01/2020 Receptor tyrosine BLU-285 Avapritinib Oral kinase inhibitor Gastrointestinal cancer 02/14/2020 ATP citrate lyase ETC-1002 Bempedoic Acid Oral inhibitor Hypercholesterolemia 02/21/2020

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MECHANISM OF ANTICIPATED DRUG NAME GENERIC NAME ROUTE INDICATION(S) ACTION APPROVAL DATE Postoperative Barhemsys Amisulpride Intravenous Atypical and vomiting 02/26/2020 Intestinal cholesterol absorption inhibitor, Bempedoic Acid / Bempedoic Acid; ATP citrate lyase Ezetimibe Ezetimibe Oral inhibitor Hypercholesterolemia 02/26/2020 Calcitonin gene- related peptide ALD403 Intravenous inhibitor Migraine 02/2020 Biguanides Sodium- glucose linked Empagliflozin; transporter 2 inhibitor, Empa + Lina + Met Linagliptin; dipeptidyl peptidase-4 XR Metformin Oral inhibitor Diabetes Mellitus 02/2020 -like -1 Receptor Teprotumumab Teprotumumab Intravenous antagonist Thyroid eye disease 03/08/2020 -like ITCA 650 Implant peptide-1 agonist Diabetes Mellitus 03/09/2020

V920 Ebola Vaccine Intramuscular Viral vaccine Ebola 03/14/2020 Enfortumab Cytotoxic agent Anti- ASG-22ME Vedotin Intravenous nectin-4 antibody Urothelial cancer 03/15/2020 Dravet syndrome, Serotonin reuptake Lennox-Gastaut Fintepla Fenfluramine Oral inhibitor syndrome 03/25/2020 Sphingosine 1- phosphate receptor Relapsing multiple Ozanimod Ozanimod Oral modulators sclerosis 03/25/2020 Nonsteroidal anti- Bupivacaine; inflammatory drugs, HTX-011 Meloxicam Injectable amide anesthetic Post-operative pain 03/26/2020 Ferric Pyrophosphate Anemia in end stage Triferic Citrate Intravenous Iron supplement renal disease 03/28/2020 receptor Ulcerative colitis, Entyvio SC Vedolizumab Subcutaneous antagonist Crohn's disease 03/2020

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MECHANISM OF ANTICIPATED DRUG NAME GENERIC NAME ROUTE INDICATION(S) ACTION APPROVAL DATE

Bronchitol Mannitol Inhaled Mucolytic Cystic fibrosis 1Q 2020 Aldosterone synthase Cushing's disease in LCI699 Osilodrostat Oral inhibitor adult patients 1Q 2020

PRO 140 Leronlimab Subcutaneous Entry inhibitor HIV infection 1Q 2020

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2019/2020 New Generic Pipeline

ANTICIPATED BRAND 2018 US BRAND NAME GENERIC NAME INDICATION(S) LAUNCH DATE MANUFACTURER SALES 12/15/2019 VAPRISOL Conivaptan Cumberland Hypervolemic and euvolemic $2M Hydrochloride hyponatremia 4Q 2019 AFINITOR (2.5 Novartis Multiple cancer indications $373M mg, 5 mg, 7.5 mg) 4Q 2019 OSMOPREP Sodium Phosphate, Salix; Valeant; Bowel cleansing $8M Dibasic, Bausch Health Anhydrous; Sodium Phosphate, Monobasic, Monohydrate 4Q 2019 SAMSCA Tolvaptan Otsuka Hypervolemic and euvolemic $113M hyponatremia 4Q 2019 ZOHYDRO ER Pernix Severe pain $42M Bitartrate Therapeutics; Currax; Persion 2H 2019 ACZONE 7.5% Dapsone Allergan; Almirall Acne vulgaris $263M 2H 2019 APRISO Mesalamine Salix; Valeant; Dr. Ulcerative colitis $312M Falk; Bausch Health 2H 2019 APTENSIO XR Methylphenidate Rhodes Attention deficit hyperactivity disorder $36M Hydrochloride (ADHD) 2H 2019 AZASITE Azithromycin Akorn Bacterial conjunctivitis $7M 2H 2019 NEXIUM 24HR Esomeprazole AstraZeneca; Heartburn TBD (tablet) Magnesium Pfizer 2H 2019 NOXAFIL Posaconazole Merck & Co Prophylaxis of $25M (suspension) invasive Aspergillus and Candida infections 2H 2019 ZYTIGA (500 Abiraterone Janssen Prostate cancer $532M mg) Acetate 2019 ADVIL PM Pfizer Relief of occasional sleeplessness $21M (Liqui-Gels) Hydrochloride; associated with minor aches and pains Ibuprofen 2019 DESONATE Desonide Bayer; LEO Atopic dermatitis $11M Pharma;

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ANTICIPATED BRAND 2018 US BRAND NAME GENERIC NAME INDICATION(S) LAUNCH DATE MANUFACTURER SALES 2019 EVZIO Naloxone Kaléo Pharma overdose $57M Hydrochloride 2019 LOTEMAX (gel) Loteprednol Bausch + Lomb; Post-operative inflammation and pain $118M Etabonate Valeant; Bausch following ocular surgery Health 2019 MOVIPREP Ascorbic Acid; Salix; Valeant; Bowel cleansing $34M Polyethylene Bausch Health Glycol 3350; Potassium Chloride; Sodium Ascorbate; Sodium Chloride; Sodium Sulfate 2019 MOXEZA Moxifloxacin Alcon; Novartis Bacterial conjunctivitis $8M Hydrochloride 2019 NORVIR Ritonavir AbbVie HIV-1 infection TBD (capsules) 2019 PREPOPIK Citric Acid; Ferring Bowel cleansing $12M Magnesium Oxide; Sodium Picosulfate 2019 PRESTALIA Amlodipine Symplmed; Marina Hypertension TBD Besylate; Biotech; Adhera Perindopril Arginine 2019 RESTASIS Cyclosporine Allergan Dry eye $1,611M 2019 SPRIX Ketorolac Egalet; Ascend Moderate to severe pain TBD Tromethamine Therapeutics; Zyla; Besins Healthcare 2019 SUPRENZA Phentermine Citius Pharma; Obesity TBD Hydrochloride Alpex Pharma; Akrimax Pharmaceuticals 2019 TRAVATAN Z Travoprost Alcon; Novartis Glaucoma or ocular hypertension $544M 2019 VIVLODEX Meloxicam Egalet; iCeutica; Osteoarthritis pain $16M Zyla 2019-2020 AFINITOR (10 Everolimus Novartis Multiple cancer indications $2M mg) 2019-2020 CUVPOSA Glycopyrrolate Merz Sialorrhea $373M

