Coverage Policy Manual
Policy #: 2021036
Category: Pharmacy
Initiated: November 2021
Last Review: August 2023
  Iobenguane I 131 (e.g., Azedra®)
Description:
Iobenguane I 131 is structurally similar to norepinephrine (NE) and taken up by NE transporter in adrenergic nerve terminals and accumulates in adrenergically innervated tissues including tumors of the neural crest. Individuals are treated with Iobenguane scan positive, unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma (PPGL) who require systemic anticancer therapy. I 131 decays with beta and gamma emissions with a physical half-life of 8.021 days. Pheochromocytoma and paraganglioma are tumors of neural crest origin that express high levels of the norepinephrine transporter on their cell surfaces. Following intravenous administration, iobenguane I 131 is taken up and accumulates within pheochromocytoma and paraganglioma cells, and radiation resulting from radioactive decay of I 131 causes cell death and tumor necrosis.
 
Regulatory Status
 
The FDA approved Iobenguane I-131 July 30, 2018, for the treatment of adults and adolescents aged 12 or older with rare tumors of the adrenal gland (pheochromocytomas and paragangliomas).  
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize a radiation oncology benefits management program, Prior Approval is required for this service and is managed through the radiation oncology benefits management program.
 
Effective August 23, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
A single course of Iobenguane I 131 meets member benefit certificate primary coverage criteria that there be scientific effectiveness in improving health outcomes as indicated for the treatment of adult and pediatric individuals 12 years and older with pheochromocytoma or paraganglioma who require systemic anticancer therapy when ALL of the following conditions are met:
 
    1. Individual is age 12 years or older AND 
    2. Iobenguane scan-positive AND 
    3. Individual has an ECOG performance status of 0-2 AND 
    4. Individual has not received prior treatment with a radiolabeled somatostatin analog AND 
    5. Adequate bone marrow reserve (platelet count > 80,000/mcL or absolute neutrophil count > 1,200/mcL) AND
    6. Unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma AND 
    7. Verify pregnancy status in females of reproductive potential prior to administering Iobenguane I 131 AND
    8. Treatment is given as per FDA weight-based dosing guidelines as administered generally as two therapeutic doses with 90 days between doses. Consideration to additional doses (up to a total of 4) may be given based on idividual case consdierations so long as the maximum cumulative radiation dose is not exceeded. (NCCN V 1.2023)
 
Dosage and Administration
Dosing per FDA Guidelines
 
Administer Iobenguane I 131 intravenously as a dosimetric dose followed by two therapeutic doses administered 90 days apart.
 
The recommended dosimetric dose is:
1.  Individuals greater than 50 kg: 185 to 222 MBq (5 to 6 mCi)
2.  Individuals 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg)
 
The recommended therapeutic dose for each of the 2 doses is:  
1.  Individuals greater than 62.5 kg: 18,500 MBq (500 mCi)
2.  Individuals 62.5 kg or less: 296 MBq/kg (8 mCi/kg)
 
Adjust Iobenguane I 131 therapeutic doses based on radiation dose estimates results from dosimetry, if needed.
 
Iobenguane I 131 is available as 555 MBq/mL (15 mCi/ml) at TOC as a clear solution in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Iobenguane I 131 does not meet member benefit primary coverage criteria that there be scientific evidence in improving health outcomes for any inidication or circumstance not described above.
 
For members with contracts without primary coverage criteria, the use of Iobenguane I 131, for any indication or circumstance not described above, is considered is investigational.
  
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective August 10, 2022 to August 22, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
A single course of Iobenguane I 131 meets member benefit certificate primary coverage criteria that there be scientific effectiveness as indicated for the treatment of adult and pediatric individuals 12 years and older with pheochromocytoma or paraganglioma who require systemic anticancer therapy when ALL of the following conditions are met:
 
FDA 2018 Indications
    1. Individual is age 12 years or older  
    2. Iobenguane scan-positive
    3. Individual has an ECOG performance status of 0-2.
    4. Individual has not received prior treatment with a radiolabeled somatostatin analog.
    5. Adequate bone marrow reserve (platelet count > 80,000/mcL or absolute neutrophil count > 1,200/mcL)
    6. Unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma
    7. Verify pregnancy status in females of reproductive potential prior to administering Iobenuane I 131.  
 
