BENZNIDAZOLE, Benznidazole Form

Benznidazole is a nitroimidazole antimicrobial. FDA Approved Indication(s) Benznidazole is indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis), caused by Trypanosoma cruzi (T. cruzi). This indication is approved under accelerated approval based on the number of treated patients who became Immunoglobulin G (IgG) antibody negative against the recombinant antigens of T. cruzi. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Policy/Criteria Provider must submit documentation (including such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria.
It is the policy of health plans affiliated with Centene Corporation® that benznidazole is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Chagas Disease (must meet all):

1. Diagnosis of Chagas disease confirmed by one of the following (a, b, or c) (see Appendix D): a. Detection of circulating T. cruzi trypomastigotes on microscopy; b. Detection of T. cruzi DNA by polymerase chain reaction assay; c. Two positive diagnostic serologic tests showing IgG antibodies to T. cruzi and meeting both of the following (i and ii): i. The two tests use different techniques (e.g., enzyme-linked immunosorbent assay [ELISA], immunofluorescent antibody test [IFA]); ii. The two tests use different antigens (e.g., whole-parasite lysate, recombinant antigens);
2. Prescribed by or in consultation with an infectious disease specialist;
   3. Member does not have Cockayne syndrome;
   4. Member has not yet received 60 days of benznidazole therapy for the current infection;

3. Dose (weight-based) does not exceed 400 mg per day (see Appendix D for off-label dosing requests). Page 1 of 7

   CLINICAL POLICY Benznidazole Approval duration: 60 days total B. Other diagnoses/indications (must meet 1 or 2):

4. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace and CP.PMN.16 for Medicaid; or
   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid.
      II. Continued Therapy A. Chagas Disease (must meet all):
5. Member meets one of the following (a or b): a. Currently receiving medication via Centene benefit or member has previously met initial approval criteria; b. Member is currently receiving medication and is enrolled in a state and product with continuity of care regulations (refer to state specific addendums for CC.PHARM.03A and CC.PHARM.03B);
6. Member has not yet received 60 days of benznidazole therapy for the current infection;
7. If request is for a dose increase, new dose (weight-based) does not exceed 400 mg per day (see Appendix D for off-label dosing requests). Approval duration: 60 days total B. Other diagnoses/indications (must meet 1 or 2):

8. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: HIM.PA.33 for health insurance marketplace and CP.PMN.255 for Medicaid; or b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: HIM.PA.103 for health insurance marketplace and CP.PMN.16 for Medicaid; or

   2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line Page 2 of 7

   CLINICAL POLICY Benznidazole of business: HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid.
   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 policies – HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid or evidence of coverage documents.
   IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key CDC: Centers for Disease Control and Prevention IgG: immunoglobulin G Appendix B: Therapeutic Alternatives
   Not applicable T cruzi: Trypanosoma cruzi WHO: World Health Organization Appendix C: Contraindications/Boxed Warnings • Contraindication(s):
   o Patients with a history of hypersensitivity reaction to benznidazole or other nitroimidazole derivatives. Reactions have included severe skin and soft tissue reactions. o Patients who have taken disulfiram within the last two weeks. Psychotic reactions may occur in patients who are using benznidazole and disulfiram concurrently.
   o Patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole, another nitroimidazole drug, structurally related to benznidazole in patients with Cockayne syndrome. • Boxed warning(s): None reported Appendix D: General Information • Diagnostic tests:
   o Laboratories offering testing for Chagas disease include ARUP Laboratories, Mayo Clinic Laboratories, and Quest Diagnostics. IgG serology is performed in the majority of cases. After obtaining initial serologic IgG test results, providers should consult their state health department and the CDC for guidance on serologic confirmation. If two results are discordant, a third assay may be needed. Donor screening tests and Immunoglobulin M (IgM) serology tests are not considered diagnostic tests. • Off-label dosing requests for Chagas disease: o Dosing for populations outside FDA-approved age ranges or for longer than 60 days may be appropriate and should be reviewed on a case-by-case basis. See CDC consultation resources below for questions. Page 3 of 7

   CLINICAL POLICY Benznidazole • State reporting requirements: o According to the CDC (https://www.cdc.gov/mmwr/volumes/67/wr/mm6726a2.htm), in 2017 Chagas disease was reportable in six states: Arizona, Arkansas, Louisiana, Mississippi, Tennessee, and Texas.
   • Consultation resources: o Centers for Disease Control and Prevention (CDC)  Parasitic Diseases: https://www.cdc.gov/parasites/chagas/ - 404-718-4745 (hotline for healthcare providers), chagas@cdc.gov  CDC recommended guidance document: Bern C, Montgomery SP, Herwaldt BL, et al. Evaluation and treatment of Chagas disease in the United States: a systematic review. JAMA 2007; 298:2171.  CDC Drug Service: 404-639-3670  CDC Parasitic Diseases Hotline for Healthcare Providers (for all non-malaria parasitic diseases): 770-488-7100
   o World Health Organization (WHO)  Outside the US: https://www.who.int/health-topics/chagas-disease
   o American Society of Tropical Medicine and Hygiene  Directory of consultants: http://www.astmh.org/education-resources/clinical- consultants-directory V. Dosage and Administration Indication Dosing Regimen Chagas disease Dose (mg)
   50 mg
   Body Weight Tablet # - Range (kg)
   12.5 mg
   4 T
   < 15 kg
   15 to < 20 kg 62.5 mg 5 T
   6 T
   20 to < 30 kg 75 mg
   --- 30 to < 40 kg 100 mg
   --- 40 to < 60 kg 150 mg
   --- 200 mg
   ≥ 60 kg
   Tablet # - 100 mg
   ½ T
   --- ¾ T
   1 T
   1 ½ T
   2 T
   Duration / Frequency PO BID for 60 days Maximum Dose 400 mg/day VI. Product Availability
   Tablets: 12.5 mg (not scored) or 100 mg (scored for halves or quarters) VII.