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ANTICIPATED BRAND 2018 US BRAND NAME GENERIC NAME INDICATION(S) LAUNCH DATE MANUFACTURER SALES 2019-2020 EMEND (for Aprepitant Merck & Co Chemotherapy-induced nausea and $8M oral vomiting suspension) 2019-2020 FERRIPROX Deferiprone ApoPharma; Treatment of chronic iron overload $113M (tablet) Apotex 2019-2020 KALETRA Lopinavir; Ritonavir AbbVie HIV-1 infection $42M (tablets) 2019-2020 NEXIUM (2.5 Esomeprazole AstraZeneca Gastroesophageal Reflux Disease $263M mg, 5 mg, 10 Magnesium (GERD) mg packets for oral suspension) and NEXIUM (20 mg and 40 mg packets for oral suspension) 2019-2020 NUVARING Ethinyl ; Organon; Merck & Pregnancy prevention $926M Etonogestrel Co 2019-2020 OMNARIS Ciclesonide Sunovion; Covis Nasal symptoms of seasonal allergic $10M Pharma; rhinitis, perennial allergic rhinitis AstraZeneca 2019-2020 SYNDROS Dronabinol Insys Therapeutics Chemotherapy-induced nausea and $3M vomiting, cachexia or an unexplained significant weight loss in AIDS 2019-2021 RESCULA Unoprostone Sucampo; R-Tech Open-angle glaucoma or ocular TBD Isopropyl Ueno hypertension 2019-2021 ULESFIA Benzyl Concordia; Head lice infection $2M Shionogi 01/01/2020 SILENOR Somaxon Insomnia $47M Hydrochloride Pharmaceuticals; Pernix Therapeutics; Currax 01/02/2020 NOVOLOG (10 Novo Nordisk Diabetes Mellitus $2,330M mL vial) Recombinant 01/02/2020 NOVOLOG Insulin Aspart Novo Nordisk Diabetes Mellitus $3,462M FLEXPEN Recombinant

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ANTICIPATED BRAND 2018 US BRAND NAME GENERIC NAME INDICATION(S) LAUNCH DATE MANUFACTURER SALES 01/02/2020 NOVOLOG Insulin Aspart Novo Nordisk Diabetes Mellitus $85M PENFILL Recombinant 01/22/2020 ONSOLIS Fentanyl Citrate BioDelivery Breakthrough cancer pain Sciences TBD International, Inc. Mitigation of fine wrinkles, mottled RENOVA 03/07/2020 Tretinoin Valeant hyperpigmentation, and tactile $4M (0.02%) roughness of facial skin Long-term treatment of acromegalic SOMATULINE 03/08/2020 Lanreotide Acetate Ipsen patients, carcinoid syndrome, $507M DEPOT neuroendocrine tumors 03/10/2020 ZORTRESS Everolimus Novartis Prophylaxis of organ rejection $146M Ethinyl Estradiol; 03/29/2020 TAYTULLA Norethindrone Allergan Pregnancy prevention $149M Acetate

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Medication with Significant Label Changes TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Absorica Boxed Warning Revised; now reads as follows: (isotretinoin) WARNING: EMBRYO-FETAL TOXICITY – CONTRAINDICATED IN PREGNANCY ABSORICA/ABSORICA LD can cause severe life-threatening birth defects and is contraindicated in pregnancy. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking any amount of ABSORICA/ABSORICA LD even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining prenatally whether an exposed fetus has been affected. If pregnancy occurs, discontinue ABSORICA/ABSORICA LD immediately and refer the patient to an Obstetrician- Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Because of the risk of embryo-fetal toxicity, ABSORICA and ABSORICA LD are available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the iPLEDGE REMS. 4 Contraindications Additions and/or revisions underlined: 4.1 Pregnancy ABSORICA/ABSORICA LD is contraindicated in pregnancy. 4.2 Hypersensitivity ABSORICA/ABSORICA LD is contraindicated in patients with hypersensitivity to isotretinoin (or Vitamin A, given the chemical similarity to isotretinoin) or to any of its components (anaphylaxis and other allergic reactions have occurred). 5 Warnings and Precautions Additions and/or revisions underlined: 5.1 Embryo-Fetal Toxicity ABSORICA/ABSORICA LD is contraindicated in pregnancy. Based on human data, ABSORICA/ABSORICA LD can cause fetal harm when administered to a pregnant patient. There is an extremely high risk that severe birth defects will result if pregnancy occurs while taking any amount of ABSORICA/ABSORICA LD even for short periods of time. Potentially any fetus exposed during pregnancy can be affected. There are no accurate means of determining prenatally whether an exposed fetus has been affected. Major congenital malformations, spontaneous abortions, and premature births have been documented following exposure to isotretinoin during pregnancy. If a pregnancy occurs during ABSORICA/ABSORICA LD treatment, discontinue ABSORICA/ABSORICA LD immediately and refer the patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure during or 1 month after ABSORICA/ABSORICA LD therapy must be reported immediately to the FDA via the MedWatch telephone

