Clinical Policy Title: Intravenous immunoglobulin

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1 Clinical Policy Title: Intravenous immunoglobulin Clinical Policy Number: Effective Date: April 1, 2015 Initial Review Date: November 19, 2014 Most Recent Review Date: May 1, 2018 Next Review Date: May 2019 Related policies: Policy contains: Primary immunodeficiency disease. Autoimmune diseases. Neuromuscular disease. Rheumatic diseases. CP# CP# Lipoprotein apheresis Omalizumab for the treatment of chronic idiopathic urticaria ABOUT THIS POLICY: Select Health of South Carolina has developed clinical policies to assist with making coverage determinations. Select Health of South Carolina s clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peerreviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by Select Health of South Carolina when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. Select Health of South Carolina s clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. Select Health of South Carolina s clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, Select Health of South Carolina will update its clinical policies as necessary. Select Health of South Carolina s clinical policies are not guarantees of payment. Coverage policy Select Health of South Carolina considers the use of intravenous immunoglobulin to be clinically proven and, therefore, medically necessary for the following U.S. Food and Drug Administration (FDA)-approved indications in accordance with prior authorization criteria (Appendix A): A. In primary immunodeficiency disease, including: 1. Congenital agammaglobulinemia. 2. Hypogammaglobulinemia (common variable immunodeficiency). 3. Severe combined immunodeficiency. 4. Wiskott-Aldrich syndrome. 5. X-linked agammaglobulinemia or Bruton s. 6. Hypergammaglobulinemia. 7. X-linked hyper immunoglobulin M syndrome. Criteria: 1

2 a. Documentation submitted includes member s immunoglobulin G level and is below normal level for indication. b. Clinically significant deficiency of humoral immunity as evidenced by one of the following: i. Documented inability to produce an adequate immunologic response to specific antigens. ii. Patient has a history of recurrent infections despite prophylactic antibiotics. iii. Dose does not exceed 400 to 800 mg/kg every 28 days. If criteria are met, approve for six months. B. In thrombocytopenia purpura, idiopathic and chronic immune: Criteria: 1. Acute: a. Active bleeding, patients requiring an urgent invasive procedure, to defer splenectomy, or platelet counts < 20,000/µl at risk for intracerebral hemorrhage or has lifethreatening bleeding. b. Dose does not exceed 1 g/kg daily for up to two days, or 400 mg/kg daily for five days. 2. Chronic: a. Duration of illness of greater than six months. b. Patient has documented trial and failure of corticosteroids and splenectomy, or has a documented medical reason why they are not able to use corticosteroids, or is at high risk for post-splenectomy sepsis. c. Dose does not exceed 1g/kg daily for up to two days, or 400mg/kg daily for five days. If criteria are met, approve for no more than five days. C. In Kawasaki disease: Criteria: 1. Intravenous immunoglobulin is being given with high-dose aspirin. 2. Requested dose does not exceed a single 2 g/kg dose or a dose of 400 mg/kg for five consecutive days. If criteria are met, approve for up to five days. D. In chronic B-cell lymphocytic leukemia: Criteria: 1. Patient s immunoglobulin G level has been provided, and is < 500 mg/dl. 2. The patient has history of severe bacterial infections. 3. Dose does not exceed 400 mg/kg every three to four weeks. If criteria are met, approve for three months. E. In bone marrow transplantation: Criteria: 1. Confirmed bone marrow transplant within the last 100 days. 2

3 2. Patient s immunoglobulin G level has been provided, and is < 400 mg/dl. 3. Dose does not exceed 500 mg/kg per week for the first 100 days post-transplant. If criteria are met, approve for three months. F. In pediatric human immunodeficiency virus: Criteria: 1. Diagnosis of human immunodeficiency virus. 2. Patient is younger than 13 years of age. 3. Either: a. Patient s immunoglobulin G level has been provided and is < 400 mg/dl. b. Clinically significant deficiency of humoral immunity as evidenced by one of the following: i. Documented inability to produce an adequate immunologic response to specific antigens. ii. Patient has a history of recurrent bacterial infections despite prophylactic antibiotics. iii. Dose does not exceed 400 mg/kg every 28 days. If criteria are met, approve for three months. G. In multifocal motor neuropathy: Criteria: 1. Duration of symptoms has been at least one month with disability. 2. Documentation submitted includes nerve conduction studies were completed to rule out other possible conditions and confirms the diagnosis of motor neuropathy. 3. Dose does not exceed 2 g/kg per month. This dose can be given over two to five days. If criteria are met, approve for up to five days for three months. H. In chronic inflammatory demyelinating neuropathy: Criteria: 1. Duration of symptoms has been at least two months with disability. 2. Documentation submitted includes nerve conduction studies completed or nerve biopsy to rule out other possible conditions and confirms the diagnosis of chronic inflammatory demyelinating neuropathy. 3. Patient has documented trial and failure of corticosteroids or has a documented medical reason why they are not able to use corticosteroids to treat the condition. In addition, if documentation is provided that patient has severe and fulminant chronic inflammatory demyelinating neuropathy, intravenous immunoglobulin can be approved as initial therapy. 4. Dose does not exceed 2 g/kg per month. This dose can be given over two to five days. If criteria are met, approve for up to five days for three months. I. In Guillain-Barré syndrome: Criteria: 1. Documentation submitted indicates severe disease with the inability to walk without aid. 3

