Subject: Infliximab Products [infliximab (Remicade ), infliximab-dyyb (Inflectra ), and infliximab-abda (Renflexis )]

Transcription

1 09-J Original Effective Date: 04/25/01 Reviewed: 09/12/18 Revised: 10/15/18 Subject: Infliximab Products [infliximab (Remicade ), infliximab-dyyb (Inflectra ), and infliximab-abda (Renflexis )] 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: Infliximab (Remicade) is one of five commercially available tumor necrosis factor (TNF)-alpha inhibitors, not counting biosimilars as separate products, in the United States, and was the first to be approved in August In April 2016 the first biosimilar version, infliximab-dyyb (Inflectra), was approved by the FDA. In April 2017 the FDA approved another biosimilar version, infliximab-abda (Renflexis). A third biosimilar, infliximab-qbtx (Ixifi), was FDA approved in December 2017, but the product will not be launched in the US. In contrast to other TNF-alpha inhibitors that are typically administered subcutaneously, infliximab products are administered via an intravenous infusion only. It is usually administered in a physician s office, patient s home, outpatient setting, or infusion center. Similar to other TNF-alpha inhibitors, the package labeling contains a Boxed Warning regarding potential increased risk of serious infections (e.g., tuberculosis) and certain malignancies during therapy. Tumor necrosis factor, a pro-inflammatory cytokine, initiates the body s defense response to local injury by stimulating the production of inflammatory mediators and signaling immune cells. TNF may augment host defense mechanisms when in low concentration, but large amounts of TNF can lead to excessive inflammation and tissue deterioration. In rheumatoid arthritis, activated T-cells migrate into the synovial lining of the joint where TNF is released and joint destruction begins. The intestinal mucosa from patients with Crohn s disease or ulcerative colitis has been associated with high levels of TNF as

2 compared to healthy individuals; a similar elevation in TNF has been demonstrated in patients with psoriasis. Biological agents exhibiting antagonistic properties for TNF bind to the cytokine with a high affinity and prevent TNF binding to receptors on immune, inflammatory, and endothelial cells. TNF-inhibitors may exert action using a variety of biologic activities that may be agent-specific or synergistic with other immunosuppressive agents. Interestingly, many individuals initially non-responsive or intolerant of one TNF-inhibitor have responded when switched to a different agent within the class. Research in this area is imperative in understanding and identifying potential risks and adverse effects associated with use. Combined data from randomized, controlled trials and safety registries have raised concerns that TNFinhibitors increase the risk of infections and malignancies; although, some studies have found no increased risk as compared to the frequency of infections and malignancies observed in a population predisposed to an immune-mediated inflammatory disease. Infliximab is approved by the US Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis, adult and pediatric Crohn s disease, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, and adult and pediatric ulcerative colitis. Infliximab also was granted orphan drug designation by the FDA for the treatment of juvenile rheumatoid arthritis (2002) and chronic sarcoidosis (2003). Biosimilar infliximab-dyyb and infliximab-abda were approved by the FDA for the same indications as Remicade with the exception of pediatric ulcerative colitis (due to Remicade s marketing exclusive for this indication until 2018).The TNF-alpha inhibitors as a class are considered to have similar efficacy and safety for the majority of indications. In 2018 the National Comprehensive Cancer Network (NCCN) began publishing its guideline Management of Immunotherapy-Related-Toxicities. Infliximab is recommended (category 2A) for various moderate-to-severe, steroid-refractory, immunotherapyrelated adverse effects including diarrhea/colitis, pneumonitis, acute renal failure, myocarditis/pericarditis/arrhythmias/impaired ventricular function, and inflammatory arthritis. In 2015, the American College of Rheumatology (ACR) published an updated guideline for treatment of rheumatoid arthritis (RA). The next update to the guideline is expected in late 2019 or early The guidelines support the use of a TNFi (e.g., infliximab or infliximab-dyyb) in the following scenarios: (1) patients with early RA if disease activity remains moderate or high despite DMARD monotherapy (with or without glucocorticoids), use combination DMARDS or a TNFi or a non-tnf biologic (all choices with or without methotrexate (MTX), in no particular order of preference); (2) patients with early RA if disease activity remains moderate or high despite DMARDs, use a TNFi over tofacitinib, (3) 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); and (4) patients with established RA if disease activity remains moderate or high despite TNFi therapy in patients who are currently not on DMARDs, add one or two DMARDs to TNFI therapy rather than continuation TNFi therapy alone. The avoidance of TNFi therapy and use of alternatives is recommended in certain high-risk conditions([i.e., congestive heart failure, hepatitis C infection and not receiving or requiring antiviral treatment, lymphoproliferative disorders, previously treated or untreated skin cancer, and previous serious infection).

