Health Plan Insights

March 2020 Updates from February 2020

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Recent FDA Approvals New Medications TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE Pizensy Braintree Oral Solution For the treatment of chronic idiopathic February 12, 2020 (lactitol) Labororatories 10 g and 20 g constipation (CIC) in adults. Procysbi Horizon Delayed-Release For the treatment of nephropathic February 14, 2020 (cysteamine Pharmaceuticals USA Oral Granules cystinosis in adults and pediatric patients bitartrate) 75 mg and 300 mg 1 year of age and older. Nexletol Esperion Tablets For use as an adjunct to diet and February 21, 2020 (bempedoic acid) Therapeutics, Inc. 180 mg maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Vyepti Lundbeck Seattle Injection For the preventative treatment of February 21, 2020 (eptinezumab- BioPharmaceuticals, 100 mg/mL migraine in adults. jjmr) Inc. Barhemsys Acacia Pharma Inc. Injection For use in adults for: (1) prevention of February 26, 2020 (amisulpride) 5 mg/2 mL postoperative nausea and vomiting (PONV), either alone or in combination with an antiemetic of a different class; (2) the treatment of PONV in patients who have received antiemetic prophylaxis with an agent of a different class or have not received prophylaxis. Nexlizet Esperion Tablets For use as an adjunct to diet and February 26, 2020 (bempedoic acid; Therapeutics, Inc. 180 mg/10 mg maximally tolerated statin therapy for the ezetimibe) treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Nurtec ODT Biohaven Orally Disintegrating For the acute treatment of migraine with February 27, 2020 (rimegepant) Pharmaceuticals, Inc. Tablet or without aura in adults. 75 mg

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New Combinations and Formulations TRADE NAME DOSAGE FORM APPROVAL MANUFACTURER INDICATION(S) (generic name) STRENGTH DATE Pemfexy Eagle Injection For use: (1) in combination with February 8, 2020 (pemetrexed) Pharmaceuticals, 25 mg/mL cisplatin for the initial treatment of Inc. patients with locally advanced or metastatic non-squamous, non-small cell lung cancer (NSCLC); (2) as a single agent for the maintenance treatment of patients with locally advanced or metastatic non-squamous NSCLC whose disease has not progressed after four cycles of platinum-based first-line chemotherapy; (3) as a single agent for the treatment of patients with recurrent, metastatic non-squamous NSCLC after prior chemotherapy. Twirla Agile Therapeutics, Transdermal System A method of contraception for use in February 14, 2020 (levonorgestrel; Inc. 120 mcg/30 mcg women of reproductive potential with a ethinyl estradiol) BMI < 30 kg/m2 for whom a combined hormonal contraceptive is appropriate. Anjeso Baudax Bio, Inc. Injection For use in adults for the management of February 20, 2020 (meloxicam) 30 mg/mL moderate-to-severe pain, alone or in combination with non-NSAID analgesics.

New Generics APPROVAL GENERIC NAME TRADE NAME DOSAGE FORM MANUFACTURER(S) DATE Olopatadine Pazeo Ophthalmic Watson Laboratories, Inc. February 19, 2020 Hydrochloride Solution Albuterol Sulfate ProAir HFA Aerosol Perrigo Pharmaceuticals February 24, 2020 Company

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Pipeline New Medication Pipeline MECHANISM OF ANTICIPATED DRUG NAME GENERIC NAME ROUTE INDICATION(S) ACTION APPROVAL DATE GSK1265744 Cabotegravir Oral Integrase strand HIV-1 infection Past expected transfer inhibitor launch Nexlizet Bempedoic Acid; Oral Intestinal cholesterol Hypercholesterolemia Launched Ezetimibe absorption inhibitor, ATP citrate lyase inhibitor ITCA 650 Exenatide Implant Glucagon-like Diabetes Mellitus 03/09/2020 peptide-1 agonist

Ozanimod Ozanimod Oral Sphingosine 1- Relapsing multiple 03/25/2020 phosphate receptor sclerosis modulators

Triferic Ferric Intravenous Iron supplement Anemia in end stage 03/28/2020 Pyrophosphate renal disease Citrate Bronchitol Mannitol Inhaled Mucolytic Cystic fibrosis 1Q 2020

LCI699 Osilodrostat Oral Aldosterone synthase Cushing's disease in Launched inhibitor adult patients PRO 140 Leronlimab Subcutaneous Entry inhibitor HIV infection 1Q 2020

Remimazolam Remimazolam Intravenous Benzodiazepine Sedation 04/05/2020

MenQuadfi Meningococcal Intramuscular Meningitis B vaccine Meningococcal disease 04/25/2020 Conjugate Vaccine Ongentys Opicapone Oral Catechol-O- Motor deficit 04/26/2020 methyltransferase inhibitor Sarclisa Isatuximab Intravenous Anti-CD38 antibody Multiple myeloma Launched

