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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-J1000-86

Original Effective Date: 01/15/13

Reviewed: 08/10/16

Revised: 09/15/16

Subject: Tofacitinib (Xeljanz®, Xeljanz® XR) Tablet and Extended-Release 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:

In the last ten years, three major advances have impacted the treatment of rheumatoid arthritis (RA): early and aggressive treatment, use of disease activity measures leading to treat to target, and availability of biologic agents. Despite these advances, better long-term outcomes and a larger proportion of individuals with RA are still not adequately controlled with the available drugs. Furthermore, at least half of individuals with RA who were previously responding to a biologic or a biologic/disease modifying anti-rheumatic drug (DMARD) combination lose the efficacy of this regimen over 5 years and need new agents for treatment.

Tofacitinib (Xeljanz®) is a novel oral Janus kinase (JAK) inhibitor that was approved by the US Food and Drug Administration (FDA) in November 2012 for the treatment of adults with moderately to severely active RA who have had an inadequate response or intolerance to methotrexate. An extended-release formulation of tofacitinib (Xeljanz® XR) was approved by the FDA in February 2016 for the same indication. The JAK family of kinases plays an important role in cytokine induced signal transduction. Tofacitinib preferentially inhibits JAK1 and JAK3, which ultimately blocks signaling for several cytokines that are integral to lymphocyte activation, proliferation, and function. It is hypothesized that this inhibition results in the modulation of multiple aspects of immune response that play a role in the pathophysiology of RA.

In 2015, the American College of Rheumatology (ACR) published an updated guideline for the treatment of rheumatoid arthritis. The guidelines support the use of tofacitinib in the following scenarios: (1) patients with established RA if disease activity remains moderate or high despite DMARD monotherapy, use combination traditional DMARDS or add a TNFi or a non-TNF biologic or tofacitinib (all choices with or without MTX, in no particular order of preference); (2) patients with established RA if disease activity remains moderate or high despite use of multiple TNFi therapies, use tofacitinib, with or without MTX, over another TNFI, with or without MTX, if use of a non-TNF biologic is not an option; and (3) patients with established RA if disease activity remains moderate or high despite use of at least one TNFi and at least one non-TNF biologic, first use another non-TNF biologic, with or without MTX, then use tofacitinib, with or without MTX, over another TNFI. Tofacitinib is also recommended as an option when patients must avoid a TNFi due to congestive heart failure.

In the 2015 TACIT pragmatic, non-inferiority, randomized controlled trial, 205 persons with established moderate to severe RA received either an anti-TNF biologic with one DMARD (e.g., methotrexate), or conventional DMARD therapy titrated upward to include combination therapy. Most persons in the DMARD group eventually received 2 or 3 DMARDs in combination (e.g., methotrexate + leflunomide). The DMARD group was shown to be non-inferior to the anti-TNF group for the primary outcome of disability measured by a patient-recorded health assessment questionnaire at 12 months with a numerical advantage towards the DMARD group. Further supporting use of combination DMARD therapy, the 2-year follow-up of the SWEFOT trial (438 persons with methotrexate-refractory RA) showed no difference in utility or QALY gain over 21 months when comparing methotrexate + infliximab vs. methotrexate + sulfasalazine + hydroxychloroquine.

While methotrexate must be avoided in women who are pregnant or trying to become pregnant, sulfasalazine has adequate data supporting safe use (pregnancy Category B), and is consider a preferred DMARD if given with folic acid when treatment is clinically necessary. Hydroxychloroquine, cyclosporine, and anti-TNF biologics are also considered to be low-risk options during pregnancy

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.

NOTE: etanercept (Enbrel), adalimumab (Humira), golimumab (Simponi), and ustekinumab (Stelara) are preferred self-administered products.

‡NOTE: if the member has failed previous biologic therapy that is FDA-approved for the requested indication listed below, the member is not required to try and fail additional non-biologic prerequisite therapy (e.g., for RA, if member has previously tried and failed etanercept, but does not have a history of combination DMARD failure, they do not have to try and fail two DMARDs in combination to meet medical necessity criteria).