3 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: Initiation of infliximab (Remicade) meets the definition of medical necessity when BOTH of the following are met ( 1 and 2 ): 1. Infliximab is administered for an indication listed in Table 1, and ALL of the indication-specific and maximum-allowable dose criteria are met 2. Infliximab is NOT used in combination with ANY of the following: a. abatacept (Orencia) b. adalimumab (Humira) c. anakinra (Kineret) d. apremilast (Otezla) e. baricitinib (Olumiant) f. brodalumab (Siliq) g. certolizumab (Cimzia) h. etanercept (Enbrel) i. golimumab (Simponi, Simponi Aria) j. guselkumab (Tremfya) k. ixekizumab (Taltz) l. other infliximab product (Inflectra, Renflexis) m. sarilumab (Kevzara) n. secukinumab (Cosentyx)

4 o. tildrakizumab-asmn (Ilumya) p. tocilizumab (Actemra) q. tofacitinib (Xeljanz, Xeljanz XR) r. ustekinumab (Stelara) s. vedolizumab (Entyvio) Initiation of infliximab-dyyb (Inflectra) meets the definition of medical necessity when ALL of the following are met ( 1, 2, and 3 ): 1. Infliximab-dyyb is administered for an indication listed in Table 1, and ALL of the indication-specific and maximum-allowable dose criteria are met 2. The member has previously tried infliximab (Remicade) and was either unable to tolerate or had an inadequate response 3. Infliximab-dyyb is NOT used in combination with ANY of the following: a. abatacept (Orencia) b. adalimumab (Humira) c. anakinra (Kineret) d. apremilast (Otezla) e. baricitinib (Olumiant) f. brodalumab (Siliq) g. certolizumab (Cimzia) h. etanercept (Enbrel) i. golimumab (Simponi, Simponi Aria) j. guselkumab (Tremfya) k. ixekizumab (Taltz) l. other infliximab product (Remicade, Renflexis) m. sarilumab (Kevzara) n. secukinumab (Cosentyx) o. tildrakizumab-asmn (Ilumya) p. tocilizumab (Actemra) q. tofacitinib (Xeljanz, Xeljanz XR) r. ustekinumab (Stelara) s. vedolizumab (Entyvio)

5 Initiation of infliximab-abda (Renflexis) meets the definition of medical necessity when ALL of the following are met ( 1, 2, and 3 ): 1. Infliximab-abda is administered for an indication listed in Table 1, and ALL of the indication-specific and maximum allowable dose criteria are met 2. The member has previously tried infliximab (Remicade) and was either unable to tolerate or had an inadequate response 3. Infliximab-abda is NOT used in combination with ANY of the following: a. abatacept (Orencia) b. adalimumab (Humira) c. anakinra (Kineret) d. apremilast (Otezla) e. baricitinib (Olumiant) f. brodalumab (Siliq) g. certolizumab (Cimzia) h. etanercept (Enbrel) i. golimumab (Simponi, Simponi Aria) j. guselkumab (Tremfya) k. ixekizumab (Taltz) l. other infliximab product(remicade, Inflectra) m. sarilumab (Kevzara) n. secukinumab (Cosentyx) o. tildrakizumab-asmn (Ilumya) p. tocilizumab (Actemra) q. tofacitinib (Xeljanz, Xeljanz XR) r. ustekinumab (Stelara) s. vedolizumab (Entyvio) Table 1 Indications and Specific Criteria Indication Specific Criteria Maximum Allowable Dose Axial spondyloarthritis (axspa) When BOTH of the following are met ( 1 and 2 ): Initial: 5 mg/kg at weeks 0, 2, and 6 [including both ankylosing 1. Member has a diagnosis of axial Maintenance: 5 mg/kg

6 spondylitis (AS) and nonradiographic axial spondyloarthritis (nraxspa)] spondyloarthritis per ASAS criteria 2. Member has had an inadequate response to, or has a contraindication to at least TWO different NSAID therapies taken continuously for at least 4 weeks each* (e.g., celecoxib, diclofenac, ibuprofen, meloxicam, naproxen) (the specific contraindications must be provided) every 6 weeks starting at week 12 Crohn s disease (CD) When BOTH of the following are met ( 1 and 2 ): Fistulizing CD 1. Member has a diagnosis of moderately to severely active CD [e.g., Crohn s Disease Activity Index (CDAI) greater than 220 points] 2. Member has had an inadequate response to at least ONE or has contraindications to ALL of the following treatments* (the specific contraindications must be provided): a. azathioprine b. mercaptopurine (6-MP) c. methotrexate d. systemic corticosteroid (e.g. oral prednisone, IV methylprednisolone) Member has CD with one or more draining fistulas for at least 3 months Pediatrics: Adults: Initial: 5 mg/kg at weeks 0, 2, and 6 Maintenance: 5 mg/kg every 8 weeks starting at week 14 Initial: 5 mg/kg at weeks 0, 2, and 6 Maintenance: 10 mg/kg every 8 weeks starting at week 14 Hidradenitis suppurativa (HS) (a.k.a., acne inversa) *Smoking cessation is highly encouraged in members who smoke. Smoking may worsen the disease and make the disease more refractory to treatment When ALL of the following are met ( 1, 2, and 3 ): 1. The initiation of treatment is prescribed by a dermatologist, infectious disease specialist, or surgeon 2. Member has had an inadequate response to at least 60 consecutive days of therapy and/or has contraindications to oral clindamycin (or minocycline) in combination with oral rifampin.* For members with a contraindication, persistent intolerable adverse effects, or unavoidable severe Initial: 5 mg/kg at weeks 0, 2, and 6 Maintenance: 10 mg/kg every 8 weeks starting at week 14

