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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J1000-45

Original Effective Date: 01/01/12

Reviewed: 11/09/16

Revised: 04/15/16

Subject: Everolimus (Afinitor®, Afinitor Disperz®) Tablets

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Position Statement Dosage/ Administration Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates  
           

DESCRIPTION:

Everolimus is currently marketed under three proprietary names: Afinitor®, Afinitor Disperz®, and Zortress®. Afinitor and Afinitor Disperz are antineoplastic agents that exert their activity through inhibition of mammalian target of rapamycin (mTOR). The mTOR pathway is dysregulated in many human cancers and inhibition of the pathway has been shown to reduce cell proliferation, angiogenesis, and glucose uptake by the tumor.

Zortress is a macrolide immunosuppressant and is structurally related to sirolimus. It is indicated for kidney and liver transplant prophylaxis. The contents of this medical coverage guideline apply only to the use of Afinitor and Afinitor Disperz.

POSITION STATEMENT:

Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

I. Initiation of everolimus (Afinitor, Afinitor Disperz) meets the definition of medical necessity when used to treat an indication listed in Table 1, all of the indication specific criteria are met, and the dose does not exceed 10 mg daily* using the fewest number of tablets:

Table 1

Indication

Specific Criteria

Afinitor

Breast cancer

ALL of the following:

1. Member is postmenopausal

2. Member has hormone receptor positive (HR+)/ human epidermal growth factor receptor type 2 (HER2)-negative breast cancer

3. Member has recurrent or metastatic disease

4. Member’s prior endocrine therapy included a nonsteroidal aromatase inhibitor (e.g., letrozole [Femara] or anastrozole [Arimidex]) or tamoxifen

5. Everolimus will be used in combination with exemestane (Aromasin)

Hodgkin Lymphoma

When used as a single agent for ONE of the following:

1. Relapsed or refractory disease in adults 18 years of age or older

2. Palliative therapy for adults greater than 60 years of age

Kidney Cancer

ALL of the following:

1. Everolimus will be used as a single agent or in combination with lenvatinib*

2. Member has relapsed or surgically unresectable stage IV disease

3. ONE of the following:

a. When used as subsequent therapy for disease with predominant clear cell histology

b. When used for treatment of disease with non-clear cell histology

Neuroendocrine tumor of the Gastrointestinal (GI) tract, Lung, or Thymus

When used for ONE of the following:

1. Unresectable locoregional disease

2. Metastatic disease

Osteosarcoma

When used as second-line therapy in combination with sorafenib and member has relapsed, refractory or metastatic disease

Pancreatic neuroendocrine tumor (pNET)

When used as a single agent in member’s with unresectable locoregional or distant metastatic disease and ONE of the following:

1. Progressive disease

2. Symptomatic disease

3. Significant tumor burden

Renal angiomyolipoma with tuberous sclerosis complex (TSC)

Member’s disease does not require immediate surgery

Soft-tissue sarcoma (STS)

When used as a single agent in members diagnosed with ONE of the following:

1. Perivascular epithelioid cell tumor(s) (PEComa)

2. Recurrent angiomyolipoma

3. Recurrent lymphangioleiomyomatosis

Subependymal giant cell astrocytoma (SEGA) with tuberous sclerosis complex (TSC)*

Member cannot be curatively resected

Thymomas or Thymic carcinoma

When used as a single agent as second-line therapy

Thyroid cancer;

Follicular carcinoma

Hurthle cell carcinoma

Papillary carcinoma

When used as a single agent for iodine-refractory symptomatic or progressive disease classified as ONE of the following:

1. Unresectable locoregional disease that is recurrent or persistent

2. Distant metastatic disease

Waldenström's macroglobulinemia / lymphoplasmacytic lymphoma

When used as a single agent for ONE of the following:

1. Relapsed disease

2. Progressive disease

3. For previously treated disease unresponsive to primary therapy

Afinitor Disperz

Subependymal giant cell astrocytoma with tuberous sclerosis complex*

Member cannot be curatively resected

HR+, hormone-receptor positive; HER2, human epidermal growth factor receptor type 2; NET, neuroendocrine tumor; PNET, pancreatic neuroendocrine tumor; RCC, renal cell carcinoma; SEGA, subependymal giant cell astrocytoma; STS, soft-tissue sarcoma; TSC, tuberous sclerosis complex