number 1-800-FDA-1088 , and also to the iPLEDGE pregnancy registry at 1-866-495-0654 or via the internet (www.ipledgeprogram.com). Patients must be informed not to donate blood during ABSORICA/ABSORICA LD therapy and for 1 month following discontinuation because the blood might be given to a pregnant patient whose fetus must not be exposed to isotretinoin. ABSORICA/ABSORICA LD is available only through a restricted program under a REMS. 5.2 iPLEDGE Program ABSORICA/ABSORICA LD are available only through a restricted program under a REMS called the iPLEDGE REMS because of the risk of embryo-fetal toxicity. Notable requirements of the iPLEDGE REMS include the following:  Prescribers must be certified with the program and comply with the following requirements:

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) o Determine reproductive status of all patients prior to initiating treatment. o Provide contraception counseling to patients who can get pregnant prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling o Provide scheduled pregnancy testing, and verify and document the negative pregnancy test result prior to writing each prescription, for no more than a 30-day supply  Patients who can become pregnant must be enrolled by signing an informed consent form and must comply with the following requirements o Comply with the pregnancy testing and contraceptive requirements. o Demonstrate comprehension of the safe-use conditions of the program every month. o Obtain the prescription within 7 days of the pregnancy test collection.  Patients who cannot become pregnant must be enrolled by signing an informed consent form and must obtain the prescription within 30 days of the office visit  Pharmacies that dispense ABSORICA/ABSORICA LD must be certified by being registered and activated in the program, must only dispense to patients who are authorized to receive ABSORICA/ABSORICA LD, and comply with the following requirements: o Only dispense a maximum of a 30-day supply with a Medication Guide. o Do not dispense refills. Dispense only with a new prescription and a new authorization from the program. o Return ABSORICA/ABSORICA LD to inventory if patients do not obtain the prescription by the “Do Not Dispense to After” date  Wholesalers and distributors must be registered with the program and must only distribute to certified pharmacies. Further information, including a list of qualified pharmacies and distributors, is available

at www.ipledgeprogram.com or 1-866-495-0654 . 5.4 Psychiatric Disorders ABSORICA/ABSORICA LD may cause depression, psychosis and, rarely, suicidal ideation, suicide attempts, suicide, and aggressive and/or violent behaviors. Healthcare providers should be alert to the warning signs of psychiatric disorders to help ensure patients receive the help they need (Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin). Prior to initiation of ABSORICA/ABSORICA LD therapy, patients and family members should be asked about any history of psychiatric disorder, and at each visit during therapy patients should be assessed for symptoms of depression, mood disturbance, psychosis, or aggression to determine if further evaluation is necessary. Patients should immediately stop ABSORICA/ABSORICA LD and the patient (or caregiver) should promptly contact their prescriber if the patient develops depression, mood disturbance, psychosis, or aggression. Discontinuation of ABSORICA/ABSORICA LD may be insufficient; further evaluation may be necessary such as a referral to a mental healthcare professional. 5.5 Intracranial Hypertension (Pseudotumor Cerebri) Isotretinoin use has been associated with cases of intracranial hypertension (pseudotumor cerebri), some of which involved concomitant use of tetracyclines. Concomitant treatment with tetracyclines should therefore be avoided with ABSORICA/ABSORICA LD use. Early signs and symptoms of intracranial hypertension include papilledema, headache, nausea and vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue ABSORICA/ABSORICA LD immediately and be referred to a neurologist for further diagnosis and care. 5.6 Serious Skin Reactions … Patients should be monitored closely for severe skin reactions, and ABSORICA/ABSORICA LD should be discontinued if they occur. 5.7 Pancreatitis 800.361.4542 | envisionrx.com 13

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Acute pancreatitis has been reported with isotretinoin use in patients with either elevated or normal serum triglyceride levels. In rare instances, fatal hemorrhagic pancreatitis has been reported. If symptoms of pancreatitis occur, discontinue ABSORICA/ABSORICA LD and seek medical attention. 5.8 Lipid Abnormalities Elevations of serum triglycerides above 800 mg/dL have been reported with isotretinoin use. In clinical trials, marked elevations of serum triglycerides, decreases in high-density lipoproteins (HDL), and increases in cholesterol levels were reported in 25%, 15%, and 7% of patients treated with isotretinoin capsules, respectively. These lipid changes were reversible upon isotretinoin capsule cessation. Some patients have been able to reverse triglyceride elevation by reduction in weight and restriction of dietary fat and alcohol while continuing isotretinoin or through dosage reduction. The cardiovascular consequences of hypertriglyceridemia associated with isotretinoin are unknown. Fasting lipid tests should be performed before ABSORICA/ABSORICA LD treatment and then at intervals until the lipid response to ABSORICA/ABSORICA LD is known, which usually occurs within 4 weeks. Careful consideration should be given to risk/benefit of ABSORICA/ABSORICA LD in patients who are at higher risk of hypertriglyceridemia (e.g., patients with diabetes, obesity, increased alcohol intake, lipid disorder or familial history of lipid metabolism disorder). If ABSORICA/ABSORICA LD therapy is instituted in such patients, more frequent checks of serum values for lipids are recommended. ABSORICA/ABSORICA LD should be stopped if hypertriglyceridemia cannot be controlled. 5.9 Hearing Impairment … Mechanism(s) and causality for this reaction have not been established. Patients who experience tinnitus or hearing impairment should discontinue ABSORICA/ABSORICA LD treatment and be referred for specialized care for further evaluation. 5.10 Hepatotoxicity Clinical hepatitis has been reported with isotretinoin use. Additionally, mild to moderate elevations of enzymes have been observed in approximately 15% of individuals treated during clinical trials with isotretinoin capsules, some of which normalized with dosage reduction or continued administration of the drug. If normalization does not readily occur or if hepatitis is suspected during treatment, ABSORICA/ABSORICA LD should be discontinued. 5.11 Inflammatory Bowel Disease In some instances, symptoms have been reported to persist after isotretinoin treatment has been stopped. Patients experiencing abdominal pain, rectal bleeding or severe diarrhea should discontinue ABSORICA/ABSORICA LD immediately. 5.12 Musculoskeletal Abnormalities Mineral Density Changes, Osteoporosis, and Fractures Isotretinoin may have a negative effect on bone mineral density (BMD) in some patients. In a of ABSORICA and another isotretinoin capsule product, 27/306 (9%) of adolescents had BMD declines, defined as greater than or equal to 4% lumbar spine or total hip, or greater than or equal to 5% femoral neck, during the 20-week treatment period. Repeat scans conducted within 2 to 3 months after the post-treatment scan showed no recovery of BMD. This would include patients diagnosed with anorexia nervosa and those who are on chronic drug therapy that causes drug-induced osteoporosis/osteomalacia and/or affects vitamin D metabolism, such as systemic corticosteroids and any . There have been spontaneous reports of osteoporosis, osteopenia, fractures and/or delayed healing of fractures in patients while on therapy with isotretinoin or following cessation of therapy with isotretinoin. Patients in early and late adolescence who participate in sports with repetitive impact may be at an increased risk of spondylolisthesis with and without pars fractures, and hip growth plate injuries have been reported. Musculoskeletal Abnormalities