Initiation of tofacitinib (Xeljanz, Xeljanz XR) meets the definition of medical necessity when ALL of the following criteria are met:

1. Member is 18 years of age or older

2. Member has a diagnosis of moderately to severely active rheumatoid arthritis (RA)

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

a. Member has tried and failed, had persistent and intolerable adverse effect(s), or has a contraindication to TWO or more of the following self-administered biologics (the specific adverse effect(s) and/or contraindications must be provided):

i. adalimumab (Humira)

ii. etanercept (Enbrel)

iii. golimumab (Simponi)

b. Member should consider alternatives to the use of an anti-TNF biologic due to current or worsening congestive heart failure

4. Member has tried and failed therapy with at least TWO DMARDs (e.g., hydroxychloroquine, methotrexate, sulfasalazine, leflunomide) used in combination. Failure of only one DMARD is sufficient if member has a contraindication to BOTH methotrexate AND either sulfasalazine or hydroxychloroquine (the specific contraindications must be provided; pregnancy is not considered a contraindication to the use of sulfasalazine or hydroxychloroquine)

5. Tofacitinib will NOT be used in combination with ANY of the following:

a. abatacept (Orencia)

b. adalimumab (Humira)

c. anakinra (Kineret)

d. apremilast (Otezla)

e. certolizumab (Cimzia)

f. etanercept (Enbrel)

g. golimumab (Simponi)

h. infliximab (Remicade)

i. ixekizumab (Taltz)

j. secukinumab (Cosentyx)

k. tocilizumab (Actemra)

l. ustekinumab (Stelara)

m. vedolizumab (Entyvio)

6. The dosage does not exceed 5 mg orally twice daily (Xeljanz) or 11 mg orally once daily (Xeljanz XR)

Approval duration: 6 months

Continuation of tofacitinib meets the definition of medical necessity when ALL of the following criteria are met:

1. Member has a history of beneficial clinical response with tofacitinib therapy for the treatment of rheumatoid arthritis

2. An authorization/reauthorization for tofacitinib has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of rheumatoid arthritis, OR the member previously met ALL indication-specific initiation criteria

3. Tofacitinib will NOT be used in combination with ANY of the following:

a. abatacept (Orencia)

b. adalimumab (Humira)

c. anakinra (Kineret)

d. apremilast (Otezla)

e. certolizumab (Cimzia)

f. etanercept (Enbrel)

g. golimumab (Simponi)

h. infliximab (Remicade)

i. ixekizumab (Taltz)

j. secukinumab (Cosentyx)

k. tocilizumab (Actemra)

l. ustekinumab (Stelara)

m. vedolizumab (Entyvio)

4. The dosage does not exceed 5 mg orally twice daily (Xeljanz) or 11 mg orally once daily (Xeljanz XR)

Approval duration: 1 year

DOSAGE/ADMINISTRATION:

FDA-approved: tofacitinib is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other non-biologic DMARDs. The recommended dose is 5 mg orally twice daily for the immediate-release (IR) tablet and 11 mg orally once daily for the extended–release (ER) tablet. Tofacitinib should not be used in combination with biologic DMARDs (e.g. tumor necrosis factor alpha inhibitors) or potent immunosuppressants such as azathioprine and cyclosporine. Tofacitinib should not be initiated in members with a lymphocyte count less than 500 cells/mm3, an absolute neutrophil count less than 1000 cell/mm3, or a hemoglobin level less than 9 g/dL.

Dose Adjustments

• Renal Impairment

o Mild renal impairment: no dosage adjustment required

o Moderate to severe renal impairment: reduce dose to 5 mg once daily (IR tablet)

• Hepatic Impairment

o Mild impairment (Child-Pugh class A, total score of 5 or 6): no dosage adjustment required

o Moderate impairment (Child-Pugh class B, total score of 7-9): Reduce dose to 5 mg once daily (IR tablet)

o Severe impairment (Child-Pugh class C, total score greater than 10): not recommended

• Drug Interactions

o Potent CYP3A4 inhibitors (e.g., ketoconazole): reduce dose to 5 mg once daily (IR tablet)

o Concomitant moderate CYP3A4 inhibitor AND potent CYP2C19 (e.g., fluconazole): reduce dose to 5 mg once daily (IR tablet)

Therapeutic Drug Monitoring: recommended dose adjustments for adverse effects are located in table 1.

