BlueCross and BlueShield of Montana Medical Policy/Codes
Hemophilia Agents
Chapter: Drugs - Pharmacy Benefit
Current Effective Date: March 15, 2014
Original Effective Date: March 15, 2014
Publish Date: January 14, 2014
Description

There are several clotting disorders caused by deficiencies of specific coagulation factors; of these the most common congenital coagulation disorder is von Willebrand Disease (vWD) with a prevalence in the general population of 1-2% followed by hemophilia A and B, with an incidence of 1 in 5,000 and 1 in 30,000 respectively. (1,2) Less common are disorders associated with other factors including deficiencies in Factor II, Factor V, Factor VII, Factor X and Factor XII.

Policy

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coverage

ALERT:  All self-injectable medications are administered under the pharmacy benefit.

The hemophilia agents are considered self-injectable agents and are administered under pharmacy benefit. Requests for medical benefit coverage should be redirected to the member’s pharmacy benefit. Nursing services to administer hemophilia agents may be approved if medically necessary.

The medical policy is a set of guidelines supporting the current standards of practice based on available peer reviewed, evidenced based literature. The requested therapy must be proven effective for the diagnosis, procedure, drug dose, frequency and duration, if applicable, and be consistent with recommendations in at least one authoritative source. The Medical Policy is supported by the FDA approved labeling, nationally recognized societies and evidenced base guidelines. These references include, but are not limited to:  Milliman, Hayes, DrugDex, NCCN, AAP, Transfusion Medicine, Biologics Compendium, Infectious Disease Society America (IDSA), American Society of Hematology, and CMS coverage policy.

The following US Food and Drug Administration (FDA) approved hemophilia agents may be considered medically necessary under the pharmacy benefit for the listed FDA approved indications (8,9,21-34), as follows:

Drug / Hemophilia Agent

FDA Approved Indication(s)

Advate

(Antihemophilic Factor [Recombinant])

  1. Control and prevention of bleeding episodes in adults and children with hemophilia A.
  2. Perioperative management in adults and children with hemophilia A.
  3. Routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adults and children with hemophilia A.

Alphanate vWF

(Antihemophilic Factor /VWF [Human])

  1. The control and prevention of bleeding episodes in adult patients with hemophilia A.
  2. Surgical and/or invasive procedures in adult and children with von Willebrand Disease (vWD) in whom desmopressin is either ineffective or contraindicated.
  3. Spontaneous and/or trauma induced bleeding in patients with vWD in whom desmopressin is either ineffective or contraindicated.

AlphaNine

(Coagulation Factor IX [Human])

  1. The prevention and control of bleeding in patients with factor IX deficiency due to hemophilia B.

Bebulin/ Bebulin VH

(Coagulation Factor IX [Recombinant])

  1. The prevention and control of hemorrhagic episodes in hemophilia B patients.

Benefix

(Coagulation Factor IX [Recombinant])

  1. The control and prevention of bleeding episodes in adults and children with hemophilia B.

FEIBA NF/ FEIBA VH

(Anti-Inhibitor Coagulant Complex)

  1. The control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and hemophilia B patients with inhibitors.

Helixate

(Antihemophilic Factor [Recombinant])

  1. The control and prevention of bleeding episodes in adults and children with hemophilia A.
  2. Surgical prophylaxis in adults and children with hemophilia A.
  3. Routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children with no pre-existing joint damage.

Hemofil

(Antihemophilic Factor [Human])

  1. Hemophilia A for the prevention and control of hemorrhagic episodes.

Humate-P (Antihemophilic Factor /VWF [Human])

  1. The control and prevention of bleeding in adults with hemophilia A.
  2. To treat adults and children with vWD for:
    • (1)treatment of spontaneous and trauma- induced bleeding episodes, and
    • (2) prevention of excessive bleeding during and after surgery.

NOTE: This applies to patients with severe vWD as well as patients with mild to moderate vWD where use of desmopressin is known or inadequate.

Koate-DVI/ Koate HP

(Antihemophilic Factor [Human])

  1. The control and prevention of bleeding episodes in adults and children with hemophilia A.
  2. Surgical prophylaxis in adults and children with hemophilia A.