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Approximately 16% of patients treated with isotretinoin capsules in a clinical trial developed musculoskeletal symptoms (including arthralgia) during treatment. In general, these symptoms were mild to moderate, but occasionally required discontinuation of isotretinoin. In a trial of pediatric patients treated with isotretinoin capsules, approximately 29% (104/358) developed back pain. Back pain was severe in 14% (14/104) of the cases and occurred at a higher frequency in female patients than male patients. Arthralgias were experienced in 22% (79/358) of pediatric patients. Arthralgias were severe in 8% (6/79) of patients. Appropriate evaluation of the musculoskeletal system should be done in patients who present with these symptoms during or after a course of ABSORICA/ABSORICA LD. Consider discontinuing ABSORICA/ABSORICA LD if any significant abnormality is found … 5.14 Hypersensitivity Reactions … Severe allergic reaction necessitates discontinuation of therapy and appropriate medical management. Allergic Reactions Due to the Inactive Ingredient (FD&C Yellow No. 5) in the 25 mg ABSORICA Capsule The 25 mg ABSORICA capsule contains FD&C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of tartrazine sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity. The 10 mg, 20 mg, 30 mg, 35 mg, and 40 mg ABSORICA capsules do not contain FD&C Yellow No. 5 and all of the ABSORICA LD capsules do not contain FD&C Yellow No. 5. Thus, in patients with allergic reactions to tartrazine, avoid using the 25 mg ABSORICA capsules. 5.15 Laboratory Abnormalities and Laboratory Monitoring for Adverse Reactions Laboratory Monitoring Pregnancy Testing A pregnancy test must be obtained prior to obtaining a prescription, repeated each month, at the end of the entire course of ABSORICA/ABSORICA LD therapy and 1 month after the discontinuation of ABSORICA/ABSORICA LD. Lipid Tests Pretreatment and follow-up fasting lipid tests should be obtained under fasting conditions. After consumption of alcohol, at least 36 hours should elapse before testing is performed. It is recommended that these tests be performed periodically until the lipid response to ABSORICA/ABSORICA LD is known. The incidence of hypertriglyceridemia is 25% in patients treated with isotretinoin capsules. Liver Function Tests As elevations of liver enzymes have been observed during clinical trials, and hepatitis has been reported in patients on isotretinoin capsules, pretreatment and follow-up liver function tests should be performed periodically until the response to ABSORICA/ABSORICA LD is known.

Admelog and 5 Warnings and Precautions 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Admelog Solostar (Subsection title revised; Additions and/or revisions are underlined) () Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of Apidra and Apridra administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated Solostar insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to unaffected area) has been reported to result ( in hypoglycemia. recombinant) Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency Basaglar of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or () localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Banzel 5 Warnings and Precautions 5.4 Multi-organ Hypersensitivity/Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) (rufinamide) (additions underlined) … DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection.

Benznidazole 5 Warnings and Precautions 5.3 Hypersensitivity Skin Reactions (benznidazole) Additions and/or revisions underlined: Serious skin and subcutaneous disorders including acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with benznidazole …

