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Horizon BCBSNJ
Uniform Medical Policy ManualSection:Drugs
Policy Number:172
Effective Date: 08/15/2019
Original Policy Date:03/27/2018
Last Review Date:
Date Published to Web: 05/15/2019
Subject:
Hemophilia Products – Congenital Factor XIII A-Subunit Deficiency: Tretten

Description:
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IMPORTANT NOTE:

The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.

Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.

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Hemophilia is a rare disorder in which the blood does not clot normally. It is a medical condition in which the ability of the blood to clot is severely reduced, causing the sufferer to bleed severely from even a slight injury. The condition is typically caused by a hereditary lack of a coagulation factor, most often factor VIII. Hemophilia A and B are X-linked recessive diseases that present in male children of carrier females. However, hemophilia must sometimes be differentiated from other bleeding disorders when the family history is negative or unknown. Differentiation between hemophilia and other conditions, such as some types of von Willebrand disease or acquired factor inhibitors, and distinction between hemophilia A and B are crucial for appropriate management.

Factor XIII deficiency belongs to a group of rare forms of bleeding disorders; a group that includes deficiencies of fibrinogen, prothrombin and factors V, VII, and X. The rare forms of bleeding disorders account for 3-5% of all bleeding disorders collectively.

Factor XIII deficiency is a rare, genetic bleeding disorder characterized by deficiency of clotting factor XIII. It is inherited as an autosomal recessive disorder. Individuals with factor XIII deficiency form blood clots like normal, but these clots are unstable and often break down, resulting in prolonged, uncontrolled bleeding episodes. FXIII consists of two subunits: subunit A and subunit B. Most of the Factor XIII deficiency states are caused by mutations in subunit A.

Table 1: The 2nd edition World Federation of Hemophilia (WFH) guidelines for management of hemophilia severity classification criteria for hemophilia
Relationship of bleeding severity to clotting factor level
SeverityClotting Factor LevelBleeding Episodes
Severe<1 IU/dl (<0.01 IU/ml) or <1% of normalSpontaneous bleeding into joints or muscles, predominantly in the absence of identifiable hemostatic challenge
Moderate1-5 IU/dl (0.01-0.05 IU/ml) or 1-5% of normalOccasional spontaneous bleeding; prolongs bleeding with minor trauma or surgery
Mild5-40 IU/dl (0.05-0.40 IU/ml) or 5-<40% of normal Severe bleeding with major trauma or surgery. Spontaneous bleeding is rare.

A diagnosis of factor XIII deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Standard tests used to diagnose bleeding disorders such as activated partial thromboplastin time (aPTT) and prothrombin time (PT) are normal and therefore ineffective. To confirm a diagnosis, the amount of factor XIII is tested in a blood sample through quantitative analysis of factor XIII. In affected individuals this will demonstrate reduced amount and activity of factor XIII.

In 2014, Tretten, a recombinant factor XIII replacement product, was approved for the prevention of bleeding in adults and children who have the rare clotting disorder congenital factor XIII A-subunit deficiency.


Policy:
(NOTE: For Medicare Advantage, please refer to the Medicare Coverage Section below for coverage guidance.)

I. When anti-hemophilia products are considered medically necessary, initial therapy will be approved based on the following:

    1. The provider must provide the actual prescribed dose with ALL of the following supporting documentation:
        a. Patient’s age
        b. Patient’s weight
        c. Severity of the factor deficiency
            i. (i.e., severe = <1% factor activity, moderate = ≥1 to ≤5% factor activity, mild = >5 to 40% factory activity)
        d. Bleed history
        e. Inhibitor status
        f. Intended use/regimen: prophylaxis, on-demand, peri-operative
II. Tretten is considered medically necessary for any of the following FDA-approved condition:

    1. Congenital Factor XIII A-subunit deficiency
        • Diagnosis of congenital factor XIII A-subunit deficiency has been confirmed by blood coagulation testing; AND
        • Tretten is not for use in patients with congenital factor XIII B-subunit deficiency
        • Used for routine prophylaxis of bleeding
        • If the request is for routine prophylaxis and the requested dose exceeds a total monthly dose of 35 IU/kg, a half-life study should be performed to determine the appropriate dose and dosing interval.
        • For members with a BMI ≥ 30, a half-life study should be performed to determine the appropriate dose and dosing interval.
        • For minimally treated patients (< 50 exposure days to factor products) previously receiving a different factor product, inhibitor testing is required at baseline in any patient that has received factor, then at every comprehensive care visit (yearly for the mild and moderate patients, semi-annually for the severe patients).
    III. When medically necessary, Tretten will be approved based on the following FDA approved dosing (see table below).
      1. Initial authorization period is specific to the indication:
        a. Routine prophylaxis of bleeding
            o Unless otherwise specified, the initial authorization for prophylaxis treatment will be 12 months and may be renewed.
      2. For patients whom PK test is recommended, initial approval will be for 3 months and renewal will be based upon completion of the PK test.
        [INFORMATIONAL NOTE: Requirements for half-life study are a part of the hemophilia management program. This information is not meant to replace clinical decision making when initiating or modifying medication therapy and should only be used as a guide.]
      3. Dispensing Requirements for Renderings Providers
        a. Prescriptions cannot be filled without an expressed need from the patient, caregiver or prescribing practitioner. Auto-filling is not allowed.
        b. Monthly, rendering provider must submit for authorization of dispensing quantity before delivering factor product. Information submitted must include:
          Original prescription information, requested amount to be dispensed and patient clinical history (including patient product inventory and bleed history)
                Factor dose should not exceed +1% of the prescribed dose and a maximum of three vials may be dispensed per dose. If unable to provide factor dosing within required range of prescribed dose, then rendering provider must provide proof of all available vial sizes from the manufacturer prior to dispensing factor product and the lowest possible dose able to be achieved above +1% should be dispensed. Prescribed dose should not be increased to meet assay management requirements.
        c. The prescriber should discuss with the patient that a treatment log should be maintained and a copy should be submitted (via prescriber or pharmacy) upon request for renewal purposes.
      Tretten
      IndicationDose
      Routine prophylaxis for bleeding Congenital factor XIII A-subunit deficiency35 international units (IU) per kilogram body weight once monthly to achieve a target trough level of FXIII activity at or above 10% using a validated assay.
    IV. For continuing therapy, Tretten is considered medically necessary and approved when ALL of the following criteria are met:
        Patient continues to meet criteria identified in section I and II and dosing identified in section III; AND
        Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include the following:
          Symptoms of allergic-anaphylactic reactions (anaphylaxis, dyspnea, rash);
          Thromboembolic events (thromboembolism, pulmonary embolism);
              o Thromboembolism may occur when using Tretten. Because of the potential risk for thromboembolism, monitor for early signs of thromboembolism and consumptive coagulopathy when administering Tretten to patients with conditions that predispose to thrombosis.
          Development of neutralizing antibodies (inhibitors); AND
              o To determine if inhibitors are present, perform a Bethesda assay. The presence of inhibitors should be suspected if the expected factor XIII activity. concentrations in plasma are not attained or if bleeding is not controlled with the recommended dose. Monitor all patients regularly for the development of inhibitors by appropriate clinical observations and laboratory tests.
        Any increases in dose must be supported by an acceptable clinical rationale (i.e. weight gain, half-life study results, increase in breakthrough bleeding when patient is fully adherent to therapy, etc.).
        For the following disease specific criteria, renewal will be approved for a12 month authorization period:
            Prevention of acute bleeding episodes
            Route prophylaxis to prevent or reduce the frequency of bleeding episodes
        Dispensing Requirements for Renderings Providers
          a. Prescriptions cannot be filled without an expressed need from the patient, caregiver or prescribing practitioner. Auto-filling is not allowed.
          b. Monthly, rendering provider must submit for authorization of dispensing quantity before delivering factor product. Information submitted must include:
          Original prescription information, requested amount to be dispensed and patient clinical history (including patient product inventory and bleed history)
                Factor dose should not exceed +1% of the prescribed dose and a maximum of three vials may be dispensed per dose. If unable to provide factor dosing within required range of prescribed dose, then rendering provider must provide proof of all available vial sizes from the manufacturer prior to dispensing factor product and the lowest possible dose able to be achieved above +1% should be dispensed. Prescribed dose should not be increased to meet assay management requirements.
        c. The prescriber should discuss with the patient that a treatment log should be maintained and a copy should be submitted (via prescriber or pharmacy) upon request for renewal purposes.
    V. All other uses of Tretten are considered investigational.


