Pending Policies - Prescription Drugs
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Medical policies are a set of written guidelines that support current standards of practice. They are based on current peer-reviewed scientific literature. A requested therapy must be proven effective for the relevant diagnosis or procedure. For drug therapy, the proposed dose, frequency and duration of therapy must be consistent with recommendations in at least one authoritative source. This medical policy is supported by FDA-approved labeling and nationally recognized authoritative references. These references include, but are not limited to: MCG care guidelines, DrugDex (IIb strength of recommendation or higher), level of evidence or higher), NCCN Guidelines (IIb level of evidence or higher), NCCN Compendia (IIb level of evidence or higher), professional society guidelines, and CMS coverage policy.
Soliris™ (eculizumab) may be considered medically necessary to reduce hemolysis for patients who have paroxysmal nocturnal hemoglobinuria (PNH) AND meet the following criteria:
• Documentation that the patient has received a meningococcal vaccine at least two weeks prior to receiving the first dose of Soliris, OR there is documentation that the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection; and
• Documentation of diagnosis of PNH through analysis by:
o Flow cytometry of erythrocytes for CD59 deficiency; or
o Granulocytes for either CD59 or CD55.
Soliris™ (eculizumab) may be considered medically necessary to treat patients with atypical hemolytic uremic syndrome (aHUS) with documentation that the patient has received a meningococcal vaccine at least two weeks prior to receiving the first dose of Soliris, OR there is documentation that the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection.
Soliris™ (eculizumab) may be considered medically necessary to treat patients 18 years of age or older with generalized myasthenia gravis (gMG) who meet all the following criteria:
• Positive serologic test for anti-acetylcholine receptor,
• Documentation that the patient has received a meningococcal vaccine at least two weeks prior to receiving the first dose of Soliris, OR there is documentation that the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection.
• Myasthenia Gravis Foundation of America (MGFA) Clinical Classification Class II to IV,
• Myasthenia Gravis Activities of Daily Living (MG-ADL) total score ≥6, AND
• One of the following:
o Failed treatment over 1 year or more with a minimum of 2 immunosuppressive therapies either in combination or as monotherapy, OR
o Failed at least 1 immunosuppressive therapy and required chronic plasmapheresis or plasma exchange or intravenous immunoglobulin (IVIg).
NOTE 1: Please refer to the Description Section for the MGFA Clinical Classification Guidelines and the MG-ADL profile.
Soliris™ (eculizumab) is considered experimental, investigational and/or unproven for all other indications, including but not limited to treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS).
NOTE 2: Per the FDA label, life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. The use of Soliris increases a patient's susceptibility to serious meningococcal infections (septicemia and/or meningitis) therefore, Soliris is contraindicated in patients who are not currently vaccinated against Neisseria meningitidis, unless the risks of delaying Soliris treatment outweigh the risks of developing a meningococcal infection.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
PNH, which usually develops in adults, is a disease characterized by red blood cells that develop abnormally. Once the abnormal cells are present in the bloodstream, naturally occurring proteins (called the complement system), designed to destroy bacteria and other infection-causing organisms, break these cells down. This leads to abnormally darkened urine and, more importantly, causes anemia. Depending upon the severity of the disorder, patients with PNH may have pain, fatigue and debilitating weakness, the need for frequent blood transfusions, blood clots, and life-threatening or fatal strokes, heart attacks and intestinal disease. Soliris™ does not cure PNH, but treats the breakdown of red blood cells, the most common characteristic of PNH. Soliris acts to block the complement system activity, including the destruction of PNH red blood cells. Terminal complement inhibition with Soliris increases the susceptibility to serious meningococcal infections. (1)
Atypical Hemolytic Uremic Syndrome (aHUS)
A rare and chronic blood disease that can lead to kidney (renal) failure and is also associated with increased risk of death and stroke. aHUS accounts for 5 to 10 percent of all cases of hemolytic uremic syndrome. The disease disproportionately affects children. Soliris will continue to be available only through a restricted program, and prescribers must enroll in a registration program and provide a medication guide to patients who receive the drug. (2)
The United States (U.S.) Food and Drug Administration (FDA) approved Soliris on March 16, 2007. Soliris is classified as an orphan drug product. (2, 4) Orphan products are developed to treat rare diseases or conditions that affect fewer than 200,000 people in the U.S. (1) The Orphan Drug Act provides a seven-year period of exclusive marketing to the first manufacturer who obtains marketing approval for a designated orphan product. (2, 3, 4)
Soliris is given through intravenous (IV) infusion. The recommended dose of Soliris is dependent on the indication for which the drug is administered and the age of the patient (adult or child). Per the FDA label, documentation that the patient has received a meningococcal vaccine at least two weeks prior to receiving the first dose of Soliris is needed unless there is documentation that the risks of delaying Soliris therapy outweigh the risk of developing a meningococcal infection. Soliris (eculizumab) is not indicated for the treatment of patients with Shiga Toxin E. coli related hemolytic uremic syndrome (STEC-HUS). Soliris is manufactured by Alexion Pharmaceuticals, Inc. (2)
This policy was created in 2008 and based on United States (U.S.) Food and Drug Administration (FDA) approved labeled indications. The policy has been routinely updated with literature searches, particularly for off-labeled use, with the most recent update including searches in the MedLine database and standard reference compendium through September 30, 2017. The following is a summary of key literature to date.