Calquence 5 Warnings and Precautions 5.1 Serious and Opportunistic Infections (acalabrutinib) (Newly Added Subsection) Fatal and serious infections, including opportunistic infections, have occurred in patients with hematologic malignancies treated with CALQUENCE. Serious or Grade 3 or higher infections (bacterial, viral, or fungal) occurred in 19% of 1029 patients exposed to CALQUENCE in clinical trials, most often due to respiratory tract infections (11% of all patients, including pneumonia in 6%). These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia, with neutropenic infection reported in 1.9% of all patients. Opportunistic infections in recipients of CALQUENCE have included, but are not limited to, hepatitis B virus reactivation, fungal pneumonia, Pneumocystis jiroveci pneumonia, Epstein-Barr virus reactivation, cytomegalovirus, and progressive multifocal leukoencephalopathy (PML). Consider prophylaxis in patients who are at increased risk for opportunistic infections. Monitor patients for signs and symptoms of infection and treat promptly. 5.2 Hemorrhage (Additions and/or revisions underlined) Fatal and serious hemorrhagic events have occurred in patients with hematologic malignancies treated with CALQUENCE. Major hemorrhage (serious or Grade 3 or higher bleeding or any central nervous system bleeding) occurred in 3.0% of patients, with fatal hemorrhage occurring in 0.1% of 1029 patients exposed to CALQUENCE in clinical trials. Bleeding events of any grade, excluding bruising and petechiae, occurred in 22% of patients. Use of antithrombotic agents concomitantly with CALQUENCE may further increase the risk of hemorrhage. In clinical trials, major hemorrhage occurred in 2.7% of patients taking CALQUENCE without antithrombotic agents and 3.6% of patients taking CALQUENCE with antithrombotic agents. Consider the risks and benefits of antithrombotic agents when co-administered with CALQUENCE. Monitor patients for signs of bleeding. Consider the benefit-risk of withholding CALQUENCE for 3-7 days pre- and post-surgery depending upon the type of surgery and the risk of bleeding. 5.3 Cytopenias (Additions and/or revisions underlined) Grade 3 or 4 cytopenias, including neutropenia (23%), anemia (8%), thrombocytopenia (7%), and lymphopenia (7%), developed in patients with hematologic malignancies treated with CALQUENCE. Grade 4 neutropenia developed in 12% of patients. Monitor complete blood counts regularly during treatment. Interrupt treatment, reduce the dose, or discontinue treatment as warranted. 5.4 Second Primary Malignancies

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) (Additions and/or revisions underlined) Second primary malignancies, including skin cancers and other solid tumors, occurred in 12% of 1029 patients exposed to CALQUENCE in clinical trials. The most frequent second primary malignancy was skin cancer, reported in 6% of patients. Monitor patients for skin cancers and advise protection from sun exposure. 5.5 Atrial Fibrillation and Flutter (Additions and/or revisions underlined) Grade 3 atrial fibrillation or flutter occurred in 1.1% of 1029 patients treated with CALQUENCE, with all grades of atrial fibrillation or flutter reported in 4.1% of all patients. The risk may be increased in patients with cardiac risk factors, hypertension, previous arrhythmias, and acute infection. Monitor for symptoms of arrhythmia (e.g., palpitations, dizziness, syncope, dyspnea) and manage as appropriate.

Campath 5 Warnings and Precautions 5.5 Immunization (alemtuzumab) (Additions and/or revisions underlined) The safety of immunization with live viral vaccines following CAMPATH therapy has not been studied. Do not administer live viral vaccines to patients or infants born to patients receiving CAMPATH. The ability to generate an immune response to any vaccine following CAMPATH therapy has not been studied.

Complera 5 Warnings and Precautions 5.9 Immune Reconstitution Syndrome (emtricitabine; (additions underlined) rilpivirine hcl; … tenofovir disoproxil Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune fumarate) hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

Cyramza 5 Warnings and Precautions 5.8 Posterior Reversible Encephalopathy Syndrome () Additions and/or revisions underlined: Posterior Reversible Encephalopathy Syndrome (PRES) (also known as Reversible Posterior Leukoencephalopathy Syndrome [RPLS]) has been reported in <0.1% of 1916 patients enrolled in five clinical studies with CYRAMZA. Symptoms of PRES include seizure, headache, nausea/vomiting, blindness, or altered consciousness, with or without associated hypertension. Confirm the diagnosis of PRES with magnetic resonance imaging and permanently discontinue CYRAMZA in patients who develop PRES. Symptoms may resolve or improve within days, although some patients with PRES can experience ongoing neurologic sequelae or death.

Depakene 5 Warnings and Precautions 5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan (valproic acid) Hypersensitivity Reactions (Additions and/or revisions underlined) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking . DRESS may be fatal or life- threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be 800.361.4542 | envisionrx.com 17

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established. 5.18 Medication Residue in the Stool (Newly Added Subsection) There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered.

Eliquis 5 Warnings and Precautions 5.2 Bleeding (apixaban) (Additions and/or revisions underlined) ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding. Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These include aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and nonsteroidal anti- inflammatory drugs (NSAIDs). Advise patients of signs and symptoms of blood loss and to report them immediately or go to an emergency room. Discontinue ELIQUIS in patients with active pathological hemorrhage. Reversal of Anticoagulant Effect An agent to reverse the anti-factor Xa activity of apixaban is available. The pharmacodynamic effect of ELIQUIS can be expected to persist for at least 24 hours after the last dose, i.e., for about two drug half- lives. Prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa may be considered, but have not been evaluated in clinical studies. When PCCs are used, monitoring for the anticoagulation effect of apixaban using a clotting test (PT, INR, or aPTT) or anti-factor Xa (FXa) activity is not useful and is not recommended. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban plasma concentration. Hemodialysis does not appear to have a substantial impact on apixaban exposure. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents (tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is no experience with systemic hemostatics (desmopressin) in individuals receiving ELIQUIS, and they are not expected to be effective as a reversal agent. 5.6 Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome (Newly added subsection) Direct-acting oral anticoagulants (DOACs), including ELIQUIS, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti–beta 2- glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Erythrocin Contraindications (erythromycin Additions and/or revisions underlined: Erythromycin is contraindicated in patients with known hypersensitivity to this antibiotic. Erythromycin is lactobionate) contraindicated in patients taking terfenadine or astemizole, cisapride, pimozide, , or . 5 Warnings and Precautions

