immune globulin replacement therapy (ivig, sq):

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Independent licensees of the Blue Cross and Blue Shield Association

Medication Policy Manual Policy No: dru020

Topic: Immune Globulin Replacement Therapy, (IVIG, SCIG):

Bivigam® Gammaplex® Carimune® NF Gamunex-C® Cuvitru™ Hizentra™ Flebogamma® DIF Hyqvia® Gammagard® Octagam® Gammagard S/D® Privigen® Gammaked™

Date of Origin: January 1996

Committee Approval Date: April 14, 2017 Next Review Date: August 2018

Effective Date: January 18, 2018

IMPORTANT REMINDER This Medication Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medication policy is to provide a guide to coverage. Medication Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Intravenous immune globulin (IVIG) and subcutaneous immune globulin (SCIG; Hizentra® or Hyqvia®) are preparations containing antibodies purified from human blood. They are used in the treatment of many different conditions resulting from immune deficiencies or other immunologic conditions.


Policy/Criteria I. Most contracts require prior authorization approval of immune globulins prior to

coverage. Immune globulins may be considered medically necessary when criteria A AND B below are met.

A. Site of care administration requirements are met. [refer to Medication Policy Manual, Site of Care Review, dru408]

AND B. At least one of the following diagnostic criteria 1. through 5. below is

met: 1. Immunodeficiency (primary or acquired), as defined in criteria a or b:

a. A diagnosis of one of the following and documented hypogammaglobulinemia (a low baseline serum IgG level):

i. Primary humoral immunodeficiency diseases (PID) (as defined in Appendix I).

ii. HIV infected children (< 13 years of age) with hypogammaglobulinemia.

iii. Hematologic malignancy-related hypogammaglobulinemia: A. Post-allogeneic bone marrow transplant (BMT) B. B-cell medicated cancer [e.g., chronic lymphocytic

leukemia (CLL), B-cell lymphoma] iv. Hypogammaglobulinemic neonates, with a low birth weight

(less than 1500g) or in a setting with high baseline infection rate or morbidity.

OR b. A diagnosis of dysgammaglobulinemia, primary or due to multiple

myeloma in patients with stable disease, and high risk of recurrent infections despite prophylactic antibiotic therapy, patients with poor IgG response to the pneumococcal vaccine, or have low normal IgG levels during acute sepsis episodes.

OR 2. Hematologic disorders (immune-mediated), not responding to

alternative therapies, or at high risk of bleeding: a. Acquired Factor VIII inhibitor, when conventional therapy is

ineffective or not tolerated. (e.g., immunosuppressive therapy with cyclophosphamide, steroids, or azathioprine).

OR b. Autoimmune hemolytic anemia (AIHA) not responding to

alternative therapies (e.g., steroids, immunosuppressive agents, plasmapheresis, rituximab and/or splenectomy).

OR c. Fetal (neonatal) alloimmune thrombocytopenia (FAIT) with

documented diagnosis.


OR d. Idiopathic thrombocytopenia purpura, also known as “immune

thrombocytopenia,” (acute; ITP), when a rapid increase in platelet count is necessary, such as in an acute bleeding episode or prior an invasive procedure (including surgery, epidural anesthesia, or Cesarean section).

OR e. ITP (chronic), when the platelet count is dangerously low, defined

as a platelet count less than 30,000 cells/mm3 in children, less than 20,000 cells/mm3 in adults, or less than 30,000 cells/mm3 along with signs/symptoms of bleeding in adults.

OR f. ITP in pregnancy, when at least one of the following criteria are

met: i. Platelet counts less than 10,000/mm3 in the third

trimester, despite an adequate course of corticosteroids, unless use of steroids are contraindicated, or not tolerated.

OR ii. Platelet counts less than 30,000/mm3 associated with

bleeding before vaginal delivery or C-section. (For IVIG use in preparation for C-section or epidural anesthesia, see criteria 2d. above)

OR g. Post-transfusion purpura (hemolytic transfusion reaction) in

severely affected patients. OR h. Pure red cell aplasia (PRCA, viral) with documented parvovirus

B19 infection and severe anemia. OR 3. Neuromuscular disorders, when significant functional impairment is

present: a. Acute inflammatory demyelinating polyneuropathy, including

Guillain-Barré syndrome (GBS), when one of criteria i. through iv. below are met: i. Deteriorating pulmonary function tests. OR ii. Rapid deterioration with symptoms for less than 2 weeks. OR iii. Rapidly deteriorating ability to ambulate. OR iv. Inability to walk independently for 10 meters.

OR


b. Chronic inflammatory demyelinating polyneuropathy (CIDP) when all of criteria i. and ii. below are met: i. Significant functional disability. AND ii. Documentation of slowing of nerve conduction velocity on

electromyogram (EMG)/ nerve conduction study (NCS). OR c. Autoimmune encephalitis, including acute demyelinating

encephalomyelitis (ADEM) or anti-NMDA receptor encephalitis, when prior therapy with corticosteroids has been ineffective or not tolerated.

OR d. Lambert-Eaton myasthenic syndrome (LEMS) when other

treatment options are ineffective or not tolerated. (e.g., pyridostigmine bromide, azathioprine, and/or prednisone).

OR e. Multifocal motor neuropathy (MMN) in patients with conduction

block. OR f. Myasthenia gravis for the treatment of acute crisis (e.g.,

respiratory failure, swallowing difficulties) OR chronic decompensation, when other treatments are ineffective or not tolerated (e.g., plasmapheresis, pyridostigmine, azathioprine, cyclosporine, and cyclophosphamide).