Table 1:

Dose adjustments

Lab Value

Recommendation

Lymphopenia

Lymphocyte count 500 cells/mm3 or greater

Maintain dose

Lymphocyte count less than 500 cells/mm3

Discontinue tofacitinib

Neutropenia

ANC greater than 1000 cells/mm3

Maintain dose

ANC 500 to 1000 cells/mm3

• Persistent decreases: interrupt dosing until ANC is greater than 1000 cells/mm3

• Reinitiate tofacitinib at 5 mg twice daily (IR) or 11 mg once daily (ER)

ANC less than 500 cells/mm3

Discontinue tofacitinib

Anemia

Hgb less than or equal to 2 g/dL decrease and greater than or equal to 9 g/dL

Maintain dose

Greater than 2 g/dL decrease or less than 8 g/dL

Interrupt until Hgb values have normalized

ANC, absolute neutrophil count; Hgb, hemoglobin

Drug Availability: tofacitinib is available as a white 5-mg, immediate-release film-coated tablet, and a pink 11-mg, extended-release film-coated tablet

PRECAUTIONS:

Boxed Warning

Infections: tuberculosis (TB), invasive fungal, and other opportunistic infections, some fatal, have occurred. Perform test for latent TB; if positive, start treatment for TB prior to starting therapy. Monitor all patients for active TB, even if initial tuberculin skin test is negative. If a serious infection develops, interrupt treatment until the infection is controlled.

Malignancy: lymphoma and other malignancies have been observed in individuals treated with tofacitinib. Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant individuals treated with tofacitinib and concomitant immunosuppressive medications.

Contraindications - None

Warnings

Gastrointestinal perforations: use with caution in members that may be at an increased risk.

Laboratory Monitoring: recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids.

Immunizations: live vaccines should not be given concurrently with tofacitinib

Severe hepatic impairment: not recommended for use in persons with severe hepatic impairment; refer to dosage and administration section for additional information.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding:

J8499

Prescription drug, oral, non-chemotherapeutic, Not otherwise specified

ICD-10 Diagnoses Codes That Support Medical Necessity: (Effective 10/01/15)

M05.00 – M05.09

Felty's syndrome

M05.10 – M05.19

Rheumatoid lung disease with rheumatoid arthritis

M05.20 – M05.29

Rheumatoid vasculitis with rheumatoid arthritis

M05.30 – M05.39

Rheumatoid heart disease with rheumatoid arthritis

M05.40 – M05.49

Rheumatoid myopathy with rheumatoid arthritis

M05.50 – M05.59

Rheumatoid polyneuropathy with rheumatoid arthritis

M05.60 – M05.69

Rheumatoid arthritis with involvement of other organs and systems

M05.70 – M05.79

Rheumatoid arthritis with rheumatoid factor without organ or systems involvement

M05.80 – M05.89

Other rheumatoid arthritis with rheumatoid factor

M05.9

Rheumatoid arthritis with rheumatoid factor, unspecified

M06.00 – M06.09

Rheumatoid arthritis without rheumatoid factor

M06.20 – M06.29

Rheumatoid bursitis

M06.30 – M06.39

Rheumatoid nodule

M06.80 – M06.89

Other specified rheumatoid arthritis

M06.9

Rheumatoid arthritis, unspecified

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

DEFINITIONS:

DMARDs: An acronym for disease-modifying antirheumatic drugs.

Rheumatoid arthritis: usually strikes between ages 20 and 50. Inflammation begins in a joint, usually those of the fingers and hands, resulting in pain, swelling, redness, and eventually joint deformity. It is considered an autoimmune disease, which can affect the entire body, causing fatigue, weight loss, weakness, fever, and loss of appetite. It affects each person differently, with symptoms ranging from mild to debilitating. In many cases, it is difficult to control. In about one in six cases, rheumatoid arthritis becomes severely debilitating and can shorten the life of the person affected.

RELATED GUIDELINES:

Abatacept (Orencia®). 09-J0000-67

Adalimumab (Humira®, 09-J0000-46

Anakinra (Kineret®), 09-J0000-45

Certolizumab Pegol (Cimzia®), 09-J0000-77

Etanercept (Enbrel®), 09-J0000-38

Golimumab (Simponi®, Simponi® Aria™), 09-J1000-11

Infliximab (Remicade®), 09-J0000-39

Rituximab (Rituxan®), 09-J0000-59

Tocilizumab (Actemra®) Injection, 09-J1000-21

OTHER:

Table 2:

Table 2: Disease Modifying Anti-Rheumatic Drugs

DMARD Generic Name

DMARD Brand Name

Auranofin (oral gold)

Ridaura®

Azathioprine

Imuran®

Chlorambucil

Leukeran®

Cyclophosphamide

Cytoxan®

Cyclosporine

Neoral, Sandimmune®

Gold sodium thiomalate (injectable gold)