7 drug interactions with the use of rifampin, a trial of at least one oral antiinfective therapy is needed (failure of ANY or contraindications to ALL of the following): a. clindamycin b. dapsone c. doxycycline d. minocycline 3. Member s HS is determined to be moderate to severe (must meet BOTH of the following a and b ): a. At least ONE of the following: Ten or more inflammatory nodules Diffuse or near-diffuse inflammatory involvement that precludes quantification of individual nodules Two or more abscesses or draining fistulas Five or more inflammatory nodules AND at least one abscess or draining fistula b. EITHER of the following: The inflammatory lesions reoccur three or more times during a continuous 6-month time period There is persistent involvement of inflammatory lesions for at least 3 months Immune checkpoint inhibitor-related adverse effects When ALL of the following are met ( 1, 2, 3, and 4 ): 1. Member has been receiving treatment with an immune checkpoint inhibitor (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, darvalumab) 5 mg/kg X 1 dose, May repeat one additional 5 mg/kg dose if the member does not have adequate improvement in symptoms.

8 2. The member has one or more of the following adverse events: a. Moderate or severe diarrhea and colitis (Grades 2 to 4) b. Severe pneumonitis (Grade 3 or 4) c. Severe or life-threatening renal failure and elevated serum creatinine (Grade 3 or 4) d. Life-threatening myocarditis, pericarditis, arrhythmias, or impaired ventricular function (Grade 4) e. Severe inflammatory arthritis with joint symptoms that are limiting the member s activities of daily living 3. Member has had an inadequate response, intolerable adverse effects, or a contraindication to an adequate trial of systemic corticosteroid treatment (the specific adverse effects and/or contraindications must be provided) 4. The members immune checkpoint inhibitor therapy will be either permanently discontinued or held during treatment with infliximab Plaque psoriasis When ALL of the following are met ( 1, 2, and 3 ): 1. Member is 18 years of age or older 2. Member s disease is moderate to severe as evidenced by EITHER of the following before or after systemic drug therapy ( a or b ): a. Psoriasis covers 10% or more of member s BSA b. Psoriasis covers less than 10% of member s BSA but affects crucial body areas necessary for daily living activities (i.e., face, palms of hands, soles of feet, or genitals) Initial: 5 mg/kg at weeks 0, 2, and 6 Maintenance: 5 mg/kg every 8 weeks starting at week 14

9 Psoriatic arthritis (PsA) [including both axial and non-axial (peripheral) PsA] 3. EITHER of the following* ( a or b ): a. Member has had an inadequate response to at least 3 months of continuous treatment with maximally tolerated methotrexate (e.g., titrated to a dosage of 25 mg per week) b. BOTH of the following ( i and ii ): i. Member has a contraindication or intolerance to methotrexate (the specific contraindication and/or intolerance must be provided) ii. Member has had an inadequate response to at least 3 months of continuous treatment with EITHER oral cyclosporine (at a dosage of at least 4 mg/kg per day) or acitretin (at a dosage of at least 25 mg per day), OR has a contraindication and/or intolerance to BOTH cyclosporine and acitretin [the specific contraindication(s) and/or intolerance(s) must be provided; pregnancy is not considered a contraindication to the use of cyclosporine] When BOTH of the following are met ( 1 and 2 ): 1. Member s disease is active (i.e., persistent joint inflammation) 2. EITHER of the following based on the dominate disease type ( a or b ): a. Axial PsA: Member has had an inadequate response to, or has a contraindication to at least TWO different NSAID therapies taken continuously for at least 4 weeks each* (e.g., celecoxib, diclofenac, ibuprofen, meloxicam, naproxen)

10 (the specific contraindications must be provided) b. Peripheral PsA: Member has has had an inadequate response to, or has a contraindication to at least ONE NSAID therapy taken continuously for at least 4 weeks* (e.g., celecoxib, diclofenac, ibuprofen, meloxicam, naproxen) (the specific contraindication must be provided) AND Member has had an inadequate response to, or has a contraindication to methotrexate therapy at the maximally tolerated dosage (e.g., methotrexate titrated to 25 mg weekly), or, if methotrexate is contraindicated, to another csdmard* (e.g., cyclosporine, leflunomide, sulfasalazine) (the specific contraindication must be provided) Rheumatoid arthritis (RA) When ALL of the following are met ( 1, 2. 3, and 4 ): 1. Member is 18 years of age or older 2. Member s disease is moderately to severely active 3. Member has had an inadequate response (i.e., unable to achieve remission or low disease activity) to at least three continuous months of therapy with TWO or more csdmards (e.g., hydroxy-chloroquine, methotrexate, sulfasalazine, leflunomide) used in combination at the maximally tolerated dosage (e.g., methotrexate titrated to 25 mg weekly). A trial of csdmard monotherapy at the maximally tolerated dosage for at least three Initial: 3 mg/kg at weeks 0, 2, and 6 Maintenance: 10 mg/kg every 8 weeks starting at week 14