OR g. Paraneoplastic opsoclonus ataxia syndrome (Opsoclonus-

myoclonus ataxia syndrome, OMS) in pediatric neuroblastoma patients with significant functional impairment and not responding to an adequate course of steroids (at least 3 to 7 days).

OR h. Pemphigoid, refractory immunobullous disease (e.g., bullous

pemphigoid, pemphigus foliaceus, pemphigus vulgaris) until conventional treatment takes effect (e.g., immunosuppressive agents and plasmapheresis).

OR i. Refractory myositis, including but not limited to autoimmune

myositis, dermatomyositis, or polymyositis, in patients with severe active illness when other treatments have been ineffective or not tolerated (e.g., corticosteroids, azathioprine, methotrexate, or cyclophosphamide).

OR


j. Dermatomyositis (juvenile, JDM), with muscle weakness and associated severe disability, with at least ONE of the following documented diagnostic criteria below: i. Evidence of myositis, demonstrated by abnormality of

muscle biopsy, MRI, OR EMG. OR

ii. Increased muscle enzymes levels (such as CPK, AST, LDH, and/or aldolase)

OR iii. Cutaneous changes, including heliotrope dermatitis (rash

on the upper eyelids) and Gottron's papules (papules over the knuckles), not responding to oral corticosteroids, methotrexate, and/or another oral immunosuppressant.

OR k. Stiff-Person Syndrome when treatment with other agents is

ineffective or not tolerated. (e.g., diazepam, baclofen, clonazepam, valproic acid, and clonidine).

OR l. Systemic lupus erythematosus, for severe active disease when

other interventions are ineffective or not tolerated (e.g., corticosteroids and immunosuppressive agents, such as cyclophosphamide or azathioprine).

OR 4. Transplant (solid organ), antibody-mediated rejection:

a. Prevention of antibody (Ab)-mediated rejection: Prior to solid organ transplant and in the peri-operative period, for patients at high risk for Ab-mediated rejection, including highly sensitized patients, and those receiving an ABO-incompatible organ.

OR b. Treatment of antibody-mediated rejection (a.k.a. vascular

rejection, humoral rejection): following solid organ transplant and confirmed by either biopsy or presence of panel reactive antibodies (PRAs).

OR 5. Other Miscellaneous conditions, when criteria are met:

a. Kawasaki syndrome, during the first ten days of diagnosis. OR b. Pediatric intractable epilepsy in candidates for surgical resection or

when other interventions are ineffective or not tolerated. Examples of other interventions include, but are not limited to, anticonvulsant medications, ketogenic diets, and steroids. [85]


II. Administration, Quantity Limitations, and Authorization Period A. Regence pharmacy services does not consider immune globulins to be self-

administered medications. B. When prior authorization is approved, immune globulins may be authorized in

quantities as follows: 1. Initial Authorization: Immune globulins may be authorized for the period

defined in Table 1, based on diagnosis. 2. Continued Authorization: If the diagnosis is eligible for re-authorization

(as listed in Table 1), the maximum number of infusions that may be authorized per year are based on the diagnosis being treated.

C. Authorization shall be reviewed as follows to confirm that current medical necessity criteria are met and that the medication is effective. 1. Initial authorization shall be reviewed at the end of the initial authorization

period (as defined in Table 1). 2. Continued authorization (after the initial period) shall be reviewed at least

annually, and clinical documentation indicating that there is disease stability or improvement must be provided (such as improvement of functional impairment from baseline).


Table 1. Initial Authorization

Indication Frequency/Duration

May be given no more frequently than:

Reauthorization Criteria/Duration

Replacement Therapy - Immunodeficiency [with documented hypogammaglobulinemia (low IgG levels) or poor immune response (dysgammaglobulinemia)]

Primary humoral immunodeficiency disease (PID)

One dose per month x 12 months Documented current evidence of clinical improvement, such as decreased occurrence of infections; May review authorization every 12 months.

Hematologic malignancy-related hypogammaglobulinemia (e.g., CLL, post-BMT)

One dose per month x 12 months

HIV+ children with hypogammaglobulinemia


Hypogammaglobulinemic neonates One dose per month x 6 months Hematologic disorders (immune-mediated)

Acquired Factor VIII Inhibitor One dose per month x 6 months Documented initial response and continued presence of Factor VIII inhibitor; x 12 months

Autoimmune hemolytic anemia, (AIHA)

One dose per month x 6 months Documented initial response and recurrence of clinically significant, symptomatic anemia; x 12 months

Fetal (neonatal) alloimmune thrombocytopenia (FAIT)

One dose per week until the estimated date of delivery.

No reauthorization

ITP (acute) Up to four doses (authorization is for up to a 6 month window).

May re-authorize under Chronic ITP; however, use of IVIG chronically is generally discouraged, given the short duration of action. On a chronic basis, IVIG may be indicated for ACUTE, intermittent use in patients with episodes of acutely low platelets.





ITP (chronic) One dose per month x 6 months. IVIG treatment only covered until conventional therapy takes effect.

Authorization x 6 months. Documented initial response to IVIG and: - Continued thrombocytopenia, defined as a platelet count of < 20,000 OR less than 30,000 cells/m3 and clinically significant bleeding. OR

- Patient is scheduled for an invasive procedure with high risk of bleeding.

ITP in pregnancy One dose per month until the estimated date of delivery.