Myochrysine®

Hydroxychloroquine sulfate

Plaquenil®

Leflunomide

Arava®

Methotrexate

Rheumatrex®, Trexall®

Minocycline

Minocin®

Penicillamine

Cuprimine®, Depen®

Sulfasalazine

Azulfidine®, Azulfidine EN-Tabs®

Grading of Severity of Rheumatoid Arthritis

Severity

Criteria

Mild

Joint pain
Inflammation of at least 3 joints
No inflammation in tissues other than the joints
Usually, a negative result on a rheumatoid factor test
An elevated erythrocyte sedimentation rate (ESR) or C reactive protein (CRP) level
No evidence of bone or cartilage damage on x-rays

Moderate

Between 6 and 20 inflamed joints
Usually no inflammation in tissues other than the joints
An elevated ESR or CRP levels
A positive rheumatoid factor test or anti-cyclic citrullinated peptide (anti-CCP) antibodies
Evidence of inflammation but no evidence of bone damage on x-rays

Severe

More than 20 persistently inflamed joints or a rapid loss of functional abilities
Elevated ESR or CRP levels
Anemia related to chronic illness
Low blood albumin level
A positive rheumatoid factor test, often with a high level
Evidence of bone and cartilage damage on x-ray
Inflammation in tissues other than joints

REFERENCES:

  1. Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumor necrosis factor inhibitors: a randomized phase 3 trial. Lancet 2013;381(9865):451-60.
  2. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.;2016. URL www.clinicalpharmacilogy-ip.com. Accessed 7/14/16.
  3. Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Eng J Med 2012;367(6):495-507.
  4. Graudal N, Hubeck-Graudal T, Tarp S, et al. Effect of combination therapy on joint destruction in rheumatoid arthritis: a network meta-analysis of randomized controlled trials. PLoS One. 2014 Sep 22;9(9):e106408.
  5. Karlsson JA, Neovius M, Nilsson JA, et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in early rheumatoid arthritis: 2-year quality-of-life results of the randomised, controlled, SWEFOT trial. Ann Rheum Dis. 2013 Dec;72(12):1927-33.
  6. Krause ML, Amin A, and Makol A. Use of DMARDs and biologics during pregnancy and lactation in rheumatoid arthritis: what the rheumatologist needs to know. Ther Adv Musculoskelet Dis. 2014 Oct; 6(5): 169–184.
  7. Lee EB, Fleischmann R, Hall S, et al. Tofacitinib versus methotrexate in rheumatoid arthritis. N Engl J Med 2014; 370: 2377-86.
  8. Micromedex® Healthcare Series [Internet Database]. Greenwood Village, Colo: Thomson Healthcare. Updated periodically. Accessed 7/14/16.
  9. National Collaborating Centre for Chronic Conditions (UK). Rheumatoid Arthritis: National Clinical Guideline for Management and Treatment in Adults. London: Royal College of Physicians (UK); 2009 Feb (updated 2015 Dec).
  10. Scott DL, Ibrahim F, Farewell V, et al. Tumour necrosis factor inhibitors versus combination intensive therapy with conventional disease modifying anti-rheumatic drugs in established rheumatoid arthritis: TACIT non-inferiority randomised controlled trial. BMJ. 2015 Mar 13;350:h1046.
  11. Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016 Jan;68(1):1-25
  12. van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. Mar 2013; 65 (3): 559-570.
  13. van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Eng J Med 2012;367(6):508-19.
  14. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012 May 5;379(9827):1712-20.
  15. Xeljanz/Xeljanz XR (tofacitinib) [package insert]. Pfizer Inc. New York (NY): March 2016.
  16. Yazici Y, Regens AL. Promising new treatments for rheumatoid arthritis: the kinase inhibitors. Bull NYU Hosp Jt Dis 2011;69(3):233-7.

COMMITTEE APPROVAL:

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

GUIDELINE UPDATE INFORMATION:

01/15/13

New Medical Coverage Guideline.

09/15/13

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

01/01/14

Revision to guideline; consisting of revising position statement

04/15/14

Revision to guideline; consisting of revising position statement.

09/15/14

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

09/15/15

Review and revision to guideline; consisting of updating position statement, warnings/precautions, billing/coding, and references.

11/01/15

Revision: ICD-9 Codes deleted.

04/15/16

Revision to guidelines consisting of updates to the description, position statement, dosage/administration, and references (new extended-release formulation)

09/15/16

Review and revision to guideline consisting of updating description, position statement, billing/coding, and references.

Date Printed: June 26, 2017: 11:31 AM