Dasotraline Dasotraline Oral Serotonin, Binge eating disorder 05/14/2020 norepinephrine and dopamine reuptake inhibitor RG7916 Risdiplam Oral Splicing modulator Spinal muscular atrophy 05/24/2020

Amphora Citric Acid; L- Intravaginal pH buffer Pregnancy prevention 05/25/2020 Lactic Acid; Potassium Bitartrate

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MECHANISM OF ANTICIPATED DRUG NAME GENERIC NAME ROUTE INDICATION(S) ACTION APPROVAL DATE INCB054828 Pemigatinib Oral Fibroblast growth Biliary tract cancer 05/30/2020 factor receptor inhibitor IMMU-132 Sacituzumab Intravenous Cytotoxic agent Anti- Breast cancer 06/02/2020 Govitecan Trop2 antibody

Fintepla Fenfluramine Oral Serotonin reuptake Dravet syndrome 06/25/2020 inhibitor Lennox-Gastaut syndrome

HTX-011 Bupivacaine; Injectable Nonsteroidal anti- Post-operative pain 06/26/2020 Meloxicam inflammatory drugs, amide anesthetic Inebilizumab Inebilizumab Intravenous Anti-CD19 antibody Neuromyelitis optica 06/2020

Botreso TBD Oral TBD Treatment of the signs 2Q 2020 and symptoms of benign prostatic hyperplasia

Orilissa Elagolix Oral Luteinizing hormone Uterine fibroids 2Q 2020 releasing hormone antagonist Selumetinib Selumetinib Oral MEK inhibitor Neurofibromatosis Type 2Q 2020 Sulphate 1

Durysta Bimatoprost Ophthalmic Prostaglandin analog Glaucoma or Ocular Launched Implant Hypertension Posimir Bupivacaine Injectable Amide anesthetic Post-operative pain 1H 2020

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2020 New Generic Pipeline ANTICIPATE BRAND US D LAUNCH BRAND NAME GENERIC NAME INDICATION(S) MANUFACTURER SALES DATE 03/10/2020 ZORTRESS Everolimus Novartis Prophylaxis of organ rejection $146M 3/29/2020 TAYTULLA Ethinyl Estradiol; Allergan Pregnancy prevention $149M Norethindrone Acetate 04/30/2020 APTIVUS Tipranavir Boehringer HIV-1 infection $4M (capsule and oral Ingelheim soultion) 04/2020 HUMALOG MIX Insulin Lispro Eli Lilly Diabetes mellitus $510M 75/25 KWIKPEN Protamine Recombinant; Insulin Lispro Recombinant 05/10/2020 NYMALIZE Nimodipine Arbor Subarachnoid hemorrhage from $28M Pharmaceuticals ruptured intracranial berry aneurysms 05/15/2020 DEPO-SUBQ Medroxyprogestero Pfizer Pregnancy prevention, Endometriosis $4M PROVERA 104 ne Acetate 05/18/2020 GEODON (oral Ziprasidone Pfizer Schizophrenia, bipolar disorder N/A suspension) Hydrochloride 06/17/2020 DENAVIR Penciclovir Sodium Mylan Herpes (cold sores) $66M 1H 2020 APTENSIO XR Methylphenidate Rhodes Attention deficit hyperactivity disorder $36M Hydrochloride 1H 2020 OSMOPREP Sodium Phosphate, Salix; Valeant; Bowel cleansing $8M Dibasic, Bausch Health Anhydrous; Sodium Phosphate, Monobasic, Monohydrate 1H 2020 SAPHRIS Asenapine Maleate Forest; Allergan Schizophrenia, bipolar disorder $120M 08/08/2020 POMALYST Pomalidomide Celgene; Bristol- Multiple myeloma $1,391M Myers Squibb 08/23/2020 VALCHLOR Mechlorethamine Helsinn Healthcare Cutaneous T-cell lymphoma $1M Hydrochloride 09/05/2020 XYZAL ALLERGY Levocetirizine Sanofi; UCB Allergic rhinitis $1M 24HR (oral Dihydrochloride solution)