Approval duration: 6 months (all indications)

II. Everolimus (Afinitor) meets the definition of medical necessity when used as a single agent for the following designated Orphan Drug indication (http://www.fda.gov/orphan/designat/list.htm) when the dose does not exceed the maximum FDA-approved dosing:

1. Hepatocellular carcinoma

Approval duration: 6 months

III. Continuation of everolimus (Afinitor®, Afinitor Disperz®,) meets the definition of medical necessity for the indications in Table 1 and orphan indications above when the following criteria are met:

A. The member’s disease has not progressed while receiving treatment with everolimus

B. The member has been previously approved by Florida Blue or another health plan in the past 2 years, OR the member has previously met all indication-specific criteria for coverage

C. The dose does not exceed 10 mg once daily* and will be provided using the fewest number of tablets

Approval duration: 1 year

*NOTE: A maximum dose of 5 mg once daily is permitted when use is in combination with lenvatinib for kidney cancer. A dose greater than 10 mg daily will be permitted for FDA-approved indications. Per FDA- labeling, subependymal giant cell astrocytoma (SEGA) with tuberous sclerosis complex (TSC) dosing is 4.5 mg/m2 once daily and may be modified to attain trough concentrations of 5-15 ng/mL. Avoid use with strong CYP3A4/P-glycoprotein inhibitors and inducers. If CYP3A4/P-glycoprotein strong inducers (e.g. phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) cannot be avoided, the dose may need to be increased to 9 mg/m2 and modified using therapeutic drug monitoring when used for SEGA with TSC. If CYP3A4/P-glycoprotein strong inducers cannot be avoided for other indications (breast cancer, pNET, RCC, renal angiomyolipoma with TSC), the dose may need to be increased using increments of 5 mg or less. A dose reduction should be considered for all labeled indications if coadministration with CYP3A4/P-glycoprotein inhibitors cannot be avoided. The dose for orphan indications should not exceed the maximum FDA approved dosing.

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

Afinitor FDA-approved indications:

• Treatment of advanced breast cancer in postmenopausal women when the disease is hormone-receptor positive, HER2-negative, the individual has failed letrozole or anastrozole and everolimus will be used in combination with exemestane.

• Adults with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic

• Adults with advanced renal cell carcinoma (RCC) following sunitinib or sorafenib failure

• Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC) not requiring immediate surgery

• Pediatrics and adults with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

Afinitor Disperz FDA-approved indications:

• Pediatrics and adults with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

Dosage

FDA-approved dosage

Indication

Recommended dose

Advanced HR+/HER2- Breast cancer

10 mg once daily with or without food

Advanced PNET/NET

Advanced RCC

Renal angiomyolipoma with TSC

SEGA with TSC

4.5 mg/m2 once daily; adjust to attain trough concentrations of 5-15 ng/mL

HR+, hormone-receptor positive; HER2, human epidermal growth factor receptor type 2; PNET, pancreatic neuroendocrine tumor; RCC, renal cell carcinoma; TSC, tuberous sclerosis complex; SEGA, subependymal giant cell astrocytoma.

Continue treatment until disease progression or unacceptable toxicity occurs.

Dose adjustments

Adverse reactions: Severe or intolerable adverse reactions may require temporary dose interruption (with or without a dose reduction) or discontinuation. If dose reduction is required, administering half of the original daily dose is recommended. See prescribing information for dose adjustment of specific adverse reactions.

Hepatic impairment: The initial dose should be reduced for hepatic impairment. For mild impairment (Child-Pugh class A) initiate at 7.5 mg and decrease to 5 mg if not well tolerated. For moderate hepatic impairment (Child-Pugh class B), initiate at 5 mg daily and decrease to 2.5 mg if not well tolerated. For severe hepatic impairment (Child-Pugh class C), if the benefit outweighs the risk of treatment, a maximum of 2.5 mg daily is recommended. For patients with SEGA who have severe hepatic impairment, the starting dose should be reduced by 50%.

