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7/17/2017

FSHP 2017 ANNUAL MEETING Disclosure #FSHP2017

The speaker of this presentation has the following disclosure: Name Company Role Outside the Box: Rebecca Gonzalez, Pharm.D., BCOP None N/A Non‐Oncologic Indications For Off label use disclosure: Chemotherapy • This session will include a discussion of off-label treatment and investigational agents not approved by the FDA for use in the US Rebecca Gonzalez, Pharm.D., BCOP Clinical Pharmacist and Marrow Transplantation Moffitt Center

2017 ANNUAL MEETING

#FSHP2017 #FSHP2017 Pharmacist Objectives Technician Objectives

1. Identify non-oncologic indications for specific 1. Identify chemotherapy and biotherapy agents that chemotherapy and biotherapy agents may be used for non-oncologic indications 2. Discuss barriers to distribution and administration of 2. Discuss barriers to distribution of chemotherapy in non- chemotherapy/biotherapy in non- settings oncology settings 3. Review common and monitoring associated 3. Describe safe storage, preparation, and disposal of with use of specific chemotherapy/biotherapy agents chemotherapy agents used in non-oncology settings

2017 ANNUAL MEETING 2017 ANNUAL MEETING

#FSHP2017 #FSHP2017 Background Background: IMIDs • Approximately 80 different result from the Historic treatment New treatment attack on its own cells, tissue and organs • Loss of regulation and differentiation of immune cells • Steroids • Chemotherapy • Irregular function and production • Production of autoantibodies • • Biotherapeutic agents • AD/IMIDs • Non-steroidal anti- Immunosuppressant or inflammatory agents immunomodulating effects • Up to 24 million Americans suffer from AD • Improve symptoms • Cancer: 9 million • Achieve remission • Heart : 22 million

AD=autoimmune Disorders; IMIDs=immune-mediated chronic inflammatory diseases IMIDs, immune-mediated chronic inflammatory diseases 2017 ANNUAL MEETING https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases. Accessed on 5/1/17. 2017 ANNUAL MEETING https://www.niaid.nih.gov/diseases-conditions/autoimmune-diseases. Accessed on 5/1/17. Zack E, et al. Clin J Oncol Nurs. 2012;16(4):E125-32

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#FSHP2017 Re-establishing the Balance in IL-17 Th Roles: Th Roles: INF-γ 1 17 Th1 • -mediated • Autoimmunity Th17 IL-22 immunity • Inflammation IL-2 • Autoimmunity INF-γ • Inflammation TNF-α Antigen Extending Landscapes of Presenting Cells Th Chemotherapy & 0

TGF-β =transforming Biotherapies growth factor-beta Th=Helper T Cells IL-10 IL-4 Use Beyond Cancer Th0=Naïve T-cell IL-35 Treg=regulatory T-cells Treg IL-5 Th2 IL=interleukin TGF-β IL-6 Th2 Roles: INF-γ=interferon gamma IL-10 • -mediated immunity Treg Roles: IL-13 • Immune tolerance • Regulation of immune responses 2017 ANNUAL MEETING Adapted from: Smith DM, et al. Nat Rev Immunol 2013;13:592-605.

Chemotherapy for Autoimmune Disorders#FSHP2017 : Overview #FSHP2017 • Suppression of the immune system Introduced in 1959 as the 8th anti-cancer • Inhibition of cell growth and • Reduction in pro-inflammatory cytokines • : Alkylating agent • /lymphocytes (IL-2, TNF and interferon-γ) • Cell-Cycle Non-Specific • Cross-links DNA strands Classification Chemotherapy Agents • Reduces DNA replication and RNA

Alkylating Agents Cyclophosphamide • Immunosuppressant/immunomodulatory: DMARD • Reduces B and T-Lymphocytes •  unwanted Th immune responses MTX 1 6-MP

MTX, ; 6-MP, 6-; IL-2, interleukin-2

TNF=tumor-necrosis factor; IFN-γ, interferon gamma 2017 ANNUAL MEETING DMARD=Disease-modifying antirhuematic ; Th1= helper t-cell 1 2017 ANNUAL MEETING Zack E, et al. Clin J Oncol Nurs. 2012;16(4):E125-32 Cyclophosphamide [package insert]. Baxter Healthcare Corporation, Derrfield, IL; May 2013.

Cyclophosphamide: Indications #FSHP2017 Cyclophosphamide #FSHP2017

Dosage Forms PO formulations: 25mg, 50mg capsules • FDA Indications: IV Concentration: 20mg/mL (500mg, 1g, 2g vials) • Hematologic : HL, NHL, MM, AML, CML • Storage: room temperature • Solid tumors: Breast, Ovarian, cancer Absorption : 75% CYP-P450:  Acrolein, phosphoramide mustard • 2B6 Activation • Off label indications: • 3A4 Inactivation • SLE, Rheumatoid Administration RA: 1.5-3mg/kg PO Daily • Scleroderma, MS SLE: • 1-3mg/kg/day PO + • HCT conditioning/GVHD • 500-1000mg/m2 IV Qmonthy x 6 doses (severe) • ITP/TTP nephritis: • 500mg IV Q2 weeks x 6 doses • 500-1000mg/m2 IV Qmonthy x 6 doses

SLE, systemic lupus erythematosus; HL, Hodgkin’s ; NHL, non-hodgkin’s lymphoma; MM, ; MS, ; GVHD, graft-versus-host-disease; ITP, idiopathic thrombocytopenic purpura,; TTP, thrombotic thrombocytopenic purpura; AML, acute RA=; SLE=Systemic Lupus Erythematosus myelogenous ; CML, Chronic Myelogenous Leukemia; HCT, hematopoietic cell transplantation2017 ANNUAL MEETING Magro-Checa C, et al. . 2016;76:459-483 2017 ANNUAL MEETING Cyclophosphamide [package insert]. Baxter Healthcare Corporation, Derrfield, IL; May 2013. Cyclophosphamide [package insert]. Baxter Healthcare Corporation, Derrfield, IL; May 2013.