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ANTICIPATE BRAND US D LAUNCH BRAND NAME GENERIC NAME INDICATION(S) MANUFACTURER SALES DATE 09/08/2020 BIDIL Hydralazine Arbor Heart failure $32M Hydrochloride; Pharmaceuticals Isosorbide Dinitrate 09/25/2020 MARQIBO KIT Vincristine Sulfate Talon Acute lymphocytic leukemia $6M Therapeutics; Spectrum; Aurobindo; Acrotech Biopharma 09/28/2020 ULTRAVATE Halobetasol Ranbaxy; Sun Plaque psoriasis $13M (lotion) Propionate 09/29/2020 TYKERB Lapatinib Ditosylate Novartis Breast cancer $66M 09/30/2020 ATRIPLA Efavirenz; Gilead HIV-1 infection $1,273M Emtricitabine; Tenofovir Disoproxil Fumarate 09/30/2020 TRUVADA (200 Emtricitabine; Gilead HIV-1 infection, prophylaxis to reduce $3,151M mg/300 mg) Tenofovir risk of sexually acquired HIV-1 Disoproxil Fumarate

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Medication with Significant Label Changes TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Afinitor and Afinitor 5 Warnings and Precautions Additions and/or revisions underlined: Disperz 5.7 Risk of Impaired Wound Healing (everolimus) Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, AFINITOR/AFINITOR DISPERZ have the potential to adversely affect wound healing. Withhold AFINITOR/AFINITOR DISPERZ for at least 1 week 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 treatment upon resolution of wound healing complications has not been established.

Bydureon 4 Contraindications Addition of the following bullet point underlined: (exenatide synthetic) BYDUREON is contraindicated in patients with: Bydureon Bcise  A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious (exenatide) bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use [see Warnings and Precautions (5.9)]. 5 Warnings and Precautions Newly added subsections: 5.2 Never Share a BYDUREON Pen Between Patients BYDUREON pens must never be shared between patients. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.9 Drug-Induced Thrombocytopenia Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported in the postmarketing setting with exenatide use. Drug-induced thrombocytopenia is an immune- mediated reaction, with exenatide-dependent anti-platelet antibodies. In the presence of exenatide, these antibodies cause platelet destruction. If drug-induced thrombocytopenia is suspected, discontinue BYDUREON immediately and do not re-expose the patient to exenatide. Upon discontinuation, thrombocytopenia can persist due to the prolonged exenatide exposure from BYDUREON (about 10 weeks) [see Adverse Reactions (6.3)].

Byetta 4 Contraindications Addition of the following bullet point underlined: (exenatide synthetic) BYETTA is contraindicated in patients with:  A history of drug-induced immune-mediated thrombocytopenia from exenatide products. Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported with exenatide use [see Warnings and Precautions (5.8)]. 5 Warnings and Precautions Additions and/or revisions underlined: 5.4 Acute Kidney Injury … Reversibility of altered renal function has been observed in many cases with supportive treatment and discontinuation of potentially causative agents, including BYETTA. Exenatide has not been found to be directly nephrotoxic in preclinical or clinical studies. BYETTA is not recommended in patients with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease and should be used with caution in patients with renal transplantation [see Use in Specific Populations (8.6)]. Because BYETTA may induce nausea and vomiting with transient hypovolemia, treatment may worsen renal function. Caution should be applied when initiating or escalating doses of BYETTA from 5 to 10 mcg in patients with moderate renal impairment (creatinine clearance 30-50 mL/min). 5.7 Hypersensitivity 800.361.4542 | envisionrx.com 8

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis and angioedema) in patients treated with BYETTA. If a hypersensitivity reaction occurs, the patient should discontinue BYETTA and other suspect medications and promptly seek medical advice. Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with BYETTA [see Adverse Reactions (6.2)]. Newly added subsection: 5.8 Drug-Induced Thrombocytopenia Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported in the postmarketing setting with exenatide use. Drug-induced thrombocytopenia is an immune- mediated reaction, with exenatide-dependent anti-platelet antibodies. In the presence of exenatide, these antibodies cause platelet destruction. If drug-induced thrombocytopenia is suspected, discontinue BYETTA immediately and do not re-expose the patient to exenatide [see Adverse Reactions (6.2)].

Cyramza 5 Warnings and Precautions 5.3 Impaired Wound Healing (ramucirumab) (subsection revised, additions underlined) … Withhold CYRAMZA for 28 days prior to elective surgery. Do not administer CYRAMZA for at least 2 weeks following a major surgical procedure and until adequate wound healing. The safety of resumption of CYRAMZA after resolution of wound healing complications has not been established.

Dextrose 5% and 4 Contraindications Additions and/or revisions underlined: Electrolyte no. 48 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) is in plastic container contraindicated in patients  with a known hypersensitivity to the product (see WARNINGS)  with clinically significant hyperglycemia (see WARNINGS) 5 Warnings and Precautions PRECAUTIONS Additions and/or revisions underlined: Patients with Renal Impairment In patients with renal impairment, administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in sodium and/or potassium or magnesium retention (see WARNINGS). Avoid 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) in patients with severe renal impairment or conditions that may cause sodium, potassium, magnesium, or phosphate retention, fluid overload, or edema. If use cannot be avoided, monitor patients with severe renal impairment for development of these adverse reactions. Patients with Hepatic Impairment In patients with severe hepatic impairment, lactate metabolism may be impaired and 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may not produce its alkalinization. Consider when monitoring serum lactate levels. Monitoring of Serum Lactate Levels Administration of 5% Dextrose and Electrolyte No. 48 Injection (Multiple Electrolytes and Dextrose Injection, Type 1, USP) may result in an iatrogenic increase in serum lactate levels in patients with severe metabolic acidosis including lactic.