May re-authorize under Chronic ITP

Post-transfusion purpura (hemolytic transfusion reaction)

Up to two doses in 2 weeks (author-ization is for up to a 2 week window)

No reauthorization

Pure red cell aplasia (PRCA), viral One dose per month x 6 months Documentation of initial response, parvovirus, and recurrence of significant anemia; x 12 months

Neuroimmunologic disorders Acute inflammatory demyelinating polyneuropathy (including GBS)

One dose per month x 3 months May re-authorize under Chronic IDP

Chronic inflammatory demyelinating polyneuropathy (CIDP)

One dose per month x 6 months Documented functional improvement; x 12 months

Autoimmune encephalitis (including ADEM or anti-NMDA receptor)

One dose per month x 3 months. Documented functional improvement; x 6 months

Dermatomyositis, refractory One dose per month x 3 months. Documented improvement in muscle strength and/or decreased CPK levels; x 6 months

Lambert-Eaton myasthenic syndrome


Documented improvement in muscle function/strength; x 12 months Multifocal motor neuropathy (MMN) One dose per month x 6 months.

Myasthenia gravis (acute and chronic)

One dose per month x 6 months.

Paraneoplastic opsoclonus ataxia syndrome

One dose (authorization is for up to a 2 week window)

Documented functional improvement; x 6 months.





Myositis, including polymyositis and autoimmune myositis

One dose per month x 3 months. Documented improvement in muscle strength and/or decreased CPK levels; x 6 months

Pemphigoid, refractory One dose per month x 6 months, until conventional therapy takes effect.

No reauthorization

Stiff-Person syndrome One dose per month x 3 months. Documented functional improvement; x 6 months Systematic lupus erythematosus One dose per month x 6 months. Documented improvement in muscle strength and/or decreased

CPK levels; x 6 months Transplant (solid organ) Prevention of acute rejection (pre- and peri-operative)

Up to 4 doses pre-transplant, then 1 dose weekly for 4 weeks post-transplant. (not to exceed 8 doses total; authorization is for up to a 3 month window)

Further authorization may be considered under “Treatment of Ab-mediated rejection”

Treatment of antibody (Ab)-mediated (humoral) rejection

One dose, once per rejection episode (authorization is for up to a 2 week window)

Documented improvement from previous course and confirmation of another episode of rejection; one dose per rejection episode may be authorized.

Other Miscellaneous disorders Kawasaki syndrome Up to two doses given within 10 days

of symptom onset (authorization is up to a 2 week window)

No reauthorization

Pediatric intractable epilepsy One dose per month x 6 months. Documented of significantly reduced frequency and/or duration of seizures; x 6 months


III. Subcutaneous administration of immune globulin (SCIG) is considered an alternative to

intravenous administration of immune globulin and may be considered medically necessary when one of the criteria in Section I is met.

V. IVIG/SCIG is considered investigational when used for all other conditions, including,

but not limited to: 1. Acute lymphocytic leukemia 2. Acute renal failure 3. Adrenoleukodystrophy 4. Adult HIV infection 5. Alzheimer's disease 6. Aplastic anemia 7. Asthma 8. Atopic dermatitis 9. Autism 10. Behçet's syndrome (Behçet’s disease) 11. Cardiomyopathy, recent-onset dilated 12. Chronic fatigue syndrome 13. Clostridium difficile, recurrent 14. Cystic fibrosis 15. Diabetes 16. Diamond-Blackfan anemia 17. Endotoxemia 18. Heart block, congenital 19. Hemolytic anemia (other than autoimmune) 20. Hemophagocytic syndrome 21. Human T-lymphocyte virus-1 myelopathy 22. Hyper IgE syndrome 23. Immune mediated neutropenia 24. Inclusion body myositis 25. Infectious disease in high risk neonates and adults following surgery or trauma 26. Lumbosacral plexopathy 27. Multiple sclerosis 28. Narcolepsy/cataplexy 29. Neonatal hemochromatosis 30. Neonatal hemolytic disease 31. Nephropathy, membranous 32. Nephrotic syndrome 33. Ophthalmopathy, euthyroid 34. Paraproteinemic neuropathy 35. Post-polio syndrome


36. Recurrent spontaneous abortion 37. Rheumatoid arthritis 38. Systemic Sclerosis, diffuse cutaneous (dcSS) 39. Stevens-Johnson Syndrome 40. Still's Disease (Systemic Juvenile Immune Arthritis, SJIA) 41. Surgery or trauma 42. Thrombocytopenia, nonimmune 43. Thrombotic Thrombocytopenic Purpura, including Hemolytic Uremic Syndrome

(TTP/HUS), neonatal autoimmune and transfusion refractory. 44. Tic disorder (Based on DSM Criteria)\ 45. Toxic epidermal necrolysis (TEN) 46. Urticaria, delayed pressure 47. Uveitis 48. Vasculitic syndromes, other systemic (not specified above), such as antineutrophil

cytoplasmic antibody- (ANCA) associated vasculitis [microscopic polyangiitis (MPA)], and eosinophilic granulomatosis with polyangiitis (EGPA) [Churg-Strauss Syndrome (CSS)].

49. Von Willebrand’s syndrome Wegener's (granulomatosis with polyangiitis, an ANCA-associated vasculitis)

Position Statement Summary Intravenous immune globulin (IVIG) - All IVIG preparations are generally considered therapeutically interchangeable. [32-34] - Minor immunoglobulin A (IgA) and immunoglobulin G (IgG) subclass differences exist.

[32-34] - IVIG preparations with low IgA content are used to minimize reactions in patients with

hypogammaglobulinemia and concurrent IgA deficiency or when anti-IgA antibodies are present in a recipient. [32-34]

- Differences in formulation may guide product selection (e.g., pre-mixed liquid vs. lyophilized powder, 5% vs. 10%, low sucrose, low osmolarity).

Subcutaneous immune globulin (SCIG) - Hizentra® is an immune globulin product for subcutaneous use, approved for patients

with primary immune deficiency (PID). [81] It is available as a 20 % solution for weekly subcutaneous infusion.

