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This is a new policy published on 5/15/2019. It will be effective on 8/15/2019 or later.
  
Horizon BCBSNJ
Uniform Medical Policy ManualSection:Drugs
Policy Number:169
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 VIII (Hemophilia A) with or without inhibitors: Hemlibra

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.

Hemophilia typically refers to an inherited bleeding disorder caused by deficiency of coagulation factor VIII (hemophilia A), factor IX (hemophilia B), or factor XI (hemophilia C). Hemophilia A – Inherited deficiency of factor VIII; is an X-linked recessive disorder. Hemophilia A is more common than hemophilia B, representing 80-85% of the total hemophilia population.

Clinical manifestations of hemophilia relate to bleeding from impaired hemostasis, sequelae from bleeding, or complications of coagulation factor infusion. Patients with moderate hemophilia often bleed in response to minor intercurrent injury and invasive procedures. Bleeding is less frequent than in severe hemophilia and typically occurs four to six times yearly. However, more frequent bleeding may occur if a target joint develops. Some patients with moderate hemophilia may express a more severe phenotype requiring the use of prophylactic treatment regimens. In contrast, individuals with mild hemophilia generally only have bleeding in response to injury/trauma or surgery, and bleeding may not become clinically apparent until later in life. Delayed bleeding can occur after minor surgical procedures such as tooth extraction, even in patients with mild disease.

The diagnostic evaluation in cases of suspected hemophilia typically begins with a thorough review of the patient's personal bleeding history and family history. Screening tests are then performed and the diagnosis is confirmed with a specific clotting factor activity measurement(s) and/or genetic testing. Laboratory testing is similar for the majority of patients with hemophilia. Initial testing includes screening tests of hemostasis, including prothrombin time (PT), activated partial thromboplastin time (aPTT), and platelet count. Mixing studies for the aPTT assay are performed if the aPTT is prolonged. If mixing studies show correction, consistent with a factor deficiency rather than an inhibitor, factor activity levels are then measured. An exception is diagnosis in a male neonate with a positive family history, in which factor levels are often measured directly on cord blood.

Table 1: The 2nd edition World Federation of Hemophilia (WFH) guidelines for management of hemophilia screening tests for hemophilia
Interpretation of screening tests
Possible diagnosis PT (prothrombin time)APTT* (activated partial thromboplastin time)BT (bleeding time)Platelet Count
NormalNormalNormalNormal Normal
Hemophilia A or B**NormalProlonged*NormalNormal
*Results of APTT measurements are highly dependent on the laboratory method used for analysis
**The same pattern can occur in presence of FXI, FXII, prekallikrein, or high molecular weight kininogen deficiencies

Table 2: 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.

Inhibitors are a serious medical problem that can occur when a person with hemophilia has an immune response to treatment with clotting factor concentrates. In the case of an inhibitor, a person's immune system reacts to proteins in factor concentrates as if they were harmful foreign substances. When this happens, antibodies form in the blood to fight against the foreign factor proteins which stops the factor concentrates from being able to fix the bleeding problem. Bleeding is very hard to control in someone with hemophilia who develops inhibitors. In patients with persistent inhibitors, if bleeding into the muscles and joints (the most common type of bleeding in hemophilia) is not controlled, permanent joint damage is likely.

It is possible to get rid of inhibitors using a technique called immune tolerance induction (ITI). With ITI therapy, factor concentrate is given regularly over a period of time until the body is trained to recognize the treatment product without reacting to it. When ITI is successful, the inhibitors disappear and the patient’s response to factor concentrates returns to normal. The majority of people who undergo ITI therapy will see an improvement within 12 months, but more difficult cases can take two years or longer.

The amount of inhibitor in an individual is referred to as a titer and it is expressed in Bethesda units. The higher the number of Bethesda units, the more inhibitor that is present. An inhibitor can also be classified as low-responding or high-responding depending on how an individual’s immune system is stimulated based on repeated exposure to factor VIII. If the inhibitor titer is very low (i.e. < 5 Bethesda units) and low-responding, then bleeding episodes in affected individuals can often be treated with replacement factor VIII in higher doses. However, replacement factor VIII is not effective in individuals with a high inhibitor titer (i.e. > 5 Bethesda units). In individuals with higher titer levels, bypassing agents (concentrates of factors that bypass the factor deficiency) are often used.

In 2017, Hemlibra (emicizumab-kxwh) was approved to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A who have developed inhibitors. Hemlibra is manufactured by Genentech, Inc.

On October 4, 2018, the FDA added a new indication for Hemlibra to be used in patients without inhibitors as well. The updated indication of Hemlibra is to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients with hemophilia A with or without inhibitors.