Dosage and Administration
    1. Administer Iobenguane I 131 intravenously as a dosimetric dose followed by two therapeutic doses administered 90 days apart.
    2. The recommended dosimetric dose is:
a.  Individuals greater than 50 kg: 185 to 222 MBq (5 to 6 mCi)
b.  Individuals 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg)
3. The recommended therapeutic dose for each of the 2 doses is:  
a.  Individuals greater than 62.5 kg: 18,500 MBq (500 mCi)
b.  Individuals 62.5 kg or less: 296 MBq/kg (8 mCi/kg)
4.  Adjust Iobenuane I 131 therapeutic doses based on radiation dose estimates results from dosimetry, if needed.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Iobenguane I 131 does not meet primary coverage criteria that there be scientific evidence of effectiveness when:
    1. The above criteria are not met and for all other indication
    2. Given as a repeat course of treatment
    3. Treatment given with Iobenguane I 131 was given in the past 90 days.
    4. Used for any other indication not included above.
 
For individuals with contracts without primary coverage criteria, the use of Iobenguane I 131 is investigational when:
    1. The above criteria are not met and for all other indication
    2. Given as a repeat course of treatment
    3. Treatment given with Iobenguane I 131 was given in the past 90 days.
    4. Used for any other indication not included above.
  
Investigational services are specific contract exclusions in most member benefit certificates of coverage.  
 
Effective November 2021 August 9, 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
A single course of Iobenguane I 131 (Azedra) meets member benefit certificate primary coverage criteria that there be scientific effectiveness as indicated for the treatment of adult and pediatric patients 12 years and older with pheochromocytoma or paraganglioma who require systemic anticancer therapy when ALL of the following conditions are met:
 
FDA 2018 Indications
  1. Individual is age 12 years or older  
  2. Iobenguane scan-positive
  3. Adequate bone marrow reserve (platelet count > 80,000/mcL or absolute neutrophil count > 1,200/mcL)
  4. Unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma
  5.  Verify pregnancy status in females of reproductive potential prior to administering AZEDRA  
 
Dosage and Administration
  1. Administer AZEDRA intravenously as a dosimetric dose followed by two therapeutic doses administered 90 days apart.
  2. The recommended dosimetric dose is:
a.  Patients greater than 50 kg: 185 to 222 MBq (5 to 6 mCi)
b.  Patients 50 kg or less: 3.7 MBq/kg (0.1 mCi/kg)
3.  The recommended therapeutic dose for each of the 2 doses is:  
a.  Patients greater than 62.5 kg: 18,500 MBq (500 mCi)
b.  Patients 62.5 kg or less: 296 MBq/kg (8 mCi/kg)
4.  Adjust AZEDRA therapeutic doses based on radiation dose estimates results from dosimetry, if needed.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
The use of Iobenguane I 131 (Azedra) does not meet primary coverage criteria that there be scientific evidence of effectiveness when:
  1. The above criteria are not met and for all other indication
  2. Given as a repeat course of treatment
  3. Treatment given with Iobenguane I 131 (Azedra) was given in the past 90 days.
 
For members with contracts without primary coverage criteria, the use of Iobenguane I 131 (Azedra) is investigational when:
  1. The above criteria are not met and for all other indication
  2. Given as a repeat course of treatment
  3. Treatment given with Iobenguane I 131 (Azedra) was given in the past 90 days.
  
Investigational services are specific contract exclusions in most member benefit certificates of coverage.  
Rationale:
Pheochromocytoma and paraganglioma are rare neuroendocrine cancers that arise from the chromaffin cells of the adrenal gland or extra-adrenal autonomic paraganglia. Hypersecretion of catecholamine often leads to hypertension, headaches, and sweating. Treatment of local disease classically has required resection or radiation therapy, while systemic disease is treated with chemotherapy. The FDA approved 131I iobenguane (Azedra®) in 2018 for the treatment of adult and pediatric patients 12 years and older with iobenguane scan-positive, unresectable, locally advanced, or metastatic pheochromocytoma or paraganglioma who require systemic anticancer therapy.
 