4 2. Onset of symptoms in the past four weeks. 3. Dosage does not exceed 2g/kg per month. If criteria are met, approve for three months. J. In any other medically accepted condition: Criteria: 1. Medical recommendation must have a I, IIa, or IIb recommendation and be used to address a condition supported by the medical compendium (Micromedex, American Hospital Formulary Service, Drug Points, and Drug Package Insert) as defined in the Social Security Act of 1927 and/or as per recognized standard of care guidelines. 2. There must be documentation of failure on other standard of care therapies as defined per recognized guidelines or a documented medical reason why other standard of care therapy cannot be used. If criteria are met, approve for three months. Select Health of South Carolina considers the use of intravenous immunoglobulin to be clinically proven and, therefore, medically necessary for the following off-label uses when the member has a documented trial and failure of all other standard of care therapies as defined per recognized guidelines or a documented medical reason why other standard of care therapy cannot be used (see the American Academy of Allergy, Asthma & Immunology guideline [Perez, 2017]): Anti-phospholipid antibody syndrome in pregnancy. Birdshot retinochoroidopathy. Chronic parvovirus B19 infection with severe anemia secondary to bone marrow suppression. Cytomegalovirus pneumonitis in solid organ transplants. Delayed pressure, urticarial. Dermatomyositis. Felty syndrome. Graves ophthalmopathy. Henoch-Schönlein purpura. High-risk, preterm, low birth weight neonatal Infections. Immunoglobulin M anti-myelin-associated glycoprotein paraprotein-associated peripheral neuropathy. Intractable childhood epilepsy. Juvenile idiopathic arthritis. Lambert-Eaton myasthenic syndrome. Macrophage activation syndrome. Myasthenia gravis. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Polyarteritis nodosa. Postpolio syndrome. Rasmussen syndrome. 4

5 Relapsing-remitting multiple sclerosis. Renal transplant to reduce risk of rejection as either prophylaxis (pre and post) in highly sensitized patients or acute rejection. Rotaviral enterocolitis. Severe rheumatoid arthritis. Stiff person syndrome. Still s disease. Toxic epidermal necrolysis. Stevens-Johnson syndrome. Limitations: For non-fda approved uses listed above, if criteria are met, approval is for three months. All other uses of intravenous immunoglobulin are not medically necessary based on insufficient evidence. For Medicare members only: Select Health of South Carolina considers intravenous immunoglobulin to be clinically proven and, therefore, medically necessary for indications specified in the following: National Coverage Determination 250.3; Local Coverage Determinations L34074, L34314, L35891, L33610, L34007, and L35093; and Local Coverage Articles A54658, A54660, A54661, A54662, A52509, A52446, A54641, A54643, A55316, A55322, A54644, A54645, A54646, A54647, and A See also Appendix B. Alternative covered services: Usual care for each indication. Background Deficiencies in the immune system involve insufficient antibody levels or function that can result in an immunodeficiency disease (American Academy of Allergy, Asthma & Immunology, 2017). Immunodeficiency diseases are classified as primary (caused by hereditary or genetics) or secondary (acquired caused by environment or exogenous factors). Primary immunodeficiency disease consists of more than 150 types, may present at any age, and manifests most commonly in repeated infection and severe infections that may be difficult to resolve. They may target specific organs, glands, cells, and tissues, and some may be connected to autoimmune disorders. Examples of secondary causes include exposure to human immunodeficiency virus, medications (chemotherapy or systemic steroids), severe burns, or malnutrition. 5

6 Treatment: Treatment options target the specific immune defects or the underlying cause of immunodeficiency. These options include transplantation (bone marrow, stem cell, or thymus), gene therapy, preventative antibiotics, strategies to manage autoimmune disease, and immunoglobulin (antibody) replacement (American Academy of Allergy, Asthma & Immunology, 2017). The objective of immunoglobulin replacement therapy is to restore immunoglobulin to levels necessary to fight infections. Immunoglobulin may be administered intravenously or subcutaneously. Intravenous immunoglobulin contains pooled antibodies, primarily of the immunoglobulin G type, extracted from blood plasma of 1,000 or more blood donors. Applications include supplying antibodies to individuals whose endogenous production is deficient due to primary or acquired immune deficiencies or to other immune-mediated diseases. Intravenous immunoglobulin also has anti-inflammatory and immunomodulation effects, leading to its use in autoimmune disorders. The FDA has approved several preparations as a fractionated plasma product for treatment of immunodeficiencies affecting the humoral immune system (FDA, 2017). Searches Select Health of South Carolina searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s (AHRQ s) National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). We conducted a search on March 19, Search terms were: Immunoglobulins, Intravenous [MeSH], Nervous System Diseases [MeSH], Transplantation [MeSH], Rheumatic Diseases [MeSH], and Immunologic Deficiency Syndromes"[MeSH]. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings 6