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. Hemlibra (emicizumab-kxwh) is considered medically necessary for any of the following FDA-approved conditions:
        1. Hemophilia A (congenital factor VIII deficiency) with factor VIII inhibitors
          Diagnosis of congenital factor VIII deficiency has been confirmed by blood coagulation testing; AND
          Confirmation the patient has inhibitors to Factor VIII; AND
          Used routine prophylaxis to prevent or reduce the frequency of bleeding episodes; AND
          Not used in combination with Immune Tolerance Induction (ITI); AND
          Patient has at least two documented episodes of spontaneous bleeding into joints; OR
          Patient has documented trial and failure of Immune Tolerance Induction (ITI); OR
          Patient has documented trial and failure of or is currently on routine prophylaxis with a bypassing agent (i.e. Novoseven, Feiba)
          For women who are not postmenopausal or surgically sterile, documented agreement to remain abstinent or use single or combined highly effective contraceptive methods
        2. Hemophilia A (congenital factor VIII deficiency) without factor VIII inhibitors
          Diagnosis of congenital factor VIII deficiency has been confirmed by blood coagulation testing; AND
          Used routine prophylaxis: AND
            Patient must have severe hemophilia A (factor VIII level of <1%); OR
            Patient has at least two documented episodes of spontaneous bleeding into joints; AND
          Patient is not a suitable candidate for treatment with shorter half-life Factor VIII (recombinant) products at a total weekly dose of 100IU/kg or less (as attested by the prescribing physician with appropriate clinical rationale)
      III. When medically necessary, Hemlibra will be approved based on the following FDA approved dosing (see table below).
        1) Initial authorization period can vary by specific indication:
          a. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes
              o Unless otherwise specified, the initial authorization for prophylaxis treatment will be 12 months and may be renewed.
        2) 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.
          Hemlibra
          IndicationDose
          Routine Prophylaxis Congenital Hemophilia A with or without inhibitors3 mg/kg administered as a subcutaneous injection once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or 3 mg/kg every two weeks, or 6 mg/kg every four weeks
        IV. For continuing therapy, Hemlibra 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) and thrombotic micoangiopathy;
                  o Cases of thrombotic microangiopathy and thrombotic events were reported when on average a cumulative amount of >100 U/kg/24 hours of activated prothrombin complex concentrate was administered for 24 hours or more to patients receiving Hemlibra prophylaxis. Monitor for the development of thrombotic microangiopathy and thrombotic events if aPCC is administered. Discontinue aPCC and suspend dosing of Hemlibra if symptoms occur.
            Any increases in dose must be supported by an acceptable clinical rationale (i.e. weight gain, increase in breakthrough bleeding when patient is fully adherent to therapy, etc.).
            The cumulative amount of medication (s) the patient has on-hand will be taken into account when authorizing. The authorization will allow up to 5 doses on-hand for the treatment of acute bleeding episodes as needed for duration of the authorization.
            For the following disease specific criteria, renewal will be approved for a 12 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.

        VI. All other uses of Hemlibra are considered investigational.


        Medicare Coverage:
        Hemophilia Products - Congenital factor VIII (Hemophilia A) with inhibitors: Hemlibra are covered when LCD L35111 criteria is met. For additional information and eligibility, refer to LCD L35111.

        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.
        Also see: National Coverage Determination (NCD) for Anti-Inhibitor Coagulant Complex (AICC) (110.3). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx.
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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 VIII (Hemophilia A) with or without inhibitors: Hemlibra
        Hemlibra
        Congenital Factor VIII with Inhibitors
        Hemophilia A with Inhibitors

        References:
        1. Hemlibra (emicizumab-kxwh) [package insert]. Genentech, Inc. South San Francisco, CA. November 2017. Accessed November 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. 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).

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

        9. 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.

        10. Collins PW, Chalmers E, Hart DP, et al. UK Haemophilia Centre Doctors. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). UK Haemophilia Centre Doctors Organization. Br J Haematol. 2013 Jan; 160(2): 153-70. Available on PubMed.

        11. Key N. Hemophilia A. National Organization for Rare Disorders. Danbury, CT. Updated 2015. Available at: https://rarediseases.org/rare-diseases/hemophilia-a/. Accessed on March 7, 2018.

        12. WFH Inhibitors Working Group. About Bleeding Disorders – How does immune tolerance induction work? World Federation of Hemophilia. Montreal, Quebec. Updated Dec 2014 Available at: https://www.wfh.org/en/page.aspx?pid=647. Accessed on March 7. 2018.

        13. WFH Inhibitors Working Group. About Bleeding Disorders – What are inhibitors? World Federation of Hemophilia. Montreal, Quebec. Available at: https://www.wfh.org/en/page.aspx?pid=651. Accessed on March 7, 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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