- Hyqvia® is also an immune globulin product for subcutaneous use, approved for patients with PID, and is available as a 10 % solution for every three to four week subcutaneous infusion [105] Gammaked®, Gamunex-C®, and Gammagard liquid® are approved for both intravenous and subcutaneous use for treatment of PID. [89-91] All three are available as a 10 % solution.

- SCIG has a lower bioavailability than IVIG, so must be given in higher doses to achieve the same serum IgG concentrations.


- However, subcutaneous delivery may result in higher steady-state IgG levels due to less variation in IgG levels.

- Multiple injection sites (three to four) are necessary for weekly infusion (Hizentra, Gammaked, Gamunex-C, Gammagard) for an average patient because of the volume that must be infused, whereas Hyqvia may be infused monthly.

- Hyqvia 10% is formulated with hyaluronidase, to allow for larger volume infusion at a single injection site. Up to 600 mL (60 grams) may be given per injection site (for patients > 40 kg) at an infusion rate up to 300 mL/hour. The recommended maximum dose per injection site for Hizentra 20% is 25 mL (5 grams), given over a maximum of 25 mL/hour.

- None of these products have been approved for SC administration for any other indications, other than PID. Because other diagnoses usually require larger doses (based on grams per kilogram) with a high volume per dose, subcutaneous administration is generally not feasible.

- Injection site swelling, redness, and itching were reported in the majority of patients.

Dosing Considerations and Therapeutic Levels for Replacement Therapy for Treatment of Immunodeficiency with Hypogammaglobulinemia - A plasma IgG level of 200 mg/dL is often a common minimum target for patients being

considered for IVIG replacement therapy. [4] - In patients with mild to moderate IgG deficiency with levels of 300 mg/dL-400mg/dL, the

decisions to treat are based on clinical symptoms and antigenic challenge. [31] - Dosing adjustment in replacement therapy is based on clinical response and IgG levels.

[4] * The trough or steady state IgG level is obtained before scheduled infusions and

frequently guides IVIG dose selection. * The minimum serum concentration of IgG necessary for protection has not been

firmly established. However, maintenance of serum trough IgG levels above 500 mg/dL has been considered a sufficient target to prevent most systemic infections. [4, 31] Some patients may require an IgG level of 400-500 mg/dL above their baseline value for protection.

* In patients with severe hypogammaglobulinemia, IgG levels (trough) should be checked every three to six months in growing children and every six to twelve months in adults. [56]

- Dosing of IVIG for conditions other than hypogammaglobulinemia do NOT require monitoring of IgG levels. Efficacy in conditions other than hypogammaglobulinemia is based on clinical response, including improvement or resolution of disease symptoms.

Clinical Efficacy IMMUNODEFICIENCY (Primary or Secondary) - Replacement Therapy for Hypogammaglobulinemia [1, 4-5, 27, 34, 43] Primary humoral immunodeficiency diseases - All available immune globulin replacement products are FDA-approved for use in

primary immunodeficiency (PID). [94]


- X-linked agammaglobulinemia (congenital agammaglobulinemia) occurs in male infants, usually presenting in the first 3 years of life.

- Common variable immunodeficiency (CVID; acquired hypogammaglobulinemia; adult onset hypogammaglobulinemia; dysgammaglobulinemia) is characterized by low to normal IgG levels and inability to produce an antibody response to protein (e.g., tetanus) or carbohydrate antigens (e.g., Pneumovax). Most patients experience severe recurrent and/or chronic infections.

- Combined immunodeficiency syndromes, including Wiskott-Aldrich syndrome, are rare, inherited syndromes.

- Immunoglobulin reference ranges vary depending on the age of the patient and the particular assay method used. The usual immune globulin maintenance dose is 100- 800mg/kg/month and therapy is usually life-long.

- Serum trough levels should be maintained at 400 – 600 mg/dl. Documentation of the rationale should be provided in the event that a trough level greater than 600 mg/dl is required. [72]

- Hypogammaglobulinemic neonates ∗ Treatment with IVIG is usually reserved for patients with recurrent severe

infections, not responding to antibiotic prophylaxis. ∗ The usual IVIG dose is 400 – 600 mg/kg/month, administered as a single dose, or

up to several months in duration. [67] Acquired Deficiencies: - Hematologic malignancy-related hypogammaglobulinemia (including B-cell cancers,

multiple myeloma, and post-bone marrow transplant (BMT) * Use of immune globulin replacement in hypogammaglobulinemic patients with

B-cell cancers (including CLL), multiple myeloma and post-allogeneic bone marrow transplant (BMT) is supported by guidelines. [83, 100]

* IVIG therapy reduces the incidence of bacterial infections in patients with hematologic malignancies to approximately 50% of the incidence without IVIG administration. [4, 34]

* Previously, use of IVIG prophylaxis post-BMT was common for prevention of graft versus host disease (GVHD); however, with improved immunosuppressant regimens, the use of routine IVIG prophylaxis is no longer supported. [100]

* Monthly IVIG infusions of 400 mg/kg are recommended to maintain the serum IgG level.

- HIV-infected children < 13 years of age [92] * Current guidelines recommend IVIG use among HIV-infected children who have

hypogammaglobulinemia (IgG <400 mg/dL), to prevent serious bacterial infections (SBIs).

* IVIG is no longer recommended for primary prevention of SBIs in children, unless hypogammaglobulinemia is present. During the pre-HAART (highly-active antiretroviral therapy) era, IVIG was shown to decrease the frequency of bacterial infections and hospitalization in children with AIDS, however only in those not receiving daily Pneumocystis carinii pneumoniae (PCP) prophylaxis.