7 While intravenous immunoglobulin has been institutionalized by FDA approvals and CMS coverage, most indications for rare, non-fatal diseases can be managed by other means. Several indications listed by CMS were not the subjects of any reviews or guidelines identified by searches for this policy: primary immunodeficiency, idiopathic thrombocytopenia purpura, and Kawasaki disease. Recruiting sufficient numbers of patients with rare diseases for adequately powered large trials can be problematic, making resolution of insufficient evidence findings unlikely. Intravenous immunoglobulin use is supported by small numbers of heterogeneous (for patient age, intravenous immunoglobulin dose, and combination with other interventions) moderate to poor quality studies with inconsistent results, leading many systematic reviews to insufficient evidence conclusions. Definitive recommendations against intravenous immunoglobulin are supported among reviewers: infections in neonates, routine prophylaxis in hematologic malignancies and stem cell transplantation, and children with Guillain-Barré syndrome. Policy updates: In 2016, we identified four new systematic reviews and one scientific statement from the American Heart Association. The systematic reviews included studies of intravenous immunoglobulin for the treatment of Stevens-Johnson syndrome and toxic epidermal necrolysis (Barron, 2015), carditis in acute rheumatic fever (Cilliers, 2015), postpolio syndrome (Koopman, 2015), and suspected or proven infection in neonates (Ohlsson, 2015, which updated their 2013 review). A scientific statement by the American Heart Association concluded that it is reasonable to include intravenous immunoglobulin as primary therapy for antibody-mediated rejection of cardiac allografts (Colvin, 2015). This recommendation was based on low-level evidence, suggesting the benefits of the procedure may outweigh the risks. While intravenous immunoglobulin is commonly used in combination with other immune therapies to treat the highly sensitized patient awaiting cardiac transplantation, it has never been systematically studied after transplantation to prophylactically reduce the incidence of antibody-mediated rejection, and very few data are available to support the use of intravenous immunoglobulin for the treatment of acute antibody-mediated rejection. These new findings would not alter the conclusions of the original policy. Therefore, no changes to the policy are warranted. In 2017, we identified four new systematic reviews (Oaklander, 2017; Farhood, 2016; Lunn, 2016; Ortiz- Salas, 2016), three systematic review updates (Hayes, 2017; Hayes, 2016a), and three evidence-based guidance documents (Perez, 2017; Enk, 2016; National Institute for Health and Care Excellence [NICE], 2016). Clinical applications of intravenous immunoglobulin continue to evolve as new molecular mechanisms, laboratory testing, and treatment alternatives are identified. The evidence continues to support intravenous immunoglobulin replacement therapy for primary and secondary humoral immunodeficiencies that align with FDA approval, with some exceptions. The clinical trial data on which the early FDA approvals were based preceded newer treatments that now represent the standard of care. For example, in treating complications from human immunodeficiency virus or 7

8 preventing infection and acute graft-versus-host disease post-bone marrow transplantation, intravenous immunoglobulin may be considered when primary therapies fail. In many cases, particularly with rare diseases, high-quality evidence is not feasible, and decisions to use intravenous immunoglobulin are made on a case-by-case basis based on lower quality evidence of efficacy, the efficacy of treatment alternatives, clinical presentation, and the likelihood of treatment benefit. Intravenous immunoglobulin should be applied where it is most supported by evidence and where it will provide the greatest clinical benefit. To that end, the American Academy of Allergy, Asthma & Immunology recently produced a comprehensive review and evidence-based guideline for intravenous immunoglobulin across multiple indications (Perez, 2017). The authors categorized each clinical indication based on the quality of available evidence and recommendations from professional guidelines and expert consensus of likely clinical benefit that represent current standards of care. Appendix B compares FDA-approved indications, CMS-approved indications, Select Health of South Carolina pharmacy prior authorization criteria, and the American Academy of Allergy, Asthma & Immunology indications. The changes in this coverage policy will reflect the findings from the American Academy of Allergy, Asthma & Immunology guideline (Perez, 2017). In March 2018, no new relevant clinical review publications or guidelines were identified. The prior authorization criteria were updated to be consistent with the most recent publication. Summary of clinical evidence: Citation Hayes (2014, update 2017) Rheumatic diseases. Perez (2017) for the American Academy of Allergy, Asthma & Immunology Guideline: Update on the use of immunoglobulin in Content, Methods, Recommendations Systematic review of 11 controlled and 28 uncontrolled peer-reviewed studies published from 1990 to June Quality of studies: low and findings inconsistent. Variety of patient ages and intravenous immunoglobulin regimens (alone or with other immunosuppressant drugs), follow up ranged from none to six years. Safe and may provide short-term benefit. Rheumatic diseases are rare and often respond to steroids or other immunosuppressant treatments. Intravenous immunoglobulin is difficult to evaluate in rare diseases; more research is needed update: new information does not change previous conclusions. Indicated as ongoing replacement therapy for patients with primary immunodeficiency disease characterized by absent or deficient antibody production; position is consistent with FDA approval. Intravenous immunoglobulin starting dose of mg/kg every three to four weeks. The decision to infuse intravenous immunoglobulin in a hospital, hospital outpatient, community office, or home-based setting must be based on patient clinical characteristics. 8