11 Takayasu arteritis (a.k.a., Takayasu s disease and aortic arch syndrome) continuous months is sufficient if the 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) 4. The infliximab product will be used in combination with methotrexate unless member has a contraindication or intolerance to methotrexate (the specific contraindication or intolerance must be provided) When ALL of the following are met ( 1 and 2 ): 1. Member s disease is refractory to or member has a contraindication to oral immunosuppressive therapy (e.g., cyclophosphamide, methotrexate, azathioprine) (the specific contraindication must be provided) 2. Member s disease is refractory to or member has a contraindication to systemic corticosteroids (the specific contraindication must be provided) Initial: 10 mg/kg at weeks 0,2, and 6 Maintenance: 10 mg/kg every 8 weeks starting at week 14 Ulcerative colitis (UC) When ALL of the following are met ( 1, 2, and 3 ): 1. Member has moderately to severely active UC 2. EITHER of the following* ( a or b ): a. Member has had an inadequate response, or has a contraindication to systemic corticosteroid therapy (the specific contraindication must be provided) b. Member is dependent on systemic corticosteroids [i.e., unable to successfully taper corticosteroids to less than 10 mg of prednisone (or equivalent) within 3 months of Initial: 5 mg/kg at weeks 0, 2, and 6 Maintenance: 5 mg/kg every 8 weeks starting at week 14

12 Uveitis initiation without return of symptoms] 3. Member has had an inadequate response to ANY, or has a contraindication to ALL of the following* (the specific contraindications must be provided): a. Oral aminosalicylate (i.e., sulfasalazine, olsalazine, mesalamine, or balsalazide) b. Non-oral aminosalicylates (e.g., enema or suppository) c. Thiopurine therapy (e.g., azathioprine or 6-mercaptopurine [6-MP]) Uveitis associated with Behcet s syndrome: The member has been diagnosed with Behcet s syndrome and has visionthreatening non-infectious intermediate, posterior or panuveitis Uveitis NOT associated with Behcet s syndrome: When BOTH of the following are met ( 1 and 2 ): 1. The member has a diagnosis of noninfectious intermediate, posterior or panuveitis 2. BOTH of the following ( a and b ): a. Member has had an inadequate response to at least ONE or has a contraindication to BOTH of the following treatments (the specific contraindication(s) must be provided) i. Antimetabolite (i.e., azathioprine, mycophenolate, or methotrexate) ii. Calcineurin antagonist (i.e., cyclosporine or tacrolimus) Initial: 10 mg/kg at weeks 0,2, and 6 Maintenance: 10 mg/kg every 8 weeks starting at week 14

13 b. EITHER of the following ( i or ii ) : i. Member has had an inadequate response to or has a contraindication to systemic corticosteroid therapy (the specific contraindication must be provided) ii. Member is dependent on systemic corticosteroids [i.e., unable to successfully taper corticosteroids to less than 10 mg of prednisone (or equivalent) within 3 months of initiation without return of symptoms] Granulomatosis with polyangiitis (GPA) When ALL of the following are met ( 1, 2, 3, and 4 ): Initial: 5 mg/kg at weeks 0 and 2 [formerly known as Wegener s granulomatosis] 1. Member s disease has been confirmed by biopsy 2. Member s disease is active Maintenance: 5 mg/kg every 4 weeks starting at week 6 3. Member s disease is refractory to or member has a contraindication to oral immunosuppressive therapy (e.g., cyclophosphamide) (the specific contraindication must be provided) 4. EITHER of the following ( a or b ): a. Member s disease is refractory to or member has a contraindication to systemic corticosteroids (the specific contraindication must be provided) b. Member is dependent on systemic corticosteroids [i.e., unable to successfully taper corticosteroids to less than 10 mg of prednisone (or equivalent) within 3 months of initiation without return of symptoms] Orphan Indications (non-fda approved)

14 Chronic sarcoidosis Diagnosis only Initial: 5 mg/kg at weeks 0, 2 and 6 Juvenile rheumatoid arthritis (JRA) [a.k.a., juvenile idiopathic arthritis (JIA)] When ALL of the following are met ( 1, 2, and 3 ): 1. Member is 2 years of age or older 2. Member s disease is moderately to severely active 3. Member has had an inadequate response to, or has a contraindication to ONE or more csdmard* (e.g., methotrexate, sulfasalazine, cyclosporine, leflunomide) (the specific contraindication must be provided) Maintenance: 5 mg/kg every 6 weeks starting at week 12 Approval duration: 6 months (all indications except immune-mediated colitis or enterocolitis induced by checkpoint inhibitor immunotherapy; 18-day approval for this indication only) ASAS, Assessment of SpondyloArthritis International Society; BSA, body surface area; csdmard, conventional synthetic disease modifying anti-rheumatic drug; NSAID, non-steroidal anti-inflammatory drug *NOTE: If the member has had an inadequate response to previous biologic therapy, other than an infliximab product, that is FDA-approved for the requested indication listed in Table 1, the member is not required to have had an inadequate response to non-biologic prerequisite therapy (e.g., for RA, if member has previously had an inadequate response to etanercept, but does not have a history of inadequate response to combination csdmard, they do not have to try two csdmards in combination to meet medical necessity criteria). Continuation of therapy with an infliximab product meets the definition of medical necessity when ALL of the following are met: 1. Member has demonstrated a beneficial clinical response to therapy with an infliximab product 2. An authorization or reauthorization for an infliximab product has been previously approved by Florida Blue or another health plan in the past 2 years for the treatment of a condition in Table 1 (except immune checkpoint inhibitor-related adverse effects; use the initiation criteria for this indication), OR the member previously met ALL indication-specific initiation criteria 3. The infliximab product is NOT administered concomitantly with ANY of the following: a. abatacept (Orencia)