AUTOIMMUNE (IMMUNE-MEDIATED) DISORDERS - Pooled immune globulin (IVIG) has been studied and found to be useful in a variety of

autoimmune disorders, including hematologic, neuromuscular and infectious disease-related diseases. However, given the rarity of many of these disorders, the evidence for safety and efficacy in some diagnoses is insufficient at this time.

- The mechanism of action of IVIG in autoimmune disorders is thought to include acute neutralization of circulating autoantibodies, toxins, and cytokine modulation, as well as long-term reduction of antibody production and suppression of T-cell cytokines. [1]

Hematologic (immune-mediated) Disorders: [83] Acquired Factor VIII inhibitor [21-25] - A sufficient treatment course is usually 6-12 weeks before attempting a different

immunosuppressive agent. Patients are generally treated until remission (elimination of the inhibitor) occurs, which may take several months.

- Treatment regimens of 1 gm/kg for 2 days or 400 mg/kg for 5 days have been studied. In one study, only 6 of 19 patients responded to IVIG within 40 days of treatment. [60]

Fetal (neonatal) alloimmune thrombocytopenia (FAIT): [58, 83] - ACOG guidelines recommend IVIG as first line treatment for documented fetal

thrombocytopenia. [58] - A trial comparing IVIG treatment with and without dexamethasone in siblings showed

that:[2] ∗ IVIG treatment was associated with an increase in mean platelet count of

69,000/mm3. ∗ There were no instances of intracranial hemorrhages, although hemorrhage had

occurred previously in 10 untreated siblings. - The recommended dose of IVIG is 1 gm/kg/week, increasing to 2 gm/kg/week in

refractory cases. [59] Idiopathic thrombocytopenia purpura (ITP) [5,83, 84] - Normal platelet count range is 115,000/mm3 to 440,000/mm3. - Acute ITP

* In various studies, 64% to 100% of IVIG recipients attained platelet counts greater than 100,000 cells/mm3 within 7 days. [4, 34]

* A maximum of 1 gm/kg/day for three or four doses of IVIG on alternate days is recommended. Acute ITP is usually seen in children and typically resolves spontaneously within 2 months.

- Chronic ITP [4, 8-10] ∗ Current evidence does not support that IVIG alters the natural course of chronic

ITP, affects long-term morbidity/mortality, or increases the rate of long-term remission.

∗ IVIG is not indicated for the maintenance of platelet counts in chronic ITP; however, IVIG maybe be used episodically in patients with chronic ITP, for acutely low platelet levels.


∗ Steroids and/or splenectomy are considered the first-line treatment of choice for chronic ITP. Although the use of IVIG may be considered as a steroid-sparing adjunctive therapy for chronic ITP, [5,83,84] other therapies with a more durable response should be considered, such as splenectomy, rituximab (Rituxan), eltrombopag (Promacta) or romiplostim (Nplate). [5,84]

∗ IVIG may be considered in patients with dangerously low platelet counts (less than 10,000 to 20,000 per mm3 in adults or less than 30,000 per mm3 in children) or patients undergoing an invasive procedure, and therefore may be at an increased risk for significant bleeding, such as intracranial hemorrhage.

∗ Choosing Wisely®, an evidence-based initiative to promote wise use of medical resources, states that patients with ITP should not be treated in the absence of bleeding or a very low platelet count. Only rarely should patients be treated when platelet counts are above 30,000, such a preparation of surgery or an invasive procedure. Unnecessary treatment exposes patients to potential adverse events and raises the overall cost of care, with unknown clinical benefit. [106]

∗ The usual dose of IVIG is 1 to 2 gm/kg divided into equal amounts and given over 2 to 5 days.

- ITP in pregnancy (a.k.a. Pregnancy-Associated ITP) [44,83,84] * The goal of therapy is to minimize the risk of bleeding complications due to

thrombocytopenia. [44] * Platelet function is typically normal so it is not necessary to maintain platelet

count in the normal range. [44] * The first line of treatment is prednisone, usual dose 1-2mg/kg/day. [44] * IVIG is useful in cases that are resistant to steroids and when a rapid rise in

platelets is necessary. A response typically occurs within 6 – 72 hours of IVIG treatment. [44]

∗ For patients nearing the end of their pregnancy and preparing for use of epidural anesthesia, IVIG coverage will be considered under “ITP, acute” criteria, for use prior to an invasive procedure. Because the evidence is less useful in determining the exact threshold platelet levels needed for prevention of bleeding, the use of IVIG is generally at the discretion of the treating anesthesiologist or surgeon, and pregnant patients are managed like non-pregnant patients. [83,84]

∗ The American College of Obstetrics and Gynecology (ACOG) recognizes the high cost of IVIG therapy and suggests consultation from a physician experienced in the treatment of ITP when considering use of IVIG therapy. [44]

. Post-transfusion purpura (hemolytic transfusion reaction) - Post-transfusion purpura is a rare condition that can occur in patients undergoing blood

transfusions. It typically develops approximately one-week after blood transfusion. - IVIG may be considered first-line therapy in severely affected patients. [1, 83] - The recommended dose of IVIG is 500 mg/kg/day for two consecutive days. Rapid

platelet recovery has been seen within days of treatment.


Pure Red Cell Aplasia (PRCA), Viral [83] - Parvovirus B19 infects and lyses red cell precursors, which can cause pure red cell

aplasia. IVIG therapy is usually reserved for patients with chronic parvovirus infection and chronic anemia.

- Chronic parvovirus infection with anemia usually occurs in immunocompromised patients. If the immunodeficiency improves, the parvovirus and anemia may spontaneously resolve.