9 Citation Content, Methods, Recommendations human disease For other indications, intravenous immunoglobulin should be applied where it is most supported by evidence and where it will provide the greatest clinical benefit. Oaklander (2017) Cochrane review Treatments for chronic inflammatory demyelinating polyradiculoneuropathy Enk (2016) European guidelines: High-dose intravenous immunoglobulin in dermatology Farhood (2016) PANDAS Hayes (2012, updated 2016) Pulmonary diseases Lunn (2016) Overview of five systematic reviews of randomized clinical trials published through October Evidence for intravenous immunoglobulin comprised five moderate- to high-quality randomized clinical trials (RCTs) (269 participants) and one unpublished, open RCT (35 total participants) of intravenous immunoglobulin. Intravenous immunoglobulin produces more short-term improvement in disability than placebo and more adverse events, although serious side effects are probably no more common than with placebo. No clear difference in short-term improvement in impairment with intravenous immunoglobulin versus intravenous methylprednisolone and probably no improvement versus either oral prednisolone or plasma exchange. Research from RCTs needed to identify predictors of treatment response and compare long-term benefits, safety, and cost-effectiveness. Indications for the use of intravenous immunoglobulin: - Severe forms of dermatomyositis, inclusion body myositis, polymyositis. - Toxic epidermal necrolysis. - Severe forms of autoimmune blistering diseases. - Severe systemic vasculitic syndromes. - Severe forms of lupus erythematodes. - Scleromyxedema. Less obvious indications: - Atopic dermatitis. - Autoimmune urticarial. - Severe forms of collagen vascular diseases. - Livedoid vasculopathy. Systematic review included one unblinded RCT and one retrospective study of intravenous immunoglobulin. There is a paucity of high-level studies. Results are inconclusive. Hayes ratings: - B: Prevention or treatment of sino-pulmonary infection in patients with primary immunodeficiency. - C: Reduction of steroid consumption in patients with steroid-dependent asthma; small older trials with conflicting results update: new information, but no changes to previous conclusions. 9

10 Citation Content, Methods, Recommendations Cochrane review: Immunoglobulin M antimyelin-associated glycoprotein antimyelin-associated glycoprotein paraprotein-associated peripheral neuropathies NICE (2016) Guideline: Myeloma: Diagnosis and management Ortiz-Salas (2016) Guillain-Barré syndrome and myasthenia gravis Barron (2015) Toxic epidermal necrolysis and Stevens- Johnson syndrome Cilliers (2015) Systematic review of eight RCTs or quasi-rcts (236 participants) analyzing intravenous immunoglobulin, interferon alfa-2a, plasma exchange, cyclophosphamide and steroids, and rituximab. Two trials of intravenous immunoglobulin (22 and 11 participants, including 20 with antibodies against myelin-associated glycoprotein), had comparable interventions and outcomes, but both were short-term trials. Inconclusive evidence for any particular immunotherapy treatment. Consider intravenous immunoglobulin replacement therapy for people who have hypogammaglobulinemia and recurrent infections. Based on low-quality evidence from a single RCT (81 total patients) with myeloma comparing polyvalent intravenous immunoglobulin with placebo. Findings suggested uncertain effect on all-cause mortality but effective in preventing major infections (5% versus 24%, respectively; risk ratio (RR): 0.20; 95% CI: ) and clinically documented infections (42% versus 93%, respectively; RR: 0.45; 95% CI: ). Use requires clarification as well as the different time points at which they should be used. Meta-analysis of 24 RCTs (4,657 total participants) comprising persons with Guillain-Barré syndrome (14 RCTs) and myasthenia gravis (10 RCTs). Overall quality: low with high risk of bias and heterogeneous study design elements. No conclusive evidence for superiority in the efficacy or safety of intravenous immunoglobulin or plasmapheresis in managing either Guillain-Barré syndrome or myasthenia gravis. Systematic review and meta-analysis of 13 studies (five uncontrolled, eight controlled). Overall quality: low. Evidence consists of poorly controlled studies and non-randomized observational studies and use of an inadequately validated prediction tool to approximate expected mortality. Meta-regression showed a strong inverse correlation between intravenous immunoglobulin dosage and the standardized mortality ratio (slope: -0.59; 95% CI: ; P = 0.009). Evidence suggests intravenous immunoglobulin at dosages of 2 g/kg significantly decrease mortality in patients with Stevens-Johnson syndrome or toxic epidermal necrolysis. A large, randomized, placebo-controlled trial with and without the concomitant use of corticosteroids is required to resolve this issue definitively. Cochrane review: Carditis in acute rheumatic fever Insufficient evidence. 10

11 Citation Koopman (2015) Cochrane review Postpolio syndrome Ohlsson (2015) Cochrane review Suspected or proven infection in neonates Robinson (2015) Content, Methods, Recommendations Moderate- and low-quality evidence that intravenous immunoglobulin has no beneficial effect on activity limitations in the short term and long term, respectively, and inconsistency in the evidence for effectiveness on muscle strength. Intravenous immunoglobulin caused minor adverse events in a substantial proportion of the participants. Inconclusive evidence. Single large trial (3,493 infants) demonstrated that intravenous immunoglobulin does not prevent morbidity or mortality in the hospital or mortality/major disability at 2 years. No further research is recommended. Cochrane review Insufficient evidence. Presumed viral myocarditis Hayes (2014) Pediatric autoimmune neurologic diseases Alejandria (2013) Cochrane review Severe sepsis and septic shock Filippini (2013) Cochrane review Multiple sclerosis Fortin (2013) Insufficient evidence. Systematic review and meta-analysis of 43 RCTs published through January 2012; 17 trials in adults (1,958 subjects) and eight trials in neonates (3,831 subjects). Polyclonal intravenous immunoglobulin reduced deaths in adults, but benefit was not seen in trials with low risk of bias. Insufficient evidence for neonates. Overall: insufficient evidence. Evidence shows an unfavorable benefit-risk balance in relapse-remitting multiple sclerosis. Not effective in decreasing disability progression in patients with progressive multiple sclerosis. Cochrane review Insufficient evidence. Wegener s granulomatosis Vo (2013) Clinical and cost- Recruitment from July 2006 to December 2011: 207 transplant patients (56 living related 11