Kogenate FS

(Antihemophilic Factor [Recombinant])

  1. The control and prevention of bleeding episodes in adults and children with hemophilia A.
  2. Surgical prophylaxis in adults and children with hemophilia A.
  3. Routine prophylactic treatment to reduce the frequency of bleeding episodes and the risk of joint damage in children with no pre-existing joint damage.

Monoclate-P

(Antihemophilic Factor [Human])

  1. The treatment of hemophilia A.
  2. Surgical prophylaxis in severe AHF deficiency can be accomplished with an appropriately-dosed pre-surgical IV bolus.

Mononine

(Antihemophilic Factor [Human])

  1. The prevention and control of bleeding in factor IX deficiency, or hemophilia B.

NovoSeven RT

(Coagulation Factor VIIA [Recombinant])

  1. The treatment of bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or factor IX and in patients with acquired hemophilia.
  2. The prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to factor VIII or factor IX and in patients with acquired hemophilia.
  3. The treatment of bleeding episodes in patients with congenital factor VII (FVII) deficiency.
  4. Prevention of bleeding in surgical interventions or invasive procedures in patients with congenital factor VIII deficiency.

Profilnine

(Coagulation Factor IX [Human])

  1. The prevention and control of bleeding in patients with factor IX deficiency due to hemophilia B.

Recombinate

(Antihemophilic Factor [Recombinant])

  1. The prevention and control of hemorrhagic episodes associated with hemophilia A.
  2. Short term spontaneous musculoskeletal prophylaxis of patients with hemophilia A.
  3. Perioperative management of patients with hemophilia A.

Wilate

(Antihemophilic Factor /VWF [Human])

  1. The treatment of spontaneous and trauma-induced bleeding episodes in patients with severe vWD as well as patients with mild or moderate vWD in whom the use of desmopressin is known or suspected to be ineffective or contraindicated.

Xyntha

(Antihemophilic Factor [Recombinant])

  1. The control and prevention of bleeding episodes in patients with hemophilia A.
  2. Surgical prophylaxis in patients with hemophilia A.

Rationale

The goal of therapy is to increase the concentration of the missing factor to prevent and treat the bleed. To treat these patients, it is necessary to infuse the deficient clotting factor concentration. (4) These differing therapies are neither pharmacologically nor therapeutically equivalent and will vary based upon purity, half-life, recovery, method of manufacturing, viral removal and inactivation processes, potential immunogenicity, etc. (5) Table 1 lists the preferred therapies for these congenital coagulation disorders and related complications.

Table 1. Preferred Therapy for Specific Congenital Coagulation Disorders

Disorder

Preferred Therapy

von Willebrand Disease

• Desmopressin

• If desmopressin is not sufficient, many of the plasma derived factor VIII products have been licensed for use in vWD

Hemophilia A

• Recombinant factor VIII Products

Hemophilia B

• Recombinant factor IX Products

Hemophilia A or B with inhibitors

• Anti-inhibitor Coagulant Complex

• Recombinant factor VIIa

Treatment of Acute Bleeding

Table 2 provides a reference for administration of recombinant factors for the control of bleeding. (6)

Table 2. Guidance for the Administration of Recombinant Factor for the Prevention of Bleeding Episodes in Adult and Children

Type of bleeding episode

 

Hemophilia A

Hemophilia B

Factor VIII level required (IU/dL)/

Dosing Frequency

Factor IXlevel required (IU/dL)/

Dosing Frequency

Minor

20-40

Every 12-24 hours

20-30

Every 12-24 hours

Moderate

30-60

Every 12-24 hours

25-50

Every 12-24 hours

Major

60-100

Every 8-24 hours

50-100

Every 12-24 hours

Most bleeding occurs internally. Typical sites of bleeding are joints, muscles, and mucous membranes. Life threatening bleeds are often central nervous system (CNS), neck/throat, and gastrointestinal (GI) bleeds. Duration of therapy differs depending on the site of the bleed. Table 3 provides guidelines on the duration of administration depending on site. (3)

Table 3. Suggested Factor Duration of Administration (When There is no Significant Resource Constraint)

TYPE OF HEMORRHAGE

HEMOPHILIA A

HEMOPHILIA B

Desired level

(IU dL-1)

Duration (days)

Desired level

(IU dL-1)

Duration (days)

Joint

40-60

1-2, may be longer if response is inadequate

40-60

1-2, may be longer if response is inadequate

Superficial muscle/no NV compromise (except iliopsoas)