Docefrez 5 Warnings and Precautions 800.361.4542 | envisionrx.com 9

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) (docetaxel) 5.2 Hepatic Impairment (subsection revised, additions underlined) Docetaxel Patients with elevations of bilirubin or abnormalities of transaminase concurrent with alkaline (docetaxel) phosphatase are at increased risk for the development of severe neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity, and toxic death.

Avoid DOCETAXEL INJECTION in patients with bilirubin > upper limit of normal (ULN), or to patients with AST and/or ALT >1.5 × ULN concomitant with alkaline phosphatase >2.5 × ULN. For patients with isolated elevations of transaminase >1.5 × ULN, consider DOCETAXEL INJECTION dose modifications. Measure bilirubin, AST or ALT, and alkaline phosphatase prior to each cycle of DOCETAXEL INJECTION therapy. 5.7 Second Primary Malignancies (subsection revised, additions underlined) Second primary malignancies, notably acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), Non- Hodgkin’s Lymphoma (NHL), and renal cancer, have been reported in patients treated with docetaxel- containing regimens. These adverse reactions may occur several months or years after docetaxel-containing therapy. Treatment-related AML or MDS has occurred in patients given anthracyclines and/or cyclophosphamide, including use in adjuvant therapy for breast cancer. In the adjuvant breast cancer trial (TAX316) AML occurred in 3 of 744 patients who received docetaxel (T), doxorubicin and cyclophosphamide (TAC) and in 1 of 736 patients who received fluorouracil, doxorubicin, and cyclophosphamide. In TAC- treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires hematological follow-up. Monitor patients for second primary malignancies. 5.8 Cutaneous Reactions (additions underlined) … Severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) have been reported in association with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and monitored closely. Permanent treatment discontinuation should be considered in patients who experience SCARs.

Doryx 5 Warnings and Precautions Additions and/or revisions underlined: (doxycycline hyclate) 5.2 Clostridioides difficile Associated Diarrhea Doryx MPC ‘Clostridioides’ replaces ‘Clostridium’ throughout this subsection. (doxycycline hyclate) Firmagon 4 Contraindications (subsection revised, additions underlined) (degarelix acetate) FIRMAGON is contraindicated in patients with history of severe hypersensitivity to degarelix or to any of the product components. 5 Warnings and Precautions 5.1 Hypersensitivity Reactions (additions underlined) FIRMAGON is contraindicated in patients with history of severe hypersensitivity to degarelix or to any of the product components. …

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) 5.4 Embryo-Fetal Toxicity (new subsection added) Based on findings in animal studies, FIRMAGON can cause fetal harm and loss of pregnancy when administered to a pregnant woman. In animal developmental and reproductive toxicity studies in rats and rabbits, oral administration of degarelix during organogenesis caused embryo-fetal lethality and abortion as well as increased post-implantation loss and decreased the number of live fetuses in animals at doses less than the clinical loading dose based on body surface area. Advise pregnant patients and females of reproductive potential of the potential risk to the fetus.

Injectafer 5 Warnings and Precautions 5.2 Symptomatic Hypophosphatemia (ferric (new subsection added) carboxymaltose) Symptomatic hypophosphatemia requiring clinical intervention has been reported in patients at risk of low serum phosphate in the postmarketing setting. These cases have occurred mostly after repeated exposure to Injectafer in patients with no reported history of renal impairment. Possible risk factors for hypophosphatemia include a history of gastrointestinal disorders associated with malabsorption of fat- soluble vitamins or phosphate, concurrent or prior use of medications that affect proximal renal tubular function, hyperparathyroidism, vitamin D deficiency and malnutrition. In most cases, hypophosphatemia resolved within three months.

Monitor serum phosphate levels in patients at risk for low serum phosphate who require a repeat course of treatment.

Lenvima 5 Warnings and Precautions 5.14 Impaired Wound Healing (lenvatinib mesylate) (subsection revised, additions underlined) Impaired wound healing been reported in patients who received LENVIMA. Withhold LENVIMA for at least 1 week 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 LENVIMA after resolution of wound healing complications has not been established.