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Cyclophosphamide #FSHP2017 Clinical Considerations #FSHP2017

Adverse Effects (AE’s) and immune suppression (Dose-limiting) Hemorrhagic cystitis (higher dose > 50-60mg/kg) Pearls Monitoring / ( doses >600mg/m2) • Administer in AM • Labs • Chronic with PO • CBC with diff (baseline and monthly) Alopecia (~30%) • Hydration • SCr Contraindications/C Hypersensitivity • Increase intake during and for 1-2 days post therapy (~2L) aution Severe myelosuppresion • Symptoms of cardiac or 2 • ANC <1500 • Doses of <1000mg/m do not pulmonary toxicity • Platelets < 50K need MESNA support • Look/Sound-Alike: cycloSPORINE Severe renal or hepatic impairment • Frequent urination or breastfeeding (Category D) • Clinical effect  ~3 weeks to Dosage Adjustments Renal: <10ml/min: 75% of normal dose months • HD: 50% of normal dose as supplement (dialyzable) • PD: 75% of normal dose as supplement (dialyzable) • Avoid live vaccinations Hepatic: 3.1-5mg/dL or AST >3x ULN: 75% of normal dose

Magro-Checa C, et al. Drugs. 2016;76:459-483 2017 ANNUAL MEETING SCr=serum creatinine, CBC with diff= with differential 2017 ANNUAL MEETING Cyclophosphamide [package insert]. Baxter Healthcare Corporation, Derrfield, IL; May 2013. Cyclophosphamide [package insert]. Baxter Healthcare Corporation, Derrfield, IL; May 2013.

Methotrexate (MTX): Overview #FSHP2017 Methotrexate: Indications #FSHP2017 Introduced in 1940’s for treatment of acute leukemia's • FDA Indications: • Anti-metabolite-Folate Analog • Oncology use in acute , , lung, head/neck • Targets thymidylate biosynthesis inhibiting dihydrofolate and reductase • RA, • Depletes and precursors • Blocking DNA and RNA synthesis • Off label indications: •  Cellular proliferation • MS, SLE • Cell-cycle specific (S-phase) • Severe Crohn's disease • Immunosupressant: DMARD 1 • Post-organ/HCT rejection • Anti-inflammatory effects ( cytokines) • Inhibits production and activity of IL-1, reduces TNFα and IL-6 RA=Rheumatoid arthritis; SLE=Systemic Lupus Erythematosus; MS= Multiple Sclerosis concentrations Cutolo M, et al. Annals of the Rheumatic Diseases. 2001;60:729-735. Cutolo M, et al. Annals of the Rheumatic Diseases. 2001;60:729-735. Methotrexate injection 50 mg/ 2 mL [package insert]. Inc., New York, NY; December 2015. Patel V, et al. Cochrane Database Syst Rev 2014; :CD006884. Methotrexate injection 1 g/40 mL [package insert]. Pfizer Inc., New York, NY; December 2015. Methotrexate injection 50 mg/ 2 mL [package insert]. Pfizer Inc., New York, NY; December 2015. Methotrexate tablets [package insert]. DAVA Pharmaceuticals, Inc., Huntsville, AL; January 2016. Methotrexate injection 1 g/40 mL [package insert]. Pfizer Inc., New York, NY; December 2015. 2017 ANNUAL MEETING Otrexup™ [package insert]. Antares Pharma, Inc., Ewing, NJ; December 2016. 2017 ANNUAL MEETING Otrexup™ [package insert]. Antares Pharma, Inc., Ewing, NJ; December 2016. Rasuvo® [packager insert]. Medac Pharma Inc., Chicago, IL; November 2014.

Methotrexate: #FSHP2017 Methotrexate: #FSHP2017 Administration Rheumatoid Arthritis (Severe): 7.5-25mg PO/IM Weekly Dosage Forms PO formulations: 2.5mg, 5mg, 7.5mg, 10mg, 15mg Tablets Alternative: Give weekly •Xatmep (2.5 mg/mL solution): FDA approved April 2017 available ~June 2017 (IV, IM, SQ or PO) • Doses >20mg  suppression •10mg SQ Weekly (Otrexup®) or 7.5mg SQ Weeklyoral (Rasuvo®) doses 2.5mg PO IV Max Concentration: 25mg/mL (50mg, 1g vials) • Titrate doses to optimum response Q12hrs x 3 doses •Storage: room temperature, protect from light Psoriasis: 10-25mg PO/IM//SQ/IV Weekly SQ formulations: Single-dose auto-injectors •Not to exceed 30mg weekly •Otrexup®: 10mg, 12.5mg, 15mg, 17.5mg, 20mg, 22.5mg, 25mg/0.4mL Crohn’s Disease: 15-25mg IM/SQ Weekly •Rasuvo®: 2.5mg/0.05mL-10 dosing options AE’s GI: , N/V/D • Dosage administration range 7.5mg-30mg @ 2.5mg increments Myelosuppresion, Hepatic fibrosis/ (transaminitis), Rash, Absorption PO: Bioavailability = 60% at dose <30mg/m2 Contraindications Black Box Warning: Impaired drug elimination with pleural effusions, ascites • at dose >80mg/m2 /Caution or renal function, pulmonary, GI or SQ: Severe renal or hepatic impairment •Bioavailability of Otrexup: Pregnancy or breastfeeding (Category D) • 17%, 13%, 31% and 36% > than PO MTX @ 10mg, 15mg, 20mg, 25mg Dosage Renal: CrCl 10-50ml/min/HD/CRRT: 50% of normal dose •AUC of Rasuvo: Adjustments • <10ml/min: Avoid use • 35%, 49%, 51% and 68% > than PO MTX @ 7.5mg, 15mg, 22.5mg, 30mg Hepatic: Bilirubin 3.1-5mg/dL or AST >3x ULN: 75% of normal dose Metabolism Liver and Intracellularly • Bilirubin >5mg/dL: Avoid use

Braun J, et al. Arthritis Rheum. 2008;58(1):73-8, Schiff MH, et al. Ann Rheum Dis. 2014;73(8):1549-1551. Pichlmeier U, et al. Clin Exp Braun J, et al. Arthritis Rheum. 2008;58(1):73-8, Schiff MH, et al. Ann Rheum Dis. 2014;73(8):1549-1551. Pichlmeier U, et al. Clin Exp Rheumatol. Rheumatol. 2014;32:563-571., Bianchi G, et al. Advances in therapy 2016;33:369-78. Methotrexate2017 injection ANNUAL 50 mg/ 2MEETING mL 2014;32:563-571., Bianchi G, et al. Advances in therapy 2016;33:369-78. Methotrexate injection 50 mg/ 2 mL [package2017 insert], ANNUAL Methotrexate MEETING injection 1 [package insert]., Methotrexate injection 1 g/40 mL [package insert]., Methotrexate tablets [package insert]. g/40 mL [package insert]., Methotrexate tablets [package insert]. ,Otrexup™ [package insert]. ,Rasuvo® [packager insert].

