Coverage Policy Manual
Policy #: 1997105
Category: Pharmacy
Initiated: December 1993
Last Review: September 2023
  Interferon Gamma-1B
Description:
Interferon gamma-1b (e.g., Actimmune) is a genetically engineered interferon gamma that has immunomodulatory properties. Interferon gamma has potent phagocyte-activating effects not seen with other interferon preparations, including generation of toxic oxygen metabolites within phagocytes, which are capable of mediating the killing of microorganisms. A randomized, double-blind, placebo controlled study in individuals (ages 1 - 44 years) with chronic granulomatous disease (an inherited disorder characterized by deficient phagocyte oxidative metabolism) decreased the incidence of serious infection when administered subcutaneously three times weekly.
 
Coding
 
See CPT/HCPCS Code section below.
 
Policy/
Coverage:
Asfotase alfa is not covered under the medical benefit. Please check the member’s pharmacy benefit for coverage. This policy applies to members whose plan utilizes AR BCBS pharmacy and has asfotase alfa as a formulary option. (Please see Coverage Policy 2020005, Self-Administered Medication)
 
Effective September 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Interferon gamma-1b meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
 
Non-oncologic:
 
    1. Individual has one of the following:
a. Chronic granulomatous disease of childhood; OR
b. Delaying time to disease progression in individuals with severe, malignant osteopetrosis; AND
2. Individual does not have idiopathic pulmonary fibrosis; AND
3. Must be dosed in accordance with the FDA label.
 
Oncologic:
 
    1. Primary Cutaneous Lymphomas:
a. Mycosis Fungoides/Sezary Syndrome
i. Preferred systemic therapy as primary treatment for:
          1. Stage IIB MF with limited tumor lesions, with or without local radiation therapy (NCCN 2A)
          2. Stage IIB MF with generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
          3. Stage III MF, with or without skin-directed therapy (NCCN 2A)
          4. Stage IVA1 or IVA2 Sezary syndrome (NCCN 2A)
ii. Preferred systemic therapy as subsequent treatment for:
          1. Stage IA MF that is refractory to multiple previous therapies, with or without skin-directed therapy (NCCN 2A)
          2. Relapsed stage IIB MF with T3 limited tumor lesions, with or without local radiation therapy (NCCN 2A)
          3. Persistent stage IIB MF with T1-3 limited tumor lesions, with or without local radiation therapy (NCCN 2A)
          4. Relapsed stage IIB MF with T3 generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
          5. Persistent stage IIB MF with T1-3 generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
          6. Relapsed or persistent stage III MF, with or without skin-directed therapy (NCCN 2A)
          7. Stage III MF that is refractory to multiple previous therapies (NCCN 2A)
          8. Relapsed or persistent stage IVA1 or IVA2 Sezary syndrome (NCCN 2A)
iii. Skin-directed/systemic combination therapy (phototherapy + interferon) or systemic/systemic combination therapy (photopheresis + interferon, photopheresis + retinoid + interferon, or retinoid + interferon) as primary treatment for:
          1. Stage IB-IIA MF with a higher skin disease burden (e.g., predominantly plaque disease), with or without skin-directed therapy (NCCN 2A)
          2. Stage IIB MF with generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
          3. Stage III MF (preferred) (NCCN 2A)
          4. Stage IVA1 or IVA2 Sezary syndrome (preferred) (NCCN 2A)
iv. Skin-directed/systemic combination therapy (phototherapy + interferon or systemic/systemic combination therapy (photopheresis + interferon, photopheresis + retinoid + interferon, or retinoid + interferon) as subsequent treatment for:
          1. Stage IB-IIA MF with a higher skin disease burden (e.g., predominantly plaque disease) that is relapsed or persistent with T1-T2 disease, with or without skin-directed therapy (NCCN 2A)
          2. Stage IB-IIA MF with a higher skin disease burden (e.g., predominantly plaque disease) that is refractory to multiple previous therapies, with or without skin-directed therapy (NCCN 2A)
          3. Relapsed stage IIB MF with T3 generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
 
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).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of interferon gamma 1b is 50 mcg/square meters for individuals whose body surface area is greater than 0.5 square meters and 1.5 mcg/kg/dose for individuals whose body surface area is equal to or less than 0.5 square meters three times weekly.
 
Interferon gamma 1b is available as 100 mcg (2 million International Units) in 0.5 mL solution in a single use vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Interferon gamma-1b, for any indication or circumstance not described, does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  
 
For members with contracts without primary coverage criteria, interferon gamma-1b for any indication or circumstance not described, is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective November 1, 2021 to August 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Interferon gamma-1b meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
 
Non-oncologic:
 
    • for patients with chronic granulomatous disease of childhood.
    • for delaying time to disease progression in patients with severe, malignant osteopetrosis
 
Oncologic:
 