- The usual dose of IVIG is 2-4 grams/kg, divided as 400 mg/kg/day for 5 – 10 days, 1 gm/kg/day for 3 days or 0.5 gm/kg weekly for 4 weeks. Initial treatment courses may be indicated with recurrence of anemia and increase in parvovirus B19 DNA. [71,83]

Neuromuscular Disorders: Inflammatory demyelinating polyneuropathy (IDP) [85, 86, 96] - Acute IDP, including Guillain-Barré syndrome (GBS) [57,97]

* IVIG appears to be effective in adult patients with Guillain-Barré syndrome when given within 2 weeks of symptom onset.

* The recommended IVIG dose is 400 mg/kg/day for 5 days. If relapse occurs within 1-2 weeks of initial therapy, an additional treatment course of IVIG may be effective. Further treatment does not improve outcomes and is not recommended.

- Chronic IDP (CIDP) * Clinical guidelines recognize the use of specific diagnostic criteria for CIDP, to

exclude other causes of neuropathy and confirm the presence of peripheral nerve demyelination. [85, 113] Objective criteria include use of electrodiagnostic (EMG) testing, along

with additional studies, such as nerve biopsy or lumbar puncture (LP) to confirm elevation of CSF protein.

Given the lack of consensus across guidelines and need to exclude neuropathies unlikely to respond to IVIG therapy, use of objective criteria are required to support a clinical diagnosis of CIDP.

* Treatment options include plasmapheresis, IVIG, and corticosteroids. * The usual IVIG dose is 400 mg/kg/day for 5 days, repeated every 6 weeks.

Autoimmune encephalitis: acute demyelinating encephalomyelitis (ADEM) or anti-NMDA receptor encephalitis - Immune-mediated encephalitis is relatively rare and include ADEM and encephalitis

syndromes associated with antibodies against neuronal tissue, such as anti-NMDA receptor encephalitis.

Acute demyelinating encephalomyelitis (ADEM) [110] - ADEM can be associated with various neurologic and psychiatric symptoms, including

cognitive and speech dysfunction, seizures, dyskinesias, altered consciousness, and autonomic instability.

- High-dose IV corticosteroid therapy is considered the first-line treatment for ADEM, with IVIG or plasma exchange reserved for patients not responding to steroid therapy.

- The usual IVIG dose is 400 mg/kg/day for 5 days.


Anti-NMDA receptor encephalitis (anti-NMDAR) [111, 112] - Anti-NMDA receptor encephalitis is a specific type of autoimmune encephalitis,

diagnosed by detection of IgG antibodies against a subunit of NMDA receptors in serum or CSF. It can be associated with various neurologic and psychiatric symptoms, including cognitive and speech dysfunction, seizures, dyskinesias, altered consciousness, and autonomic instability.

- Based on large case series and years of experience in clinical practice, use of immunosuppression therapy is the standard of care, with corticosteroids, IVIG, plasma exchange, cyclophosphamide, or rituximab. IVIG (400 mg/kg/day for 5 days) in combination with high-dose methylprednisolone or plasma exchange may be useful in treating patients with anti-NMDA receptor encephalitis in the first-line setting. Rituximab and/or cyclophosphamide may be of benefit in patients not responding to IVIG and steroids within 10 days. Children are generally managed with monotherapy (cyclophosphamide or rituximab).

Dermatomyositis (DM), adult and pediatric (juvenile) - High-dose IVIG is a safe and effective treatment for refractory dermatomyositis

unresponsive to corticosteroid therapy. [5,7,27,33,36, 85,86,95] - For adults, abnormalities on EMG or elevations in CPK are accepted diagnostic criteria. - Juvenile dermatomyositis (JDM) is characterized by a vasculopathy affecting both the

muscle and the skin. For pediatric patients, a number of muscle enzymes, including CPK, LDH, AST or aldolase, may be used to confirm the diagnosis. Myositis may also be confirmed by an abnormal muscle biopsy, EMG or MRI. Children can also have specific skin manifestations associated with the dermatomyositis, including Gottron papules on the dorsal surface of the knuckles and heliotrope rash over the eyelids. [107-109]

- The recommended IVIG dose is 2 gm/kg per month. Lambert-Eaton myasthenic syndrome (LEMS) [39, 85-87] - LEMS is a rare acquired autoimmune disorder characterized by proximal weakness of

extremities, decreased reflexes, and dryness of mouth and eyes. - Patients reported improved limb, respiratory muscle, and bulbar muscle strength with

IVIG, compared to placebo in a small randomized crossover trial (n = 9). [73] - The recommended dose of IVIG is 2 gm/kg administered over 2 – 5 days. Multifocal motor neuropathy (MMN) [75-79, 85, 86] - Small controlled trials demonstrate significant increase in muscle strength associated

with IVIG administration, long-term benefits, and safety. [6,26] - The recommended IVIG dose is 2 gm/kg/month, administered over 2 – 5 days. - Conduction block is the hallmark of this disease. Additionally, patients with anti-GM1

antibodies show an increased chance of response to IVIG However, anti-GM antibodies are present in only 30-80% of patients with MMN and are not specific to MMN. In addition, patients who lack anti-GM1 antibodies may have a favorable response to IVIG; therefore the clinical utility of monitoring anti-GM1 antibodies is uncertain. [75]

Myasthenia gravis (MG) [85, 86] - Randomized trials examining short-term treatment of myasthenia gravis with IVIG

have shown no difference between IVIG and plasma exchange or IVIG and methylprednisolone[69]


- IVIG may be useful in treating patients with severe myasthenia gravis who fail to respond to the maximum tolerated doses of corticosteroids and/or immunosuppressants. [70]

- There is no evidence to determine whether IVIG improves function or reduces steroid requirements for moderate to severe myasthenia gravis. [69]

- The recommended dose of IVIG is 1 – 2 gm/kg/month administered over 2 – 5 days. [69] Paraneoplastic opsoclonus ataxia syndrome (Opsoclonus-myoclonus) [85, 101] - Opsoclonus-myoclonus is a rare neurological syndrome characterized by an unsteady

gait, brief shock-like muscle spasms, and irregular rapid eye movements and can be a paraneoplastic (e.g., with neuroblastoma) or non-paraneoplastic syndrome.