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#FSHP2017 #FSHP2017 Methotrexate: Clinical Pearls Methotrexate: Clinical Considerations • Administration • Give lowest effective dose • Intervals less than 1 week apart  • Clinical effect may take ~3-6 weeks • Higher bioavailability with SQ administration • Reduce toxicity • SQ injections given in abdomen or thigh • Administer with folic acid 1mg PO Daily or leucovorin 5mg PO weekly • Monitoring • Check Indication before dispensing!!! • Baseline LFT’s, total bilirubin, Scr, CBC with diff, B/C testing • Use in alcoholic liver or chronic hepatic disease is contraindicated • Monthly CBC with differential, LFT’s when use in NON-oncology indication • Signs/Symptoms of • SQ injections are NOT approved for use in therapy • Stop therapy at least 3-months before planned conception

LFT, liver function tests (AST, ALT, ALK phosphatase); CBC with diff=complete blood count with differential Methotrexate injection 50 mg/ 2 mL [package insert]. Pfizer Inc., New York, NY; December 2015. Methotrexate injection 50 mg/ 2 mL [package insert]. Pfizer Inc., New York, NY; December 2015. Methotrexate injection 1 g/40 mL [package insert]. Pfizer Inc., New York, NY; December 2015. Methotrexate injection 1 g/40 mL [package insert]. Pfizer Inc., New York, NY; December 2015. Methotrexate tablets [package insert]. DAVA Pharmaceuticals, Inc., Huntsville, AL; January 2016. Methotrexate tablets [package insert]. DAVA Pharmaceuticals, Inc., Huntsville, AL; January 2016. Otrexup™ [package insert]. Antares Pharma, Inc., Ewing, NJ; December 2016. 2017 ANNUAL MEETING Otrexup™ [package insert]. Antares Pharma, Inc., Ewing, NJ; December 2016. 2017 ANNUAL MEETING Rasuvo® [packager insert]. Medac Pharma Inc., Chicago, IL; November 2014. Rasuvo® [packager insert]. Medac Pharma Inc., Chicago, IL; November 2014.

Patient Assistance Programs #FSHP2017 6-Mercaptopurine (6-MP) #FSHP2017

Otrexup® (methotrexate injection)-855-OTREXUP (855-687-3987) • Introduced in early 1950’s •TotalCare Co-Pay Assistance Program •TotalCare Patient Assistance program • Anti-metabolitePurine Analog: Rasuvo® (methotrexate injection)-855-33MEDAC (855-336-3322) • and •Core Connections Rasuvo Co-pay Assistance Program • Inhibits DNA/RNA synthesis (S-phase specific) •Core Connections Medac Pharma Patient Assistance Program • Immunomodulator: Eligibility: • Anti-inflammatory effects ( cytokines/interleukins) •Commercially insured •Does NOT include , Medicare Advantage, Medicare Part D, Medicaid, VA, or TriCare •Income requirements

Purinethol® [package insert]. DSM Pharmaceuticals, Inc., Greenville, NC; August 2003., Otrexup™ [package insert]. Antares Pharma, Inc., Ewing, NJ; December 2016. 2017 ANNUAL MEETING Purixan™ [package insert]. Rare Disease Therapeutics, Inc., Franklin, TN; April 2014. 2017 ANNUAL MEETING Rasuvo® [packager insert]. Medac Pharma Inc., Chicago, IL; November 2014. Lichtenstein GR, et al. Gastroenterology 2006; 130:940.

6-MP: Indications #FSHP2017 6-MP: Adult Dosing #FSHP2017

• FDA Indications: Dosage Forms PO formulations: 50mg tablets, 20mg/mL suspension • ALL Absorption Bioavailability: 50% Metabolism Liver, GI mucosa (first-pass metabolism) • Off label indications: •Active: 6-thioguanine, Inactive: methylmercaptopurine, 6- • CML thiouric acid • APL • 6-MP undergoes methylation  inactivation via • Crohn’s disease or Ulcerative colitis methylation by TPMT • Histiocytosis • Homozygous-deficient polymorphisms (~0.3%)= ↑ 6- MP TOXICITY • Oxidation by xanthine oxidase Administration Crohn’s: 1-1.5mg/kg PO Daily (PO only) Ulcerative Colitis: 50-125mg PO Daily

ALL=acute lymphoblastic leukemia; APL=acute promyelocytic leukeima TPMT= S-methyltransferase Purinethol® [package insert]. DSM Pharmaceuticals, Inc., Greenville, NC; August 2003., 2017 ANNUAL MEETING Purinethol® [package insert]. DSM Pharmaceuticals, Inc., Greenville, NC; August 2003. 2017 ANNUAL MEETING Purixan™ [package insert]. Rare Disease Therapeutics, Inc., Franklin, TN; April 2014. Purixan™ [package insert]. Rare Disease Therapeutics, Inc., Franklin, TN; April 2014.

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#FSHP2017 #FSHP2017 6-MP: Adult Dosing 6-MP: Clinical Pearls Adverse Effects Headache, N/V/D • Assess for TPMT deficiency (AE’s) Malaise, arthralgias Rash • Heterozygous Stomatitis • Reduce dose based on toxicity standard dosing Pancreatitis • Homozygous Hyperpigmentation • Up to a 90% dose reduction Hepatotoxicity Contraindications/ Caution in TMPT deficiency • Reduce dose by up to 75% when given concurrently with Caution Pregnancy(Category D), Breastfeeding (possible unsafe)  risk of infections Dose-related • Clinical effect ~3-6 months w/ steroids Dosage Adjustments Renal: CrCl <50ml/min: Administer Q48hrs Hepatic: Consider dosage reduction

Purinethol® [package insert]. DSM Pharmaceuticals, Inc., Greenville, NC; August 2003., 2017 ANNUAL MEETING Purinethol® [package insert]. DSM Pharmaceuticals, Inc., Greenville, NC; August 2003., 2017 ANNUAL MEETING Purixan™ [package insert]. Rare Disease Therapeutics, Inc., Franklin, TN; April 2014. Purixan™ [package insert]. Rare Disease Therapeutics, Inc., Franklin, TN; April 2014.