    • Primary Cutaneous Lymphomas:
        • Mycosis Fungoides/Sezary Syndrome
              • preferred systemic therapy as primary treatment for:
                  • stage IIB MF with limited tumor lesions, with or without local radiation therapy (NCCN 2A)
                  • stage IIB MF with generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
                  • stage III MF, with or without skin-directed therapy (NCCN 2A)
                  • stage IVA1 or IVA2 Sezary syndrome (NCCN 2A)
              • preferred systemic therapy subsequent treatment for:
                  • stage IA MF that is refractory to multiple previous therapies, with or without skin-directed therapy (NCCN 2A)
                  • relapsed stage IIB MF with T3 limited extent lesions, with or without local radiation therapy (NCCN 2A)
                  • persistent stage IIB MF with T1-3 limited tumor lesions, with or without local radiation therapy (NCCN 2A)
                  • relapsed stage IIB MF with T3 generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
                  • persistent stage IIB MF with T1-3 generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
                  • relapsed or persistent stage III MF, with or without skin-directed therapy (NCCN 2A)
                  • stage III MF that is refractory to multiple previous therapies (NCCN 2A)
                  • relapsed or persistent stage IVA1 or IVA2 Sezary syndrome (NCCN 2A)
              • Skin-directed/systemic combination therapy (phototherapy + interferon) or systemic/systemic combination therapy (photopheresis + interferon, photopheresis + retinoid + interferon, or retinoid + interferon) as primary treatment for:
                  • stage IB-IIA MF with a higher skin disease burden (eg, predominantly plaque disease), with or without skin-directed therapy (NCCN 2A)
                  • stage IIB MF with generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
                  • stage III MF (preferred) (NCCN 2A)
                  • stage IVA1 or IVA2 Sezary syndrome (preferred) (NCCN 2A)
              • Skin-directed/systemic combination therapy (phototherapy + interferon or systemic/systemic combination therapy (photopheresis + interferon, photopheresis + retinoid + interferon, or retinoid + interferon) as subsequent treatment for:
                  • stage IB-IIA MF with a higher skin disease burden (eg, predominantly plaque disease) that is relapsed or persistent with T1-T2 disease, with or without skin-directed therapy (NCCN 2A)
                  • stage IB-IIA MF with a higher skin disease burden (eg, predominantly plaque disease) that is refractory to multiple previous therapies, with or without skin-directed therapy (NCCN 2A)
                  • relapsed stage IIB MF with T3 generalized tumor lesions, with or without skin-directed therapy (NCCN 2A)
 
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).
 
Dosage and administration
 
    • Per FDA label guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Interferon gamma-1b for any other disease, including but not limited to idiopathic pulmonary fibrosis, does not meet primary coverage criteria that there be scientific evidence of effectiveness.  
 
For members with contracts without primary coverage criteria, the use of interferon gamma-1b for any other disease not specifically listed as covered is considered investigational.  
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
 
Effective October 2019 to October 31, 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Interferon gamma-1b, or Actimmune®, meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
 
    • for patients with chronic granulomatous disease of childhood.
    • for infants with osteopetrosis
 
NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
 
Dosage and administration:
 
  • Per FDA label guidelines
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Interferon gamma-1b for any other disease, including but not limited to idiopathic pulmonary fibrosis, does not meet primary coverage criteria that there be scientific evidence of effectiveness.  
 
For members with contracts without primary coverage criteria, the use of interferon gamma-1b for any other disease not specifically listed as covered is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective October 2018 to September 2019
 
Interferon gamma-1b, or Actimmune®, meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
    • for patients with chronic granulomatous disease of childhood .
    • for infants with osteopetrosis
    • NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030
 
Interferon gamma-1b for any other disease, including but not limited to idiopathic pulmonary fibrosis, does not meet primary coverage criteria that there be scientific evidence of effectiveness.  
 
For members with contracts without primary coverage criteria, the use of interferon gamma-1b for any other disease not specifically listed as covered is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective prior to October 2018
 
Interferon gamma-1b, or Actimmune, meets primary coverage criteria for effectiveness and is covered for patients with chronic granulomatous disease of childhood.  Interferon gamma-1b meets primary coverage criteria for effectiveness and is covered for infants with osteopetrosis.  
 
Interferon gamma-1b for any other disease, including but not limited to idiopathic pulmonary fibrosis, does not meet Primary Coverage Criteria.  The Criteria exclude coverage of interventions if there is a lack of scientific evidence regarding the intervention, or if the available scientific evidence is in conflict or the subject of continuing debate. certificate primary coverage criteria.
 
For members with contracts without primary coverage criteria, the use of  interferon gamma-1b for any other disease not specifically listed as covered  is considered investigational.  Investigational services are an exclusion in the member certificate of coverage.
Rationale:
In 2004 Raghu et. al. published results of a study of 330 patients at 58 centers.  Sixty patients discontinued treatment prematurely, 33 of 162 in the interferon gamma-1b group and 27 of 168 in the placebo group.  An average of all scheduled doses received was 94% for the test drug group and 92% for the placebo group.  "No treatment effect was discernible with respect to the mean change from base line to week 48 in the FVC (-2.0 liter in the interferon gamma-1b group and 0.16 liter in the placebo group), the P(A-a)O2 (3.3 and 2.9 mm Hg, respectively).  There was also no significant difference between the groups in the mean change in lung fibrosis on high-resolution CT…"  During this study a trend toward enhanced overall survival (not an endpoint) was observed in the randomized patients receiving interferon gamma-1b.  An absolute reduction in the risk of death was 7% in the placebo group and 9% in the drug group. The study design and data did not allow researchers to draw treatment inferences.  
 