Drug Interactions: Avoid use with strong CYP3A4/P-glycoprotein inhibitors and inducers. See prescribing information for dose adjustments if co-administration cannot be avoided.

Food Interactions: Avoid use with foods or nutritional supplements known to inhibit or induce CYP3A4/P-glycoprotein.

Drug Availability

• Afinitor: supplied as a 2.5-, 5-, 7.5-, and 10 mg tablet

• Afinitor Disperz: supplied as 2-, 3-, and 5 mg tablets for oral suspension.

PRECAUTIONS:

Contraindication:

Everolimus in contraindicated in persons with a hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients contained in the formulation.

Warnings/Precautions:

• Non-infectious pneumonitis: Monitor for clinical symptoms or radiological changes; fatal cases have occurred. Manage by dose reduction or discontinuation until symptoms resolve, and consider use of corticosteroids

• Infections: Increased risk of infections, some fatal. Monitor for signs and symptoms, and treat promptly

• Angioedema: Patients taking concomitant ACE inhibitor therapy may be at increased risk

• Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis are common. Management includes mouthwashes and topical treatments

• Renal failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed

• Impaired wound healing: Use caution and monitor signs and symptoms in the peri-surgical period due to increased risk of wound-related complications.

• Laboratory test alterations: Elevations of serum creatinine, urinary protein, blood glucose, and lipids may occur. Decreases in hemoglobin, neutrophils, and platelets may also occur. Monitor renal function, blood glucose, lipids, and hematologic parameters prior to treatment and periodically thereafter

• Vaccinations: Avoid live vaccines and close contact with those who have received live vaccines

• Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant woman. Apprise women of potential harm to the fetus

BILLING/CODING INFORMATION:

HCPCS Coding

C9399

Unclassified drugs or biologicals

J8999

Prescription drug, oral, chemotherapeutic, NOS

ICD-10 Diagnoses Codes That Support Medical Necessity:

C22.0

Liver cell carcinoma

C25.4

Malignant neoplasm of endocrine pancreas

C37

Malignant neoplasm of thymus

C40.00 – C40.92

Malignant neoplasm of bone and articular cartilage of limbs

C41.0 – C41.9

Malignant neoplasm of bone and articular cartilage of other and unspecified sites

C47.8

Malignant neoplasm of overlapping sites of peripheral nerves and autonomic nervous system

C49.00 – C49.9

Malignant neoplasm of other connective and soft tissue

C50.011 – C50.929

Malignant neoplasm of breast

C64.1 – C64.9

Malignant neoplasm of unspecified kidney, except renal pelvis

C65.1 – C65.9

Malignant neoplasm of unspecified renal pelvis

C73

Malignant neoplasm of thyroid gland

C7A.00 – C7A.8

Malignant neuroendocrine tumors

C7B.00 – C7B.09

Secondary neuroendocrine carcinoid tumors

C81.10C81.19

Nodular sclerosis classical Hodgkin Lymphoma

C81.20C81.29

Mixed cellularity classical Hodgkin Lymphoma

C81.30C81.39

Lymphocyte depleted classical Hodgkin Lymphoma

C81.40 – C81.49

Lymphocyte rich classical Hodgkin Lymphoma

C81.70 – C81.79

Other classical Hodgkin lymphoma

C81.90C81.99

Hodgkin Lymphoma unspecified

C83.00 – C83.09

Small cell B-cell lymphoma

C83.80 – C83.89

Other non-follicular lymphoma

C88.0

Waldenstrom macroglobulinemia

D15.0

Benign neoplasm of thymus

D49.2

Neoplasm of unspecified behavior of bone, soft tissue, and skin

E16.1

Hypoglycemia, other

E16.3

Increased secretion of glucagon

E16.8

Other specified disorders of pancreatic internal secretion

E34.0

Carcinoid syndrome

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Advantage Products: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline revised date.

Medicare Advantage: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline

DEFINITIONS:

Table 2: Eastern Cooperative Oncology Group (ECOG) Performance Status

Grade

Description

0

Fully active, able to carry on all pre-disease performance without restriction

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

2

Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

3

Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4

Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair

5

Dead

RELATED GUIDELINES:

Erythropoiesis Stimulating Agents, 09-J0000-31
Gemcitabine (Gemzar®), 09-J0000-96

Radiofrequency Ablation of Solid Tumors Other Than Liver Tumors, 02-99221-13

OTHER:

TABLE 3: Stages of Renal Cell Cancer

Stage I

The tumor is 7 centimeters or smaller and is found only in the kidney.