12 Citation effectiveness of desensitization with intravenous immunoglobulin and rituximab in highly sensitized kidney transplant recipients Walker (2013) Content, Methods, Recommendations donors, 151 deceased). After desensitization, patients transplanted with acceptably cross-matched donor. Four-year outcomes: desensitized (patient survival 95%; graft survival 87.5%); dialysis (patient survival 79%). Costs: desensitized ($219,914); dialysis ($238,667). Desensitization is clinically effective and cost effective but benefits are limited by organ availability and allocation policies. Cochrane review No significant difference versus placebo. Focal epilepsy syndromes Patwa (2012) Guideline: neuromuscular disorders Wu (2012) Recommendations for intravenous immunoglobulin: - For Guillain-Barré syndrome in adults (insufficient evidence for children). - For chronic inflammatory demyelinating polyradiculoneuropathy (but insufficient evidence for comparative effectiveness versus prednisolone). - For myasthenia gravis (but insufficient evidence for comparative effectiveness versus plasma pheresis). - Possibly formultifocal motor neuropathy: probably effective. - Not for post-polio syndrome: insufficient evidence. - Possibly for Lambert-Eaton myasthenic syndrome: may be considered. Cochrane review Insufficient evidence. Preventing infection in nephrotic syndrome Keogh (2011) Cochrane review Lambert-Eaton myasthenic syndrome Rayment (2011) Systematic review of four RCTs in adults and children (54 total subjects) published through January 2010 that studied 3,4-diaminopyridine. One cross-over trial for intravenous immunoglobulin (nine subjects): clinical improvement for up to eight weeks. Overall: insufficient evidence to quantify effectiveness of any treatment. Cochrane review Fetomaternal alloimune thrombocytopenia Insufficient evidence. References 12

13 Professional society guidelines/other: Colvin MM, Cook JL, Chang P, et al. Antibody-mediated rejection in cardiac transplantation: emerging knowledge in diagnosis and management: a scientific statement from the American Heart Association. Circulation. 2015; 131(18): Enk AH, Hadaschik EN, Eming R, et al. European Guidelines (S1) on the use of high-dose intravenous immunoglobulin in dermatology. J Eur Acad Dermatol Venereol. 2016; 30(10): Myeloma: diagnosis and management Feb p. (NICE guideline; no. 35). National Collaborating Centre for Cancer. NICE website. Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2012; 78(13): Perez EE, Orange JS, Bonilla F, et al. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. 2017; 139(3s): S1 S46. Available at: Peer-reviewed references: Alejandria MM, Lansang MA, Dans LF, Mantaring JB, 3rd. Intravenous immunoglobulin for treating sepsis, severe sepsis and septic shock. Cochrane Database Syst Rev. 2013; 9: Cd Ameratunga R, Brewerton M, Slade C, et al. Comparison of diagnostic criteria for common variable immunodeficiency disorder. Front Immunol. 2014; 5: 415. Barron SJ, Del Vecchio MT, Aronoff SC. Intravenous immunoglobulin in the treatment of Stevens- Johnson syndrome and toxic epidermal necrolysis: a meta-analysis with meta-regression of observational studies. Int J Dermatol. 2015; 54(1): Cilliers A, Adler AJ, Saloojee H. Anti-inflammatory treatment for carditis in acute rheumatic fever. Cochrane Database Syst Rev. 2015;5:Cd Farhood Z, Ong AA, Discolo CM. PANDAS: A systematic review of treatment options. Int J Pediatr Otorhinolaryngol. 2016; 89: Filippini G, Del Giovane C, Vacchi L, et al. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2013;6:CD

14 Fortin PM, Tejani AM, Bassett K, Musini VM. Intravenous immunoglobulin as adjuvant therapy for Wegener's granulomatosis. Cochrane Database Syst Rev. 2013;1:Cd Hayes Inc., Hayes Medical Technology Report. Intravenous immunoglobulin (IVIG) for treatment of pediatric autoimmune neurologic diseases. Lansdale, Pa. Hayes Inc.; August Hayes Inc., Hayes Medical Technology Report. Intravenous immunoglobulin for pulmonary diseases. Lansdale, Pa. Hayes Inc.; December 28, Updated Hayes Inc., Hayes Medical Technology Report. Intravenous immunoglobulin for rheumatic diseases. Lansdale, Pa. Hayes Inc.; February 13, Updated Keogh M, Sedehizadeh S, Maddison P. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database Syst Rev. 2011;(2):Cd Koopman FS, Beelen A, Gilhus NE, de Visser M, Nollet F. Treatment for postpolio syndrome. Cochrane Database Syst Rev. 2015;5:Cd Lunn MP, Nobile-Orazio E. Immunotherapy for IgM anti-myelin-associated glycoprotein paraproteinassociated peripheral neuropathies. Cochrane Database Syst Rev. 2016;10:Cd Neunert C, Lim W, Crowther M, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011;117(16): Oaklander AL, Lunn MP, Hughes RA, et al. Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. Cochrane Database Syst Rev. 2017;1:Cd Ohlsson A, Lacy JB. Intravenous immunoglobulin for suspected or proven infection in neonates. Cochrane Database Syst Rev. 2015;3:Cd Ortiz-Salas P, Velez-Van-Meerbeke A, Galvis-Gomez CA, Rodriguez QJ. Human Immunoglobulin Versus Plasmapheresis in Guillain-Barre Syndrome and Myasthenia Gravis: A Meta-Analysis. J Clin Neuromuscul Dis. 2016;18(1):1 11. Primary Immunodeficiency Disease. AAAAI website. Rayment R, Brunskill SJ, Soothill PW, et al. Antenatal interventions for fetomaternal alloimmune thrombocytopenia. Cochrane Database Syst Rev. 2011;(5):CD

