See Important Reminder at the end of this policy for important regulatory and legal information.

Transcription

1 Clinical Policy: (Rituxan), and Hyaluronidase (Rituxan Hycela) Reference Number: CP.CPA.147 Effective Date: Last Review Date: Line of Business: Commercial Revision Log See Important Reminder at the end of this policy for important regulatory and legal information. Description (Rituxan ) is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. and Hyaluronidase (Rituxan Hycela ) is a combination of rituximab and human hyaluronidase that is used to increase the dispersion and absorption of the co-administered drugs when given subcutaneously. FDA approved indication Rituxan is indicated: For the treatment of Non-Hodgkin`s Lymphoma (NHL): - Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent - Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as single-agent maintenance therapy - Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP (cyclophosphamide, vincristine, prednisone) chemotherapy - Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or other anthracycline-based chemotherapy regimens For the treatment of Chronic Lymphocytic Leukemia (CLL): - In combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL. For the treatment of Rheumatoid Arthritis (RA) - In combination with methotrexate, for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF (tumor necrosis factor) antagonist therapies. For the treatment of Granulomatosis with Polyangiitis (GPA) (Wegener`s Granulomatosis) and Microscopic Polyangiitis (MPA) - In combination with glucocorticoids, for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener`s Granulomatosis) and Microscopic Polyangiitis (MPA). Limitation of use: Rituxan is not recommended for use in patients with severe, active infections Page 1 of 13

2 Rituxan Hycela is indicated: For the treatment of Follicular Lymphoma (FL): - Relapsed or refractory, follicular lymphoma as a single agent. - Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy. - Non-progressing (including stable disease), follicular lymphoma as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. For the treatment of adult patients with previously untreated diffuse large B-cell lymphoma in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens. In combination with fludarabine and cyclophosphamide (FC), for the treatment of adult patients with previously untreated and previously treated CLL. Limitation of use: Initiate treatment with Rituxan Hycela only after patients have received at least one full dose of a rituximab product by intravenous infusion. Rituxan Hycela is not indicated for the treatment of non-malignant conditions. Policy/Criteria Provider must submit documentation (which may include office chart notes and lab results) supporting that member has met all approval criteria It is the policy of health plans affiliated with Centene Corporation that Rituxan is medically necessary when the following criteria are met: I. Initial Approval Criteria A. Non-Hodgkin`s Lymphoma (NHL) (must meet all): 1. Diagnosis of Non-Hodgkin`s Lymphoma (NHL); 2. Dose does not exceed 375 mg/m 2 IV infusion; 1,400 mg/23,400 Units SC. B. Chronic Lymphocytic Leukemia (CLL) (must meet all): 1. Diagnosis of Chronic Lymphocytic Leukemia (CLL); 2. Dose does not exceed 500 mg/m 2 IV infusion; 1,600 mg/26,800 Units SC. C. Rheumatoid Arthritis (RA) (must meet all): 1. Diagnosis of Rheumatoid Arthritis (RA); 2. Request is for Rituxan; Page 2 of 13

3 3. Prescribed by or in consultation with a Rheumatologist OR defined at baseline prior to disease modifying anti-rheumatic drug (DMARD) treatment initiation by the ACR (American College of Rheumatology) criteria (refer to General Information for ACR criteria); 4. One of the following (a or b): a. Being used in in combination with methotrexate (MTX); b. One of the following (i or ii): i. Failure of maximally tolerated doses of MTX in the last year for patients who are new to biologics, unless clinically significant adverse effects are experienced; ii. If patient is not a candidate for MTX (i.e. patient is a smoker [increased risk of MTX lung disease] or MTX is contraindicated, then failure or clinically significant adverse effects to sulfasalazine or 1 other DMARD; 5. Failure to a 3-month minimum trial of Humira AND either, Remicade or Simponi, unless all are contraindicated or clinically significant adverse effects are experienced; 6. Dose does not exceed 1000 mg IV infusion every two weeks. Two infusions D. Granulomatosis with Polyangiitis (GPA) (Wegener`s Granulomatosis) and Microscopic Polyangiitis (MPA) (must meet all): 1. Diagnosis of Granulomatosis with Polyangiitis (GPA) (Wegener`s Granulomatosis) or Microscopic Polyangiitis (MPA); 2. Request is for Rituxan; 3. Prescribed in combination with a glucocorticoid (e.g., prednisone, prednisolone, dexamethasone); 4. Dose does not exceed 375 mg/m 2 IV infusion weekly. E. Antibody-Mediated Rejection (aka acute humoral rejection) in Renal Transplants (off-label) (must meet all): 1. Request is for Rituxan; 2. Failure to plasmapharesis and IVIG (IV Immune globulin), unless clinically significant adverse effects are experienced; 3. Prescribed in combination with plasmapheresis and IVIG; 4. Dose does not exceed 375mg/m 2 IV infusion (single infusion) F. Mantle Cell Lymphoma (off-label) (must meet all): 1. Diagnosis of mantle cell lymphoma; Page 3 of 13