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) PRECAUTIONS Additions and/or revisions underlined: Exacerbation of Myasthenia gravis There have been reports that erythromycin may aggravate the weakness of patients with myasthenia gravis. Development of Drug-Resistant Bacteria Prolonged or repeated use of erythromycin may result in an overgrowth of non-susceptible bacteria or fungi. There have been reports of increased anticoagulant effects, which may be more pronounced in elderly when erythromycin and oral anticoagulants (e.g., warfarin) are used concomitantly. Newly added information: Colchicine is a substrate for both CYP3A4 and the efflux transporter P-glycoprotein (P-gp). Erythromycin is considered a moderate inhibitor of CYP3A4. A significant increase in colchicine plasma concentration is anticipated when co-administered with moderate CYP3A4 inhibitors such as erythromycin. If co- administration of colchicine and erythromycin is necessary, the starting dose of colchicine may need to be reduced, and the maximum colchicine dose should be lowered. Patients should be monitored for clinical symptoms of colchicine toxicity. Erythromycin has been reported to increase the systemic exposure (AUC) of sildenafil. Reduction of sildenafil dosage should be considered (See sildenafil prescribing information). Erythromycin has been reported to decrease the clearance of , and related , and thus may increase the pharmacological effect of these benzodiazepines. Post-marketing reports indicate that co-administration of erythromycin with ergotamine or dihydroergotamine has been associated with acute ergot toxicity characterized by vasospasm and ischemia of the central nervous system, extremities and other tissues. WARNINGS Additions and/or revisions underlined: Hepatotoxicity There have been reports of hepatic dysfunction, with or without jaundice occurring in patients receiving oral erythromycin products. Since erythromycin is principally excreted by the liver, monitor for liver toxicity when erythromycin is administered to patients with impaired hepatic function. Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with the use of nearly all antibacterial agents, including erythromycin, and may range in severity from mild diarrhea to fatal colitis. QT Prolongation Life-threatening episodes of ventricular tachycardia associated with prolonged QT intervals (torsades de pointes) have been reported … Newly added information: Infantile Hypertrophic Pyloric Stenosis (IHPS) There have been reports of IHPS occurring in infants following erythromycin therapy. Since erythromycin may be used in the treatment of conditions in infants which are associated with significant mortality or morbidity (such as pertussis or chlamydia), the benefit of erythromycin therapy needs to be weighed against the potential risk of developing IHPS. Parents or caregivers of infants receiving erythromycin should be informed to contact their physician if vomiting or irritability with feeding occurs. Drug Interactions Serious adverse reactions have been reported in patients taking erythromycin concomitantly with CYP3A4 substrates. These include colchicine toxicity with colchicine; rhabdomyolysis with simvastatin, lovastatin, and atorvastatin; and hypotension with calcium channel blockers metabolized by CYP3A4 (e.g. , amlodipine, diltiazem, vasospasm and ischemia with ergotamine/dihydroergotamine).

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Humalog and 5 Warnings and Precautions 5.2 Hyper- or Hypoglycemia with Changes in Insulin Regimen Humalog KwikPen (Additions and/or revisions underlined) (insulin lispro Changes in insulin strength, manufacturer, type, or method of administration may affect glycemic control and recombinant), predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously and under close Humalog Mix, medical supervision and the frequency of blood glucose monitoring should be increased. Humalog Mix 50/50 KwikPen, Humalog Mix 50/50 Pen, Humalog Mix 75/25, Pen, and KwikPen (insulin lispro protamine recombinant; insulin lispro recombinant) Humulin 70/30 and 5 Warnings and Precautions 5.2 Hyperglycemia and Hypoglycemia with Changes in Insulin Regimen 70/30 Pen (insulin Additions and/or revisions underlined: recominant human; Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of insulin susp. administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. isophane Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has recombinant been reported to result in hypoglycemia. human), Make any changes to a patient's insulin regimen under close medical supervision with increased frequency Humulin R, Pen, of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or and KwikPen localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products (insulin human), may be needed. Humulin N (insulin susp. isophane recombinant human) Hyzaar 5 Warnings and Precautions 5.1 Fetal Toxicity (hydrochlorothiazide; Additions and/or revisions underlined: losartan potassium) HYZAAR can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin- angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function …

Korlym 5 Warnings and Precautions 5.6 Use of Strong CYP3A Inhibitors (mifepristone) Additions and/or revisions underlined: … KORLYM should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 900 mg per day.

Lantus and Lantus 5 Warnings and Precautions 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen SoloStar 800.361.4542 | envisionrx.com 20

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) (insulin glargine Additions and/or revisions underlined: Changes in an insulin regimen (e.g., insulin, insulin strength, manufacturer, type, injection site or method of recombinant) administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments in concomitant oral antidiabetic treatment may be needed.

Levemir, Levemir 5 Warnings and Precautions 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen FlexPen, Levemir (Subsection title revised; Additions and/or revisions are underlined) FlexTouch, Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of Levemir Innolet, administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated and Levemir Penfill insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to ( result in hypoglycemia. recombinant) Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant antidiabetic products may be needed. As with all insulin preparations, the time course of action for LEVEMIR may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity.

Levetiracetam in 5 Warnings and Precautions Withdrawal Seizures Sodium Chloride (Additions and/or revisions underlined) (levetiracetam) As with most antiepileptic drugs, levetiracetam should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

Lumason 5 Warnings and Precautions Hypersensitivity Reactions (sulfur hexafluoride Change in subsection title, from “Anaphylactoid Reactions” to “Hypersensitivity Reactions” lipid-type A Additions and/or revisions underlined: microspheres) Hypersensitivity reactions such as skin erythema, rash, urticaria, flushing, throat tightness, dyspnea, or anaphylactic shock have uncommonly been observed following the injection of Lumason. These reactions may occur in patients with no history of prior exposure to sulfur hexafluoride lipid containing microspheres. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to Lumason administration and monitor all patients for hypersensitivity reactions. Serious Cardiopulmonary Reactions Change in subsection title, from “Cardiopulmonary Reactions” to “Serious Cardiopulmonary Reactions” Systemic Embolization

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Additions and/or revisions underlined: When administering Lumason to patients with cardiac shunt, microspheres can bypass filtering by the lung and enter the arterial circulation. Assess patients with shunts for embolic phenomena following Lumason administration. Lumason is only for intravenous and/or intravesical administration; do not administer Lumason by intra-arterial injection. Ventricular Arrhythmia Related to High Mechanical Index Change in subsection title, from “High Mechanical Index” to “Ventricular Arrhythmia Related to High Mechanical Index” Additions and/or revisions underlined: High ultrasound mechanical index values may cause microsphere cavitation or rupture and lead to ventricular arrhythmias. Additionally, end-systolic triggering with high mechanical indices has been reported to cause ventricular arrhythmias. Lumason is not recommended for use at mechanical indices greater than 0.8.