15 Robinson J, Hartling L, Vandermeer B, Klassen TP. Intravenous immunoglobulin for presumed viral myocarditis in children and adults. Cochrane Database Syst Rev. 2015;5:Cd Vaccines, Blood & Biologics. Immune Globulin Intravenous (IGIV) Indications. FDA website. Updated March 8, blas/fractionatedplasmaproducts/ucm htm. Vo AA, Petrozzino J, Yeung K, et al. Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab. Transplantation. 2013;95(6): Walker L, Pirmohamed M, Marson AG. Immunomodulatory interventions for focal epilepsy syndromes. Cochrane Database Syst Rev. 2013;6:Cd Wu HM, Tang JL, Cao L, Sha ZH, Li Y. Interventions for preventing infection in nephrotic syndrome. Cochrane Database Syst Rev. 2012;4:Cd CMS National Coverage Determinations (NCDs): Intravenous Immune Globulin for the Treatment of Autoimmune Mucocutaneous Blistering Diseases. CMS website. Local Coverage Determinations (LCDs): L34074 Immune Globulin Intravenous (IVIg). CMS website. KeyWord=Immune+Globulin+Intravenous&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAA ACAAAAAA&. L34314 Immune Globulin Intravenous (IVIg). CMS website. KeyWord=Immune+Globulin+Intravenous&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAA ACAAAAAA&. L35891 Intravenous Immune Globulin. CMS website. KeyWord=Immune+Globulin+Intravenous&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAA ACAAAAAA&. 15

16 L33610 Intravenous Immune Globulin. CMS website. L34007 Intravenous Immune Globulin. CMS website. KeyWord=Immune+Globulin+Intravenous&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAA ACAAAAAA&. L35093 Intravenous Immune Globulin (IVIG). CMS website. KeyWord=Immune+Globulin+Intravenous&KeyWordLookUp=Title&KeyWordSearchType=And&bc=gAAA ACAAAAAA&. A54658 Coverage of Intravenous Immune Globulin for Treatment of Primary Immune Deficiency Diseases in the Home Medicare Benefit Policy Manual, Chapter 15, CMS website. A54660 Coverage of Intravenous Immune Globulin for Treatment of Primary Immune Deficiency Diseases in the Home Medicare Benefit Policy Manual, Chapter 15, CMS website. A54661 Coverage of Intravenous Immune Globulin for Treatment of Primary Immune Deficiency Diseases in the Home Medicare Benefit Policy Manual, Chapter 15, CMS website. A54662 Coverage of Intravenous Immune Globulin for Treatment of Primary Immune Deficiency Diseases in the Home Medicare Benefit Policy Manual, Chapter 15, CMS website. A52509 Intravenous Immune Globulin - Policy Article. CMS website. A52446 Intravenous Immune Globulin (IVIG) - Related to LCD L CMS website. 16

17 l&keyword=immune+globulin+intravenous&keywordlookup=title&keywordsearchtype=and&bc=ga AAACAAAAAA&. A54641 Intravenous Immune Globulin (IVIg)-NCD CMS website. A54643 Intravenous Immune Globulin (IVIg)-NCD CMS website. A55316 Intravenous Immune Globulin revision to the Part AB LCD. CMS website. A55322 Intravenous Immune Globulin revision to the Part AB LCD. CMS website. A54644 Response to Comments: Immune Globulin Intravenous (IVIg). CMS website. A54645 Response to Comments: Immune Globulin Intravenous (IVIg). CMS website. A54646 Response to Comments: Immune Globulin Intravenous (IVIg). CMS website. A54647 Response to Comments: Immune Globulin Intravenous (IVIg). CMS website. A54137 Response to Comments: Intravenous Immune Globulin (IVIG) L CMS website. Commonly submitted codes Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill accordingly. 17