- IVIG is a therapeutic option for pediatric neuroblastoma patients with paraneoplastic opsoclonus ataxia syndrome, along with other immunologic treatments, including glucocorticoids, cyclophosphamide, mycophenolate and plasma exchange. [85,101]

- Evidence supporting the use of IVIG in this condition consists of retrospective chart reviews and case reports. However, a randomized phase II trial is currently investigating the use of IVIG in treating children with opsoclonus-myoclonus associated with neuroblastomas. [73,74,102]

Refractory pemphigoid bullous (e.g., pemphigus foliaceus, pemphigus vulgaris) [27, 38, 88] - IVIG is typically given in combination with conventional treatments, such as

immunosuppressive agents and plasmapheresis, and is discontinued once conventional treatment (such as corticosteroids, azathioprine, cyclophosphamide, etc.) takes effect. IVIG is not considered a maintenance therapy for pemphigus foliaceus, pemphigus vulgaris or other autoimmune mucocutaneous blistering diseases.

- The usual dose of IVIG is 1-2 gm/kg administered over 3 days. This regimen may be repeated every 3-4 weeks.

Polymyositis [85, 86, 95]

- Polymyositis is an inflammatory myopathy with no unique clinical features. It is typically a diagnosis of exclusion in patients with slowly progressive muscle weakness. Traditional therapies include immunosuppressive medications or steroids.

- IVIG may be considered for patients not responding to first-line immunosuppression. - The recommended dose of IVIG is 2 gm/kg/month administered over 2 – 5 days. Stiff Person Syndrome [37, 85] - Sixteen patients were randomized to IVIG or placebo for 3 months, and then crossed

over to the alternate treatment after a 1 month washout period. IVIG patients demonstrated decreased stiffness scores, decreased frequency of falls, ability to walk more easily without assistance, and improved ability to perform work-related tasks. Benefits lasted 6 weeks to 1 year without additional treatment.

- The usual dose of IVIG is 400 mg/kg/day for 3 – 5 days. Systemic Lupus Erythematosus - Small case series suggest some benefit from treatment with IVIG when compared to

cyclophosphamide. - The usual dose of IVIG is 400 mg/kg/day for 5 days.


Transplant (Solid Organ) – Antibody-mediated rejection [27, 98] - Acute allograft (organ) rejection may be cellular (T-cell mediated) or humoral (antibody-

mediated) (AHR, AMR). - Pre-treatment with IVIG (desensitization) may reduce the risk of AMR in highly

sensitized renal transplant patients. [27,98] - A randomized, double-blind trial comparing IVIG to placebo in 101 highly sensitized

renal transplant candidates concluded that IVIG is better than placebo in improving transplantation rates. [68]

- Acute humoral rejection (AHR) is also an AMR and can occur outside of the peri-operative period, but most commonly within 6 months after transplant. The diagnosis is confirmed by a renal biopsy. The goal of therapy is early antibody elimination with IVIG, pheresis, or a combination of modalities.

- A variety of protocols have been developed for the use of IVIG in treating AMR after solid organ transplant. [27,98]

Other Miscellaneous Disorders: Kawasaki syndrome - IVIG in conjunction with aspirin given within the first 10 days of illness can reduce the

incidence of coronary artery abnormalities by 65% - 78%, compared with treatment with aspirin alone. [4, 34-35,99] IVIG is not effective if more than ten days have elapsed from onset of symptoms.

- The usual dose of IVIG is 2 gm/kg as a single dose, but may be repeated if the patient fails to defervesce. [99]

INVESTIGATIONAL CONDITIONS [1, 5, 13-15, 17-20, 27, 46-52] - The University Hospital Consortium (UHC), an alliance of 68 academic health centers,

performed a critical assessment of off-label IVIG uses. - The UHC determined published data to be inadequate to support the use of IVIG in

various conditions. [1] - Asthma: Further trials in asthma patients are necessary to delineate patient subsets

that would best benefit from IVIG therapy, and define optimal dosing in this condition. [17-20]

- HIV (adults): The use of IVIG in HIV-infected adults is not definitive to substantiate a positive benefit on overall long-term health outcomes. [3]

- Multiple sclerosis, progressive: There is not substantial evidence to support IVIG in the treatment of chronic progressive multiple sclerosis. [28-30, 64]

- Multiple sclerosis; relapsing-remitting type: IVIG may provide some benefit in reducing the acute exacerbation rate in relapsing-remitting multiple sclerosis. [5, 27, 54] * Trials are generally limited to small numbers of patients and have lacked

complete data on clinical outcomes. * Current evidence suggests little benefit with regard to slowing disease

progression.


* The American Academy of Neurology does not consider IVIG to be a first-line therapy in the treatment of relapsing-remitting multiple sclerosis.

