Iron Chelating Agents - BMC HealthNet Plan

congestive heart failure, endocrinopathies, hepatic fibrosis and death. Iron chelatingtherapies are used to reduce iron levels or reverse the aforementioned toxicities of irondeposition in patients with conditions associated with iron overload. Such conditionsinclude sickle-cell anemia, thallassemia and myelodysplastic syndromes. There arecurrently three iron chelators available – deferoxamine (Desferal ® ), deferasirox(Exjade ® ), and deferiprone (Ferriprox ® ).Deferoxamine is indicated for the treatment of chronic iron overload secondary to bloodtransfusions. It is administered parenterally as a continuous intravenous or subcutaneousinfusion due to its poor oral absorption and short half-life. Use of deferoxamine is limitedby the burden and pain associated with infusions which adversely affect adherence. Sideeffectsinclude ocular and audiological toxicity as well as Yesinia & klebsiella spinfections.Exjade ® (deferasirox) is an oral iron chelating agent that is indicated for the treatment ofchronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients2 years of age and older and to treat patients aged 10 years and older who have chroniciron overload resulting from a genetic blood disorder called non-transfusion-dependentthalassemia (NTDT). Exjade ® carries a black box warning related to the risk of causingrenal impairment and failure, hepatic impairment and failure, and GI hemorrhage. Thisrequires close monitoring of serum creatinine/creatinine clearance, serum transaminasesand bilirubin. To minimize adverse effects, the recommendation is to interruptdeferasirox therapy when serum ferritin is consistently below 500mcg/L.Ferriprox ® (deferiprone) is another oral iron chelating agent indicated for the treatment ofpatients with transfusional iron overload due to thalassemia syndromes when currentchelation therapy is inadequate. The safety and effectiveness have not been establishedfor the treatment of transfusional iron overload in patients with other chronic anemias.It carries a black box warning regarding the risk of agranulocytosis/neutropenia that canlead to serious infections and death. Therefore measurement of absolute neutrophil count(ANC) prior to initiating therapy and weekly thereafter is recommended. Therapy shouldbe interrupted if neutropenia or infections develops.Choice of chelating therapy should be individualized based on tolerability, safety profile,ease of use, adherence, and trends of organ-specific iron loading. There is clinicalevidence showing efficacy of a combination of deferiprone and deferoxamine inimproving cardiac function in patients with cardiac iron burden. Safety and efficacy ofother combination chelator therapy regimen have not been extensively studied.This guideline provides information on BMC HealthNet Plan clinical criteria and claims adjudication processing guidelines. Theuse of this guideline is not a guarantee of payment and will not determine how a specific claim(s) will be paid. Reimbursement isbased on member benefits and eligibility, medical necessity review, where applicable, coordination of benefits, adherence to Planpolicies, clinical coding criteria, and the BMC HealthNet Plan agreement with the rendering or dispensing provider.Reimbursement policies may be amended at BMC HealthNet Plan’s discretion. BMC HealthNet Plan will always use the mostrecent CPT and HCPCS coding guidelines. All Plan policies are developed in accordance with state, federal and accreditingorganization guidelines and requirements, including NCQA.This document is subject to further revision in response to additional terms and requirements imposed under the Integrated CareProgram, including the ICP contract.BMCHP refers to Boston Medical Center HealthNet Plan in Massachusetts and Well Sense Health Plan in New Hampshire.Boston Medical Center HealthNet Plan and Well Sense Health Plan are trade names used by Boston Medical Center Health Plan,Inc.BMC HealthNet Plan – Iron Chelating Agents2 of 6