Lotrel 5 Warnings and Precautions Additions and/or revisions underlined: (amlodipine 5.1 Fetal Toxicity besylate; benazepril Lotrel can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin- hcl) angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios … 5.2 Angioedema and Anaphylactoid Reactions Head and Neck Angioedema: Angioedema of the face … in patients treated with benazepril. This may occur at any time during treatment. Angioedema associated with edema of the larynx, tongue, or glottis can compromise the airway and be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Lotrel and treat immediately. Patients with a history of angioedema may be at increased risk for angioedema while receiving Lotrel. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks. 5.4 Hypotension Lotrel can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure, or death. Symptomatic hypotension is most likely to occur in patients who have heart failure, severe aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy or have been volume or salt

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) depleted as a result of diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume and salt depletion before starting therapy with benazepril. If hypotension occurs, place the patient in the supine position and give physiological saline intravenously if needed. Continue treatment with benazepril once blood pressure and volume have returned to normal. In patients with congestive heart failure …

Lumizyme 5 Warnings and Precautions 5.2 Immune-Mediated Reactions (alglucosidase alfa) (additions underlined) … Immune tolerance induction administered in conjunction with LUMIZYME may also aide tolerability of alglucosidase alfa under the management of a clinical specialist knowledgeable in immune tolerance induction in pediatric Pompe disease. 5.5 Risk of Antibody Development (additions underlined) Patients with infantile-onset Pompe disease should have a cross-reactive immunologic material (CRIM) assessment early in their disease course and be managed by a clinical specialist knowledgeable in immune tolerance induction in Pompe disease to optimize treatment. Immune tolerance induction administered prior to and in conjunction with initiation of alglucosidase alfa has been reported to aide tolerability of alglucosidase alfa in CRIM-negative patients. CRIM status has been shown to be associated with immunogenicity and patients’ responses to enzyme replacement therapies. CRIM-negative infants with infantile-onset Pompe disease treated with alglucosidase alfa have shown poorer clinical response in the presence of high sustained IgG antibody titers and positive inhibitory antibodies compared to CRIM-positive infants. In clinical studies, the majority of patients developed IgG antibodies to alglucosidase alfa, typically within 3 months of treatment. There is evidence to suggest that some patients who develop high and sustained IgG antibody titers, including CRIM-negative patients (i.e., patients in whom no endogenous GAA protein was detected by Western blot analysis and/or predicted based on the genotype), may experience reduced clinical alglucosidase alfa treatment efficacy, such as loss of motor function, ventilator dependence, or death. 5.6 Monitoring: Laboratory Tests (additions underlined) … Testing services for antibodies against alglucosidase alfa are available through Genzyme Corporation. Contact Genzyme Corporation at 1-800-745-4447 for information on testing

Myozyme 5 Warnings and Precautions 5.2 Immune-Mediated Reactions (alglucosidase alfa) (additions underlined) … Immune tolerance induction administered in conjunction with MYOZYME may also aid tolerability of alglucosidase alfa under the management of a clinical specialist knowledgeable in immune tolerance induction in pediatric Pompe disease. 5.5 Risk of Antibody Development (new subsection added) Patients with infantile onset Pompe disease should have a cross-reactive immunologic material (CRIM) assessment early in their disease course and be managed by a clinical specialist knowledgeable in immune tolerance induction in Pompe disease to optimize treatment. Immune tolerance induction administered prior to and in conjunction with initiation of alglucosidase alfa has been reported to aid tolerability of alglucosidase alfa in CRIM-negative patients. CRIM status has been shown to be associated with immunogenicity and patients’ responses to enzyme replacement therapies. CRIM-negative infants with infantile-onset Pompe

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) disease treated with alglucosidase alfa have shown poorer clinical response in the presence of high sustained IgG antibody titers and positive inhibitory antibodies compared to CRIM-positive infants. 5.7 Monitoring: Laboratory Tests (additions and/or revisions underline) … Testing services for antibodies against alglucosidase alfa are available through Genzyme Corporation. Contact Genzyme Corporation at 1-800-745-4447 for information on testing.

Nerlynx 5 Warnings and Precautions 5.1 Diarrhea (neratinib maleate) (additions 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 cycle. The majority of patients (70%) had diarrhea in the first cycle 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. Antidiarrheal prophylaxis has been shown to lower the incidence and severity of diarrhea. Instruct patients to initiate antidiarrheal prophylaxis with loperamide along with the first dose of NERLYNX and continue during the first 56 days of treatment; after day 56 titrate dose to achieve 1-2 bowel movements per day and not to exceed 16 mg loperamide per day. Consider adding other agents to loperamide as clinically indicated. … 5.2 Hepatotoxicity (additions underlined) … In the NALA study, in NERLYNX and capecitabine-treated patients, 7% experienced an ALT or AST >3x ULN, 2% experienced ALT or AST >5x ULN, 7% experienced a bilirubin >1.5x ULN, and 1.3% experienced a bilirubin >3x ULN. Hepatotoxicity or increases in liver transaminases led to drug discontinuation in 0.3% of NERLYNX and capecitabine-treated patients.

