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09-J1000-48

Original Effective Date: 01/01/12

Reviewed: 02/08/17

Revised: 03/15/17

Subject: Nilotinib (Tasigna®) Capsules

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:

Nilotinib (Tasigna®), a second-generation tyrosine kinase inhibitor (TKI), was approved by the US Food and Drug Administration (FDA) in October 2007 for the treatment of adults with chronic-phase (CP) and accelerated-phase (AP) Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) resistant to or intolerant of prior treatment with imatinib (Gleevec®). Nilotinib has also shown efficacy in the treatment of Ph+ acute lymphoblastic leukemia (ALL) and gastrointestinal stromal tumors (GISTs). The FDA had previously granted nilotinib orphan designation status for the treatment of CML in 2006 and for the treatment of GISTs in 2007.

Chronic myelogenous leukemia (CML) is a hematopoietic stem cell disease characterized by a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Philadelphia (Ph) chromosome. The median age of disease onset is 67 years, but CML occurs in all age groups. CML occurs in three different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Untreated chronic phase CML will eventually progress to advanced phase disease in 3 to 5 years. The introduction of small molecule tyrosine kinase inhibitors (TKIs) changed the treatment armamentarium and this “targeted” approach has dramatically altered the natural history of the disease and improved 10-year overall survival from approximately 20% to 80 to 90%.

The National Comprehensive Cancer Network (NCCN) guidelines for CML (Version 2.2017) list imatinib, nilotinib, or dasatinib (Sprycel®) as category 1 options for the treatment of chronic phase CML in patients with a low-risk Sokal or Hasford score. For patients with an intermediate- or high-risk score, the three TKIs are all listed as category 2A options; however, dasatinib and nilotinib are labeled as preferred. Age, tolerance of adverse effects, and comorbid conditions also may affect initial choice of treatment. For example, nilotinib may be preferred in in individuals prone to fluid retention; dasatinib may be preferred in persons with liver disease. Subsequent treatment for chronic phase CML is determined by assessment of response every 3 months. The efficacy of CML therapy is assessed by monitoring hematologic, cytogenetic, and molecular responses.

Despite positive outcomes observed with TKIs in the treatment of CML, drug resistance has been identified. One of the most common mechanisms of resistance involves point mutations in the kinase domain of BCR-ABL, which impairs the activity of TKIs. One important mutation, the T315I, is known as the “gatekeeper” mutation, as it displays resistance to all TKIs, with the exception of ponatinib (Iclusig®). Current guidelines recommend checking mutational analysis in the following situations: if there is inadequate initial response, any sign of loss of response, and in disease progression to accelerate-phase or blast-phase CML (CML-AP and CML-BP, respectively). In vitro studies have shown that some mutations confer resistance specifically to one second generation TKI and not the other. For example, T315A, V299L, and F359V confer resistance to dasatinib only, whereas Y253H, E255K/V, L273M, and F359V specifically to nilotinib.

Acute lymphoblastic leukemia (ALL) is a heterogenous hematologic disease characterized by the proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs. ALL represents approximately 20% of all leukemias among adults. The long-term prognosis for adults with ALL remains poor, with cure rates of only 30% to 40%. The treatment approach to ALL represents one of the most complex and intensive programs in cancer therapy. In general, treatment phases can be largely grouped into induction, consolidation, and maintenance. All phases of treatment also include central nervous system (CNS) prophylaxis and/or treatment to clear leukemic cells within sites that cannot be readily accessed with systemic chemotherapy due to the blood-brain barrier. During the past decade, the advent of novel agents targeted to specific genetic abnormalities, such as those associated with Ph+ ALL, or to specific cell antigens, has contributed to improvements in outcomes in some subtypes of ALL. These agents include BCR-ABL selective TKIs for Ph+ ALL. NCCN guidelines for ALL list dasatinib and imatinib as the preferred TKIs for induction and maintenance regimens for newly diagnosed Ph+ ALL. Dasatinib, ponatinib (for patients with a Y253H, E255K/V, or F359V/C/I mutation), and imatinib are listed as preferred options for relapsed or refractory ALL. Nilotinib is also listed as an option but is not preferred and should be reserved for patients with a F317L/V/I/C, T315A, or V299L mutation.