40-60

2-3, sometimes longer if response is inadequate

40-60

2-3, sometimes longer if response is inadequate

Iliopsoas and deep muscle with NV injury, or substantial blood loss: 

Initial 

Maintenance

 

 

 

80-100 

30-60

 

 

1-2 

3-5, sometimes longer as secondary prophylaxis  during physiotherapy

 

 

 60-80

 30-60

 

 

1-2

3-5, sometimes longer as secondary prophylaxis  during physiotherapy

CNS/head: 

Initial 

Maintenance

 

80-100

 50

 

1-7

8-21

 

60-80

30

 

1-7

8-21

Throat and neck: 

Initial 

Maintenance

 

80-100

50

 

1-7

8-14

 

60-80

30

 

1-7

8-14

Gastrointestinal: 

Initial 

Maintenance

  

80-100

50

 

7-14

 

 

 30-80

 30

 

7-14

Renal

50

3-5

40

3-5

Deep laceration

50

5-7

40

5-7

Surgery (major): 

Pre-op 

Post-op

 

80-100

60-80

40-60

30-50

 

 

1-3

4-6

7-14

 

 60-80

40-60

30-50

20-40

 

 

1-3

4-6

7-14

Surgery (minor): 

Pre-op 

Post-op

 

50-80

 30-80

 

 

1-5, depending on type of procedure

 

50-80

30-80

 

 

1-5, depending on type of procedure

NV, neurovascular

Prophylactic Therapy

In some instances, lower doses of factor products are given prophylactically to hemophilia patients. Prophylaxis is recommended as the optimal treatment modality for individuals with severe hemophilia by MASAC/NHF and the World Health Organization (WHO). (4,12) The goal of prophylaxis is to prevent spontaneous bleeding and joint destruction. Prophylaxis was conceived from the idea that moderate hemophilia patients with a factor level > 1 IU/dL rarely have spontaneous bleeds and have much better joint function.3 It is unclear whether all patients should remain on prophylaxis long term. Table 4 outlines the two protocols for which there is long term data; however treatment should be individualized to the specific patient. (3)

Table 4. Prophylactic Protocols Currently Used for Hemophilia Patients

Prophylaxis Protocol

Respective Factor Concentrate Dose

Administration for Hemophilia A

Administration for Hemophilia B

Malmo Protocol

25-40 IU/kg/dose

3x/week

2x/week

Utrecht Protocol

15-30 IU/kg/dose

3x/week

2x/week

Note: In patients with repeated bleeding, short term prophylaxis for 4-8 weeks has been shown to interrupt the bleeding cycle

Hemophilia with inhibitors

In some patients with hemophilia, administered factor VIII concentrate or factor IX concentrate is recognized as a foreign protein and anti-factor VIII or factor IX antibodies are produced. Because they inhibit the activity of factor VIII and factor IX, the anti-factor antibodies are known as inhibitors. This phenomenon is most predominant in hemophilia A (25-35% of patients). (7) When this occurs, anti-inhibitor coagulant complex or recombinant factor VIa concentrate may be used to treat bleeding episodes. (2,7) The anti-inhibitor complex, marketed as FEIBA, is indicated for the control of spontaneous bleeding episodes or to cover surgical interventions in hemophilia A and B patients with inhibitors. FEIBA contains activated factors IIa, VIIa, and Xa- factors that are able to bypass an inhibitor to factor VIII or Factor IX in order to promote hemostatis. (8,9) The other available medication, recombinant factor VIIa concentrate, NovoSeven, is indicated for the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to factor VIII or factor IX. (8)

A retrospective analysis evaluated whether the type of factor VIII product and/or switching among these products was associated with the development of clinically relevant inhibitory antibodies in previously untreated children with severe hemophilia A (N =574). Primary outcomes were defined as inhibitor development (defined as ≥ 2 positive inhibitor testes with decreased in vivo recovery of factor VIII levels). (18) Results showed that plasma derived products conferred a risk of inhibitor development similar to recombinant products (adjusted hazard ratio vs. recombinant products, 0.96; 95% CI, 0.62 to 1.49). (18) The content of vWF in the products and switching among products was not associated with the risk of inhibitor development. (18)