4 2. As first line induction therapy, prescribed in combination with an anthracycline-based regimens (e.g., CHOP, hypercvad [cyclophosphamide, vincristine, doxorubicin and dexamethasone], and others); 3. Dose does not exceed 375 mg/m 2 IV infusion every 3 weeks; 1,400 mg/23,400 Units SC. G. Waldenstrom Macroglobulinemia (off-label) (must meet all): 1. Diagnosis of waldenstrom macroglobulinemia; 2. Prescribed as monotherapy or in combination with other agents (e.g.,velcade, cyclophosphamide, dexamethasone) 3. Dose does not exceed 375 mg/m 2 IV infusion monthly; 1,400 mg/23,400 Units SC. H. Focal Segmental Glomerulosclerosis (FSGS) (off-label) (must meet all): 1. Diagnosis of focal segmental glomerulosclerosis (FSGS); 2. Request is for Rituxan; 3. Failure of maximally tolerated doses of corticosteroids unless contraindicated or clinically significant adverse effects are experienced; 4. Failure of maximally tolerated doses of cyclosporine or tacrolimus unless contraindicated or clinically significant adverse effects are experienced; 5. Dose does not exceed 375mg/m 2 IV infusion (single infusion). I. Other diagnoses/indications 1. Refer to CP.CPA.09 if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) II. Continued Therapy A. Rheumatoid Arthritis (RA) (must meet all): 1. Currently receiving medication via a health plan affiliated with Centene Corporation or member has previously met initial approval criteria; 1. Documentation of positive response to therapy (e.g. reduction in ESR, CRP, reduction in duration of morning stiffness and/or number of swollen/painful joints); 2. At least 16 weeks since previous course of Rituxan therapy; 3. Dose does not exceed 1000 mg IV infusion every two weeks. 6 months or renewal period, whichever is longer B. All Other Indications in Section I (must meet all): Page 4 of 13

5 1. Currently receiving medication via a health plan affiliated with Centene Corporation or member has previously met initial approval criteria; 2. Documentation of positive response to therapy; 3. Dose does not exceed the maximum recommended dose for the relevant indication (as stated in Section I, Initial Approval Criteria). C. Other diagnoses/indications (must meet 1 or 2): 1. Currently receiving medication via a health plan affiliated with Centene Corporation and documentation supports positive response to therapy. Duration of request or 12 months (whichever is less); or 2. Refer to CP.CPA.09 if diagnosis is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) III. Diagnoses/Indications for which coverage is NOT authorized: A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policy CP.CPA.09 or evidence of coverage documents IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key NHL: Non-Hodgkin`s Lymphoma CLL: Chronic Lymphocytic Leukemia RA: Rheumatoid Arthritis GPA: Granulomatosis with Polyangiitis MPA: Microscopic Polyangiitis FSGS: Focal segmental glomerulosclerosis FL: Follicular lymphoma Appendix B: General Information: The 2010 ACR/European League Against Rheumatism classification criteria for RA (score-based algorithm: add score of categories A D; a score of >/= 6/10 is needed for classification of a patient as having definite RA). A. Joint involvement (swollen or tender) 1 large joint, score = large joints, score = small joints (with or without involvement of large joints), score = small joints (with or without involvement of large joints), score = 3 >10 joints (at least 1 small joint), score = 5 B. Serology (at least 1 test result is needed for classification) Negative RF (rheumatoid factor) and negative ACPA (anti-citrullinated protein antibody), score = 0 Low-positive RF or low-positive ACPA, score = 2 High-positive RF or high-positive ACPA, score = 3 Page 5 of 13