Paroxysmal Nocturnal Hemoglobinuria (PNH)
The U.S. FDA approval of Soliris™ was based on the results of three multi-national clinical studies:
• TRIUMPH, a placebo-controlled 26-week Phase 3 study involving 87 PNH patients,
• SHEPHERD, an open-label 52-week Phase 3 trial involving 97 PNH patients, and
• E05-001, a long-term extension study.
These studies showed that Soliris reduced hemolysis in every treated patient. Hemolysis was dramatically reduced from a baseline lactate dehydrogenase (LDH) of 2,032 U/L to 239 U/L at week 26 (p<0.001). The reductions in hemolysis occurred within one week of initiating treatment and were sustained for periods of up to 54 months with continued dosing of Soliris. The reduction in hemolysis expands the number of circulating PNH cells and, thereby, increases the hemoglobin level. Hemoglobin stabilization and the number of transfused packed red blood cell units, the pivotal study's co-primary endpoints, were both achieved. Half of the Soliris-treated patients achieved hemoglobin stabilization compared with none of the patients in the placebo group; the median number of transfusions was reduced from 10 units/patient to 0 units/patient, respectively (p < 0.001 in both cases). Soliris patients reported less fatigue and improved health-related quality of life. There were fewer thrombotic events with Soliris treatment than during the same period of time prior to treatment. (2, 5-7)
In 2017, UpToDate evaluated all related evidence related to the treatment and prognosis of PNH and provided the following summary of recommendations (8):
• “PNH is a chronic disease with significant morbidity and mortality. The approach to therapy depends on the severity of symptoms and the degree of hemolysis. For patients with classical PNH, allogeneic hematopoietic cell transplantation (HCT) and complement inhibition with eculizumab are the only established therapies.
• For patients with significant disease manifestations attributable to hemolysis, including disabling fatigue, transfusion-dependence, frequent pain paroxysms, worsening renal insufficiency, thrombosis, or other end-organ complications, we recommend eculizumab (Grade 1A). Grade 1A recommendation is a strong recommendation, and applies to most patients in most circumstances without reservation. Clinicians should follow a strong recommendation unless a clear and compelling rationale for an alternative approach is present. Grade A means that the best estimates of the critical benefits and risks come from consistent data from well-performed, Randomized, controlled trials (RCTs) or overwhelming data of some other form (e.g., well-executed observational studies with very large treatment effects). Further research is unlikely to have an impact on the confidence in the estimates of benefit and risk.
• All patients should be vaccinated against Neisseria meningitidis at least 2 weeks prior to the first dose of eculizumab, in addition to receiving daily oral antibiotic prophylaxis. Iron supplementation is not routinely used during eculizumab therapy.
• Allogeneic Hematopoietic Cell Transplantation (HCT) is the only curative therapy for PNH. Several barriers to the use of HCT necessitate its limitation to the most severely affected patients. Results from haploidentical transplants have been encouraging, and we pursue this option for patients with severe cytopenias, those whose disease response to eculizumab is suboptimal, and some patients who do not have access to eculizumab. Such decisions must be made on a case-by-case basis.”
Atypical hemolytic uremic syndrome (aHUS)
Soliris’ safety and effectiveness for aHUS were established in two single-arm trials in 37 adults and adolescent patients with aHUS and one retrospective study in 19 pediatric patients and 11 adult patients with aHUS. Patients treated with Soliris in these studies experienced a favorable improvement in kidney function, including elimination of the requirement for dialysis in several patients with aHUS that did not respond to plasma therapy. Patients treated with Soliris also exhibited improvement in platelet counts and other blood parameters that correlate with aHUS disease activity.
There are no other FDA-approved treatments for aHUS, and the safety and effectiveness of current standard treatment, plasma therapy (plasma exchange or fresh frozen plasma infusion), have not been studied in well controlled trials.