6-MP: Clinical Considerations #FSHP2017 Biotherapies #FSHP2017 • Biological response modifiers • Administration • Genetically tailored monoclonal antibody • Take on empty stomach • Derived from mouse, non-human and/or combined genetic material • Avoid/reduce dosage with additional agents with • Bind to a specific antigen (cells or ) myelosuppressive properties • Utilized since mid 1970’s • Monitoring • 5 different classes of : IgM, IgG, IgA, IgE and IgD

• Monitor CBC and LFT’s baseline then Q1week x 4 weeks, then Variable region Q2weeks x 3mo, then Q3mo Structure • Amylase/Lipase Q2weeks x 2mo Light chain • 4 chains: 2 light/2 heavy Fab region • Fab contains variable • Look/Sound-Alike: Purinethol ® – propylthiouracil, domain=antibody specificity methotrexate Fc region

Fc=fragment constant Fab=fragment-antigen binding Purinethol® [package insert]. DSM Pharmaceuticals, Inc., Greenville, NC; August 2003., 2017 ANNUAL MEETING O'Shea JJ, et al. Nat Rev Immunol. 2002;2:37-45 2017 ANNUAL MEETING Purixan™ [package insert]. Rare Disease Therapeutics, Inc., Franklin, TN; April 2014. Chan AC, et al. Nat Rev Immunol . 2010;10:301-316

#FSHP2017 #FSHP2017 ABC’s of Monoclonal Antibody (mAbs) ABC’s of Monoclonal Antibody (mAbs) • Inhibit bioactive cytokines, augment or modulate • Suffix “-mab”=mAbs autoimmune processes • Different preceding word parts (morphemes) • Recognize foreign antigens and providing immune response to them • Structure and function • Provide immunologic memory • The sub-stem denotes the animal where the antibody is obtained • Therapeutic effects • Key elements: • Complement-medicated cytolysis • 1. Prefix + • ADCC • 2. infix (disease/target) + • CDC • 3. sub-stem (source) + • -o- =murine • -xi- =chimeric • -zu- =humanized • -ixzu- =chimeric/humanized • -u- =human ADCC=antibody-dependent cell-mediated ; CDC=cell-mediated cytotoxicity • 4. stem (–mab) Reprinted with permissions from Macmillan Publishers Ltd: Nature Reviews immunology O'Shea JJ, et al. Nat Rev Immunol. 2002;2:37-45, copyright 2002 http://www.who.int/medicines/services/inn/Generalpoliciesformonoclonalantibodies2009.pdf. Accessed on April 10, 2017. Maneiro JR, et al. JAMA Intern Med. 2013;173(15):1416-1428 2017 ANNUAL MEETING Chan AC, Carter PJ. Nat Rev Immunol. 2010; 10:301-316. 2017 ANNUAL MEETING Chan AC, et al. Nat Rev Immunol . 2010;10:301-316 Figure adapted from: https://en.wikipedia.org/wiki/File:Chimeric_and_humanized_antibodies.svg. Accessed on April 10, 2017.

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#FSHP2017 Infusion Reactions #FSHP2017 ABC’s of Monoclonal Antibody (mAbs) • , chills, rigors, nausea, headache, hypotension, pruritus • Occur ~1-2 hours of administration Product Target/Disease Specific Antibody Meaning Specific (Therapeutic Use) Type/Source -mab (prefix) (infix) (sub-stem) (stem) • Why do infusion reactions occur? • Immunogenicity: “ci” cardiovascular • Non-human components are recognized as a foreign antigens “tu” cancer • Immune system can remove antibody and/or trigger allergic response “vi” Viral • The more “human” the mAb =  infusion reactions • -dependent: “li” inflammation • CRS triggered by release of cytokines from target cells “ba”- bacterial “fu” fungal • Combination of DMARD’s + mAb • Reduces antibodies towards agent and  hypersensitivity/CRS reactions inf li xi mab Infliximab ri tu xi mab

CRS=cytokine-release syndrome 2017 ANNUAL MEETING Chung CH. The Oncologist 2008;13:725-732 2017 ANNUAL MEETING http://www.who.int/medicines/services/inn/Generalpoliciesformonoclonalantibodies2009.pdf. Accessed on April 10, 2017. Maneiro JR, et al. JAMA Intern Med. 2013;173(15):1416-1428

#FSHP2017 #FSHP2017 Monoclonal Antibody (mAb’s): Infusion Reactions Rituximab st Prevention: Pre- given ~30 minutes prior • One of the 1 biotherapies for cancer and RA Acetaminophen 650mg x 1 • Chimeric antibody to CD20 on mature B-Cells Antihistamine • Human protein with antigen (Fab) derived from mice Diphenhydramine 50mg IV/PO x1 OR • Binding to B-cells results in depletion of peripheral B-cells Cetirizine 10mg PO x 1 • Complement and antibody-mediated cytotoxicity PRN Hypersensitivity Reaction Medications: • Inhibits B-cell activation/maturation to plasma cells Methylprednisolone 125mg IV Push x 1 •Recovery takes up to 6 months Diphenhydramine 25mg IV Push x1 HYDROmorPHONE 0.5mg IV Push x1 PRN rigors/chills • Immunosuppressant: DMARD 1 -xi- May repeat in 15 minutes x 1 if symptoms present • Anti-inflammatory effects •  cytokines (IL-1, T-cell activation, autoantibodies) EpINEPHrine 0.3mg SQ auto-injector x 1 PRN