6 C. Acute-phase reactants (at least 1 test result is needed for classification) Normal CRP (C-reactive protein) and normal ESR (erythrocyte sedimentation rate), score = 0 Abnormal CRP or abnormal ESR, score = 1 D. Duration of symptoms < 6 weeks, score = 0 >/= 6 weeks, score = 1 In the pivitol trial for Rituxan use in RA (REFLEX trial), all patients had an inadequate response to anti-tnf therapies and MTX. These patients had active disease which was defined as 8 or more swollen joints, 8 or more tender joints, a C reactive protein level of 1.5 mg/dl or more or an erythrocyte sedimentation rate of 28 mm/hr or more, and radiographic evidence of at least 1 joint with definite erosion attributable to RA. Black Box warnings include fatal infusion reactions, severe mucocutaneous reactions (some with fatal reactions), Hepatitis B virus reactivation, and Progressive Multifocal Leukoencephalopathy (PML). In Antibody-Mediated Rejections (AMR) of renal transplants, removal of antibodies with plasmapheresis or immunoadsorption in combination with neutralizing and immunomodulatory intravenous immunoglobulin are therapy standards in the majority of transplant centers worldwide. The addition of rituximab with the aim to reduce the number of B-cells may offer advantage in some cases. The use of Rituxan in Mantle cell lymphoma has a NCCN Drugs and Biologics Compendium rating of 2A and a Micromedex strength of recommendation of Class I The use of Rituxan in Waldenstrom macroglobulinemia has a NCCN Drugs and Biologics Compendium rating of 2A and a Micromedex strength of recommendation of Clas IIa. In a study by Ruggenenti P, et al. evaluated the effects of Rituxan followed by immunosuppression withdrawal on disease recurrence in children and adults with minimal change disease /mesangial proliferative glomerulonephritis or FSGS who had suffered greater than or equal to 2 recurrences over the previous year and were in steroid induced remission for greater than or equal to 1 month. Participants received one dose or two doses of Rituxan (375 mg/m^2 intravenously). At one year, all patients were in remission: 18 were treatment-free and 15 never relapsed. In a study by Gulati A, et al. Thirty-three patients with steroid-resistant nephrotic syndrome (SRNS) with mean age of 12.7 SD (9.1) and 24 with steroid-dependent nephrotic syndrome (SDNS) with a mean age of 11.7 SD (2.9) years were included. Six months after Rituxan therapy, 9 (27.2%) patients with SRNS showed complete remission, 7 (21.2%) had partial remission and 17 (51.5%) had no response. At 21.5 SD (11.5) months, remission was sustained in 15 patients. Of 24 patients with SDNS, remission was sustained in 20 (83.3%) at 12 months and in 17 (71%) at follow-up of 16.8 SD (5.9) months. The mean difference in relapses before and 12 months after treatment with Rituxan was 3.9 episodes/patient per year. All patients must first receive at least one full dose of a rituximab product by intravenous infusion without experiencing severe adverse reactions before starting treatment with Rituxan Hycela. If patients are not able to receive one full dose by intravenous infusion, they should continue subsequent cycles with a rituximab Page 6 of 13

7 product by intravenous infusion and not switch to Rituxan Hycela until a full intravenous dose is successfully administered. Appendix C: Therapeutic Alternatives Drug Dosing Regimen Dose Limit/Maximum Dose azathioprine Rheumatoid Arthritis 2.5 mg/kg/day (Imuran ) 1 mg/kg/day PO given QD or BID Cimzia Rheumatoid Arthritis 400 mg/dose (certolizumab pegol)* 400 mg SC initially and at Weeks 2 and 4. Maintenance dose: 200 mg SC every other week or 400 mg SC every 4 weeks Enbrel Rheumatoid Arthritis 100 mg/week (etanercept)* 50 mg SC once weekly Humira Rheumatoid Arthritis 40 mg/week (adalimumab)* 40 mg SC QOW hydroxychloroquine Rheumatoid Arthritis 600 mg/day (Plaquenil ) Initial dose: mg/day PO Maintenance dose: mg/day PO methotrexate Rheumatoid Arthritis 30 mg/week (Rheumatrex ) 7.5 mg/week PO or 2.5 mg PO Q12 hr for 3 doses/week Orencia (abatacept)* Rheumatoid Arthritis For IV infusion: mg (weight based dosing) every 2 weeks for 3 doses, then every 4 weeks thereafter.. For IV use: 1000 mg/dose For SC use: 125 mg/dose For SC administration: May be used with or without an IV loading dose. If IV loading dose is used, follow with the first 125 mg SC injection within a day of the IV infusion. Thereafter, 125 mg SC once a week. Remicade Rheumatoid Arthritis 10 mg/kg/dose (infliximab)* 3 mg/kg IV initially and at weeks 2 and 6, then every 8 weeks. Should be given in combination with methotrexate. For incomplete response dosing adjustments up to 10 mg/kg or treating every 4 weeks can be considered. Simponi Rheumatoid Arthritis 50 mg/dose (golilumab)* 50 mg SC once a month sulfasalazine (Azulfidine ) Rheumatoid Arthritis 2 gm/day PO in divided doses 3 gm/day Therapeutic alternatives are listed as Brand name (generic) when the drug is available by brand name only and generic (Brand name ) when the drug is available by both brand and generic. *Requires prior authorization. Page 7 of 13

