7/17/2017 FSHP 2017 ANNUAL MEETING Disclosure #FSHP2017 The speaker of this presentation has the following disclosure: Name Company Role Chemotherapy 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 Blood and Marrow Transplantation Moffitt Cancer 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-oncology settings oncology settings 3. Review common toxicities 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 diseases result from the Historic treatment New treatment immune system attack on its own cells, tissue and organs • Loss of regulation and differentiation of immune cells • Steroids • Chemotherapy • Irregular function and production cytokines • Production of autoantibodies • Analgesics • 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 Disease: 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 1 7/17/2017 #FSHP2017 Re-establishing the Balance in Autoimmunity IL-17 Th Roles: Th Roles: INF-γ 1 17 Th1 • Cell-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 • Antibody-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 Cyclophosphamide: Overview #FSHP2017 • Suppression of the immune system Introduced in 1959 as the 8th anti-cancer therapy • Inhibition of cell growth and apoptosis • Reduction in pro-inflammatory cytokines • Nitrogen Mustard: Alkylating agent • Macrophages/lymphocytes (IL-2, TNF and interferon-γ) • Cell-Cycle Non-Specific • Cross-links DNA strands Classification Chemotherapy Agents • Reduces DNA replication and RNA transcription Alkylating Agents Cyclophosphamide • Immunosuppressant/immunomodulatory: DMARD • Reduces B and T-Lymphocytes • unwanted Th immune responses MTX 1 Antimetabolites 6-MP MTX, methotrexate; 6-MP, 6-Mercaptopurine; IL-2, interleukin-2 TNF=tumor-necrosis factor; IFN-γ, interferon gamma 2017 ANNUAL MEETING DMARD=Disease-modifying antirhuematic drug; 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 malignancies: HL, NHL, MM, AML, CML • Storage: room temperature • Solid tumors: Breast, Ovarian, Lung cancer Absorption Bioavailability: 75% Metabolism CYP-P450: Prodrug Acrolein, phosphoramide mustard • 2B6 Activation • Off label indications: • 3A4 Inactivation • SLE, Rheumatoid vasculitis Administration RA: 1.5-3mg/kg PO Daily • Scleroderma, MS SLE: • 1-3mg/kg/day PO + corticosteroids • HCT conditioning/GVHD • 500-1000mg/m2 IV Qmonthy x 6 doses (severe) • ITP/TTP Lupus nephritis: • 500mg IV Q2 weeks x 6 doses • 500-1000mg/m2 IV Qmonthy x 6 doses SLE, systemic lupus erythematosus; HL, Hodgkin’s lymphoma; NHL, non-hodgkin’s lymphoma; MM, multiple myeloma; MS, multiple sclerosis; GVHD, graft-versus-host-disease; ITP, idiopathic thrombocytopenic purpura,; TTP, thrombotic thrombocytopenic purpura; AML, acute RA=Rheumatoid Arthritis; SLE=Systemic Lupus Erythematosus myelogenous leukemia; CML, Chronic Myelogenous Leukemia; HCT, hematopoietic cell transplantation2017 ANNUAL MEETING Magro-Checa C, et al. Drugs. 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. 2 7/17/2017 Cyclophosphamide #FSHP2017 Clinical Considerations #FSHP2017 Adverse Effects (AE’s) Bone and immune suppression (Dose-limiting) Hemorrhagic cystitis (higher dose > 50-60mg/kg) Pearls Monitoring Nausea/Vomiting ( 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 Pregnancy 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: Bilirubin 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=complete blood count 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 leukemias, lymphomas, lung, head/neck • Targets thymidylate biosynthesis inhibiting dihydrofolate and breast cancer reductase • RA, psoriasis • Depletes purine and pyrimidine 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]. Pfizer 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 bone marrow 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: Stomatitis, N/V/D • Dosage administration range 7.5mg-30mg @ 2.5mg increments Myelosuppresion, Hepatic fibrosis/cirrhosis (transaminitis), Rash, Headache Absorption PO: Bioavailability = 60% at dose <30mg/m2 Contraindications Black Box Warning: Impaired drug elimination with pleural effusions,