The effectiveness of Soliris in aHUS is based on the effects on thrombotic microangiopathy (TMA) and renal function. Prospective clinical trials in additional patients are ongoing to confirm the benefit of Soliris in patients with aHUS. (3)
In 2017, UpToDate evaluated all related evidence related to the treatment and prognosis of mediated hemolytic uremic syndrome and provided the following summary of recommendations: (9):
• “Recommend the use of eculizumab, a humanized monoclonal antibody to C5, in patients with severe complement-mediated HUS who are at risk for death or End Stage Renal Disease (ESRD; e.g., patients with CFH mutations) (Grade 1B. In patients with severe disease, we suggest plasma therapy as an alternative option (Grade 2B).
• In patients with ESRD, we recommend renal transplantation from a nonrelated donor (Grade 2B). Prior to transplantation, patients should undergo complement genotyping to determine whether or not there is an underlying gene mutation. Living-related donor transplantation is not recommended unless genetic testing has been performed to ensure that the same mutation is not present in the potential living donor.
• Recommend prophylactic administration of eculizumab to prevent recurrent disease in the allograft for renal transplant recipients who are at risk for recurrent disease in the allograft (Grade 1B). These include patients with an identified mutation in CFH, CFI, C3, or CFB, those with high titers of CFH antibodies, or in those with a previous post-transplant episode of recurrent disease. In some patients at risk allograft failure due to recurrent disease, we suggest plasma therapy as an alternative option (Grade 2B).
• Combined liver-renal transplantation provides a definitive cure for complement-mediated HUS with mutations of CFH, CFI, CFB, and C3. However, this procedure carries a significant risk of death in the postoperative period. It should only be performed in pediatric centers with expertise in solid combined organ transplantation and after careful consideration of the risks and benefits for the individual patient”.
UpToDate classifies recommendations, based on grade of evidence.
• “Grade 1B recommendation is a strong recommendation which the best estimates of the critical benefits and risks come from RCTs with important limitations (e.g., inconsistent results, methodologic flaws, imprecise results, extrapolation from a different population or setting) or very strong evidence of some other form. Further research (if performed) is likely to have an impact on our confidence in the estimates of benefit and risk, and may change the estimates.
• Grade 2B recommendation is a weak recommendation; alternative approaches may be better for some patients under some circumstances. The best estimates of the critical benefits and risks come from RCTs with important limitations (e.g., inconsistent results, methodologic flaws, imprecise results, extrapolation from a different population or setting) or very strong evidence of some other form. Further research (if performed) is likely to have an impact on our confidence in the estimates of benefit and risk”.
Other Medical Conditions
In 2015, Cornell et al. (10) examined outcomes beyond 1 year in eculizumab-treated positive crossmatch kidney transplants compared to a historical control group (n=48). The study demonstrated eculizumab treatment does not prevent chronic antibody-mediated rejection in recipients with persistently high B flow crossmatch after positive crossmatch kidney transplantation.
Eculizumab has been investigated for numerous off label conditions/indications, including but not limited to refractory generalized myasthenia gravis, prevention of delayed graft function, acute antibody mediated rejection, systemic lupus erythematosus, and stem-cell transplant-associated thrombotic microangiopathy.
Available studies reported that there were no significant improvements with eculizumab and/or the studies were limited by small and/or heterogeneous patient populations; short-term follow-ups; lack of a control group; potential reporting and publication bias; and heterogeneity of inclusion criteria, outcome measures (for example, methods for determining disease progression) and eculizumab dosing. (11-14)
Professional Guidelines and Position Statements
To date, there are no published practice guidelines for the treatment of PNH or aHUS.
Summary of Evidence
There is inadequate published peer reviewed literature to permit scientific conclusions regarding the safety and efficacy of Soliris (eculizumab) outside of the FDA approved labeled indications for paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS). Additional well-conducted RCTs with sufficiently large sample sizes are needed for other conditions outside of the FDA approved label indication. Per the FDA label, Soliris (eculizumab) is not indicated for the treatment of patients with Shiga Toxin E. coli related hemolytic uremic syndrome (STEC-HUS).
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Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.
The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.
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The following codes may be applicable to this Medical policy and may not be all inclusive.
ICD-9 Diagnosis Codes
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ICD-9 Procedure Codes
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ICD-10 Diagnosis Codes
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ICD-10 Procedure Codes
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The Centers for Medicare and Medicaid Services (CMS) does not have a national Medicare coverage position. Coverage may be subject to local carrier discretion.
A national coverage position for Medicare may have been developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.
1. National Organization of Rare Disorders. Paroxysmal Nocturnal Hemoglobinuria. (2016). Available at <https://rarediseases.org> (accessed October 11, 2017).
2. FDA - Department of Health and Human Services - Soliris® (eculizumab) - Approval Labeling (2007, revised January 2017). Available at <http://www.FDA.gov> (accessed October 10, 2017).
3. FDA - Orphan Drug Act-Relevant Excerpts. Food and Drug Administration. (2013). Available at <http://www.fda.gov> (accessed October 11, 2017).
