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09-J2000-37

Original Effective Date: 06/15/15

Reviewed: 05/11/16

Revised: 02/16/17

Subject: Panobinostat (Farydak) Capsule

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   Previous Version
           

DESCRIPTION:

Panobinostat (Farydak®) is a first‐in‐class, oral histone deacetylase (HDAC) inhibitor. Inhibition of HDAC activity results in increased acetylation of histone proteins ultimately leading to cell cycle arrest and/or apoptosis of certain cancer cells. Panobinostat was approved by the FDA in February 2015 for the treatment of patients with multiple myeloma (MM) who have received at least two prior regimens, including bortezomib (Velcade®) and an immunomodulatory agent. This was an accelerated approval based on progression-free survival (PFS) improvement, and continued approval may be dependent upon verification of clinical benefit in a confirmatory trial. The FDA granted panobinostat orphan designation for the treatment of MM in 2012.

Multiple myeloma is a malignant neoplasm of plasma cells that accumulate in bone marrow, leading to bone destruction and marrow failure. An estimated 26,850 new cases of MM occurred in the United States in 2015, with 11,240 deaths. About 75% of patients are diagnosed with MM over 70 years of age. Patients with active (symptomatic) MM and eligible for a stem cell transplant are initially treated with primary therapy that typically consists of lenalidomide (Revlimid®) + dexamethasone, or bortezomib + dexamethasone (± cyclophosphamide, doxorubicin, lenalidomide, or thalidomide). The National Comprehensive Cancer Network (NCCN) Multiple Myeloma Version 3.2016 Guidelines list the following as Category 1 preferred regimens for patients with previously treated MM who have relapsed or have progressive disease: bortezomib monotherapy, bortezomib + liposomal doxorubicin (Doxil®), carfilzomib (Kyprolis®) + lenalidomide + dexamethasone, elotuzumab (Empliciti®) + lenalidomide + dexamethasone, ixazomib (Ninlaro®) + lenalidomide + dexamethasone, lenalidomide + dexamethasone, pomalidomide + dexamathasone, and panobinostat + bortezomib + dexamethasone. Panobinostat + carfilzomib dual regimen is listed under “Other Regimens” as a Category 2A recommendation.

In a multinational, randomized, double-blind, phase III trial (PANORAMA 1) treatment with panobinostat, bortezomib, and dexamethasone (n=387) was compared to placebo, bortezomib, and dexamethasone (n=381) in patients with relapsed or relapsed and refractory multiple myeloma who had received one to three prior therapies. Treatment was administered for a maximum of 16 cycles (48 weeks).The median number of prior therapies was 1; 48% of patients received 2 or 3 prior lines of therapy. Approximately 57% of patients had previously received a stem-cell transplantation. At a median follow-up time of 29 months, the median PFS was significantly improved in the panobinostat arm (12 months) vs. the placebo arm (8.1 months) [hazard ratio (HR) = 0.63; 95% CI, 0.52 to 0.76]. Overall survival (OS) was not significantly improved at the interim analysis, but the data were premature for the OS analysis. Of note, the approval of panobinostat was based upon a prespecified subgroup analysis of 193 patients who had received prior treatment with both bortezomib and an immunomodulatory agent and a median of two prior therapies as the benefit to risk ratio appeared to be greater in this more heavily pretreated population (PFS of 12.5 months vs. 4.7 months in placebo group) as compared to the overall trial population. In December 2015, the overall survival results were released. For the overall study population, patients in the panobinostat group demonstrated a non-statistically significant increase in median OS of 4.5 months vs, the placebo group (p=0.54). However, more patients in the placebo group received post-study therapy (48.8% vs. 37.7%) that may have confounded the OS results.

POSITION STATEMENT:

Comparative Effectiveness

The FDA 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 panobinostat (Farydak) meets the definition of medical necessity when ALL of the following are criteria met:

1. The member has a diagnosis of relapsed or refractory multiple myeloma (MM)

2. The member is 18 years of age or older

3. The member has been previously treated for MM with at least TWO separate prior courses of treatment

4. The member has been previously treated for MM with BOTH of the following:

a. Bortezomib (Velcade)

b. At least ONE of the following immunomodulatory agents:

i. Lenalidomide (Revlimid)

ii. Pomalidomide (Pomalyst)

iii. Thalidomide (Thalomid)

5. The member is to receive panobinostat in combination with EITHER of the following:

a. BOTH bortezomib AND dexamethasone

b. Carfilzomib (Kyprolis).