    Medicare Coverage:
    There is no National Coverage Determination (NCD) specific to Congenital Factor XIII A-subunit deficiency: Tretten. In the absence of an NCD, coverage decisions are left to the discretion of Local Medicare Carriers. Novitas Solutions, Inc, the Local Medicare Carrier for jurisdiction JL, has determined that congenital deficiencies of clotting are covered when LCD 35111 criteria is met.

    For additional information about Medicare coverage of other hemophilia products, see National Coverage Determination (NCD) for Anti-Inhibitor Coagulant Complex (AICC) (110.3) regarding factor VIII and Local Coverage Determination (LCD): Hemophilia Factor Products (L35111) for factor VIII, IX, XI and other acquired and congenital deficiencies of clotting.

    Local Coverage Determination (LCD): Hemophilia Factor Products (L35111). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46.
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    Horizon BCBSNJ Medical Policy Development Process:

    This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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    Index:
    Hemophilia Products – Congenital Factor XIII A-Subunit Deficiency: Tretten
    Tretten
    Congenital Factor XIII A-Subunit Deficiency

    References:
    1. Tretten [package insert]. Bagsvaerd, Denmark; Novo Nordisk; April 2014. Accessed March 2018.

    2. MASAC RECOMMENDATIONS CONCERNING PRODUCTS LICENSED FOR THE TREATMENT OF HEMOPHILIA AND OTHER BLEEDING DISORDERS. 2013 National Hemophilia Foundation. MASAC Document #240; February 2016. Available at: http://www.hemophilia.org. Accessed June 2016.

    3. First Coast Service Options, Inc. Local Coverage Determination (LCD): Hemophilia Clotting Factors (L33684). Centers for Medicare & Medicaid Services, Inc. Updated on 01/21/2016 with effective date 01/01/2016. Accessed February 2016.

    4. Novitas Solutions, Inc. Local Coverage Determination (LCD): Hemophilia Clotting Factors (L35111). Centers for Medicare & Medicaid Services, Inc. Updated on 01/22/2016 with effective date 01/01/2016. Accessed February 2016.

    5. Annual Review of Factor Replacement Products. Oklahoma Health Care Authority Review Board. Updated April 2016. Access June 2016.

    6. Graham A1, Jaworski K. Pharmacokinetic analysis of anti-hemophilic factor in the obese patient. Haemophilia. 2014 Mar;20(2):226-9.

    7. Croteau SE1, Neufeld EJ. Transition considerations for extended half-life factor products. Haemophilia. 2015 May;21(3):285-8.

    8. Mingot-Castellano, et al. Application of Pharmacokinetics Programs in Optimization of Haemostatic Treatment in Severe Hemophilia a Patients: Changes in Consumption, Clinical Outcomes and Quality of Life. Blood. 2014 December; 124 (21).

    9. Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12:1935.

    10. Guidelines for the management of hemophilia, 2nd edition. 2012 World Federation of Hemophilia. July 2012. Available at: https://www1.wfh.org/publication/files/pdf-1472.pdf. Accessed March 2018.

    11. Inbal AI. Factor XIII Deficiency. National Organization for Rate Disorders. Danbury, CT. Updated 2016. Available at: https://rarediseases.org/rare-diseases/factor-xiii-deficiency/. Accessed on March 2018.

    Codes:
    (The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

    CPT*
      HCPCS

      * CPT only copyright 2019 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.

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      Medical policies can be highly technical and are designed for use by the Horizon BCBSNJ professional staff in making coverage determinations. Members referring to this policy should discuss it with their treating physician, and should refer to their specific benefit plan for the terms, conditions, limitations and exclusions of their coverage.

      The Horizon BCBSNJ Medical Policy Manual is proprietary. It is to be used only as authorized by Horizon BCBSNJ and its affiliates. The contents of this Medical Policy are not to be copied, reproduced or circulated to other parties without the express written consent of Horizon BCBSNJ. The contents of this Medical Policy may be updated or changed without notice, unless otherwise required by law and/or regulation. However, benefit determinations are made in the context of medical policies existing at the time of the decision and are not subject to later revision as the result of a change in medical policy

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