4. FDA Approves Alexion's Soliris™ for All Patients With PNH - First Therapy Approved for This Rare and Life-Threatening Blood Disease. Alexion Pharmaceuticals, Inc., 2006. Available at: <http://ir.alexion.com> (accessed October 11, 2017).
5. Hillmen P, Young N, Schubert J, et al. The Complement Inhibitor Eculizumab in Paroxsysmal Nocturnal Hemoglobinuria. N Engl J Med (2006 September 21); 355(12):1233- 43. PMID 16990386
6. Young N, Antonioli E, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in patients with paroxysmal nocturnal hemoglobinuria: SHEPHERD phase III clinical study results. Blood (2006); 108:971.
7. Hillmen P, Muus P, et al. The terminal complement inhibitor eculizumab reduces thrombosis in patients with paroxysmal nocturnal hemoglobinuria. Blood (2006); 108:123.
8. Brodsky, R. Treatment and prognosis of paraoxysmal nocturnal hemaglobinuria. In: UpToDate Post TW (Ed), UpToDate, Waltham, MA. Topic last updated: August 09, 2017. Available at: <http://www.uptodate.com> (Accessed October 10, 2017).
9. Niaudet P. Complement-mediated hemolytic uremic syndrome. In: UpToDate Post TW (Ed), UpToDate, Waltham, MA. Topic last updated: June 30, 2017. Available at: <http://www.uptodate.com> (Accessed October 10, 2017).
10. Cornell L, Schinstock C, Gandhi M, et al. Positive crossmatch kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. Am J Transplant. 2015 May; 15(5):1293-302. PMID 25731800
11. Howard Jr JF, Barohn R, Cutter G, et al. A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle & Nerve. Mar 20 2013; 48:76-84. PMID 23512355
12. Kim M, Martin S, Townsend K, et al. Antibody-mediated rejection in kidney transplantation: a review of pathophysiology, diagnosis, and treatment options. Pharmacotherapy 2014; 34(7):733-44. PMID 24753207
13. de Fontbrune F, Galambrun C, Sirvent A, et al. Use of eculizumab in patients with allogeneic stem cell transplant-associated thrombotic microangiopathy: A study from the SFGM-TC. Transplantation. 2015 Sep; 99(9):1953-9. PMID 25651309
14. El-Husseini A, Hannan S, Awad A, et al. Thrombotic microangiopathy in systemic lupus erythematosus: efficacy of eculizumab. Am J Kidney Dis. 2015 Jan; 65(1):127-30. PMID 25446020
15. DrugPoint® Summary—Eculizumab. Thomson Reuters (Healthcare) Inc., Microdex®1.0 (Healthcare Series). Available at <http://www. http://www.micromedexsolutions.com> (accessed September 26, 2017).
|11/15/2018||Reviewed. No changes.|
|6/1/2018||Document updated with literature review. The following changes were made in Coverage: 1) Added requirement for documentation that the risk of delaying Soloris therapy outweigh the risk of developing a meningococcal infection to the paroxysmal nocturnal hemoglobinuria (PNH) criteria and atypical hemolytic uremic syndrome criteria. 2) Added medical necessity criteria for generalized myasthenia gravis due to new FDA approved indication; 2) Added note 1 to refer to the Description Section for the MGFA Clinical Classification Guidelines and the MG-ADL profile. 3) Added note 2 : Per FDA label, life-threatening and fatal meningococcal infections have occurred in patients treated with Soliris. The use of Soliris increases a patient's susceptibility to serious meningococcal infections (septicemia and/or meningitis) therefore, Soliris is contraindicated in patients who are not currently vaccinated against Neisseria meningitidis , unless the risks of delaying Soliris treatment outweigh the risks of developing a meningococcal infection. 4) Added references 1, 4, 8-15.|
|12/1/2016||Reviewed. No changes.|
|1/1/2015||Document updated with literature review. Coverage unchanged.|
|12/15/2012||Document updated with literature review. The following was added: 1) Soliris (eculizumab) may be considered medically necessary to treat patients with atypical hemolytic uremic syndrome (aHUS) with documentation that the patient has received a meningococcal vaccine at least two weeks prior to receiving the first dose of Soliris. 2) Treatment of patients with Shiga toxin E. coli related hemolytic uremic syndrome (STEC-HUS) was added as an example of experimental, investigational, and unproven indications. Title changed from Soliris for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH).|
|1/1/2011||Document updated with literature review. Coverage unchanged.|
|1/15/2008||New medical document|
|Title:||Effective Date:||End Date:|
|Soliris for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH)||01-01-2011||12-14-2012|
|Soliris for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH)||02-15-2009||12-31-2010|
|Soliris for the Treatment of Paroxysmal Nocturnal Hemoglobinuria (PNH)||01-01-2008||02-14-2009|