Ninlaro 5 Warnings and Precautions 5.6 Thrombotic Microangiopathy (ixazomib citrate) (new subsection added) Cases, sometimes fatal, of thrombotic microangiopathy, including thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), have been reported in patients who received NINLARO. Monitor for signs and symptoms of TTP/HUS. If the diagnosis is suspected, stop NINLARO and evaluate. If the diagnosis of TTP/HUS is excluded, consider restarting NINLARO. The safety of reinitiating NINLARO therapy in patients previously experiencing TTP/HUS is not known.

Onexton 5 Warnings and Precautions 5.3 Concomitant Topical Medications (benzoyl peroxide; (new subsection added) clindamycin Concomitant topical acne therapy should be used with caution since a possible cumulative irritancy effect phosphate) may occur, especially with the use of peeling, desquamating, or abrasive agents. If irritancy or dermatitis occurs, reduce frequency of application or temporarily interrupt treatment and resume once the irritation subsides. Treatment should be discontinued if the irritation persists.

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Ontak 5 Warnings and Precautions 5.1 Infusion Reactions (denileukin diftitox) (Additions and/or revisions underlined) ... Resuscitative equipment should be available during Ontak administration. Immediately stop and permanently discontinue Ontak for Grade 3 or higher infusion reactions.

Stivarga 5 Warnings and Precautions Additions and/or revisions underlined: (regorafenib) 5.9 Risk of Impaired Wound Healing Impaired wound healing complications can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, STIVARGA has the potential to adversely affect wound healing. Withhold STIVARGA for at least 2 weeks 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 STIVARGA after resolution of wound healing complications has not been established.

Trulicity 5 Warnings and Precautions 5.1 Risk of Thyroid C-cell Tumors (dulaglutide) (additions underlined) … One case of MTC was reported in a patient treated with TRULICITY in the phase 3 clinical program. This patient had pretreatment calcitonin levels approximately 8 times the upper limit of normal (ULN). An additional case of C-cell hyperplasia with elevated calcitonin levels following treatment was reported in the cardiovascular outcomes trial (REWIND). Cases of MTC in patients treated with liraglutide, another GLP-1 receptor agonist, have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and GLP-1 receptor agonist use in humans. … 5.7 Diabetic Retinopathy Complications in Patients with a History of Diabetic Retinopathy (new subsection added) In a cardiovascular outcomes trial with a median follow up of 5.4 years involving patients with type 2 diabetes with established cardiovascular disease or multiple cardiovascular risk factors, diabetic retinopathy complications occurred in patients treated with TRULICITY 1.5 mg (1.9%) and placebo (1.5%). These events were prospectively ascertained as a secondary composite endpoint. The proportion of patients with diabetic retinopathy complications was larger among patients with a history of diabetic retinopathy at baseline (TRULICITY 8.5%, placebo 6.2%) than among patients without a known history of diabetic retinopathy (TRULICITY 1.0%, placebo 1.0%). Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.

Vasostrict 5 Warnings and Precautions 5.2 Reversible Diabetes Insipidus (vasopressin) (new subsection added) Patients may experience reversible diabetes insipidus, manifested by the development of polyuria, a dilute urine, and hypernatremia, after cessation of treatment with vasopressin. Monitor serum electrolytes, fluid status and urine output after vasopressin discontinuation. Some patients may require readministration of vasopressin or administration of desmopressin to correct fluid and electrolyte shifts.

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Velphoro 5 Warnings and Precautions 5.1 Monitoring in Patients with Gastrointestinal Disorders or Iron Accumulation Disorders (sucroferric Additions and/or revisions underlined: oxyhydroxide) Each chewable tablet contains 500 mg iron (equivalent to 2,500 mg sucroferric oxyhydroxide) [see Clinical Pharmacology (12.3)]. Patients with peritonitis during peritoneal dialysis …

Vemlidy 5 Warnings and Precautions 5.4 Lactic Acidosis/Severe Hepatomegaly with Steatosis (tenofovir (Additions and/or revisions underlined) alafenamide Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the fumarate) use of nucleoside analogs, including tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, alone or in combination with other antiretrovirals. Treatment with VEMLIDY should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Vibativ Boxed Warning (additions underlined) (telavancin hcl) …  Embryofetal Toxicity: VIBATIV may cause fetal harm. In animal reproduction studies, adverse developmental outcomes were observed in 3 animal species at clinically relevant doses. Verify pregnancy status in females of reproductive potential prior to initiating VIBATIV. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VIBATIV and for 2 days after the final dose. 5 Warnings and Precautions 5.4 Embryo-Fetal Toxicity (additions underlined) Based on findings in animal reproduction studies, VIBATIV may cause fetal harm. VIBATIV caused adverse developmental outcomes in 3 animal species at clinically relevant doses. Verify pregnancy status in females of reproductive potential prior to initiating VIBATIV. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with VIBATIV and for 2 days after the final dose.