8 V. Dosage and Administration Rituxan Indication Dosing Regimen Maximum Dose Non-Hodgkin`s Lymphoma (NHL) 375 mg/m 2 IV infusion according to the following schedules: *Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL: administer once weekly for 4 or 8 doses *Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL: administer once weekly for 4 doses. *Previously Untreated, Follicular, CD20- Positive, B-cell NHL: administer on Day 1 of each cycle of chemotherapy, for up to 8 doses; In patients with complete or partial response, initiate Rituxan maintenance eight weeks following completion of Rituxan in combination with chemotherapy. Administer Rituxan as a single-agent every 8 weeks for 12 doses. *Non-progressing, Low-Grade, CD20- Positive, B-cell NHL, after first-line CVP [cyclophosphamide, vincristine, prednisone] chemotherapy: following completion of 6-8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses *Diffuse Large B-Cell NHL: administer on Day 1 of each cycle of chemotherapy for up to 8 doses total 375 mg/m 2 IV infusion according to the above schedules Chronic Lymphocytic Leukemia (CLL) Doses may vary for chemotherapy regimens and are based on patient body surface area. Refer to oncology literature. 375 mg/m 2 IV infusion on day 0 of the first cycle of chemotherapy with fludarabine and cyclophosphamide 500 mg/m 2 per day Page 8 of 13

9 chemotherapy, then 500 mg/m2 on Day 1 of cycles 2-6 (every 28 days) Rheumatoid Arthritis (RA) Two-1000 mg IV infusions separated by 2 weeks (i.e. day 1 and day 15). Rituxan is used in combination with methotrexate. Granulomatosis with Polyangiitis (GPA) (Wegener`s Granulomatosis) and Microscopic Polyangiitis (MPA) Antibody-Mediated Rejection (aka acute humoral rejection) in renal transplants (off-label) Mantle cell lymphoma (off-label) Waldenstrom macroglobulinemia (offlabel) Focal segmental glomerulosclerosis (FSGS) (off-label) 375 mg/m 2 IV once weekly for 4 weeks in combination with a glucocorticoid 375mg/m 2 IV as a single dose. Some studies used weekly doses for 2-5 weeks 375 mg/m 2 IV on day 0 in combination with an anthracycline containing regimen (e.g. CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone]. Repeat every 3 weeks for 6 cycles. 375 mg/m 2 IV on day 1 every month for 4 cycles either alone or in combination with other agents. 375mg/m 2 IV as a single dose. Some studies used weekly doses for 4-5 weeks 1000 mg per week 375 mg/m 2 per week 375 mg/m mg/m 2 every 3 weeks 375 mg/m 2 per month 375 mg/m 2 Rituxan Hycela Indication Dosing Regimen Maximum Dose Follicular Lymphoma (FL) First dose must be with IV rituximab. 1,400 mg/23,400 Units SC 1,400 mg rituximab and 23,400 Units hyaluronidase SC according to the following schedules: Relapsed or Refractory, Follicular Lymphoma: once weekly for 3 or 7 weeks (i.e., 4 or 8 weeks in total) Retreatment for Relapsed or Refractory, Follicular Lymphoma: once weekly for 3 weeks (i.e., 4 weeks in total). Page 9 of 13