A follow up study to include patients with less advanced disease. FVC > 55% of predicted and a DLCO of > 35% of predicted was started in Dec 2003, the INSPIRE trial.  On 3/9/07 the FDA notified healthcare professionals of the early termination of the INSPIRE clinical study of Interferon Gamma 1-b for the treatment of idiopathic pulmonary fibrosis (IPF).  The study was discontinued when an interim analysis showed no benefit in IPF patients who received the drug.  The trial compared survival in patients receiving Interferon Gamma 1-b to patients who received a placebo.  The analysis showed 14.5% of patients receiving Interferon Gamma 1-b died compared to 12.7% of patients who received the placebo.
 
In 2006 several authors (Nathan, Walter, Daniels) all agreed that long-term survival in idiopathic pulmonary fibrosis is poor and treatment remains controversial.
 
2008 Update
A search of PubMed through August 2008 failed to find reports of any trials or studies that would change the current coverage statements.
 
2011 Update
A search of the MEDLINE database was conducted through February 2011.  There was no new literature identified that would prompt a change in the coverage statement.
 
King and colleagues reported on a multi-center randomized, placebo controlled trial assessing the effectiveness of interferon gamma-1B in the treatment of patients with idiopathic pulmonary fibrosis (King, 2009).  The INSPIRE trial enrolled 826 patients from 81 centers in Europe, United States and Canada.  The trial was terminated after data from the second interim analysis failed to show benefit in patients treated with interferon gamma-1B compared with those treated with placebo. After an average duration of 64 weeks of treatment, 15% of patients treated with interferon gamma-1B had died compared with 13% in the placebo group.  The authors concluded that the results of their study, “the largest randomised controlled clinical trial in patients with idiopathic pulmonary fibrosis, conclusively refute the findings that interferon gamma-1B improves survival”.  The results of this study further supports our coverage statement regarding the treatment of idiopathic pulmonary fibrosis with interferon gamma-1B.
 
2012 Update
A search of the MEDLINE database was conducted through September 2012.  There was no new information identified that would prompt a change in the coverage statement. Interferon Gamma-1B is currently approved by the U.S. Food and Drug Administration (FDA) only for the treatment of chronic granulomatous disease and osteopretrosis.
 
2014 Update
A search of the MEDLINE database was conducted through September 2014. There was no new information identified that would prompt a change in the coverage statement.
  
2015 Update
A literature search conducted through September 2015 did not reveal any new information that would prompt a change in the coverage statement.
 
2016 Update
A search of the MEDLINE database was conducted through September 2016. There was no new information identified that would prompt a change in the coverage statement.
 
2018 Update
A search of the MEDLINE database was conducted through September 2018. There was no new information identified that would prompt a change in the coverage statement.
 
2019 Update
A literature search conducted through October 2019 did not reveal any new information that would prompt a change in the coverage statement.
 
2020 Update
A literature search conducted through October 2020 did not reveal any new information that would prompt a change in the coverage statement.
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2021. No new literature was identified that would prompt a change in the coverage statement.
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
J9216Injection, interferon, gamma 1 b, 3 million units
References: Daniels CE, Ryu JH.(2006) Treatment of idiopathic pulmonary fibrosis. Semin Respir Crit Care Med. 2006; 27(6):668-76.

FDA Labeling 1993.

King Jr. TE, Albera C, Bradford WZ et al.(2009) Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomized, placebo-controlled trial. Lancet 2009; 374:222-228.

Nathan SD.(2005) Therapeutic Intervention. Assessing the role of the International Consensus Guidelines. Chest. 2005; 128:533S-539S.

Nathan SD.(2006) Therapeutic management of idiopathic pulmonary fibrosis: an evidence-based approach. Clin Chest Med. 2006; 27(1 suppl 1):S27-35.

National Comprehensive Cancer Network (NCCN).(2021) Primary Cutneous Lymphomas v.2.2021. Accessed at https://www.nccn.org/professionals/drug_compendium/content/. Accessed August 31, 2021.

Pacanowski MA, Amsden GW.(2005) Interferon gamma-1b in the treatment of idiopathic pulmonary fibrosis. Ann Pharmacother. 2005; 39(10):1678-86.

Raghu G, Brown KK, et al.(2004) A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. New Eng J Med. 2004; 350:125-33.

Teirstein AS.(2004) The elusive goal of therapy for usual interstitial pneumonia. New Engl J Med. 2004;350:181-3.

Walter N, Collard HR, King TE Jr.(2006) Current perspectives on the treatment of idiopathic pulmonary fibrosis. Proc Am Thorac Soc. 2006; 3(4):330-8.

www.clinical trials.gov accessed 9/30/08.
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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