2017 ANNUAL MEETING 2017 ANNUAL MEETING Rituxan® [package insert]. Genentech, Inc., San Francisco, CA; April 2016.

Rituximab #FSHP2017 Rituximab: #FSHP2017 Dosage Forms IV Concentration: 10mg/mL (100mg, 500mg single-use vials) • FDA Indications: • Storage: Refrigerated • NHL, CD-20 + CLL Pre-Medications Acetaminophen + antihistamine • RA (moderate-severe) Half-life 18-32 days • Off label indications: Metabolism Unknown • PTLD Administration Rheumatoid Arthritis: 1000mg IV Q2 weeks x 2 doses • Treatment of graft-versus-host-disease • In combo with methotrexate • ITP/TTP/autoimmune hemolytic • Given Q16-24 weeks based on response Initial infusion rate: Infuse at 50mg/hr (____ml/hr) x 30 minutes and increase rate by 50mg/hr (____ml/hr) every 30 minutes up to a maximum of 400mg/hr (____ml/hr) Subsequent infusion rate (2+): Infuse at 100mg/hr (____ml/hr) x 30 minutes and increase rate by 100mg/hr (____ml/hr) every 30 minutes up to a maximum of 400mg/hr (____ml/hr) Rapid Infusion: Infuse at 150mg/hr (____ml/hr) x 30 minutes then increase to of 275ml/hr until completion ITP=Idiopathic thrombocytopenic purpura; TTP=Thrombotic thrombocytopenic purpura; CLL=chronic lymphocytic leukemia; PTLD=post transplant lymphoproliferative disorder 2017 ANNUAL MEETING 2017 ANNUAL MEETING Rituxan® [package insert]. Genentech, Inc., San Francisco, CA; April 2016. Rituxan® [package insert]. Genentech, Inc., San Francisco, CA; April 2016.

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#FSHP2017 #FSHP2017 Rituximab: Rituximab: Clinical Pearls Adverse Effects (AE’s) Infusion reaction: Fever, chills, rigors, hypotension • NOT recommended in patients with severe or active infections Headache, myalgia's Rhinitis, cough • Screen all patients for HBV before initiating  Infections (bacterial=viral > fungal) • HBsAg and anti-HBc Contraindications/Cau Do NOT administer as IV push or bolus • Consider HBV prophylaxis in higher risk patients tion BBW: Infusion reactions-serious or fatal reactions (80% with 1st • Live NOT recommended infusion30-120min), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML) • Antihypertensives should be held ~12 hours pre-infusion reactivation • 24 hour stability at room temp, additional 24 hours if refrigerated Cardiac and angina Pregnancy Category C Monitoring: CBC with diff baseline and Q2-4 months, s/sx of hepatitis Dosage Adjustments None or HBV reactivation Consider lower infusion rate in patients with history of prior infusion reaction Patient Assistance Program: RITUXAN Access Solutions:1-888-249-4918

2017 ANNUAL MEETING HBV=hepatitis B virus; HBsAg=Hepatitis B surface antigen; anti-HBc=Hepatitis B core antibody 2017 ANNUAL MEETING Rituxan® [package insert]. Genentech, Inc., San Francisco, CA; April 2016. Rituxan® [package insert]. Genentech, Inc., San Francisco, CA; April 2016.

Infliximab #FSHP2017 Infliximab: #FSHP2017 • Introduced in 1998 • FDA Indications: • Chimeric anti-TNF antibody • Crohn’s disease and ulcerative colitis • RA, Psoriatic Arthritis, Plaque Psoriasis • Fused to IgG 1 • Off Label Indications: • Binds/inhibits TNF communication with TNF receptors on • GVHD Treatment inflammatory cells • Sjogren's syndrome • Soluble and membrane-bound TNFα • Refractory sarcoidosis

• TNF Inhibitor: DMARD 2 • Anti-inflammatory effects (TNFα) • Blocking synovial tissue and intestinal inflammation -xi-

TNF= GVHD=Graft versus Host Disease Remicade® [package insert]. Janssen Biotech, Inc., Horsham, PA; November 2013. 2017 ANNUAL MEETING Remicade® [package insert]. Janssen Biotech, Inc., Horsham, PA; November 2013. 2017 ANNUAL MEETING Inflectra™ [package insert]. Hospira, A Pfizer Company, Lake Forest, IL; April 2016. Inflectra™ [package insert]. Hospira, A Pfizer Company, Lake Forest, IL; April 2016.

Infliximab: #FSHP2017 Infliximab: #FSHP2017

Dosage Forms IV Concentration: 25mg/mL (100mg single-use vials) Adverse Effects (AE’s) Infusion reaction: Fever, chills, rigors • Storage: refrigerated (do not freeze) Headache, nausea • Infusion should begin within 3 hours of reconstitution and dilution /abscesses (Crohn’s disease) Transaminitis Pre-Medications Acetaminophen + antihistamine Respiratory Infections Excretion Half-life 8-9.5 days Development of antinuclear antibodies (50%) Metabolism Unknown Contraindications/Cau Do NOT administer as IV push or bolus Administration Rheumatoid Arthritis: 3mg/kg IV @ 0, 2, 6 weeks In combo with MTX, tion BBW: Serious infections w/concomitant immunosuppressant's then Q8 weeks (MTX, Steroids) • Increase to 10mg/kg or give Q4 weeks if incomplete response STOP therapy if: active tuberculosis/reactivation of latent IBD: 5-10mg/kg IV given at 0, 2, 6 weeks, then Q8 weeks , invasive fungal infections, opportunistic infections Psoriasis: 5mg/kg IV @ 0, 2, 6 weeks, then Q8 weeks +/- MTX Risk of malignancy-lymphomas and non- Pregnancy Category B Infusion rate: Infuse over 1 to 2 hours (250ml NaCl) • Infusion may be stopped until infusion sx improve, then titrated Dosage Adjustments None slowly every 30minutes Moderate-Severe Heart Failure (NYHA class III or IV): Not to exceed 5mg/kg

Remicade® [package insert]. Janssen Biotech, Inc., Horsham, PA; November 2013. 2017 ANNUAL MEETING Remicade® [package insert]. Janssen Biotech, Inc., Horsham, PA; November 2013. 2017 ANNUAL MEETING Inflectra™ [package insert]. Hospira, A Pfizer Company, Lake Forest, IL; April 2016. Inflectra™ [package insert]. Hospira, A Pfizer Company, Lake Forest, IL; April 2016.