Stage II

The tumor is larger than 7 centimeters and is found only in the kidney.

Stage III

The tumor is any size and cancer is found only in the kidney and in 1 or more nearby lymph nodes; or cancer is found in the main blood vessels of the kidney or in the layer of fatty tissue around the kidney. Cancer may be found in 1 or more nearby lymph nodes.

Stage IV

Cancer has spread beyond the layer of fatty tissue around the kidney and may be found in the adrenal gland above the kidney with cancer, or in nearby lymph nodes; or to other organs, such as the lungs, liver, bones, or brain, and may have spread to lymph nodes.

TABLE 4: Child-Pugh Score and Classification

 

1 point

2 points

3 points

Total bilirubin

< 2

2-3

> 3

Serum albumin

> 3.5

2.8-3.5

< 2.8

INR

> 1.7

1.71-2.20

< 2.20

Ascites

None

Mild

Severe

Hepatic encephalopathy

None

Grade I-II

Grade III-IV

Classification of Result:
Class A: 5-6 points
Class B: 7-9 points
Class C: 10-15 points

REFERENCES:

  1. Afinitor, Afinitor Disperz (Everolimus) [package insert]. Novartis Pharmaceuticals Corp. East Hanover (NJ): June 2016.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.;2016. URL www.clinicalpharmacilogy-ip.com Accessed 10/20/16.
  3. Everolimus. In McEvoy GK, editor. AHFS drug information 2016 [monograph on the internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2016 [cited Oct 20 2016].
  4. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 10/20/16.
  5. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 03/06/17.
  6. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 1.2017. Bone Cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/bone.pdf Accessed 10/25/16.
  7. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 2.2016. Breast Cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf Accessed 10/15/16.
  8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 3.2016. Hodgkin Lymphoma. Available at http://www.nccn.org/professionals/physician_gls/PDF/hodgkin.pdf Accessed 10/25/16.
  9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 1.2017. Kidney Cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/kidney.pdf Accessed 10/20/16.
  10. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 1.2017 Neuroendocrine tumors. Available at http://www.nccn.org/professionals/physician_gls/PDF/neuroendocrine.pdf Accessed 03/06/17.
  11. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 2.2017 Small Cell Lung Cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/sclc.pdf Accessed 10/24/16.
  12. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 2.2016 Soft tissue sarcoma. Available at http://www.nccn.org/professionals/physician_gls/PDF/sarcoma.pdf Accessed 10/24/16.
  13. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 3.2016. Thymomas and thymic carcinomas. Available at http://www.nccn.org/professionals/physician_gls/PDF/thymic.pdf Accessed 10/24/16.
  14. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 1.2016. Thyroid cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/thyroid.pdf Accessed 10/20/16.
  15. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Version 2.2016 Waldenstrom’s Macroglobulinemia/Lymphoplasmacytic Lymphoma. Accessed 10/25/16.
  16. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016 [2016 Oct 20]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on11/09/16.

GUIDELINE UPDATE INFORMATION:

01/01/12

New Medical Coverage Guideline.

07/15/12

Revision to guideline; consisting of updating position statement, precautions, coding and references.

11/15/12

Review and revision to guideline; consisting of reformatting position statement and adding new indication, add contraindication, update coding, program exceptions and references.

01/01/13

Revision to guideline; consisting of updating codes.

12/15/13

Review and revision to guideline; consisting of revising positing statement, description, dosage/administration, and precautions section; updated references and program exceptions.

12/15/14

Review and revision to guideline; consisting of revising position statement and updating references.

12/15/15

Review and revision to guideline; consisting of revising position statement and updating dosage, precautions, coding and references.

07/15/16

Revision to guideline; consisting of updating position statement, dosing and references.

12/15/16

Review and revision to guideline; consisting of revising position statement, coding and updating references.

04/15/17

Revision to guideline; consisting of updating position statement, coding and references.

Date Printed: October 20, 2017: 08:40 AM