15 b. adalimumab (Humira) c. anakinra (Kineret) d. apremilast (Otezla) e. baricitinib (Olumiant) f. brodalumab (Siliq) g. certolizumab (Cimzia) h. etanercept (Enbrel) i. golimumab (Simponi, Simponi Aria) j. guselkumab (Tremfya) k. ixekizumab (Taltz) l. other infliximab product (Remicade, Inflectra, Renflexis) m. sarilumab (Kevzara) n. secukinumab (Cosentyx) o. tildrakizumab-asmn (Ilumya) p. tocilizumab (Actemra) q. tofacitinib (Xeljanz, Xeljanz XR) r. ustekinumab (Stelara) s. vedolizumab (Entyvio) 4. The dosage prescribed does not exceed any of the following unless previously approved by another health plan or Florida Blue: 10 mg/kg every 8 weeks 7.5 mg/kg every 6 weeks 5 mg/kg every 4 weeks Approval duration: 1 year DOSAGE AND 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. Table 2: FDA-approved indications and recommended dosing Indication Dosage

16 Ankylosing Spondylitis Initial: 5 mg/kg at weeks 0, 2, and 6 Maintenance: 5 mg/kg every 6 weeks (beginning at week 12) Crohn s Disease (CD): Adults and Children (greater than 6 years of age) Adults and Children (greater than 6 years of age): Initial: 5 mg/kg at weeks 0, 2, and 6 Maintenance: 5 mg/kg every 8 weeks (beginning at week 14) Note: In adult members the dose may be increased to 10 mg/kg in members who initially respond but then lose their response. Plaque Psoriasis Initial: 5 mg/kg at weeks 0, 2, and 6 Psoriatic Arthritis (PsA) Maintenance: 5 mg/kg every 8 weeks (beginning at week 14) Ulcerative Colitis (UC) Adults and Children* (greater than 6 years of age) Rheumatoid Arthritis (RA) Initial: 3 mg/kg at weeks 0,2,6 Administered as an intravenous infusion Maintenance: 3 mg/kg every 8 weeks (beginning at week 14) Incomplete response: the dose can be increased up to 10 mg/kg or treatment interval can be decreased to every 4 weeks Should be given in combination with methotrexate *Inflectra and Renflexis do not have an indication for pediatric UC. However, it was determined as safe and effective by the FDA for another pediatric indication (i.e., Crohn s disease). Dose Adjustment Renal Impairment: dosage adjustments are not required for members with renal impairment. Hepatic Impairment: although specific dosage adjustments are not available, infliximab products should be used with caution in members with hepatic impairment. Drug Availability: Remicade mg lyophilized infliximab in a single-use vial for injection Inflectra mg lyophilized infliximab-dyyb in a single-use vial for injection Renflexis mg lyophilized infliximab-abda in a single-use vial for injection

17 PRECAUTIONS: Boxed Warning WARNING: SERIOUS INFECTIONS and MALIGNANCY SERIOUS INFECTIONS Patients treated with infliximab products are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Infliximab products should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: Active tuberculosis, including reactivation of latent tuberculosis. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent tuberculosis before infliximab product use and during therapy. Treatment for latent infection should be initiated prior to infliximab product use. Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with infliximab product should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with infliximab product, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including infliximab products. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including infliximab products. These cases have had a very aggressive disease course and have been fatal. Almost all patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and most were in adolescent and young adult males. Contraindications