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Infliximab: Clinical Pearls #FSHP2017 Infliximab Biosimilar #FSHP2017 • Discontinue therapy if lack of response @ 14weeks for IBD indication Infliximab-dyyb (Inflectra™)-approved April 2016 • Risk of antibodies towards infliximab (immunogenicity) •Indications: Includes all original indications for reference product • Recommendation for concomitant Biosimilars mimic existing biologic agents • Combo of MTX + infliximab superior to MTX alone in RA •Same amino acid sequence and • Different inactive ingredients, manufacturing processes, host cell line • Screen all patients for TB and HBV before initiating •Have no clinical meaningful differences in safety, purity, potency or • HBsAg and anti-HBc immunogenicity • Consider HBV prophylaxis in higher risk patients Reimbursement? • Live vaccines NOT recommended •Medicare: Part B-slightly higher than ASP (ASP+6% of reference agent) •Medicare: Part D- “branded” (ineligible for 50% coverage gap discount) Monitoring: CBC with diff baseline and Q2-4 months, s/sx of hepatitis or •Commercial: based on cost differential, therapeutic indication, interchangeability HBV reactivation, dermatologic exam baseline and periodically Infliximab Patient Assistance: Janssen CarePath 877-CarePath (877-227- Patient assistance program: Inflectra (infliximab-dyyb) 1-844-722-6672 3728)

TB, tuberculosis; IBD, irritable bowel disease. 2017 ANNUAL MEETING Inflectra™ [package insert]. Hospira, A Pfizer Company, Lake Forest, IL; April 2016. 2017 ANNUAL MEETING Magro F, et al. Biodrugs. 2010;24(1):3-14., Remicade® [package insert., Inflectra™ [package insert]. Jørgensen KK, et al. Lancet. 2017.[Epub ahead of print].

#FSHP2017 Rheumatoid Arthritis #FSHP2017

• Chronic inflammatory condition  dysregulated humoral and cell mediated systems • Production of antibodies= rheumatoid factors (+ in 60-70%) • Chronic inflammation of synovial lining in  Pannus formation • Erosion of bone/cartilage and destruction • Symptoms may include Clinical Application • , weakness, low grade fever and loss of appetite Non-Oncologic Disease Specific Indications • Symmetric joint pain and stiffness

Colmegna I, et al. Clin Pharmacol Ther. 2012;91:607–620. Singh JA, et al. Arthritis Care Res (Hoboken) 2016;68:1–25. 2017 ANNUAL MEETING Saag KG, et al. Arthritis Rheum. 2008;59:762–84. 2017 ANNUAL MEETING Smolen JS, et al. Ann Rheum Dis. 2014 Mar;73(3):492-509.

#FSHP2017 1. Activated T-cells produce cytotoxins Rheumatoid Arthritis: Pathophysiology and cytokines • Release of inflammatory • Cascade effect: Activation/amplification of immune response cytokines: TNF, IL-1 and IL-6 by immunoglobulin's (Ig’s) • Triggering a cascade inflammatory response • Triggered by complement system Activated B and T lymphocytes 2. Activated B-cells produce plasma cells • Cytokines released from both B and T cells can enhance and memory B-cells inflammation and augment the immune attack by a triad of • Autoantibodies produced from Ig's • Autoantibodies • Cellular damage to synovium • Antigen presentation and bone • Cytokine secretion 3. Vasoactive substances released: Histamine, prostaglandins, kinins •  blood flow and vascular permeability • , erythema, pain Colmegna I, et al. Clin Pharmacol Ther. 2012;91:607–620. Singh JA, et al. Arthritis Care Res (Hoboken) 2016;68:1–25. Saag KG, et al. Arthritis Rheum. 2008;59:762–84. 2017 ANNUAL MEETING IL=interleukin Smolen JS, et al. Ann Rheum Dis. 2014 Mar;73(3):492-509 Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Rheumatology. 2015;11, 313–317, copyright 2015

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Rheumatoid Arthritis: Therapeutic Agents#FSHP2017 Irritable Bowel Disease (IBD) #FSHP2017 • Chronic inflammation of the digestive tract • Goals of therapy: reduce symptoms (swelling, stiffness, pain), • TNFα = key mediator in dysregulated immune response/inflammatory cascade preserve ROM, improve QOL and prevent systemic complications • Leaky mucosal barriers,  permeability and  epithelial resistance • Disease-modifying Targets • Pro-inflammatory responses mistakenly triggered by commensal bacterial in gut • Epithelial cells may trigger t-cell activation • Anti-inflammatory=  cytokines • Imbalance of effector T-cells and regulatory T-cells • MTX: established use in late 1950’s/early 1960’s • Release of pro-inflammatory cytokines TNF , reactive /nitrogen • Clinical onset 2-3 weeks • Tissue damage/stricture • Cyclophosphamide • Symptoms may include • Biologic response modifiers (Biologics) • Abdominal Pain, (possibly bloody), rectal • Infliximab: anti-TNF • Weight loss ROM=range of motion • Rituximab: B-cell depletion • Painful bowel movements (Ulcerative Colitis) ROM=range of motion; QOL=quality of life. • Mouth ulcers (Crohn’s) Colmegna I, et al. Clin Pharmacol Ther. 2012;91:607–620. Singh JA, et al. Arthritis Care Res (Hoboken) 2016;68:1–25. Saag KG, et al. Arthritis Rheum. 2008;59:762–84. 2017 ANNUAL MEETING Khan KJ, et al. Am J Gastroenterol. 2011; 106:630. 2017 ANNUAL MEETING Smolen JS, et al. Ann Rheum Dis. 2014 Mar;73(3):492-509 Herfarth HH, et al. inflamm Bowel Dis. 2016;22(1):224-233.

IBD: Therapeutic Agents #FSHP2017 #FSHP2017

• Crohn’s Disease: Affects any part of the GI tract (mouth-perianal area) • Most commonly-distal ileum and colon • Ulcerative colitis: Disease activity limited to the colon • Goals of therapy: achieving remissions, maintaining remissions, improving QOL • Disease-modifying Targets • Anti-inflammatory=  cytokines Ensuring Safe and Effective • MTX: established use >20 years • 6-MP Treatment • Biologic response modifiers (Biologics) Behind the scenes-from prescribing-administration-disposal • Infliximab: anti-TNF • Early initiation may improve outcomes/natural course of disease • Steroid-sparing effect

Magro F, et al. Biodrugs. 2010;24(1):3-14. Khan KJ, et al. Am J Gastroenterol 2011; 106:630. 2017 ANNUAL MEETING 2017 ANNUAL MEETING Lichtenstein GR, et al. Gastroenterology 2006; 130:940.