10 Diffuse Large B-Cell Lymphoma (DLBCL) Chronic Lymphocytic Leukemia (CLL) Previously Untreated, Follicular Lymphoma: Administer on Day 1 of Cycles 2 8 of chemotherapy (every 21 days), for up to 7 cycles (i.e., up to 8 cycles in total). In patients with complete or partial response, initiate maintenance treatment 8 weeks following completion of Rituxan Hycela in combination with chemotherapy. Administer as a singleagent every 8 weeks for 12 doses. Non-progressing, Follicular Lymphoma after first line CVP chemotherapy: Following completion of 6 8 cycles of CVP chemotherapy and a full dose of a rituximab product by intravenous infusion at week 1, administer once weekly for 3 weeks (i.e., 4 weeks in total) at 6 month intervals to a maximum of 16 doses. First dose must be with IV rituximab. 1,400 mg rituximab and 23,400 Units hyaluronidase SC on Day 1 of Cycles 2 8 of CHOP chemotherapy for up to 7 cycles (i.e., up to 6 8 cycles in total) First dose must be with IV rituximab. 1,600 mg/26,800 Units on Day 1 of Cycles 2 6 (every 28 days) for a total of 5 cycles (i.e., 6 cycles in total) 1,400 mg/23,400 Units SC 1,600 mg/26,800 Units SC VI. Product Availability Drug Rituxan Rituxan Hycela Availability Single use vial: 100 mg/10 ml and 500 mg/50 ml Single-dose vial: rituxan/hyaluronidase 1,400 mg/23,400 Units in 11.7 ml, 1,600 mg/26,800 Units in 13.4 ml VII. References 1. Rituxan [Prescribing Information]. South San Francisco, CA: Genentech Inc.; August Available at Accessed January 7, Rituxan Hycela [Prescribing Information]. South San Francisco, CA: Genentech Inc.; June American Hospital Formulary Service Drug Information. Available at: Accessed January 29, Page 10 of 13

11 4. Micromedex Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed January 13, Clinical Pharmacology Web site. Available at: Accessed January 13, National Comprehensive Cancer Network Drugs and Biologics Compendium. Available at: Accessed January 18, Aletaha D, Neogi T, Silman AJ, et al Rheumatoid Arthritis Classification Criteria. Arthritis Rheum 2010;62(9): Singh JA, Furst DE, Bharat A, et al Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012;64(5): Cohen SB, Emery P, Greenwald MW, et al. for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Arthritis Rheum 2006;54: Keystone E, Fleischmann R, Emery P, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis. Arthritis Rheum 2007;56: Blume OR, Yost SE, and Kaplan B. Antibody-mediated rejection: pathogenesis, prevention, treatment, and outcomes. J Transplant 2012;2012: Jordan SC, Reinsmoen N, Peng A, et al. Advances in diagnosing and managing antibodymediated rejection. Pediatr Nephrol 2010;25: Putarajappa C, Shapiro R, Tan HP. Antibody-mediated rejection in kidney transplantation: a review. J Transplant 2012; 2012: Cravedi P, Ruggenenti P, SghirlanzoniMC, Remuzzi G: Titrating rituximab to circulating B-cells to optimize lymphocytolytic therapy in idiopathic membranous nephropathy. Clin J Am Soc Nephrol 2007:2; Ruggenenti P, Ruggiero B, Cravedi P, et al. in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. J Am Soc Nephrol 2014;25: Gulati A, Sinha A, Jordan SC, et al. Efficacy and safety of treatment with rituximab for difficult steroid-resistant and -dependent nephrotic syndrome: multicentric report. Clin J Am Soc Nephrol. 2010;5: Reviews, Revisions, and Approvals Date P&T Approval Date Converted to new template. Minor changes to verbiage and grammar. References updated. Added Rituxan Hycela to criteria Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in Page 11 of 13

12 developing this clinical policy. This clinical policy is consistent with standards of medical practice current at the time that this clinical policy was approved. Health Plan means a health plan that has adopted this clinical policy and that is operated or administered, in whole or in part, by Centene Management Company, LLC, or any of such health plan s affiliates, as applicable. The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures. This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time. This clinical policy does not constitute medical advice, medical treatment or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care, and are solely responsible for the medical advice and treatment of members. This clinical policy is not intended to recommend treatment for members. Members should consult with their treating physician in connection with diagnosis and treatment decisions. Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan. This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, members and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, members and their representatives agree to be bound by such terms and conditions by providing services to members and/or submitting claims for payment for such services Centene Corporation. All rights reserved. All materials are exclusively owned by Centene Corporation and are protected by United States copyright law and international copyright law. No part of this publication may be reproduced, copied, modified, distributed, displayed, stored in a retrieval system, transmitted in any form or by any means, or otherwise published without the prior written permission of Centene Corporation. You may not alter or remove any trademark, copyright or other notice contained herein. Centene and Centene Corporation are registered trademarks exclusively owned by Centene Corporation. Page 12 of 13

13 Page 13 of 13