18 Infliximab products are contraindicated in members who have experienced a severe hypersensitivity reaction to infliximab, infliximab-abda, or infliximab-dyyb, to the inactive components of the product, or to any murine proteins. Infliximab products at doses greater than 5 mg/kg should not be administered to members with moderate to severe heart failure (New York Heart Association [NYHA] Functional Class III/IV). Precautions/Warnings Serious Infections: infliximab products should not be initiated in members during an active infection. If an infection develops, monitor carefully, and discontinue infliximab if infection becomes serious. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants such as corticosteroids or methotrexate may be at greater risk of infection. Invasive fungal infections: If a member develops a systemic infection while on infliximab product therapy, consider empiric antifungal therapy for those who reside or travel to regions where mycoses are endemic. Anaphylaxis: anaphylaxis or serious allergic reactions may occur. Hepatitis B virus reactivation: members who are HBV caries should be monitored during and several months after therapy. If reactivation occurs during therapy, discontinue the infliximab product and initiate anti-viral therapy. Hepatotoxicity: rare severe hepatic reactions, some fatal or necessitating liver transplantation have occurred in those administered infliximab products. If jaundice and/or marked liver enzyme elevations occur, discontinue the infliximab product. Demyelinating disease: exacerbation of new onset may occur Cytopenia: advise members to seek immediate medical attention if symptoms develop and consider discontinuing the infliximab product Heart failure: worsening or new onset heart failure may occur. Lupus-like syndrome: discontinue the infliximab product if syndrome develops. Drug Interactions: avoid concomitant use with abatacept (Orencia) and anakinra (Kineret), due to increased risk of serious infection. Live vaccines: avoid administration of live vaccines (e.g., varicella and MMR) in members taking an infliximab product Pregnancy and Lactation o o Infliximab products are classified as pregnancy category B. Developmental toxicity studies performed in animals have revealed no evidence of harm to the fetus. There are no studies in pregnant women and use during pregnancy should only occur if clearly needed. Because many immunoglobulins are secreted in milk and the potential for serious adverse reactions exists, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

19 BILLING/CODING INFORMATION: The following codes may be used to report these services: HCPCS Coding: J1745 Q5103 Q5104 Injection, infliximab, excludes biosimilar, 10 mg Injection, infliximab-dyyb, biosimilar, (inflectra), 10 mg Injection, infliximab-abda, biosimilar, (renflexis), 10 mg ICD-10 Diagnosis Codes That Support Medical Necessity: D86.0 D86.9 Sarcoidosis H H Secondary noninfectious iridocyclitis H H Panuveitis I30.8 Other forms of acute pericarditis I30.9 Acute pericarditis, unspecified I40.8 Other acute myocarditis I40.9 Acute myocarditis, unspecified I50.9 Heart failure, unspecified J70.2 Acute drug-induced interstitial lung disorders J70.4 Drug-induced interstitial lung disorders, unspecified K31.6 Fistula of stomach and duodenum K50.00 K Crohn's disease (regional enteritis) K51.00 K Ulcerative colitis K52.1 Toxic gastroenteritis and colitis

20 K52.3 Indeterminate colitis K60.3 Anal fistula K60.4 Rectal fistula K60.5 Anorectal fistula K63.2 Fistula of intestine L40.0 Psoriasis vulgaris L40.50 L40.59 Arthropathic psoriasis L73.2 Hidradenitis suppurativa 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

21 M06.20 M06.29 Rheumatoid bursitis M06.30 M06.39 Rheumatoid nodule M06.4 Inflammatory polyarthropathy M06.80 M06.89 Other specified rheumatoid arthritis M06.9 Rheumatoid arthritis, unspecified M08.00 M08.09 Unspecified Juvenile rheumatoid arthritis M08.1 Juvenile ankylosing spondylitis M08.20 M08.29 Juvenile rheumatoid arthritis with systemic onset M08.3 Juvenile rheumatoid polyarthritis (seronegative) M08.40 M08.48 Pauciarticular juvenile rheumatoid arthritis M08.80 M08.89 Other juvenile arthritis M08.80 M08.99 Juvenile arthritis, unspecified M31.30 M31.31 Wegener s granulomatosis M31.4 Aortic arch syndrome [Takayasu] M45.0 M45.9 Ankylosing spondylitis M46.81 M46.89 Other specified inflammatory spondylopathies N17.8 Other acute kidney failure N17.9 Acute kidney failure, unspecified N82.2 Fistula of vagina to small intestine N82.3 Fistula of vagina to large intestine

22 N82.4 Other female intestinal-genital tract fistulae R19.7 Diarrhea, 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: No National Coverage Determination (NCD) was found at the time of the last guideline review date. The following Local Coverage Determination (LCD) was reviewed on the last guideline revised date: Infliximab (Remicade), (L33704) located at fcso.com. DEFINITIONS: Axial PsA (a.k.a., psoriatic spondylitis): a subset of psoriatic arthritis that affects the spine (i.e., spondylitis) and/or spinal joints (e.g., the sacroiliac joint between the sacrum and ilium of pelvis). Axial PsA shares similar clinical findings to patients with ankylosing spondylitis (AS); however, patients with axial PsA are often less symptomatic, have asymmetric disease, and tend to have less severe disease. In addition, the psoriatic plaques or nail changes present in patients with axial PsA are absent in patients with AS. About 5% of PsA patients have exclusively axial involvement, and 20 to 50% have both spinal and peripheral involvement, with peripheral joint involvement being the predominant pattern. Axial Spondyloarthritis (SpA): an inflammatory disease where the main symptom is back pain, and where the x-ray changes of sacroiliitis may or may not be present. In ankylosing spondylitis (AS), the x- ray changes are clearly present. In non-radiographic axial spondyloarthritis (nr-axspa); the x-ray changes are not present but you have symptoms. It is thought that nr-axspa may be an earlier form of AS. Crohn's Disease: is an inflammatory bowel disease characterized by severe, chronic inflammation of the intestinal wall or any portion of the gastrointestinal tract. The lower portion of the small intestine (ileum) and the rectum are most commonly affected by this disorder. Symptoms may include watery diarrhea and abdominal pain. The symptoms of Crohn's Disease can be difficult to manage and diagnosis is often delayed. DMARDs: An acronym for disease-modifying antirheumatic drugs. These are drugs that modify the rheumatic disease processes, and slow or inhibit structural damage to cartilage and bone. These drugs are unlike symptomatic treatments such as NSAIDs that do not alter disease progression. DMARDs can be further subcategorized. With the release of biologic agents (e.g., anti-tnf drugs), DMARDs were divided into either: (1) conventional, traditional, synthetic, or non-biological DMARDs; or as (2)