Role of Pharmacy Team #FSHP2017 #FSHP2017 Nursing Tasks: Review of Orders: Chemotherapy or biotherapy 1. Final verification of correct Physician Tasks: patient, route, freq and • Hazardous? Nurse 1. Prescribing of therapy with dose • Safe Handling practices indication for use 2. Patient education 2. Patient education 3. Management of toxicities • Prevention of medication errors 3. Management of toxicities • Look/Sound-Alike medications Physician • Correct formulation • Right Technician Tasks: Patient 1. Preparation of • Correct dose for indication medications (admixture or • Right frequency Pharmacist Tasks: filling PO medication) 1. Verification of therapy Pharmacy 2. Assistance with hazardous  Refill history-too soon, too late? dose/freq/route for indication Technician spills • Laboratory labs assessed (when possible) 2. Preparation of medications 3. Disposal of hazardous (admixture or filling PO med) materials • Drug/Drug-Herbal interactions or disease state histories considered 3. Dispensing of therapy Pharmacist 4. Patient education • Assess for previous or current toxicities 5. Assistance with hazardous spills • Holding/delaying of medication 6. Disposal of hazardous materials 7. Management of toxicities 2017 ANNUAL MEETING 2017 ANNUAL MEETING

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Hazardous Waste: Why You Should Care#FSHP2017 Safe Handling and Disposal of Waste#FSHP2017

• Waste disposed of improperly can contaminate soil, ground water and Do Don’t drinking supply • Inspect all areas for outdated products • Never remove hazardous waste without • Potential to impact wildlife and fish if disposed of improperly near a body of water • Designate a clearly marked area for proper PPE outdated pharmaceuticals/products • Dispose of to a drain or septic tank unless • Includes pharmaceuticals that are: permitted to • Outdated medications not-returnable for credit • Designate separate area to store cytotoxic agents • Place oral cytotoxic agents in automatic • Used in compounding or IV preparations dispensing machines • Follow guidelines for personal protective • Spilled, broken or unusable products equipment (PPE) • Combine hazardous and non-hazardous waste or biomedical waste • Items used to clean up a spill • Gloves (single) should be worn during receiving, unpacking, and placing in • Designated waste bins for specific • Hazardous waste may be ignitable, toxic, corrosive or reactive storage agents • P-listed medications (acutely hazardous): ex. Warfarin, nitroglycerin, • Use one tray to dispense oral cytotoxic • U-listed medications (toxic): ex. Cyclophosphamide, , agents • Minimize risk of contaminating other

Am J Health-Syst Pharm. 2006; 63:1172-93. ASHP guidelines on handling . Am J Health Syst Pharm. 2006;63(12):1172-1191, Protection FDoE, Solid FCf, Management HW. A Guide on Hazardous Waste Management for 2017 ANNUAL MEETING Protection FDoE, Solid FCf, Management HW. A Guide on Hazardous Waste Management for 2017 ANNUAL MEETING Florida's Pharmacies: Florida Department of Environmental Protection; 2006. Florida's Pharmacies: Florida Department of Environmental Protection; 2006.

What Goes Where? #FSHP2017 Patient Education #FSHP2017

Regular Trash: • Skewed perceptions of chemotherapy or biotherapy • EMPTY non-hazardous drug vials, IV bags and • Media, internet or personal/family experience tubing • Hesitant about taking similar agents used to treat cancer • Electrolytes, NS, dextrose or amino acids • Barriers: financial burden, transportation issues, coordination with retail/mail • Sink or toilet if >3% of contents is waste order pharmacies for RX’s

• EMPTY hazardous non-P listed drug (U, D or • Improve patient acceptance and adherence by discussing: NIOSH-listed) vials and IV bags/tubing • Medication administration schedule/timing • Ex. Other chemotherapy, biotherapy • Lower dosages for autoimmune indications Black Bin: • Common side effects and supportive medications • EMPTY or Partial P-listed Hazardous Drugs (i.e • Verbally and in written form arsenic) • Discuss when and how to notify provider if major side effect occurs • Partial non-P listed drugs w/ >3% content and non hazardous drug bag/vials • Providing detailed instructions for safe administration • Chemo spill cleanup • Hazardous medications-avoid skin contact, proper hand washing and Sharps container: storage • EMPTY drug syringes and needles 2017 ANNUAL MEETING 2017 ANNUAL MEETING ASHP guidelines on handling hazardous drugs. Am J Health Syst Pharm. 2006;63(12):1172-1191

#FSHP2017 #FSHP2017 Patient Education Take Home Points • PRO-actively discuss potential $$ for treatment Treatment of autoimmune conditions with traditional chemotherapy and • Send RX ahead of time biotherapy will continue to grow • Social workers and/or financial counselors • AD are a heterogeneous group that effects many different organ • Utilize drug assistance from pharmaceutical companies and/or advocacy systems groups when possible • Assume nothing and look at the whole patient picture • Needy Meds: www.needymeds.org/pap • Newer targeted biotherapies are emerging specifically for autoimmune • Partnership for Prescription Assistance: https://www.pparx.org/ disorders • Pharmaceutical based-assistance programs: https://www.medicare.gov/pharmaceutical-assistance-program/ Specific attention should be made to ensure these patients receive • Crohn’s & colitis foundation: http://www.crohnscolitisfoundation.org/living-with- individualized care and education beyond the oncologic use crohns-colitis/helpful-links.html • Prevent medication errors, unsafe handling practices and misinformation • Arthritis Foundation: http://www.arthritis.org/living-with-arthritis/health- • Encourage patient empowerment care/paying-for-care/drug-specific-patient-assistance-programs.php • Routinely check for ability to afford medication and avoid non-compliance Understanding potential toxicities and management of these agents will allow continued use of these agents in non-oncology settings