18 CPT Code Description Comment N/A ICD-10 Code Description Comment C91.10 Chronic lymphocytic leukemia of B-cell type not having achieved remission C91.11 Chronic lymphocytic leukemia of B-cell type in remission C91.12 Chronic lymphocytic leukemia of B-cell type in relapse C91.90 Lymphoid leukemia, unspecified not having achieved remission D69.3 Immune thrombocytopenic purpura D80.0 Hereditary hypogammaglobulinemia D80.5 Immunodeficiency with increased immunoglobulin M [IgM] D81.0 Severe combined immunodeficiency [SCID] with reticular dysgenesis D81.1 Severe combined immunodeficiency [SCID] with low T- and B-cell numbers D81.2 Severe combined immunodeficiency [SCID] with low or normal B-cell numbers D81.6 Major histocompatibility complex class I deficiency D81.7 Major histocompatibility complex class II deficiency D81.89 Other combined immunodeficiencies D81.9 Combined immunodeficiency, unspecified D82.0 Wiskott-Aldrich syndrome D82.4 Hyperimmunoglobulin E [IgE] syndrome D83.0-D83.9 Common variable immunodeficiency D84.8 Other specified immunodeficiencies D84.9 Immunodeficiency, unspecified D89.2 Hypergammaglobulinemia, unspecified D89.82 Autoimmune lymphoproliferative syndrome [ALPS] G61.0 Guillain-Barre syndrome G61.81 Chronic inflammatory demyelinating polyneuritis G61.89 Other inflammatory polyneuropathies G61.9 Inflammatory polyneuropathy, unspecified G62.81 Critical illness polyneuropathy G62.89 Other specified polyneuropathies G62.9 Polyneuropathy, unspecified G64 Other disorders of peripheral nervous system G70.00 Myasthenia gravis without (acute) exacerbation G70.01 Myasthenia gravis with (acute) exacerbation G70.80 Lambert-Eaton syndrome, unspecifie G70.81 Lambert-Eaton syndrome in disease classified elsewhere G73.1 Lambert-Eaton syndrome in neoplastic disease M33.00 Juvenile dermatopolymyositis, organ involvement unspecified M33.01 Juvenile dermatopolymyositis with respiratory involvement M33.02 Juvenile dermatopolymyositis with myopathy M33.09 Juvenile dermatopolymyositis with other organ involvement M33.10 Other dermatopolymyositis, organ involvement unspecified 18

19 ICD-10 Code Description Comment M33.11 Other dermatopolymyositis with respiratory involvement M33.12 Other dermatopolymyositis with myopathy M33.19 Other dermatopolymyositis with other organ involvement M33.20 Polymyositis, organ involvement unspecified M33.21 Polymyositis with respiratory involvement M33.22 Polymyositis with myopathy M33.29 Polymyositis with other organ involvement M33.90 Dermatopolymyositis, unspecified, organ involvement unspecified M33.91 Dermatopolymyositis, unspecified with respiratory involvement M33.92 Dermatopolymyositis, unspecified with myopathy M33.99 Dermatopolymyositis, unspecified with other organ involvement M36.0 Dermato(poly)myositis in neoplastic disease Z Encounter for aftercare following bone marrow transplant Z94.81 Bone marrow transplant status HCPCS Level II Code J1459 J1557 J1566 J1568 J1572 J1599 Description Injection, immune globulin (Privigen), intravenous, nonlyophilized, 500 mg Injection, immune globulin, (Gammaplex), intravenous, nonlyophilized, 500 mg Injection, immune globulin, intravenous, lyophilized, not otherwise specified, 500 mg Injection, immune globulin, (Octagam), intravenous, nonlyophilized, 500 mg Injection, immune globulin, (Flebogamma/Flebogamma Dif), intravenous, nonlyophilized, 500 mg Injection, immune globulin, intravenous, nonlyophilized, not otherwise specified, 500 mg Comment Appendix A PerformRx Prior Authorization Criteria for IVIG ALL REQUESTS MUST HAVE A CONFIRMED DIAGNOSIS BY A SPECIALIST. FOR ALL INDICATIONS: Patient has documented trial and failure of all other standard of care therapies as defined per recognized guidelines, or have a documented medical reason why patient is not able to use other standard of care therapy. IVIG will be considered for the following indications provided the required information is present: 1. Primary immunodeficiency. 2. Thrombocytopenia purpura, Idiopathic and chronic immune. 3. Kawasaki disease. 19

20 4. Chronic B- cell lymphocytic leukemia. 5. Bone marrow transplantation. 6. Pediatric HIV. 7. Multifocal motor neuropathy. 8. Chronic inflammatory demyelinating neuropathy. 9. Guillain-Barre syndrome. 10. Other medically accepted indications. If criteria are met, the request will be approved for the duration listed below. If criteria are not met, the request is referred to a Medical Director/Clinical reviewer for medical necessity review. Primary immunodeficiency disease: Congenital agammaglobulinemia. Hypogammaglobulinemia (common variable immunodeficiency). Severe combined immunodeficiency. Wiskott-Aldrich syndrome. X-linked agammaglobulinemia or Bruton s. Hypergammaglobulinemia. X-linked Hyper IgM syndrome. Thrombocytopenia purpura, idiopathic and chronic immune Acute: Documentation submitted includes patient s immunoglobulin G level and is below normal level for indication. Clinically significant deficiency of humoral immunity as evidenced by ONE of the following: Documented inability to produce an adequate immunologic response to specific antigens. Patient has history of recurrent infections despite prophylactic antibiotics. Dose does not exceed mg/kg every 28 days. If criteria are met, approve for six months. Active bleeding, patients requiring an urgent invasive procedure, to defer splenectomy, or platelet counts < 20,000/ul at risk for intracerebral hemorrhage or has life-threatening bleeding). Dose does not exceed 1g/kg daily for up to two days, or 400mg/kg daily for five days. Chronic: Duration of illness of greater than six months. Patient has documented trial and failure of corticosteroids and splenectomy, or has a documented medical reason why they are not able to use corticosteroids or patient is at high risk for postsplenectomy sepsis. Dose does not exceed 1g/kg daily for up to two days, or 400mg/kg daily for five days. If criteria is met, approve for up to five days. Kawasaki disease IVIG is being given with high dose aspirin Requested dose does not exceed a single 2g/kg dose or a dose of 400mg/kg for five consecutive days If criteria are met, approve for up to five days. Chronic B-cell lymphocytic leukemia Patient s immunoglobulin G level has been provided, and is < 500mg/dL. The patient has history of severe bacterial infections. Dose does not exceed 400mg/kg every 3-4 weeks. If criteria are met, approve for three months. 20