- Post-Polio: Two published trials of post-polio syndrome failed to demonstrate a statis-tically significant benefit compared to placebo in improvement of muscle strength. [65, 66]

- Recurrent pregnancy loss, or recurrent spontaneous abortion (due to anti-phospholipid or anti-cardiolipin antibodies): * Recurrent pregnancy loss is defined as three or more pregnancies resulting in

spontaneous abortion prior to 20 weeks of gestational age. These women often have immunologic abnormalities, particularly antiphospholipid antibodies. [27]

* IVIG has not been established as a safe or effective therapy to prevent recurrent spontaneous abortion in women with immunologic abnormalities, such as elevated natural killer cells, defective cytokines, or defective growth factors. [13-15,

62] * One randomized controlled trial comparing IVIG to thyroid replacement therapy

for the prevention of miscarriages found IVIG to be less effective. There was a statistically significant higher rate of live birth among women treated with thyroid replacement therapy. [61]

* A small randomized controlled trial in 85 women with a history of three or more spontaneous abortions before 10 weeks of gestation compared low molecular heparin (LMW) plus aspirin with IVIG therapy. The percentage of live births in the LMW plus aspirin versus the IVIG treatment group was 72.5% and 39.5%, respectively. [80]

* A randomized controlled trial in 82 women with a history of idiopathic secondary miscarriage compared live birth rates in those who received intravenous immune globulin versus placebo infusion (saline). There was no statistical difference between treatment groups. [82]

* ACOG recommendations state: If results are positive for the same antibody on two consecutive tests 6 to

8 weeks apart, initiate heparin and low-dose aspirin with next pregnancy attempt.

IVIG is not effective in preventing recurrent pregnancy loss. [55]

- Additional conditions for which published data is determined to be inconclusive or inadequate to support the use of IVIG include Alzheimer's disease, atopic dermatitis, recurrent C. difficile, narcolepsy/cataplexy, neonatal hemochromatosis, chronic sinusitis, tic disorder, delayed pressure urticaria, systemic sclerosis (diffuse cutaneous, dcSS) and toxic epidermal necrolysis. [27, 46-52, 63,103, 104]


Cross References

BlueCross BlueShield Association Medical Policy # 8.01.05; Intravenous Immune Globulin Therapy (6/2013)

Maximum Drug Dosage Policy, Medication Policy Manual, Policy No. dru237

Nplate®, romiplostim, Medication Policy Manual, Policy No. dru162

Promacta®, eltrombopag, Medication Policy Manual, Policy No. dru180

Rituxan®, rituximab, Medication Policy Manual, Policy No. dru214

Site of Care Review, Medication Policy Manual, Policy No. dru408

Codes Number Description

CPT 90780-90781 IV infusion for therapy

CPT 90284 Immune globulin (SCIg), human, for SC use

CPT 90283 Immune globulin (IVIG), human, for IV use

HCPCS J1459 Injection, Immune Globulin (Privigen), IV, non-lyophilized (e.g., liquid) 500 MG

HCPCS J1557 Injection, Immune Globulin (Gammaplex), IV, non-lyophilized (e.g., liquid) 500 MG

HCPCS J1559 Injection, Immune Globulin (Hizentra), 100 mg

HCPCS J1561 Injection, Immune Globulin, (Gamunex), IV, non-lyophilized, (e.g., liquid), 500 MG Injection, Immune Globulin, (Gammaked), IV, non-lyophilized, (e.g., liquid), 500 MG

HCPCS J1566 Injection, Immune Globulin (Carimune), IV, lyophilized, 500 MG

HCPCS J1568 Injection, Immune Globulin (Octagam), IV, non-lyophilized (e.g., liquid) 500 MG

HCPCS J1569 Injection, Immune Globulin, (Gammagard), IV, non-lyophilized, (e.g., liquid), 500 MG

HCPCS J1572 Injection, Immune Globulin, (Flebogamma), IV, non-lyophilized, (e.g., liquid), 500 MG

HCPCS Unassigned Immune Globulin, (BIVIGAM)


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Appendix I: Primary Humoral Immunodeficiencies, as defined by the following diagnostic criteria: 1. X-linked agammaglobulinemia (congenital agammaglobulinemia) diagnosis accompanied

by marked deficits or absence of all five immunoglobulin classes (IgG, IgM, IgA, IgE, and IgD), decreased circulating B lymphocytes, and normal numbers of functioning T lymphocytes.

OR

2. Hypogammaglobulinemia (a general term describing serum levels of IgG which are below the lower limits of normal).

OR

3. Common variable immunodeficiency (CVID; acquired hypogammaglobulinemia; adult onset hypogammaglobulinemia; dysgammaglobulinemia) documented with low to normal IgG levels and the inability to produce an antibody response to protein (e.g., tetanus) or carbohydrate antigens (e.g., Pneumovax).

OR

4. Immunoglobulin subclass deficiency (e.g., X-Linked immunodeficiency with hyper-IgM) accompanied by very low serum concentrations of IgG, IgA, and IgE, with normal or, more frequently, greatly elevated polyclonal IgM concentrations.

OR 5. Combined immunodeficiency syndromes, including Wiskott-Aldrich syndrome,

accompanied by marked deficits in IgG, IgA and IgM, low lymphocyte counts, and absent or below normal levels of both B- and T-lymphocytes.

Revision History

Revision Date Revision Summary

1/18/2018 - Add Gammaked to policy.

4/14/2017 - Clarify coverage criteria for CIDP - Add coverage criteria for refractory acute demyelinating

encephalomyelitis (ADEM) and anti-NMDA encephalitis - Clarify re-authorization period for Immunodeficiency

(Replacement Therapy) 11/11/2016 Removed site of care language from the individual drug policy;

however, requirements still apply. Reference to Site of Care Review, dru408 is provided as part of criterion IA.

9/15/2016 Add Cuvitru to policy.

4/8/2016 - Reworded coverage criteria for Polymyositis to Refractory Myositis. Move Dermatomyositis (juvenile) criteria, to follow after Refractory Myositis.

- Delete requirement for IgG levels for reauthorization for hypogammaglobulinemia in re-authorization table (typographical error).

immune globulin replacement therapy (ivig, sq):

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