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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-J2000-64

Original Effective Date: 09/15/16

Reviewed: 08/10/16

Revised: 06/15/17

Subject: Venetoclax (Venclexta®) Tablet

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.

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

DESCRIPTION:

Venetoclax (Venclexta) is a selective inhibitor of B-cell lymphoma-2 (BCL-2) protein, an anti-apoptotic protein. The overexpression of BCL-2 in chronic lymphocytic leukemia (CLL) tumor cells enhances cell survival and is associated with resistance to chemotherapy. Venetoclax was approved by the FDA in April 2016 for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. The indication was approved under accelerated approval based on overall response rate (ORR), and continued approval may be contingent upon verification of clinical benefit in a confirmatory trial. Venetoclax was previously granted orphan drug designation by the FDA for the treatment of CLL in September 2012.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a mature B-cell lymphoma that comprises approximately 7% of newly diagnosed cases of Non-Hodgkin’s Lymphoma (NHL). CLL and SLL are different manifestation of the same disease and are managed in much the same way. The main difference is that in CLL the abnormal lymphocytes are found in bone marrow and blood, while in SLL they are predominately found in the lymph nodes and bone marrow. The diagnosis of CLL requires the presence of at least 5,000 clonal B-cells/mcL in the peripheral blood as determined by flow cytometry quantification. Cytogenic abnormalities that can be detected by fluorescence in situ hybridization (FISH) testing are present in over 80% of previously untreated CLL patients. The 17p chromosome deletion, del(17p) mutation, which reflects the loss of the TP53 gene, is associated with the worst outcomes and poor response to chemotherapy. About 7% of newly diagnosed patients have a del(17p) mutation. The treatment options for CLL have changed drastically in the last several decades. The introduction of monoclonal antibodies targeting cell surface antigens (e.g., CD20, CD52), immunomodulating agents, and, most recently, novel small molecules inhibiting tyrosine kinases and other proteins, have led to new and more effective regimens. Recommended treatments are based on newly diagnosed vs. refractory disease, and the patient’s mutation status, age, and other comorbidities.

The safety and efficacy of venetoclax leading to FDA approval was established in an open-label, single-arm, multicenter clinical trial of 106 patients with CLL with del(17p) who had received at least one prior therapy. Of note, for this study, del(17p) was confirmed in peripheral blood specimens using Vysis CLL FISH Probe Kit, which is now FDA-approved for selection of patients for venetoclax treatment. Patients received venetoclax via a weekly ramp-up schedule starting at 20 mg and ramping to 50 mg, 100 mg, 200 mg and finally 400 mg once daily. Patients continued to receive 400 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) as assessed by an independent committee using the International Workshop for Chronic Lymphocytic Leukemia (IWCLL) updated National Cancer Institute-sponsored Working Group (NCI-WG) guidelines. The ORR is a composite of complete remission (CR), complete remission with incomplete marrow recovery (CRi), nodular partial remission (nPR), and partial remission (PR).

The median age of patients was 67 years and the median number of prior therapies was 2.5. The median time on treatment at the time of evaluation was 12.1 months (range: 0 to 21.5 months). The median time to first response was 0.8 months (range: 0.1 to 8.1 months). Median duration of response (DOR) has not been reached with approximately 12 months median follow-up. The DOR ranged from 2.9 to 19.0+ months. An ORR was observed in 80.2% (95% CI 71.3 to 87.3%, n=85) of patients, with the majority achieving partial remission (69.8%, n=74). Other responses were as follows: CR – 5.7% (n=6), CRi – 1.9% (n=2), and nPR – 2.38% (n=3). The most common adverse reactions (≥20%) of any grade were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue. The most common grade 3 to 4 adverse events were neutropenia (40%), infection (20%), anemia (18%), and thrombocytopenia (15%). Discontinuations due to adverse reactions occurred in 8.3% of patients. The most frequent adverse reactions leading to drug discontinuation were thrombocytopenia and autoimmune hemolytic anemia (AIHA). Dosage adjustments due to adverse reactions occurred in 9.6% of patients. The most frequent adverse reactions leading to dose adjustments were neutropenia, febrile neutropenia, and thrombocytopenia.

The National Comprehensive Cancer Network (NCCN) Guidelines for CLL/SLL (Version 2.2017) list venetoclax monotherapy or in combination with rituximab (Rituxan) as a treatment option for patients with relapsed or refractory disease with or without del(17p) mutation (category 2A recommendations). For CLL/SLL without a del(17p) mutation, NCCN includes a footnote of “particularly for patients deemed intolerant or refractory to ibrutinib or idelalisib”. Use in patients without a del(17p) mutation is extrapolated from the benefits seen in patients with the mutation. The NCCN also includes recommendations for tumor lysis syndrome (TLS) prophylaxis and monitoring based on tumor burden when initiating venetoclax treatment. The NCCN Guidelines for B-cell Lymphomas (Version 1.2017) list venetoclax monotherapy as a category 2A option for the second-line treatment of mantle cell lymphoma.