23 biological DMARDs. However, with the release of newer targeted non-biologic drugs and biosimilars, DMARDs are now best categorized as: (1) conventional synthetic DMARDs (csdmard) (e.g., MTX, sulfasalazine), (2) targeted synthetic DMARDs (tsdmard) (e.g., baricitinib, tofacitinib, apremilast), and (3) biological DMARDs (bdmard), which can be either a biosimilar DMARD (bsdmard) or biological originator DMARD (bodmard). Enterocutaneous fistula: a fistula between the intestine and skin of the abdomen. Hidradenitis suppurativa (HS) (a.k.a., acne inversa): a chronic, inflammatory, recurrent, debilitating skin disease of the hair follicle that usually presents after puberty with painful, deep-seated, inflamed lesions in the apocrine gland-bearing areas of the body, most commonly the axillae, inguinal and anogenital regions. HS may have a large impact on quality of life, often causing depression, impaired sexual health, and embarrassment. Squamous cell carcinoma may arise from chronic (10-30 years of evolution) lesions. The main goals of treatment are to prevent the formation of new lesion, treat new lesions, and eliminate existing nodules and sinus tract to limit or prevent scar formation. Immune checkpoint inhibitors: drugs that target molecules on certain immune cells that need to be activated (or inactivated) to start an immune response. Some types of cancer cells use these checkpoints to avoid being attacked by the body s own immune system. Examples include CTLA-4 inhibitors [e.g., ipilimumab (Yervoy)]; PD-1 inhibitors (e.g., pembrolizumab (Keytruda), nivolumab (Opdivo)]; and PD-L1 inhibitors (e.g., atezolizumab (Tecentriq)]. Mild-Moderate Crohn s Disease: Mild-moderate Crohn's disease applies to ambulatory members able to tolerate oral alimentation without manifestations of dehydration, toxicity (high fevers, rigors, prostration), abdominal tenderness, painful mass, obstruction, or >10% weight loss. Moderate-Severe Crohn s Disease: Moderate-severe disease applies to members who have failed to respond to treatment for mild-moderate disease or those with more prominent symptoms of fevers, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia. Monoclonal antibody: derived from a single cell; pertaining to a single clone. Widely used to measure proteins and drugs in the serum, type tissue and blood, identify infectious agents, identify classification and follow-up therapy of leukemias and lymphomas, and identify tumor antibodies. Non-axial or peripheral PsA: a subset of psoriatic arthritis that does NOT affect the spine or spinal joints [e.g. elbow, wrist, knees, hands, feet, and digits (dactylitis)]. Peripheral involvement may be polyarticular (5 or more joints affected) or oligoarticular (a.k.a., pauciarticular) (4 or fewer joints affected). Approximately 95% of patients with PsA have involvement of the peripheral joints, predominantly the polyarticular form, whereas a minority has the oligoarticular form. Plaque psoriasis: It is the most common form of psoriasis. It affects 80 to 90% of people with psoriasis. Plaque psoriasis typically appears as raised areas of inflamed skin covered with silvery white scaly skin. These areas are called plaques.

24 Psoriatic arthritis (PsA): joint inflammation that occurs in about 5% to 10% of people with psoriasis (a common skin disorder). It is a severe form of arthritis accompanied by inflammation, psoriasis of the skin or nails, and a negative test for rheumatoid factor. Enthesitis refers to inflammation of entheses, the site where ligaments or tendons insert into the bones. It is a distinctive feature of PsA and does not occur with other forms of arthritis. Common locations for enthesitis include the bottoms of the feet, the Achilles' tendons, and the places where ligaments attach to the ribs, spine, and pelvis. Remission: Remission refers to members who are asymptomatic or without inflammatory sequelae and includes members who have responded to acute medical intervention or have undergone surgical resection without gross evidence of residual disease. Members requiring steroids to maintain well-being are considered to be "steroid-dependent" and are usually not considered to be "in remission." 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. Severe-Fulminant Disease: Severe-fulminant disease refers to members with persisting symptoms despite the introduction of steroids as outpatients, or individuals presenting with high fever, persistent vomiting, and evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess. Ulcerative colitis: a chronic inflammatory disease of the colon that is of unknown cause and is characterized by diarrhea with discharge of mucus and blood, cramping abdominal pain, and inflammation and edema of the mucous membrane with patches of ulceration. RELATED GUIDELINES: Abatacept (Orencia), 09-J Adalimumab (Humira), 09-J Anakinra (Kineret), 09-J Apremilast (Otezla) Tablet, 09-J Baricitinib (Olumiant), 09-J Brodalumab (Siliq) Injection, 09-J Canakinumab (Ilaris) Injection, 09-J Certolizumab Pegol (Cimzia), 09-J