The Medical and Scientific Advisory Committee of the National Hemophilia Foundation (MASAC/NHF) state that for high-titer inhibitors, immune tolerance induction (ITI) is the best option. ITI helps restore the clinical response to factor VIII/ factor IX concentrates over time. ITI involves giving regular doses of factor VIII concentrate to eradicate the inhibitor and achieve immunogenic acceptance of the administered factor VIII. The main goal of therapy is for the inhibitors to disappear and for the patient to respond normally to concentrated factors. (10,11) There are currently no definitive guidelines on dosing or duration of ITI therapy although there are a number of established protocols including the Bonn protocol, the Malmo Protocol and the vanCreveld Protocol. (20) While it is difficult to know when to discontinue ITI therapy in patients with a suboptimal response a review article by Benson et al suggests a reasonable duration of therapy to be between 9 and 33 months. (20)

Safety and Efficacy

Factor Concentrate

While all plasma-derived human anti-hemophilia factor products carry the risk of iatrogenic infection via blood-borne pathogens, (13) improvements in the viral-depleting process and donor screening processes have resulted in plasma derived factor concentrates with reduced risk of transmission of HIV, hepatitis B and C. Recombinant factor use decreases the risk of viral infection, allergic reaction and thromboembolic complications associated with factor treatment. (3) Hemolysis has been associated with the administration of large doses of concentrate to patients with blood groups A, B or AB.

Plasma and recombinant factor agents exhibit similar hemostatic properties and ability to correct factor deficiencies. No concrete evidence of differences in efficacy exists.

MASAC/NHF Guidelines recommend recombinant factor VIII or factor IX concentrate as the treatment of choice for hemophilia A or B. (15) Factors to consider when choosing plasma derived vs. recombinant derived factor are the reliability of the supply, degree of scientific validation, patient convenience, and preference. Some countries (such as Canada, Sweden, Norway, UK, and Ireland) have chosen to switch all hemophilia patients to recombinant products, whereas the United States has adopted a more gradual approach. (17) There is insufficient data to recommend one recombinant product over another.

Anti-Inhibitor Complex/ Recombinant Factor VIIa

Use of anti-inhibitor coagulant complex (FEIBA) has been associated with allergic reactions including urticaria, rash, pruritus, fever, chills, and anaphylactoid reactions. (8) Adverse reactions occurring in >5% of the patients treated with recombinant factor VIIa include fever, decreased serum fibrinogen levels, hypertension, and non-specific bleeding. The incidence of thrombotic events with NovoSeven is low; only 22 cases in over 700,000 treatment courses have been reported. (14)

The FEIBA NovoSeven Comparative Study (FENOC) was an open label, randomized, crossover, equivalency design used to test for equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. The percentage of patients who reported efficacy in response to FEIBA and/or NovoSeven 6 hours after treatment was the parameter of interest. Data from 96 bleeding episodes contributed by 48 participants were analyzed. The statistical criterion for declaring the 2 products equivalent was not met. At 6 hours after infusion, 80.9% reported efficacy with FEIBA and 78.7% reported efficacy for NovoSeven. The confidence interval exceeded the predefined 15% boundary (-11.4%, -15.7%) needed to claim equivalency. The main finding is that FEIBA and NovoSeven appear to exhibit similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. (19)

Coding

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

ICD-9 Codes

Refer to ICD-9-CM Manual.

ICD-10 Codes

Refer to ICD-10-CM Manual.