Xgeva 5 Warnings and Precautions 5.3 Hypocalcemia (denosumab) Additions and/or revisions underlined: Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre- existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels, throughout Xgeva therapy, especially in the first weeks of initiating therapy, and administer calcium, magnesium, and vitamin D as necessary. Concomitant use of calcimimetics and other drugs that can lower calcium levels may worsen hypocalcemia risk and serum calcium should be closely monitored. Advise patients to contact a healthcare provider for symptoms of hypocalcemia.

Zejula 5 Warnings and Precautions 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia (niraparib tosylate) (additions underlined) Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with fatal outcome, have been reported in patients who received ZEJULA. In Trial 1 (NOVA), MDS/AML occurred in 5 out of 367 800.361.4542 | envisionrx.com 15

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) (1.4%) of patients who received ZEJULA and in 2 out of 179 (1.1%) patients who received placebo. Overall, MDS/AML has been reported in 7 out of 751 (0.9%) patients treated with ZEJULA in clinical studies.

The duration of ZEJULA treatment in patients prior to developing MDS/AML varied from <1 month to 2 years. All patients had received previous chemotherapy with platinum and some had also received other DNA damaging agents and radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed.

Zerviate 5 Warnings and Precautions 5.1 Contamination of Tip and Solution (cetirizine hcl) (Additions and/or revisions underlined) As with any eye drop, care should be taken not to touch the eyelids or surrounding areas with the dropper tip of the bottle or tip of the single-use container in order to avoid injury to the eye and to prevent contaminating the tip and solution. Keep the multi-dose bottle closed when not in use. Discard the single- use container after using in each eye.

Zypitamag 4 Contraindications (Additions and/or revisions underlined) (pitavastatin ZYPITAMAG is contraindicated in the following conditions: magnesium)  Known hypersensitivity to pitavastatin or any inactive ingredient in ZYPITAMAG. Hypersensitivity reactions including angioedema, rash, pruritus, and urticaria have been reported with pitavastatin.  Concomitant use of cyclosporine.  Active liver disease including unexplained persistent elevations of hepatic transaminase levels.  Pregnancy.  Lactation. It is not known if pitavastatin is present in human milk; however, another drug in this class passes into breast milk. Since HMG-CoA reductase inhibitors have the potential for serious adverse reactions in breastfed infants, females who require pitavastatin treatment should not breastfeed their infants. 5 Warnings and Precautions 5.1 Myopathy and Rhabdomyolysis (Subsection title revised; Additions and/or revisions underlined) ZYPITAMAG may cause myopathy (muscle pain, tenderness, or weakness with creatine kinase (CK) above ten times the upper limit of normal) and rhabdomyolysis (with or without acute renal failure secondary to myoglobinuria). Rare fatalities have occurred as a result of rhabdomyolysis with statin use, including pitavastatin. Risk Factors for Myopathy Risk factors for myopathy include age 65 years or greater, uncontrolled hypothyroidism, renal impairment, concomitant use of certain drugs, and higher ZYPITAMAG dosage. Dosages of pitavastatin greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. The maximum recommended dose of ZYPITAMAG is 4 mg once daily. Steps to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis ZYPITAMAG is contraindicated in patients taking cyclosporine and not recommended in patients taking gemfibrozil. There are ZYPITAMAG dosage restrictions for patients taking erythromycin or rifampin. The following drugs when used concomitantly with ZYPITAMAG may also increase the risk of myopathy and rhabdomyolysis: lipid-modifying dosages of niacin (>1grams/day), fibrates, and colchicine. Discontinue ZYPITAMAG if markedly elevated CK levels occur or myopathy is diagnosed or suspected. Muscle symptoms and CK increases may resolve if ZYPITAMAG is discontinued. Temporarily discontinue ZYPITAMAG in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis, e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy. 800.361.4542 | envisionrx.com 16