6. Laboratory documentation of the member’s baseline (i.e., within 30 days prior to initiating treatment with panobinostat) serum monoclonal protein (M-protein) AND 24-hour urine M-protein, as detected by serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP), respectively, is provided*

7. The member’s baseline Fridericia's corrected QT interval (QTcF) is less than 450 msec

8. The dosage of panobinostat does not exceed one capsule (all strengths) for six doses during each 21-day cycle

* If the M-protein is undetectable by both SPEP and UPEP, documentation of a serum free light chain assay (SFLCA) must also be provided.

Duration of approval: 24 weeks (total of eight 21-day treatment cycles)

Continuation of panobinostat (Farydak) meets the definition of medical necessity when ALL of the following criteria are met:

1. The member was previously approved by Florida Blue for the treatment of MM in the past year or meets all of Florida Blue’s initiation criteria

2. Laboratory documentation of the member’s follow-up serum M-protein AND 24-hour urine M-protein, after at least two cycles of treatment with panobinostat, is provided

3. Documentation of response must be provided, and must include M-protein labs changes, change in size/number of lytic bone lesions (if any), and change in soft tissue plasmacytoma size (in any)

4. The member has achieved a minimal response (MR) or better, as defined by the Revised Uniform Response Criteria by the International Myeloma Working Group, while receiving treatment with panobinostat. This includes ALL of the following‡,§

a. Serum M-protein value decrease of 25% or more compared to baseline, or is undetectable

b. 24-hour urine M-protein value decrease of 50% or more compared to baseline, or is undetectable

c. If present at baseline, at least a 25% reduction in the size of any soft tissue plasmacytomas

d. No increases in the size or number of lytic bone lesions

5. The member is not experiencing unresolved severe [i.e., Common Terminology Criteria for Adverse Events (CTCAE) Grade 3] or medically significant toxicity from the previous cycle of panobinostat treatment

6. The member has NOT been previously approved for continuation of treatment with panobinostat (i.e., only one treatment continuation is permitted for an overall treatment period of 16 total cycles)¥

†If the M-protein was undetectable by both SPEP and UPEP at baseline and a baseline SFCLA is available, a follow-up SFLCA must be provided as necessary documentation of response to treatment.

‡ If the M-protein was undetectable by both SPEP and UPEP at baseline and a baseline SFCLA is available, a decrease of 25% or more in the difference between the light chain produced by the myeloma cells (lambda or kappa) and the other light chain must also be achieved.

§ An exception is permitted if the baseline M-protein labs are unavailable. In these cases the physician may provide an attestation of a meaningful clinical response. However, the non-lab requirements still must be met (i.e., no increase in the size or number of lytic bone lesion, reduction in plasmacytoma size).

¥ An exception is permitted if adverse effects resulted in prolonged panobinostat interruptions during MM treatment. The second continuation may only be approved for the duration necessary to finish a total of 16 treatment cycles.

Duration of approval: 24 weeks (8 additional 21-day treatment cycles)

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

• Panobinostat, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least two prior regimens, including bortezomib and an immunomodulatory agent.

• The recommended starting dose of panobinostat is 20 mg orally once every other day for 3 doses per week in Weeks 1 and 2 of each 21‐day cycle (on Days 1, 3, 5, 8, 10, and 12) for up to 8 cycles. Swallow capsules whole with a full glass of water; do not open, crush, or chew capsules. Consider continuing treatment for an additional 8 cycles for patients with clinical benefit who do not experience unresolved severe or medically significant toxicity. The total duration of treatment may be up to 16 cycles (48 weeks). Panobinostat is administered in combination with bortezomib and dexamethasone. The recommended dose of bortezomib is 1.3 mg/m2 given as an injection. The recommended dose of dexamethasone is 20 mg orally per scheduled day, on a full stomach. View the prescribing information for the complete dosing recommendations.

Dose Adjustments

Toxicity - Management of adverse drug reactions may require treatment interruption and/or dose reductions. If dose reduction is required, the dose of panobinostat should be reduced in increments of 5 mg (i.e., from 20 mg to 15 mg, or from 15 mg to 10 mg). If the dosing is to be reduced below 10 mg given 3 times per week, discontinue treatment. View the prescribing information for the complete dosing recommendations.

o Thrombocytopenia [platelets <50 x 109/L (CTCAE Grade 3) with bleeding, or platelets <25 x 109/L (CTCAE Grade 4)]

- Interrupt panobinostat treatment

- Monitor platelet counts at least weekly until ≥50 x 109/L, then restart at reduced dose

o Neutropenia [absolute neutrophil count (ANC) 0.5 to 0.75 x 109/L (CTCAE Grade 3) on two or more occurrences)]

- Interrupt panobinostat treatment

- Monitor until ANC ≥1 x 109/L, then restart at same dose

o Neutropenia [ANC <1 x 109/L (CTCAE Grade 3) with febrile neutropenia, or ANC <0.5 x 109/L (CTCAE Grade 4)]