21 Bone marrow transplantation Confirmed bone marrow transplant within last 100 days. Patient s immunoglobulin G level has been provided, and is < 400mg/dL. Dose does not exceed 500mg/kg/wk for the first 100 days posttransplant. If criteria are met, approve for three months. Pediatric HIV Diagnosis of HIV. Patient is < 13 years of age. Either: - Patient s immunoglobulin G level has been provided, and is < 400mg/dL. - Clinically significant deficiency of humoral immunity as evidenced by ONE of the following: Documented inability to produce an adequate immunologic response to specific antigens. Patient has history of recurrent bacterial infections despite prophylactic antibiotics. Dose does not exceed 400mg/kg every 28 days. If criteria are met, approve for three months. Multifocal motor neuropathy Duration of symptoms has been at least one month with disability. Documentation submitted includes nerve conduction studies were completed to rule out other possible conditions and confirms the diagnosis of multifocal motor neuropathy. Dose does not exceed 2 g/kg/month. This dose can be given over two to five days. If criteria are met, approve for up to five days for three months. Chronic inflammatory demyelinating Duration of symptoms has been at least two months with disability. polyradiculoneuropathy Documentation submitted includes nerve conduction studies were completed or nerve biopsy to rule out other possible conditions and confirms the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy. Patient has documented trial and failure of corticosteroids or has a documented medical reason why they are not able to use corticosteroids to treat the condition. In addition, if documentation is provided that patient has severe and fulminant chronic inflammatory demyelinating polyradiculoneuropathy, intravenous immunoglobulin can be approved as initial therapy. Dose does not exceed 2 g/kg per month. This dose can be given over two to five days. If criteria are met, approve for up to five days for three months. Guillain-Barré syndrome Documentation submitted indicates severe disease with the inability to walk without aid. Onset of symptoms within the last four weeks. Dose does not exceed 2 g/kg per month. If criteria are met, approve for three months. Any other medically accepted indication For any other indication, medical recommendation must have a I, IIa, or IIb recommendation and be used for a medical condition that is 21

22 Review/revision date 11/2017 supported by the medical compendium (Micromedex, American Hospital Formulary Service, Drug Points, and Drug Package Insert) as defined in the Social Security Act 1927 and/or per recognized standard of care guidelines. Patient has documented trial and failure of all other standard of care therapies as defined per recognized guidelines or has a documented medical reason why the patient is not able to use other standard of care therapy. If criteria are met, approve for three months. Appendix B Comparison of approved indications for IVIG across FDA, CMS, Select Health of South Carolina, and the American Academy of Allergy, Asthma & Immunology. Clinical indications for IVIG FDA CMS Perform Rx Perez (2017) for the AAAAI* Primary humoral immunodeficiency MMN Prevention of bacterial infections in patients with hypogammaglobulinemia and recurrent bacterial infection due to B-cell chronic B- cell lymphocytic leukemia Prevention or control of bleeding in idiopathic thrombocytopenic purpura Prevention of coronary artery aneurysms in Kawasaki syndrome CIDP Pediatric HIV Post bone marrow transplantation Other medically accepted indications Off-label uses Autoimmune Mucocutaneous Blistering Diseases Dermatomyositis Pemphigus and Pemphigoid Other Specified Bullous Dermatoses Erythema Multiforme TEN and SJS Polymyositis Guillain-Barre Syndrome (GBS) Hyperimmunoglobulinemia E. Syndrome LEMS MG 22

23 Clinical indications for IVIG FDA CMS Perform Rx Perez (2017) for the AAAAI* Relapsing-remitting MS High-risk, preterm, low birth weight neonatal infections Chronic parvovirus B19 infection with severe anemia secondary to bone marrow suppression Renal transplant- reducing HLA/ABO antibodies: Prophylaxis - reduction of renal transplant rejection (pre and post). Acute rejection. Stiff person syndrome Graves ophthalmopathy Birdshot retinochoroidopathy Henoch-Sch onlein purpura Juvenile idiopathic arthritis Anti phospholipid antibody syndrome in pregnancy Severe rheumatoid arthritis Still s disease Felty syndrome Macrophage activation syndrome Polyarteritis nodosa CMV pneumonitis in solid organ transplants Rotaviral enterocolitis IgM anti-myelin associated glycoprotein paraprotein-associated peripheral neuropathy Intractable childhood epilepsy Postpolio syndrome Rasmussen syndrome Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection Delayed pressure urticarial *Clinical indications categorized as definitely beneficial, probably beneficial, or may provide benefit with Level I or II supportive evidence (i.e., from meta-analysis of RCTs, at least one RCT, at least one controlled trial without randomization, or at least one other type of quasi-experimental study). 23