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TRADE NAME SUMMARY OF LABEL CHANGES (generic name) Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the ZYPITAMAG dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness or weakness particularly if accompanied by malaise or fever. 5.2 Immune-Mediated Necrotizing Myopathy (Subsection title revised; Additions and/or revisions underlined) There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; and improvement with immunosuppressive agents. Additional neuromuscular and serologic testing may be necessary. Treatment with immunosuppressive agents may be required. 5.3 Hepatic Dysfunction (Subsection title revised; Additions and/or revisions underlined) Increases in serum transaminases have been reported with ZYPITAMAG. In most cases, the elevations were transient and either resolved or improved on continued therapy or after a brief interruption in therapy. There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. Patients who consume substantial quantities of alcohol and/or have a history of liver disease may be at increased risk for hepatic injury. Consider liver enzyme testing before the initiation of ZYPITAMAG and thereafter, when clinically indicated. ZYPITAMAG is contraindicated in patients with active liver disease including unexplained persistent elevations in hepatic transaminase levels. If serious hepatic injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs, promptly discontinue ZYPITAMAG. 5.4 Increases in HbA1c and Fasting Serum Glucose Levels (Subsection title revised; Additions and/or revisions underlined) Increases in HbA1c and fasting serum glucose levels have been reported with statins, including pitavastatin. Optimize lifestyle measures, including regular exercise, maintaining a healthy body weight, and making healthy food choices.

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Treatment Guideline Updates

TITLE CITATION / LINK Chronic Insomnia Disorder and Obstructive Mysliwiec V, Martin JL, Ulmer CS, et al. The Management of Chronic Insomnia Sleep Apnea Clinical Practice Guidelines Disorder and Obstructive Sleep Apnea: Synopsis of the 2019 U.S. Department (VA/DoD, 2020) of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines. Ann Intern Med. 2020 Feb 18. https://annals.org/aim/fullarticle/2761421/management-chronic-insomnia- disorder-obstructive-sleep-apnea-synopsis-2019-u Vaccinations in Adults Clinical Practice Centers for Disease Control and Prevention. Recommended Immunization Guidelines (ACIP, 2020) Schedule for Adults Aged 19 Years or Older, United States 2020. February 3, 2020; Accessed: February 26, 2020. https://www.cdc.gov/vaccines/schedules/hcp/adult.html Latent Tuberculosis Infection (LTBI) Clinical Sterling TR, Njie G, Zenner D, Cohn DL, Reves R, Ahmed A, et al. Guidelines Practice Guidelines (CDC, 2020) for the Treatment of Latent Tuberculosis Infection: Recommendations from the National Tuberculosis Controllers Association and CDC, 2020. MMWR Recomm Rep. 2020 Feb 14. 69 (1):1- 11. https://www.cdc.gov/mmwr/volumes/69/rr/rr6901a1.htm?s_cid=rr6901a1_w Radiation Therapy for Basal and Squamous Likhacheva A, Awan M, Barker CA, et al. Definitive and Postoperative Radiation Cell Cancers of the Skin Clinical Practice Therapy for Basal and Squamous Cell Cancers of the Skin: Executive Summary Guidelines (2020) of an American Society for Radiation Oncology Clinical Practice Guideline. Pract Radiat Oncol. Jan-Feb 2020; 10(1):8-20. Available at: https://www.practicalradonc.org/article/S1879-8500(19)30323-6/fulltext. Surgical Management of Thyroid Disease Patel KN, Yip L, Lubitz CC, Grubbs EG, Miller BS, Shen W, et al. The American Clinical Practice Guidelines (2020) Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults. Ann Surg. 2020 Mar;271(3):e21-e93. Available at: https://journals.lww.com/annalsofsurgery/FullText/2020/03000/The_American _Association_of_Endocrine_Surgeons.28.aspx.

Ulcerative Colitis Clinical Practice Guidelines Feuerstein JD, Isaacs KL, Schneider Y, Siddique SM, Falck-Ytter Y, Singh S, for (AGA, 2020) the American Gastroenterological Association Institute Clinical Guidelines Committee. AGA clinical practice guidelines on the management of moderate to severe ulcerative colitis. Gastroenterology. 2020 Jan 13. pii: S0016- 5085(20)30018-4. https://www.gastrojournal.org/article/S0016-5085(20)30018- 4/pdf

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TITLE CITATION / LINK Exercise-Associated Hyponatremia Clinical Bennett BL, Hew-Butler T, Rosner MH, Myers T, Lipman GS. Wilderness Practice Guidelines (2020) Medical Society Clinical Practice Guidelines for the Management of Exercise- Associated Hyponatremia: 2019 Update. Wilderness Environ Med. 2020 Feb 7. https://www.wemjournal.org/article/S1080-6032(19)30206-6/fulltext Liver Failure Management in the ICU: Clinical Nanchal R, Subramanian R, Karvellas CJ, et al. Guidelines for the management Practice Guidelines (2020) of adult acute and acute-on-chronic liver failure in the ICU: cardiovascular, endocrine, hematologic, pulmonary, and renal considerations. Crit Care Med. 2020 Mar;48(3):e173- 91. https://journals.lww.com/ccmjournal/FullText/2020/03000/Guidelines_for_the _Management_of_Adult_Acute_and.29.aspx

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