- Interrupt panobinostat treatment

- Monitor until ANC ≥1 x 109/L, then restart at reduced dose

o Amenia [hemoglobin <8 g/dL (CTCAE Grade 3)]

- Interrupt panobinostat treatment

- Monitor until Hb ≥10 g/dL, then restart at reduced dose

o Moderate diarrhea [4 to 6 stools/day (CTCAE Grade 2)]

- Interrupt panobinostat treatment until resolved

- Restart at same dose.

o Severe diarrhea [≥7 stools/day, IV fluids, or hospitalization required (CTCAE Grade 3)]

- Interrupt panobinostat treatment until resolved

- Restart at reduced dose

o Life-threatening Diarrhea (CTCAE Grade 3)

- Permanently discontinue panobinostat treatment

o Nausea or Vomiting [severe or life-threatening (CTCAE Grade 3/4)]

- Interrupt panobinostat treatment until resolved

- Restart at reduced dose

• Hepatic Impairment

o Mild (Child-Pugh Class A)

- Reduce the starting dose to 15 mg

o Moderate (Child-Pugh Class B)

- Reduce the starting dose to 10 mg

o Severe (Child-Pugh Class C)

- Avoid use

Use with Strong CYP3A Inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir)

o Reduce the starting dose to 10 mg

Drug Availability

• Panobinostat is available in 6-count blister packs containing 10-, 15-, or 20-mg capsules.

PRECAUTIONS:

Boxed Warning

• FATAL AND SERIOUS TOXICITIES: SEVERE DIARRHEA AND CARDIAC TOXICITIES

o Severe diarrhea occurred in 25% of panobinostat treated patients. Monitor for symptoms, institute antidiarrheal treatment, interrupt panobinostat and then reduce dose or discontinue panobinostat.

o Severe and fatal cardiac ischemic events, severe arrhythmias, and ECG changes have occurred in patients receiving panobinostat. Arrhythmias may be exacerbated by electrolyte abnormalities. Obtain ECG and electrolytes at baseline and periodically (e.g., every 1 to 2 months) during treatment as clinically indicated.

Contraindications

• None

Precautions/Warnings

Hemorrhage: Fatal and serious cases of gastrointestinal and pulmonary hemorrhage. Monitor platelet counts and transfuse as needed.

Myelosuppression: Panobinostat causes myelosuppression, including severe thrombocytopenia, neutropenia and anemia. Obtain a baseline CBC and monitor the CBC at least weekly during treatment. Monitor CBCs more frequently in patients over 65 years of age due to the increased frequency of myelosuppression in these patients.

Infections: Monitor patients for signs and symptoms of infections during treatment; if a diagnosis of infection is made, institute appropriate anti-infective treatment promptly and consider interruption or discontinuation of panobinostat.

Hepatotoxicity: Monitor hepatic enzymes and adjust dosage if abnormal liver function tests are observed during panobinostat therapy.

Embryo-Fetal Toxicity: Can cause fetal harm. Advise women of the potential hazard to the fetus and to avoid pregnancy while taking panobinostat.

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 (Effective 10/01/15)

C90.00

Multiple myeloma not having achieved remission

C90.02

Multiple myeloma in relapse

C90.10

Plasma cell leukemia not having achieved remission

C90.12

Plasma cell leukemia in relapse

C90.20

Extramedullary plasmacytoma not having achieved remission

C90.22

Extramedullary plasmacytoma in relapse

C90.30

Solitary plasmacytoma not having achieved remission

C90.32

Solitary plasmacytoma 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 the last guideline review date.

DEFINITIONS:

Common Terminology Criteria for Adverse Events (CTCAE) - standardized definitions for adverse events published by the National Cancer Institute to describe the severity of organ toxicity for patients receiving cancer therapy. Toxicity is graded as mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4), with specific parameters according to the organ system involved.

Heavy chain – the larger component of an immunoglobulin. There are five types: IgG, IgA, IgM, IgD, and IgE.

Immunoglobulins (a.k.a., antibodies) proteins made by normal plasma cells that have an important role in fighting infection as part of the humoral immune response. Antibodies are composed of two heavy chains and two light chains that form a larger complex. Each plasma cell produces only one type of heavy chain and one type of light chain.

Light chain – the smaller component of an immunoglobulin. There are two types: kappa and lambda.

Minimal response (MR) (according to the Revised Uniform Response Criteria by the International Myeloma Working Group)ALL of the following:

• ≥25% but ≤49% reduction of serum M-protein

• Reduction in 24-hour urine M-protein by 50% to 89%

• In addition, if present at baseline, 25% to 49% reduction in size of soft tissue plasmacytomas is also required

• No increase in size or number of lytic bone lesions (development of compression fractures dose not exclude response).