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 nilotinib (Tasigna®) meets the definition of medical necessity when ALL of the following criteria are met:

1. Member is NOT taking another tyrosine kinase inhibitor (TKI) (i.e., imatinib, dasatinib, bosutinib, or ponatinib) or omacetaxine mepesuccinate (Synribo®) concurrently with nilotinib.

2. Dosage of nilotinib does not exceed 400 mg twice daily (i.e., 800 mg total per day) and will be achieved using the fewest number of capsules per day.

3. The member is receiving treatment for ANY of the following conditions, and ALL associated criteria are met:

a. Chronic- , accelerated-, or blast-phase Philadelphia (Ph) chromosome-positive chronic myelogenous leukemia (CML) (including post-transplant relapse)

i. Member does NOT have a Y253H, E255K/V, F359V/C/I, or T315I mutation (only applicable if a BCR-ABL kinase domain mutation analysis has been performed)

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

a. Member has an intermediate- or high-risk Sokal or Hasford score as determined prior to treatment initiation (at least one calculated score must be provided)

b. Member has previously tried imatinib treatment and EITHER failed (i.e., inadequate initial treatment response or relapse during treatment – see definitions) OR had persistent intolerable adverse effects despite appropriate dose modification (the specific adverse effect must be provided), UNLESS either of the following apply:

o Member has documented genetic resistance to imatinib (lab documentation of F317L/V/I/C, T315A, or V299L mutation must be submitted)

o Member has an FDA-labeled contraindication to imatinib (the specific contraindication must be provided)

b. Relapsed or refractory Ph-positive acute lymphoblastic leukemia (ALL)

i. Member has ANY of the following mutations (lab documentation must be submitted):

• F317L/V/I/C

• T315A

• V299L

c. Ph-positive ALL with a complete response to induction chemotherapy

i. Member is receiving nilotinib as consolidation treatment following a hematopoietic stem cell transplant (HSCT)

ii. Member does NOT have a Y253H, E255K/V, F359V/C/I, or T315I mutation (only applicable if a BCR-ABL kinase domain mutation analysis has been performed)

iii. Member has previously tried imatinib treatment and EITHER failed (i.e., inadequate initial treatment response or relapse during treatment) OR had persistent intolerable adverse effects despite appropriate dose modification (the specific adverse effect must be provided), UNLESS either of the following apply:

• Member has documented genetic resistance to imatinib (lab documentation of F317L/V/I/C, T315A, or V299L must be submitted)

• Member has an FDA-labeled contraindication to imatinib (the specific contraindication must be provided)

d. Progressive gastrointestinal stromal tumors (GIST),

i. Member meets any of the following in reference to at least TWO first-line GIST treatments [i.e., imatinib, sunitinib (Sutent®), or regorafenib (Stivarga®)] one of which must be imatinib:

• Did not achieve recommended initial treatment goals or experienced disease relapse during treatment

• Had persistent intolerable adverse effects despite appropriate dose modification (the specific adverse effect must be provided)

• Has documented genetic resistance (lab documentation must be submitted)

• Has an FDA-labeled contraindication (the specific contraindication must be provided)

Approval duration: 6 months (all indications)

Continuation of nilotinib (Tasigna®) meets the definition of medical necessity when ALL of the following criteria are met:

1. The member has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of CML, ALL, or GIST, OR the member has previously met all indication-specific criteria

2. Member does NOT have a Y253H, E255K/V, F359V/C/I, or T315I mutation (only applicable if a BCR-ABL kinase domain mutation analysis has been performed and does NOT apply if nilotinib is being used for treatment of GIST).

3. Member’s disease has not progressed during treatment with nilotinib.

4. Member is NOT taking another TKI (i.e., imatinib, dasatinib, bosutinib, or ponatinib) or omacetaxine concurrently with nilotinib.