Table of contents1 INTRODUCTION......................................................................................................................11.1 BACKGROUND ................................................................................................................................................... 11.2 MEMBRANE DESIGN ............................................................................................................................................ 12 SAMPLE PROCESS FLOW ......................................................................................................42.1 SURFACE MICRO-MACHINED CIRCULAR MEMBRANE DESIGN.......................................................................... 43 THERMO ELECTRO MECHANICAL (TEM) ANALYSIS.....................................................73.1 EXPORTING TO THE TEM MODULE.................................................................................................................. 73.2 MANIPULATING YOUR VIEW SETTINGS............................................................................................................. 83.3 MESH REFINEMENT.............................................................................................................................................. 93.4 MATERIAL PROPERTIES, LOADS AND BOUNDARY CONDITIONS .................................................................103.4.1 Material properties .................................................................................................................................................103.4.2 Boundary conditions................................................................................................................................................123.4.3 Loads...........................................................................................................................................................................133.5 NATURAL FREQUENCY ANALYSIS....................................................................................................................133.6 STATIC BEHAVIOR.............................................................................................................................................153.6.1 Static Stress Analysis with Residual stress effects...........................................................................................153.6.2 Incorporating stress gradient effects into the model......................................................................................183.6.3 Capacitance vs. Pressure curve............................................................................................................................203.6.4 Capacitance vs. Voltage effects ...........................................................................................................................283.6.5 Pull-in and membrane collapse............................................................................................................................303.6.6 Overpressure effects (stress effects) ..................................................................................................................363.7 DYNAMIC BEHAVIOR........................................................................................................................................393.7.1 Settling time to a step response..........................................................................................................................393.7.2 Frequency/Spectrum response.............................................................................................................................423.8 SYSTEM MODEL EXTRACTION..........................................................................................................................463.8.1 Dominant and relevant modes ............................................................................................................................483.8.2 Strain energy capture .............................................................................................................................................503.8.3 Electrostatic energy calculations..........................................................................................................................543.8.4 Exporting the system model .................................................................................................................................553.9 SIMULATING YOUR MACROMODEL IN SYNPLE............................................................................................563.9.1 Wiring your circuit...................................................................................................................................................563.9.2 Transient Force vs. displacement simulation....................................................................................................653.9.3 Compatibility with system modeling tools: PSpice and SIMetrix.................................................................703.9.3.1 Result Comparison of SYNPLE, PSpice and SIMetrix ....................................................................................704 SYSTEM LEVEL MODELING.................................................................................................784.1 SYSTEM LEVEL SIMULATION..............................................................................................................................784.1.1 High level readout circuitry...................................................................................................................................784.1.2 Transistor level design ............................................................................................................................................865 CONCLUSION.........................................................................................................................935.1 REVIEW OF CONCEPTS.....................................................................................................................................935.2 PUTTING IT ALL TOGETHER.............................................................................................................................935.3 SUMMARY..........................................................................................................................................................93

(demonstrated by at least 2 lab values in the previous 3 months);AND4. An absolute neutrophil count (ANC) >1.5 x 10 9 /L; AND5. The prescriber is a hematologist or oncologist.Continuation of TherapyExjade ® Documentation of the following:1. For chronic transfusional iron overload due to blood transfusions:Clinical response to treatment and continues to require therapy forserum ferritin level consistently >500mcg/L (demonstrated by atleast 2 lab values in the previous 3 months); OR2. For non-transfusion-dependent thalassemia (NTDT):Clinical response to treatment. (demonstrated by decreased liveriron levels in the previous 6 months compared to baseline but noless than 3mg/g, and serum ferritin level no less than 300mcg/Lwithin last month)Ferriprox ®Documentation of the following:1. Clinical response to treatment and continues to require therapy forserum ferritin level consistently >500mcg/L (demonstrated by atleast 2 lab values in the previous 3 months); AND2. An absolute neutrophil count (ANC) >1.5 x 10 9 /LLimitations:BMC HealthNet Plan will not approve coverage of Exjade ® , Ferriprox ® in the followinginstances:1. When the criteria above are not met.This guideline provides information on BMC HealthNet Plan clinical criteria and claims adjudication processing guidelines. Theuse of this guideline is not a guarantee of payment and will not determine how a specific claim(s) will be paid. Reimbursement isbased on member benefits and eligibility, medical necessity review, where applicable, coordination of benefits, adherence to Planpolicies, clinical coding criteria, and the BMC HealthNet Plan agreement with the rendering or dispensing provider.Reimbursement policies may be amended at BMC HealthNet Plan’s discretion. BMC HealthNet Plan will always use the mostrecent CPT and HCPCS coding guidelines. All Plan policies are developed in accordance with state, federal and accreditingorganization guidelines and requirements, including NCQA.This document is subject to further revision in response to additional terms and requirements imposed under the Integrated CareProgram, including the ICP contract.BMCHP refers to Boston Medical Center HealthNet Plan in Massachusetts and Well Sense Health Plan in New Hampshire.Boston Medical Center HealthNet Plan and Well Sense Health Plan are trade names used by Boston Medical Center Health Plan,Inc.BMC HealthNet Plan – Iron Chelating Agents4 of 6