Procedural Codes: 85732, J7180, J7183, J7185, J7186, J7187, J7189, J7190, J7191, J7192, J7193, J7194, J7195, S9345
References
  1. MASAC. Recommendations regarding the treatment of von Willebrand disease. MASAC Recommendation #196. Available at: http://www.hemophilia.org Accessed April 2013.
  2. Mark T. Reding, M. D. Assistant Professor of Medicine, Division of Hematology, Oncology, and Transplantation. Co-Director, Hemophilia and Thrombosis, University of Minnesota. Physician consultation on hemophilia CTL. Received January 23, 2006.
  3. World Federation of Hemophilia. Guidelines for the Management of Hemophilia. The Official Journal of the World Federation of Hemophilia. Received June 6, 2012.
  4. MASAC. Recommendation Concerning Prophylaxis (Regular Administration of Clotting Factor Concentrate to Prevent Bleeding). Recommendation #179. November 2007. Available at: http://www.hemophilia.org Accessed April 2013.
  5. MASAC. Recommendation Regarding Factor Concentrate Prescriptions and Formulary Development and Restrictions. Recommendation #159. Available at: http://www.hemophilia.org Accessed April 2013.
  6. Micromedex 2.0. Hemophilia. Diseasedex Emergency Medicine Clinical Review. February 21, 2013.
  7. MASAC. Resolution regarding the use of bypassing agents in patients with hemophilia A or B and inhibitors. Recommendation #167. Available at: http://www.hemophilia.org Accessed April 2013.
  8. FEIBA NF Prescribing Information. Baxter Healthcare Corp. Westlake Village, CA. July 2010
  9. NovoSeven RT Prescribing Information. Novo Nordisk. Princeton, NJ. January 2013.
  10. Santagostino E et al. More than a decade of international experience with a pdFVIII/VWF concentrate in immune tolerance. Haemophilia. 2013; 19 (Suppl. 1):8–11.
  11. Escuriola Ettingshauren C, Kreuz W. The immune tolerance induction (ITI) dose debate: does the International ITI Study provide a clearer picture? Haemophilia. 2013; 19 (Suppl. 1):12–17.
  12. Hoots, WK, Nugent DJ. Evidence for the benefits of prophylaxis in the management of hemophilia A. Thrombosis and Haemostasis. 2006; 96:433-440.
  13. Clinical Pharmacology Online Version. 2010. Accessed at: http://cpip.gsm.com .
  14. Journal of Biotechnology. 2006; 124:747-757.
  15. MASAC. Recommendations concerning products licensed for the treatment of hemophilia and other bleeding disorders. Recommendation # 215. Revised November 2012. Available at: http://www.hemophilia.org Accessed April 2013
  16. Journal of Pediatrics. Superior response of recombinant factor VII concentrate in children with hemophilia A. 1997; 130(4):537-540.
  17. Kelly KM, Butler RB et al. Critical Reviews in Oncology/Hematology. 2012; 83:11–20.
  18. Gouw SC, et al. Factor VIII Products and Inhibitor Development in Severe Hemophilia A. New England Journal of Medicine. 2013; 368(3):231-239.
  19. Astermark, J. et al. A Randomized Comparison of Bypassing Agents in Hemophilia Complicated by an Inhibitor: The FEIBA NovoSeven Comparative (FENOC) Study. Blood Journal. September 21, 2006.
  20. Benson G,Auerswald G Elezovic I et al. Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice. Eur J Hematol. 2012; 88:371-379.
  21. Advate prescribing information. Baxter Healthcare Corporation. July 2012.
  22. Alphanate prescribing information. Grifols Biologicals Inc. June 2011.
  23. AlphaNine SD prescribing information. Grifols Biologicals Inc. December 2011.
  24. Bebulin VH prescribing information. Baxter Healthcare Corporation. September 2006.
  25. Benefix prescribing information. Wyeth Pharmaceuticals Inc. November 2011.
  26. Helixate FS prescribing information. CSL Behring LLC. January 2013.
  27. Hemofil M prescribing information. Baxter Healthcare Corporation. November 2010.
  28. Humate-P prescribing information. CSL Behring LLC. May 2012.
  29. Koate-DVI prescribing information. Talecris Biotherapeutics, Inc. June 2011.
  30. Kogenate FS prescribing information. Bayer HealthCare LLC. January 2013.
  31. Monoclate-P prescribing information. CSL Behring LLC. October 2010.
  32. Mononine prescribing information. CSL Behring LLC. October 2011.
  33. Profilnine prescribing information. Grifols Biologicals Inc. August 2011.
  34. Recombinate prescribing information. Baxter Healthcare Corporation. December 2012.
History
March 2014  New medical document. Coverage states: All self-injectable medications are administered under the pharmacy benefit. The hemophilia agents are considered self-injectable agents and are administered under pharmacy benefit. The following US Food and Drug Administration (FDA) approved hemophilia agents may be considered medically necessary under the pharmacy benefit for the listed FDA approved indications. (The listed hemophilia agents are: Advate, Alphanate vWF, AlphaNine, Bebulin/Bebulin VH, Benefix, FEIBA NF/FEIBA VH, Helixate, Hemofil, Humate-P, Koate-DVI/Koate HP, Kogenate FS, Monoclate-P, Mononine, NovoSeven RT, Profilnine, Recombinate, Wilate, Xyntha.) 
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Hemophilia Agents