In an open-label, single-arm, multicenter phase II clinical trial (Study IB12B [NCT00874614]), patients (N = 81) 12 years and older with iobenguane scan-positive, unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma were treated with iobenguane I 131. Of 81 patients enrolled, 74 patients received a dosimetric dose of iobenguane I 131. Sixty-eight patients received 1 therapeutic dose (FA) and 50 received 2 as per protocol (PP). At study entry, 52% (35/68) had prior surgery and systemic therapy (I-131 MIBG and/or chemotherapy) for pheochromocytoma or paraganglioma. Greater than 50% tumor reduction occurred in 25% (95% CI, 16%-37%) of FA and 32% (95% CI, 21%-46%) of PP patients. The 12-month overall survival was 91% in FA patients and the median overall survival was 36.7 months (95% CI, 29.9-49.1). Survival was not affected by lung or liver metastases (Pryma et al. 2019). Also included in the FDA review was the Phase II trial (Trial 1[NCT01413503]) used for refinement of dosing and for evaluation of adverse events. The most common grade 3-4 adverse reactions (≥ 10%) were lymphopenia, neutropenia, thrombocytopenia, fatigue, anemia, increased international normalized ratio, nausea, dizziness, hypertension, and vomiting. In the pooled safety population, 6.8% of patients who received a therapeutic dose of iobenguane I 131 developed myelodysplastic syndrome or acute leukemia (US FDA, 2018).
 
In a 1997 review of 116 pheochromocytoma patients treated with 131I metaiodobenzylguanidine, Loh et al reported that initial symptomatic improvement was achieved in 76% of patients, tumor response in 30%, and hormonal response in 45%.33 Additional smaller studies have resulted in similar findings (Rose et al. 2003; Fitzgerald et al. 2006; Rutherford et al. 2015; Noto et al. 2018; Mukherjee et al. 2001; Krempf, et al. 1991) .Objective response rates are approximately 30% with a larger proportion having stabilized disease. Limited evidence supports the use of larger doses (above 500mCi), and therefore should only be used in the setting of a clinical trial (Rose et al. 2003; Gonias et al. 2009).
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
A9508Iodine i 131 iobenguane sulfate, diagnostic, per 0.5 millicurie
A9590Iodine i 131, iobenguane, 1 millicurie
References: Fitzgerald PA, Goldsby RE, Huberty JP, et al.(2006) Malignant pheochromocytomas and paragangliomas: a phase II study of therapy with high-dose 131I-metaiodobenzylguanidine (131I-MIBG). Ann N Y Acad Sci. 2006;1073:465-90. PMID: 17102115

Gonias S, Goldsby R, Matthay KK, et al.(2009) Phase II study of high-dose [131I]metaiodobenzylguanidine therapy for patients with metastatic pheochromocytoma and paraganglioma. J Clin Oncol. 2009;27(25):4162-8. PMID: 19636009

Krempf M, Lumbroso J, Mornex R, et al.(1991) Use of m-[131I]iodobenzylguanidine in the treatment of malignant pheochromocytoma. J Clin Endocrinol Metab. 1991;72(2):455-61. PMID: 1991814

Matthay KK, et al.(1997) The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients. J Endocrinol Invest. 1997;20(11):648-58. PMID: 9492103

Mukherjee JJ, Kaltsas GA, Islam N, et al.(2001) Treatment of metastatic carcinoid tumours, phaeochromocytoma, paraganglioma and medullary carcinoma of the thyroid with (131)I-meta-iodobenzylguanidine [(131)I-mIBG]. Clin Endocrinol (Oxf). 2001;55(1):47-60. PMID: 11453952

National Comprehensive Cancer Network (NCCN).(2023) National Comprehensive Cancer Network, Inc. 2023 Practice Guidelines in Oncology-Neuroendocrine and Adrenal Tumors v.1.2023. Iobenguane I 131. Available at nccn.org. Accessed August 22, 2023.

Noto RB, Pryma DA, Jensen J, et al.(2018) Phase 1 study of high-specific-activity I-131 MIBGfor metastatic and/or recurrent pheochromocytoma or paraganglioma. J Clin Endocrinol Metab. 2018;103(1):213-20. PMID: 29099942

Pryma DA, Chin BB, Noto RB, et al.(2019) Efficacy and safety of high-specific-activity 131-I-MIBG therapy in patients with advanced pheochromocytoma or paraganglioma. J Nucl Med. 2019;60(5):623-30. PMID: 30291194

Rose B, Matthay KK, Price D, et al.(2003) . High-dose 131I-metaiodobenzylguanidine therapy for 12 patients with malignant pheochromocytoma. Cancer. 2003;98(2):239-48. PMID: 12872341

Rutherford MA, Rankin AJ, Yates TM, et al.(2015) Management of metastatic phaeochromocytoma and paraganglioma: use of iodine-131-meta-iodobenzylguanidine therapy in a tertiary referral centre. QJM. 2015;108(5):361-8. PMID: 25267727

U.S. Food and Drug Administration (FDA). (2018)(2018) Azedra. Prescribing Information. [Revised 7/2018]) Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/209607s000lbl.pdf. Last accessed July 26,2021.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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