5. Dosage of nilotinib does not exceed 400 mg twice daily (800 mg total per day) and will be achieved using the fewest number of capsules per day.

Approval duration: 1 year

NOTE: Quest Diagnostics® can perform the BCR-ABL kinase domain mutation test. Current NCCN guidelines recommend checking mutational analysis in the following situations: if there is inadequate initial response, any sign of loss of response, and in disease progression to accelerate-phase or blast-phase CML (CML-AP and CML-BP, respectively).

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: nilotinib is indicated for the treatment of newly diagnosed adult persons with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). It is also indicated for the treatment of CP and accelerated phase (AP) Ph+ CML in adults resistant to or intolerant of prior therapy that included imatinib. The recommended dose is 300 mg orally twice daily for newly diagnosed Ph+ CML-CP and 400 mg twice daily for resistant or intolerant Ph+ CML-CP and CML-AP. Nilotinib should be administered approximately 12 hours apart and must be taken on an empty stomach. The capsules should be swallowed whole with water.

Dose Modifications

Concomitant Strong CYP3A4 Inhibitors: Avoid the concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). Avoid grapefruit products since they may also increase serum concentrations of nilotinib. Should treatment with any of these agents be required, therapy with nilotinib should be interrupted. If patients must be coadministered a strong CYP3A4 inhibitor consider a dose reduction to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML-CP. There are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inhibitors. Also, monitor closely for prolongation of the QT interval. If a strong inhibitor is discontinued, a washout period should be allowed before the nilotinib dose is adjusted upward to the indicated dose.

Concomitant Strong CYP3A4 Inducers: Avoid the concomitant use of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort). Based on the nonlinear pharmacokinetic profile of nilotinib, increasing the dose of nilotinib when coadministered with such agents is unlikely to compensate for the loss of exposure.

• Selected Non-hematologic Laboratory Abnormalities

Table 1

Dose Adjustments for Selected Non-hematologic Laboratory Abnormalities

Elevated serum lipase or amylase ≥ Grade 3

1. Withhold nilotinib, and monitor serum lipase or amylase
2. Resume treatment at 400 mg once daily if serum lipase or amylase returns to ≤ Grade 1

Elevated bilirubin ≥ Grade 3

1. Withhold nilotinib, and monitor bilirubin
2. Resume treatment at 400 mg once daily if bilirubin returns to ≤ Grade 1

Elevated hepatic transaminases ≥ Grade 3

1. Withhold nilotinib, and monitor hepatic transaminases
2. Resume treatment at 400 mg once daily if hepatic transaminases returns to ≤ Grade 1

• Myelosuppression - Absolute Neutrophil Count (ANC) <1 x 109/L and/or Platelet Counts <50 x 109/L

1. Stop nilotinib, and monitor blood counts

2. Resume within 2 weeks at prior dose if ANC >1 x 109/L and platelets >50 x 109/L

3. If blood counts remain low for >2 weeks, reduce the dose to 400 mg once daily

• QT Interval Prolongation: ECGs With QTc > 480 msec

1. Withhold nilotinib, and perform an analysis of serum potassium and magnesium, and if below lower limit of normal, correct to within normal limits. Concomitant medication usage must be reviewed.

2. Resume within 2 weeks at prior dose if QTcF returns to < 450 msec and to within 20 msec of baseline.

3. If QTcF is between 450 msec and 480 msec after 2 weeks, reduce the dose to 400 mg once daily.

4. If, following dose-reduction to 400 mg once daily, QTcF returns to > 480 msec, nilotinib should be discontinued.

5. An ECG should be repeated approximately 7 days after any dose adjustment.

Table 2

Dose Adjustments for Hepatic Impairment (At Baseline)

Indication

Child-Pugh Class

Dose

Newly diagnosed Ph+ CML

Any (A, B, or C)

Initial dose: 200 mg twice daily; escalate dose to 300 mg twice daily based on tolerability

Resistant or intolerant Ph+ CML

A, B

Initial dose 300 mg twice daily; escalate dose to 400 mg twice daily based on tolerability

C

Initial dose 200 mg twice daily; sequential escalation to 300 mg twice daily and then to 400 mg twice daily based on tolerability

Drug Availability: nilotinib is available as 150 mg (red) and 200 mg (light yellow) capsules.