Moxatag 5 Warnings and Precautions Additions and/or revisions underlined: (amoxicillin) 5.2 Clostridioides difficile-Associated Diarrhea (CDAD) Clostridioides difficile Associated Diarrhea (CDAD) has been reported with nearly all antibacterial agents, including amoxicillin, and may range in severity from mild diarrhea to fatal colitis … 5.5 False-Positive Urinary Glucose Tests High concentrations of ampicillin may result in false-positive reactions when testing for the presence of glucose in urine using glucose tests based on the Benedict’s copper reduction reaction that determines the amount of reducing substances like glucose in the urine. Since this effect may also occur with amoxicillin, it is recommended that glucose tests based on enzymatic glucose oxidase reactions should be used.

Novolin 70/30 5 Warnings and Precautions 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen (insulin recombinant (Additions and/or revisions are underlined) human; insulin susp. Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of Isophane administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated recombinant insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to human), Novolin N result in hypoglycemia. (insulin susp. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency isophane of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or recombinant localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products human), Novolin R may be needed. (insulin recombinant human), Novolog (insulin aspart recombinant), Novolog Mix 50/50 and 70/30 (insulin aspart protamine

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) recombinant; insulin aspart recombinant) Pradaxa 5 Warnings and Precautions 5.6 Increased Risk of Thrombosis in Patients with Triple-Positive Antiphospholipid Syndrome (dabigatran etexilate (Newly added section) mesylate) Direct-acting oral anticoagulants (DOACs), including PRADAXA, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple- positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

Provocholine Boxed Warning PLR conversion; revised as below: (methacholine WARNING: SEVERE BRONCHOCONSTRICTION chloride) Severe bronchoconstriction can result from Provocholine administration (including the lowest dose). The use of Provocholine is contraindicated in pediatric and adult patients with baseline FEV1 <60% predicted or adults with FEV1 <1.5 L. Because of the potential for severe bronchoconstriction, the use of Provocholine in patients with clinically apparent asthma or wheezing is not recommended. Emergency equipment and medication should be immediately available to treat acute respiratory distress. If severe bronchoconstriction occurs, reverse immediately with a rapid- acting inhaled bronchodilator agent (?-agonist). If baseline spirometry is not performed or measured inaccurately, the initial FEV1 may be underestimated. In this situation, decreases in FEV1 may not be detected after administration of escalating Provocholine doses, which may result in administration of unnecessary higher doses and an increased risk for excessive bronchoconstriction. 4 Contraindications PLR conversion; additions and/or revisions underlined: Provocholine is contraindicated in the following situations:  Hypersensitivity to methacholine or other parasympathomimetic agents. Reactions have included rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.  Baseline FEV1 <60% predicted (adults or pediatric patients) or <1.5 L (adults) 5 Warnings and Precautions PLR conversion; subsection titles as below (see label for complete information): 5.1 Risk of Severe Bronchoconstriction 5.2 Risks to Healthcare Providers Administering Provocholine 5.3 Coexisting Diseases and Conditions

Ryzodeg 70/30 5 Warnings and Precautions 5.2 Hypoglycemia or Hypoglycemia with Changes in Insulin Regimen (insulin aspart; Additions and/or revisions underlined: ) Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for 800.361.4542 | envisionrx.com 23

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) hypoglycemia. For patients with type 2 diabetes, adjustments in concomitant oral anti-diabetic treatment may be needed. When converting from other insulin therapies to RYZODEG 70/30 follow dosing recommendations.

Soliqua 5 Warnings and Precautions 5.4 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen (insulin glargine; (Additions and/or revisions are underlined) ) Changes in insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. Adjustments in concomitant oral antidiabetic treatment may be needed. When converting from basal insulin therapy or a GLP-1 receptor agonist to SOLIQUA 100/33 follow dosing recommendations.

Stelara 5 Warnings and Precautions Additions and/or revisions underlined: (ustekinumab) 5.1 Infections STELARA® may increase the risk of infections and reactivation of latent infections. Serious bacterial, mycobacterial, fungal, and viral infections were observed in patients receiving STELARA®. Serious infections requiring hospitalization, or otherwise clinically significant infections, reported in clinical studies included the following:  Psoriasis: diverticulitis, cellulitis …  Psoriatic arthritis: cholecystitis.  Crohn’s disease: anal abscess, gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeria meningitis.  Ulcerative colitis: gastroenteritis, ophthalmic herpes zoster, pneumonia, and listeriosis. 5.6 Reversible Posterior Leukoencephalopathy Syndrome … No cases of RPLS were observed in clinical studies of Crohn’s disease or ulcerative colitis.

Supprelin LA 4 Contraindications ‘Pregnancy’ replaces ‘possibility exists that spontaneous abortion may occur’ (histrelin acetate)

Synribo 5 Warnings and Precautions 5.4 Embryo-Fetal Toxicity (omacetaxine (Additions and/or revisions underlined) mepesuccinate) Based on findings from animal reproduction studies and the drug’s mechanism of action, SYNRIBO can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with SYNRIBO and for 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with SYNRIBO and for 3 months after the final dose.