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.

Initiation of venetoclax (Venclexta®) meets the definition of medical necessity for members meeting ALL of the following criteria:

1. EITHER of the following (“a” or “b”):

a. The member has a diagnosis of relapsed or refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)

b. The member has a diagnosis of relapsed or refractory mantle cell lymphoma (MCL)

2. The member has received at least one prior therapy for treatment of their disease

3. ONE of the following based on the disease being treated:

a. For CLL/SLL – venetoclax will be used as either single-agent treatment or in combination with rituximab

b. For MCL - venetoclax will be used as single-agent treatment

4. The member’s tumor burden [i.e., absolute lymphocyte count (ALC) and lymph node sizes via CT scan] and other risk factors for tumor lysis syndrome (TLS) have been assessed, and the member will receive appropriate prophylaxis as necessary

5. The dosage does not exceed 400 mg daily - the dose must be achieved using the fewest number of tablets possible

Duration of approval: 6 months

Continuation of venetoclax meets the definition of medical necessity for members meeting ALL of the following criteria:

1. Authorization or reauthorization for venetoclax has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of CLL/SLL or mantle cell lymphoma, OR the member previously met ALL indication-specific initiation criteria.

2. The member has not had disease progression during treatment with venetoclax

3. ONE of the following based on the disease being treated:

a. For CLL/SLL – venetoclax will be used as either single-agent treatment or in combination with rituximab

b. For MCL - venetoclax will be used as single-agent treatment

1. The dosage does not exceed 400 mg daily - the dose must be achieved using the fewest number of tablets possible

Duration of approval: 1 year

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.

FDA-approved

• The treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA approved test, who have received at least one prior therapy. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Safety and effectiveness have not been established in pediatric patients.

• Initiate therapy at 20 mg once daily for 7 days, followed by a weekly ramp-up dosing schedule to the recommended daily dose of 400 mg. Take until disease progression or unacceptable toxicity is observed.

• Tablets should be taken orally once daily with a meal and water. Do not chew, crush, or break tablets.

o Week 1 – 20 mg

o Week 2 – 50 mg

o Week 3 – 100 mg

o Week 4 – 200 mg

o Week 5 and beyond – 400 mg

• Treatment can cause rapid reduction in tumor and thus poses a risk for tumor lysis syndrome (TLS) in the initial 5-week ramp-up phase. Perform prophylaxis for TLS as recommend on the product labeling.

Dose Adjustments

• Drug-Related Toxicities

o Interrupt dosing or reduce the dose for toxicities. Refer to the product labeling for the recommended dosage reduction and interruption time period. For patients who have had a dosing interruption greater than 1 week during the first 5 weeks of ramp-up phase or greater than 2 weeks when at the daily dose of 400 mg, reassess for risk of TLS to determine if reinitiation with a reduced dose is necessary.

• Hepatic Impairment

o No dose adjustment is recommended in patients with mild or moderate hepatic impairment; however, a trend for increased adverse events was observed in patients with moderate hepatic impairment; monitor these patients more closely for signs of toxicity during the initiation and dose ramp-up phase.

o A recommended dose has not been determined for patients with severe hepatic impairment.

• Renal Impairment:

o Patients with reduced renal function (CrCl <80 mL/min) are at increased risk of TLS. These patients may require more intensive prophylaxis and monitoring.

o No dose adjustment is needed for patients with mild or moderate renal impairment (CrCl ≥30 mL/min)

o A recommended dose has not been determined for patients with severe renal impairment (CrCl <30 mL/min) or patients on dialysis.

• Drug Interactions

o If a moderate CYP3A inhibitor or a P-gp inhibitor must be used, reduce the venetoclax dose by at least 50%.

o If a strong CYP3A inhibitor must be used after the ramp-up phase, reduce the venetoclax dose by at least 75%.

o If a narrow therapeutic index P-gp substrate must be used, it should be taken at least 6 hours before venetoclax.

Drug Availability

• 10 mg, 50 mg, and 100 mg film-coated tablets as described below:

Packaging Presentation

Number of Tablets

National Drug Code (NDC)

Starting Pack

Each pack contains four weekly wallet blister packs:

o Week 1 (14 x 10 mg tablets)

o Week 2 (7 x 50 mg tablets)

o Week 3 (7 x 100 mg tablets)

o Week 4 (14 x 100 mg tablets)

0074-0579-28

10 mg Wallet

14 x 10 mg tablets

0074-0561-14

50 mg Wallet

7 x 50 mg tablets

0074-0566-07

10 mg Unit Dose

2 x 10 mg tablets

0074-0561-11

50 mg Unit Dose

1 x 50 mg tablet

0074-0566-11

100 mg Unit Dose

1 x 100 mg tablet

0074-0576-11

100 mg Bottle

120 x 100 mg tablets

0074-0576-22

PRECAUTIONS:

Boxed Warning

• None

Contraindications

• Concomitant use of venetoclax with strong inhibitors of CYP3A at initiation and during ramp-up phase

Precautions/Warnings

• Tumor Lysis Syndrome (TLS): TLS, including fatal events and renal failure requiring dialysis, has occurred in previously treated CLL patients with high tumor burden when treated with venetoclax. Anticipate TLS; assess risk in all patients. Premedicate with anti-hyperuricemics and ensure adequate hydration. Employ more intensive measures (intravenous hydration, frequent monitoring, hospitalization) as overall risk increases. See the product labeling for specific recommendations.

Neutropenia: Grade 3 or 4 neutropenia occurred in 41% (98/240) of patients treated with venetoclax. Monitor blood counts and for signs of infection; manage as medically appropriate.

• Immunization: Do not administer live attenuated vaccines prior to, during, or after venetoclax treatment.

• Embryo-Fetal Toxicity: May cause embryo-fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment.

• Lactation: Discontinue breastfeeding.

• Drug Interactions: If possible, avoid concomitant use of venetoclax with moderate CYP3A inhibitors, strong or moderate CYP3A inducers, P-gp inhibitors, or narrow therapeutic index P-gp substrates.

• Adverse Reactions: The most common adverse reactions (≥20%) were neutropenia, diarrhea, nausea, anemia, upper respiratory tract infection, thrombocytopenia, and fatigue.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding

C9399

Unclassified drugs or biologicals (Hospital Outpatient Use ONLY)

J8999

Prescription drug, oral, chemotherapeutic, Not Otherwise Specified

ICD-10 Diagnoses Codes That Support Medical Necessity

C83.10 – C83.19

Mantle cell lymphoma

C91.10

Chronic lymphocytic leukemia of B-cell type not having achieved remission

C91.12

Chronic lymphocytic leukemia of B-cell type in relapse

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

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

DEFINITIONS:

None

RELATED GUIDELINES:

Allogeneic Bone Marrow and Stem Cell Transplantation, 02-38240-01

Autologous Bone Marrow and Stem Cell Transplantation, 02-38241-01

Bendamustine HCl (Bendeka®, Treanda®) Injection

Ibrutinib (Imbruvica), 09-J2000-09

Idelalisib (Zydelig) Oral Tablet, 09-J2000-23

Immune Globulin Therapy, 09-J0000-06

Obinutuzumab (Gazyva) Injection, 09-J2000-07

Rasburicase (Elitek), 09-J2000-43

Rituximab (Rituxan), 09-J0000-59

OTHER:

None

REFERENCES:

  1. Besbes S, Pocard M, Mirshahi M, et al. The first MCL-1-selective BH3 mimetics have therapeutic potential for chronic lymphocytic leukemia. Crit Rev Oncol Hematol 2016;100:32-36.
  2. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2016 [cited 2016 Jun 10]. Available from: http://www.clinicalpharmacology.com/.
  3. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2016 Jun 10]. Available from: http://www.thomsonhc.com/.
  4. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008 Jun 15;111(12):5446-56.
  5. National Comprehensive Cancer Network®. NCCN clinical practice guidelines in oncology (NCCN Guidelines®). B-cell Lymphomas. 1.2017 [cited 2016 Dec 16]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
  6. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology (NCCN Guidelines). Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Version 2.2017) [cited 2017 May 1]. Available from: https://www.nccn.org/professionals/physician_gls/pdf/cll.pdf
  7. NCCN Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2017 [cited 2017 May 1]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/.
  8. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2016 [cited 2016 Jun 10]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.
  9. Roberts AW , Davids MS , Pagel JM , et al: Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2016; 374(4):311-322.
  10. Roberts AW, Davids MS, Seymour JF. New Agents to Treat Chronic Lymphocytic Leukemia. N Engl J Med. 2016 Jun 2;374 (22):2186-7.
  11. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017 Feb;18(2):230-240.
  12. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016 Jun;17(6):768-78.
  13. Venclexta (venetoclax) [package insert]. Intercept Pharmaceuticals, Inc.. New York, NY. May 2016.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 08/10/16.

GUIDELINE UPDATE INFORMATION:

09/15/16

New Medical Coverage Guideline.

12/15/16

Revision to guideline consisting of updating the description section, position statement, and references based on updated NCCN guidelines for CLL/SLL.

02/15/17

Revision to guideline consisting of updating the description section, position statement, billing/coding, and references based on updated NCCN guidelines for B-cell lymphomas.

06/15/17

Revision to guideline consisting of updating the description section, position statement, and references based on updated NCCN guideline for CLL/SLL.

Date Printed: June 23, 2017: 11:43 AM