PRECAUTIONS:

CONTRAINDICATIONS

BOXED WARNING:

WARNINGS

BILLING/CODING INFORMATION:

HCPCS Coding

J8999

Prescription drug, oral, chemotherapeutic, nos

ICD-10 Diagnoses Codes That Support Medical Necessity

C49.A0 – C49.A9

Gastrointestinal stromal tumor

C91.00

Acute lymphoblastic leukemia not having achieved remission

C91.01

Acute lymphoblastic leukemia, in remission

C91.02

Acute lymphoblastic leukemia, in relapse

C92.10

Chronic myeloid leukemia, bcr/abl-positive, not having achieved remission

C92.11

Chronic myeloid leukemia, bcr/abl-positive, in remission

C92.12

Chronic myeloid leukemia, bcr/abl-positive, 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 Advantage Products: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline review date.

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

DEFINITIONS:

Acute lymphoblastic leukemia: an aggressive (fast-growing) type of leukemia (blood cancer) in which too many immature white blood cells are found in the blood and bone marrow. Also called acute lymphocytic leukemia and ALL.

Chronic myelogenous leukemia: also known as chronic granulocytic leukemia (CGL), is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood

Inadequate chronic-phase CML treatment response: BCR-ABL1 transcript levels >10% or lack of partial cytogenetic response (i.e., >35% Ph-positive metaphases) at 3 or 6 months; or lack of a complete response (i.e., Ph-positive metaphases are detectable), BCR-ABL1 transcript levels >1%, or cytogenetic relapse at 12 months

Ph+ ALL complete response criteria to induction chemotherapy:

1. No circulating blasts or extramedullary disease

2. Trilineage hematopoiesis (TLH) and less than 5% blasts

3. ANC greater than 1,000/microL

4. Platelet count greater than 100,000/microL

5. No recurrence for 4 weeks

Philadelphia chromosome or Philadelphia translocation: is a specific chromosomal abnormality that is associated CML or ALL.

Relapse: the return of a disease or the signs and symptoms of a disease after a period of improvement. Specifically for CML a relapse is defined as “any sign of loss response” (defined as hematologic or cytogenic relapse). A 1-log increase in BCR-ABL transcript levels with loss of MMR should prompt bone marrow evaluation for loss of complete cytogenic response is not itself defined as relapse.

Refractory: cancer that does not respond to treatment; the cancer may be resistant at the beginning of treatment or it may become resistant during treatment. Also called resistant cancer.

RELATED GUIDELINES:

Allogeneic Bone Marrow and Stem Cell Transplantation, 02-38240-01
Autologous Bone Marrow and Stem Cell Transplantation, 02-38241-01

Azacitidine (Vidaza®) Injection, 09-J0000-84

Bosutinib (Bosulif®) Tablets, 09-J1000-84

Dasatinib (Sprycel®) Tablets, 09-J1000-43

Erythropoiesis Stimulating Agents, 09-J0000-31

Imatinib (Gleevec®) Tablets, 09-J1000-46

Immune Globulin Therapy, 09-J0000-06

Interferon alfa-n3 (Alferon N Injection®), 09-J0000-33

Interferons for Oncology Use, 09-J1000-37

Lenalidomide (Revlimid®), 09-J0000-80

Sunitinib (Sutent), 09-J1000-51

Regorafenib (Stivarga®), 09-J1000-83

Ponatinib (Iclusig®) Tablet, 09-J1000-89

Omacetaxine (Synribo®) Injection, 09-J1000-87

OTHER:

CML Risk Scores

Study

Calculation

Risk Definition by Calculation

Sokal et al, 1984

Exp 0.0116 x (age in years – 43.4) + (spleen – 7.51) + 0.188 x [(platelet count/700)2 – 0.562] + 0.0887 x (blast cell -2.10)