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FSHP 2017 ANNUAL MEETING References #FSHP2017 • Magro-Checa C, Zirkzee EJ, Huizinga TW, Steup-Beekman GM. Management of Neuropsychiatric Systemic Lupus Erythematosus: Current Approaches and Future Perspectives. Drugs. 2016;76:459-483. • Cutolo M, Sulli A, Pizzorni C, et al. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Annals of the Rheumatic Diseases. 2001;60:729-735. • Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer JM, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and Chemotherapy Outside the Box: biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012;64: 625–39. • Saag KG, Teng GG, Patkar NM, Anuntiyo J, Finney C, Curtis JR, et al. American College of Rheumatology 2008 Non‐Oncologic Indications For recommendations for the use of nonbiologic and biologic diseasemodifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008;59:762–84 • Smolen JS, Lawdewe R, Breedveld FC, Et al. EULAR recommendations for the management of rheumatoid Chemotherapy arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update.Ann Rheum Dis. 2014 Mar;73(3):492-509. • Braun J, Kästner P, Flaxenberg P, et al. Comparison of the clinical and safety of subcutaneous versus Rebecca Gonzalez, Pharm.D., BCOP oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthritis Rheum. 2008;58(1):73-8 Clinical Pharmacist Blood and Marrow Transplantation • Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2016;68:1–25. Moffitt Cancer Center • Colmegna I, Ohata BR, Menard HA. Current understanding of rheumatoid arthritis therapy. Clin Pharmacol Ther. 2012;91:607–20. • Cyclophosphamide [package insert]. Baxter Healthcare Corporation, Derrfield, IL; May 2013. https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/012141s090,012142s112lbl.pdf. Accessed April 25, 2017. • Methotrexate injection 50 mg/ 2 mL [package insert]. Pfizer Inc., New York, NY; December 2015. https://www.pfizerinjectables.com/sites/default/files/prod/child/uspi/434139.pdf. Accessed April 20, 2017. • Methotrexate injection 1 g/40 mL [package insert]. Pfizer Inc., New York, NY; December 2015. http://labeling.pfizer.com/ShowLabeling.aspx?id=5379. Accessed April 20, 2017.2017 ANNUAL MEETING

References #FSHP2017 References #FSHP2017 • Methotrexate tablets [package insert]. DAVA Pharmaceuticals, Inc., Huntsville, AL; January 2016. • O'Shea JJ, Ma A, Lipsky P. Cytokines and autoimmunity. Nat Rev Immunol. 2002;2:37-45. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/008085s066lbl.pdf. Accessed April 20, 2017. • Chung CH. Managing and the Risk for Reactions to Infusional Monoclonal Antibody Therapy. • Otrexup™ [package insert]. Antares Pharma, Inc., Ewing, NJ; December 2016. The Oncologist 2008;13:725-732 http://www.otrexup.com/files/4014/8909/8025/Otrexup_PII-13-001_Rev_8.pdf. Accessed April 20, 2017. • Maneiro JR, Salgado E, Gomez-Reino JJ. Immunogenicity of Monoclonal Antibodies Against Tumor Necrosis • Rasuvo® [packager insert]. Medac Pharma Inc., Chicago, IL; November 2014. http://www.rasuvo.com/wp- Factor Used in Chronic Immune-Mediated Inflammatory Conditions Systematic Review and Meta-analysis. content/uploads/2016/12/Prescribing-Information-current.pdf. Accessed April 20, 2017. JAMA Intern Med. 2013;173(15):1416-1428 • Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomised, crossover study of oral versus subcutaneous • Chan AC, Carter PJ: Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol. 2010; methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses 10:301-316. ≥15 mg may be overcome with subcutaneous administration. Ann Rheum Dis. 2014;73(8):1549-1551. • Herfarth HH, Kappelman MD, Long MD, Isaacs KL. Use of Methotrexate in the Treatment of Inflammatory Bowel • Patel V, Wang Y, MacDonald JK, et al. Methotrexate for maintenance of remission in Crohn's disease. Diseases. Inflamm Bowel Dis. 2016; 22(1), 224-233. Cochrane Database Syst Rev 2014; :CD006884. • Magro F, Portela F. Management of inflammatory bowel disease with infliximab and other anti-tumor necrosis • Pichlmeier U, Heuer KU. Subcutaneous administration of methotrexate with a prefilled autoinjector pen factor alpha therapies. BioDrugs : clinical immunotherapeutics, and therapy 2010;24 results in a higher relative bioavailability compared with oral administration of methotrexate. Clinical and Suppl 1:3-14 experimental rheumatology 2014;32:563-71. • Remicade® [package insert]. Janssen Biotech, Inc., Horsham, PA; November 2013. • Bianchi G, Caporali R, Todoerti M, Mattana P. Methotrexate and Rheumatoid Arthritis: Current Evidence https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/103772s5359lbl.pdf. Accessed April 25, 2017. Regarding Subcutaneous Versus Oral Routes of Administration. Advances in therapy 2016;33:369-78. • Inflectra™ [package insert]. Hospira, A Pfizer Company, Lake Forest, IL; April 2016. • Purinethol® [package insert]. DSM Pharmaceuticals, Inc., Greenville, NC; August 2003. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125544s000lbl.pdf. Accessed April 25, 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/09053s024lbl.pdf. Accessed April 22, 2017. • Jørgensen KK, Olsen IC, Goll GL, Lorentzen M, et al. Switching from originator infliximab to biosimilar CT-P13 • Purixan™ [package insert]. Rare Disease Therapeutics, Inc., Franklin, TN; April 2014. compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205919s000lbl.pdf. Accessed April 22, 2017. double-blind, non-inferiority trial. Lancet. 2017 May 11. pii: S0140-6736(17)30068-5.[Epub ahead of print] • Khan KJ, Dubinsky MC, Ford AC, et al. Efficacy of immunosuppressive therapy for inflammatory bowel • Rituxan® [package insert]. Genentech, Inc., San Francisco, CA; April 2016. disease: a systematic review and meta-analysis. Am J Gastroenterol 2011; 106:630. https://www.gene.com/download/pdf/rituxan_prescribing.pdf. Accessed April 25, 2017. • Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute technical • US Pharmacopeial Convention. Chapter <800> Hazardous drugs—handling in healthcare settings. In: The review on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. United States Pharmacopeia, 39th rev, and The National Formulary, 34th ed. First Supplement. Rockville, MD: US Gastroenterology 2006; 130:940. Pharmacopeial Convention; 2016. Official from July 1, 2018. • American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health- 2017 ANNUAL MEETING Syst Pharm. 2006; 63:1172-93. 2017 ANNUAL MEETING

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