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Toujeo SoloStar 5 Warnings and Precautions 5.1 Never Share a TOUJEO Solostar or TOUJEO Max Solostar Pen Between Patients and Toujeo Max (Additions and/or revisions underlined) SoloStar TOUJEO SoloStar or TOUJEO Max SoloStar single-patient-use prefilled pens must never be shared (insulin glargine between patients, even if the needle is changed. Pen sharing poses a risk for transmission of blood-borne recombinant) pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Additions and/or revisions underlined: Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, dosage adjustments of concomitant oral antidiabetic products may be needed. Changing to TOUJEO from other On a unit-to-unit basis, TOUJEO has a lower glucose lowering effect than LANTUS. In clinical trials, patients who changed to TOUJEO from other basal insulins experienced higher average fasting plasma glucose levels in the first weeks of therapy compared to patients who were changed to LANTUS. Higher doses of TOUJEO were required to achieve similar levels of glucose control compared to LANTUS in clinical trials. The onset of action of TOUJEO develops over 6 hours following an injection. In type 1 diabetes patients treated with IV insulin, consider the longer onset of action of TOUJEO before stopping IV insulin. The full glucose lowering effect may not be apparent for at least 5 days. To minimize the risk of hyperglycemia when initiating TOUJEO monitor glucose daily, titrate TOUJEO as described in this prescribing information, and adjust coadministered glucose- lowering therapies per standard of care.

Treanda 5 Warnings and Precautions 5.1 Myelosuppression (bendamustine hcl) (Additions and/or revisions underlined) TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies (see Table 4). Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). Monitor complete blood counts, including leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently… 5.7 Other Malignancies (Additions and/or revisions underlined) There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with bendamustine hydrochloride therapy has not been determined. 5.9 Embryo-Fetal Toxicity (Additions and/or revisions underlined) Based on findings from animal reproduction studies and the drug’s mechanism of action, TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of 800.361.4542 | envisionrx.com 25

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) bendamustine (that approximated the maximum recommended human dose based on body surface area) to pregnant mice and rats during organogenesis caused adverse developmental outcomes, including an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use an effective method of contraception during treatment with TREANDA and for at least 6 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with TREANDA and for at least 3 months after the final dose.

Tresiba 5 Warnings and Precautions 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen (insulin degludec) (Additions and/or revisions are underlined) Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, adjustments in concomitant anti-diabetic treatment may be needed. When converting from other insulin therapies to TRESIBA follow dosing recommendations.

Xadago 5 Warnings and Precautions 5.2 Serotonin Syndrome (safinamide (Additions and/or revisions underlined) mesylate) The development of a potentially life-threatening serotonin syndrome has been reported in patients on concomitant treatment with MAOIs (including selective MAO-B inhibitors), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants, cyclobenzaprine, opioid drugs (e.g., meperidine and meperidine derivatives, propoxyphene, tramadol), and methylphenidate, amphetamine, and their derivatives . Concomitant use of XADAGO with these drugs is contraindicated. In clinical trials, serotonin syndrome was reported in a patient treated with XADAGO and a selective serotonin reuptake inhibitor (SSRI). Use the lowest effective dose of SSRIs in patients treated with concomitant XADAGO. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Xultophy 100/3.6 5 Warnings and Precautions 5.4 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen (insulin degludec; (Subsection title revised; Additions and/or revisions are underlined) ) Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia. Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. Adjustments in concomitant oral anti-diabetic treatment may be needed. When initiating XULTOPHY 100/3.6, follow dosing recommendations.

Zaltrap 5 Warnings and Precautions 5.11 Embryo-Fetal Toxicity (ziv-aflibercept) (Newly added subsection) Based on findings from animal studies and its mechanism of action, ZALTRAP can cause fetal harm when administered to pregnant women. Administration of Ziv-aflibercept during the period of organogenesis was embryotoxic and teratogenic in rabbits at exposure levels approximately 0.3 times the human exposure at the 4 mg per kg dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with ZALTRAP and for 1 month following the last dose.

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Treatment Guideline Updates

TITLE CITATION / LINK

Out-of-Hospital Hypothermia Clinical Practice Wilderness Medical Society Clinical Practice Guidelines for the Out-of- Guidelines (2019) Hospital Evaluation and Treatment of Accidental Hypothermia: 2019 Update. Dow J, Giesbrecht GG, Danzl DF, et al. Wilderness Environ Med. 2019 Nov 15. pii: S1080-6032(19)30173-5. Available at: https://www.wemjournal.org/article/S1080-6032(19)30173- 5/fulltext#sec2.6. Pilonidal Disease Clinical Practice Guidelines Johnson EK, Vogel JD, Cowan ML, et al. The American Society of Colon (2019) and Rectal Surgeons' Clinical Practice Guidelines for the Management of Pilonidal Disease. Dis Colon Rectum. 2019 Feb;62(2):146-157. Full text available at: https://www.fascrs.org/sites/default/files/downloads/publication/the- american-society-of-colon-practical-guideline-sinus-pilonidalis.pdf. Diabetes in Wilderness Athletes: Clinical Practice VanBaak KD, Nally LM, Finigan RT, et al. Wilderness Medical Society Guidelines (2019) clinical practice guidelines for diabetes management. Wilderness Environ Med. 2019 Nov 18. https://www.wemjournal.org/article/S1080- 6032(19)30174-7/fulltext Awake Tracheal Intubation Clinical Practice Ahmad I, El-Boghdadly K, Bhagrath R, et al. Difficult Airway Society Guidelines (2019) guidelines for awake tracheal intubation (ATI) in adults. Anaesthesia. 2019 Nov 14. Available at: https://onlinelibrary.wiley.com/doi/full/10.1111/anae.14904.

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