• Low: <0.8

• Intermediate: 0.8 to 1.2

• High: >1.2

Hasford et al, 1998

0.666 when age ≥50 years + (0.042 x spleen) + 1.0956 when platelet count >1,500 x 103/L + (0.0584 x blast cells) + 0.20399 when basophils >3% + (0.0413 X eosinophils) x 100

• Low: ≤780

• Intermediate: 781 to 1,480

• High: >1,480

Age is in years. Spleen is in centimeters below the costal margin (maximum distance). Blast cells, eosinophils, and basophils are in percents of peripheral blood differential. All factors must be collected prior to any treatment.

Online risk calculator can be found at: http://www.icsg.unibo.it/rrcalc.asp

REFERENCES:

  1. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2016. Available at: www.clinicalpharmacilogy-ip.com. Accessed 1/12/17.
  2. Jain P, Kantarjian H, Alattar ML, et al. Long-term molecular and cytogenetic response and survival outcomes with imatinib 400 mg, imatinib 800 mg, dasatinib, and nilotinib in patients with chronic-phase chronic myeloid leukaemia: retrospective analysis of patient data from five clinical trials. Lancet Haematol. 2015 Mar;2(3):e118-28.
  3. Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51.
  4. Kantarjian HM, Hochhaus A, Saglio G, et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial. Lancet Oncol. 2011 Sep;12(9):841-51.
  5. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012 Oct;26(10):2197-203.
  6. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 1/12/17.
  7. National Comprehensive Cancer Network. Cancer Guidelines. Cancer Guidelines and Drugs and Biologics Compendium. Accessed 1/12/17.
  8. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Version 2.2016. Acute Lymphoblastic Leukemia. Available at http://www.nccn.org/professionals/physician_gls/PDF/all.pdf. Accessed 1/25/17.
  9. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Version 2.2017. Chronic Myeloid Leukemia. Available at http://www.nccn.org/professionals/physician_gls/PDF/cml.pdf. Accessed 1/25/17.
  10. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology Version 1.2016. Soft Tissue Sarcoma. Available at http://www.nccn.org/professionals/physician_gls/PDF/sarcoma.pdf. Accessed 1/7/16.
  11. Reichardt P, Blay JY, Gelderblom H, et al. Phase III study of nilotinib versus best supportive care with or without a TKI in patients with gastrointestinal stromal tumors resistant to or intolerant of imatinib and sunitinib. Ann Oncol. 2012 Jul;23(7):1680-7.
  12. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010 Jun 17;362(24):2251-9.
  13. Tasigna (nilotinib) [package insert]. Novartis Pharmaceuticals Corp. East Hanover (NJ): September 2016.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 02/08/17.

GUIDELINE UPDATE INFORMATION:

01/01/12

New Medical Coverage Guideline.

11/15/12

Review and revision to guideline; consisting of updating position statement, adding contraindications, updating precautions, coding, program exceptions, related guidelines and references.

03/15/13

Review and revision to guideline; consisting of reformatting and revising position statement to include treatment of acute lymphoblastic leukemia; reformatting and revising description, dosage/administration, and precautions sections; adding definitions and related guidelines; and updating coding and references.

03/15/14

Review and revision to guideline; consisting of reformatting/revising position statement; reformatting precautions section; updating program exceptions and references.

03/15/15

Review and revision to guideline; consisting of revising position statement and decision tree, and updating the description, dosage/administration, warnings, and references.

11/01/15

Revision: ICD-9 Codes deleted.

03/15/16

Review and revision to guideline consisting of description, position statement, definitions, and references.

09/15/16

Revision to guideline consisting of updating the position statement and definitions.

10/01/16

Revision: ICD-10 code updates.

01/15/17

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

03/15/17

Review and revision to guideline consisting of updating the position statement, description section, dosage/administration section, precautions section, and references.

Date Printed: June 26, 2017: 11:26 AM