Clinical Background Information and References:1. Product Information. Exjade ® , deferasirox. Novartis PharmaceuticalsCorporation. East Hanover, New Jersey 07936. January 2013.2. Schrier, S, Bacon, B. Chelation therapy for iron overload states. UptoDate ®Accessed 2013 Feb; available from http://uptodate.com3. Kwiatkowski JL. Management of transfusional iron overload – differentialproperties and efficacy of iron chelating agents. Journal of Blood Medicine2011:2 135-149Policy History:Effective Date: 07/13/2006Date of Review/Revision03/13/2008 – P&T annual review, title changed from, “Oral Iron Chelating Agents” to“Exjade ® ”03/12/2009 – P&T annual review, no changes required.03/11/2010 – P&T annual review, no changes required03/10/2011 – P&T annual review, specified timeframe for lab values for initial therapyand added continuation of therapy criteria.07/14/2011 – policy applied to Commercial03/08/2012 – P&T annual review, added criteria for Ferriprox ® , modified continuation oftherapy criteria, title changed to “Iron Chelating Agents”Last Review Date: 03/14/2013 – P&T annual review, added initial and continuation oftherapy criteria for Exjade ® for treating non-transfusion-dependent thalassemiaNext Review Date: 03/13/2014Approval DatesRegulatory Approval: N/AInternal Approval:Initial approval by Pharmacy & Therapeutics Committee – July 13, 2006Authorizing entityThis guideline provides information on BMC HealthNet Plan clinical criteria and claims adjudication processing guidelines. Theuse of this guideline is not a guarantee of payment and will not determine how a specific claim(s) will be paid. Reimbursement isbased on member benefits and eligibility, medical necessity review, where applicable, coordination of benefits, adherence to Planpolicies, clinical coding criteria, and the BMC HealthNet Plan agreement with the rendering or dispensing provider.Reimbursement policies may be amended at BMC HealthNet Plan’s discretion. BMC HealthNet Plan will always use the mostrecent CPT and HCPCS coding guidelines. All Plan policies are developed in accordance with state, federal and accreditingorganization guidelines and requirements, including NCQA.This document is subject to further revision in response to additional terms and requirements imposed under the Integrated CareProgram, including the ICP contract.BMCHP refers to Boston Medical Center HealthNet Plan in Massachusetts and Well Sense Health Plan in New Hampshire.Boston Medical Center HealthNet Plan and Well Sense Health Plan are trade names used by Boston Medical Center Health Plan,Inc.BMC HealthNet Plan – Iron Chelating Agents5 of 6

IMPORTANT NOTE:‣ Not all services are covered for all products or employer groups. This medical policyexpresses the Plan's determination of whether certain services or supplies are medicallynecessary, experimental or investigational or cosmetic. The Plan has reached theseconclusions based upon the regulatory status of the technology and a review of clinicalstudies published in peer-reviewed medical literature. Even though this policy mayindicate that a particular service or supply is considered covered or not covered, thisconclusion is not based upon the terms of a member’s particular benefit plan. Eachbenefit plan contains its own specific provisions for coverage and exclusions. Not allservices that are determined to be medically necessary will necessarily be coveredservices under the terms of a member’s benefit plan. Members and their providers needto consult the applicable benefit plan document (e.g., Evidence of Coverage) todetermine if there are any exclusions or other benefit limitations applicable to this serviceor supply. If there is a discrepancy between this medical policy and the benefit plandocument, the provisions of the benefit plan document will govern. In addition, this policyand the benefit plan document are subject to applicable state and federal laws that maymandate coverage for certain services and supplies.‣ To the extent applicable, this Policy and/or Procedure applies to BMCHP subcontractorsand downstream entities, if any, providing services with respect to BMCHP’s IntegratedCare Program.This guideline provides information on BMC HealthNet Plan clinical criteria and claims adjudication processing guidelines. Theuse of this guideline is not a guarantee of payment and will not determine how a specific claim(s) will be paid. Reimbursement isbased on member benefits and eligibility, medical necessity review, where applicable, coordination of benefits, adherence to Planpolicies, clinical coding criteria, and the BMC HealthNet Plan agreement with the rendering or dispensing provider.Reimbursement policies may be amended at BMC HealthNet Plan’s discretion. BMC HealthNet Plan will always use the mostrecent CPT and HCPCS coding guidelines. All Plan policies are developed in accordance with state, federal and accreditingorganization guidelines and requirements, including NCQA.This document is subject to further revision in response to additional terms and requirements imposed under the Integrated CareProgram, including the ICP contract.BMCHP refers to Boston Medical Center HealthNet Plan in Massachusetts and Well Sense Health Plan in New Hampshire.Boston Medical Center HealthNet Plan and Well Sense Health Plan are trade names used by Boston Medical Center Health Plan,Inc.BMC HealthNet Plan – Iron Chelating Agents6 of 6