Myeloma Protein (M-Protein) – a nonfunctional immunoglobulin protein or protein fragment produced by malignant plasma cells (or myeloma cells). Since myeloma cells are monoclonal, the M-proteins for a given patient are structurally identical. Both portions of an immunoglobulin (the heavy chain and light chain) can be found in the serum, while only light chains can be found in the urine.

Plasma cell - a fully differentiated B lymphocyte (a type of white blood cell) that is specialized for immunoglobulin production and is found primarily in bone marrow.

Plasmacytoma – a discrete tumor consisting of neoplastic, monoclonal (originating from a single cell) plasma cells in either bone or soft tissue (extramedullary).

Primary refractory MM - patients who never achieve at least a MR to initial induction therapy and progress while on therapy

Progressive MM - at least a 25% increase from nadir in the serum M-protein (absolute increase must be ≥0.5 g/dL) or urine M-protein (absolute increase must be ≥200mg/24 hours), or in the difference between involved and uninvolved serum-free light-chain (FLC) levels (with an abnormal FLC ratio and FLC difference >100 mg/L).

Relapsed and refractory MM - patients who never achieve at least a MR or who progress within 60 days of their last therapy

Serum free light chain assay (SFLCA) – a test that detects the amount of unbound or free light chains (i.e., not attached to a heavy chain) in the serum. Normal values - kappa: 3.3 to 19.4 mg/L, lambda: 5.71 to 26.3 mg/L, kappa/lambda ratio: 0.26–1.65 (0.37–3.1 if renal impairment).

Serum Protein Electrophoresis (SPEP) – a test that detects and quantifies the amount of M-protein in the serum. An serum M-protein of greater than 30 g/L is consistent with a diagnosis of MM.

Urine Protein Electrophoresis (UPEP) - a test that detects and quantifies the amount of M-protein (light chain component only) in the urine. This is typically done using a sample of urine collected over a 24-hour period.

RELATED GUIDELINES:

Allogeneic Bone Marrow and Stem Cell Transplantation, 02-38240-01
Bortezomib (Velcade) IV, 09-J0000-92

Carfilzomib (Kyprolis) IV, 09-J1000-81

Daratumumab (Darzalex) IV, 09-J2000-49

Doxorubicin HCl Liposome (Doxil) IV, 09-J0000-91

Elotuzumab (Empliciti) Injection, 09-J2000

Interferons for Oncology Use, 09-J1000-37

Ixazomib (Ninlaro) Capsule, 09-J2000-51

Lenalidomide (Revlimid), 09-J0000-80

Pomalidomide (Pomalyst) Capsule, 09-J1000-95

Thalidomide (Thalomid) Capsules, 09-J1000-56

OTHER:

None

REFERENCES:

  1. American Society of Hematology, Final Analysis of Overall Survival from the Phase 3 Panorama 1 Trial of Panobinostat Plus Bortezomib and Dexamethasone Versus Placebo Plus Bortezomib and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma. 57th Annual Meeting & Exposition. December 6, 2015. Available at: https://ash.confex.com/ash/2015/webprogram/Paper79871.html
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. Available from: http://www.clinicalpharmacilogy-ip.com. Accessed 4/21/2016. .
  3. Farydak (panobinostat) [prescribing information]. Novartis; East Hanover (NJ). February 2016.
  4. International Myeloma Foundation. Accessed 4/24/14 at http://myeloma.org.
  5. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 4/21/2016.
  6. National Comprehensive Cancer Network (NCCN). Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 4/21/2016.
  7. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 3.2016. http://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf. Accessed 4/21/2016.
  8. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2015. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/. Accessed 4/21/16.
  9. Palumbo A, Rajkumar SV, Man Miguel JF, et al. International Myeloma Working Group Consensus Statement for the Management, Treatment, and Supportive Care of Patients With Myeloma Not Eligible for Standard Autologous Stem-Cell Transplantation. J Clin Oncol. 2014;32:527-600.
  10. Richardson PG, Schlossman RL, Alsina M, et al. PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma. Blood. 2013 Oct 3;122(14):2331-7. Epub 2013 Aug 15.
  11. San‐Miguel JF, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double‐blind phase 3 trial. Lancet Oncol 2014;15:1195‐206.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 05/11/16.

GUIDELINE UPDATE INFORMATION:

06/15/15

New Medical Coverage Guideline.

11/01/15

Revision: ICD-9 Codes deleted.

06/15/16

Review and revision to guideline consisting of updating the description section, position statement, definitions, billing/coding, related guidelines, and references.

02/16/17

Revision: Update to Position Statement.

Date Printed: June 26, 2017: 01:24 AM