25 Etanercept (Enbrel), 09-J Golimumab (Simponi, Simponi Aria), 09-J Guselkumab (Tremfya), 09-J Ixekizumab (Taltz), 09-J Natalizumab (Tysabri) Injection, 09-J Rituximab (Rituxan), 09-J Sarilumab (Kevzara), 09-J Secukinumab (Cosentyx), 09-J Tildrakizumab-asmn (Ilumya), 09-J Tocilizumab (Actemra) Injection, 09-J Tofacitinib (Xeljanz, Xeljanz XR) Tablets, 09-J Ustekinumab (Stelara), 09-J Vedolizumab (Entyvio) Injection, 09-J OTHER: Table 3: Conventional Synthetic DMARDs Generic Name Brand Name Auranofin (oral gold) Azathioprine Cyclosporine Hydroxychloroquine Leflunomide Methotrexate Sulfasalazine Ridaura Imuran Neoral, Sandimmune Plaquenil Arava Rheumatrex, Trexall Azulfidine, Azulfidine EN-Tabs

26 Assessment of Spondyloarthritis International Society (ASAS) Diagnostic Criteria for Axial Spondylarthritis (SpA) Patients with chronic ( 3 months) back pain, the onset of which occurs at <45 years of age, AND EITHER of the following: 1. Imaging arm: a. Sacroiliitis on imaging* AND b. 1 SpA feature 2. Clinical arm: SpA features: a. HLA-B27 positive AND b. 2 other SpA features Inflammatory back pain Arthritis Enthesitis (heel) Uveitis Dactylitis Psoriasis Crohn s/colitis Good response to NSAIDs Family history of SpA HLA-B27 Elevated CRP *Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA, or definite radiographic sacroiliitis according to modified New York criteria Table 4: Grading of Severity of Rheumatoid Arthritis Severity Criteria Mild Joint pain

27 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 Severe 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 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. Alhusayen R, Shear NH. Pharmacologic interventions for hidradenitis suppurativa: what does the evidence say? Am J Clin Dermatol Oct 1;13(5): Armstrong AW, Siegel MP, Bagel J, et al. From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis. J Am Acad Dermatol Feb;76(2): Bansback N, Phibbs CS, Sun H, et al; CSP 551 RACAT Investigators.Triple Therapy Versus Biologic Therapy for Active Rheumatoid Arthritis: A Cost-Effectiveness Analysis. Ann Intern Med Jul 4;167(1): Barry RJ, Nguyen QD, Lee RW, et al. Pharmacotherapy for uveitis: current management and emerging therapy. Clin Ophthalmol Sep 22;8: doi: /OPTH.S Beukelman T, Patkar NM, Saag KG, et al American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care Res 2011;63(4): Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol Jun 10;36(17): Bressler B, Marshall JK, Bernstein CN, et al. Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus. Gastroenterology May;148(5): e3. 8. Buchner AM, Blonski W, Lichtenstein GR. Update on the management of Crohn s disease. Curr Gastroenterol Rep 2011;13:

28 9. Callhoff J, Sieper J, Weiß A, et al. Efficacy of TNFα blockers in patients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann Rheum Dis Jun;74(6): Canadian Psoriasis Guidelines Addendum Committee Addendum to the Canadian Guidelines for the Management of Plaque Psoriasis J Cutan Med Surg Sep;20(5): Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; Available at: Accessed 8/28/ Coates LC, Kavanaugh A, Mease PJ et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis: Treatment Recommendations for Psoriatic Arthritis Arthritis Rheumatol 2016;68: Dogra S, Jain A, Kanwar AJ. Efficacy and safety of acitretin in three fixed doses of 25, 35 and 50 mg in adult patients with severe plaque type psoriasis: a randomized, double blind, parallel group, dose ranging study. J Eur Acad Dermatol Venereol Mar;27(3):e Dogra S, Krishna V, Kanwar AJ. Efficacy and safety of systemic methotrexate in two fixed doses of 10 mg or 25 mg orally once weekly in adult patients with severe plaque-type psoriasis: a prospective, randomized, double-blind, dose-ranging study. Clin Exp Dermatol Oct;37(7): FDA Orphan Drug Designations and Approvals [Internet]. Washington, D.C. [cited 2018 August 28]. Available from: Friedman CF, Proverbs-Singh TA, and Postow MA. Treatment of the Immune-Related Adverse Effects of Immune Checkpoint Inhibitors: A Review. JAMA Oncol Jun Gener G, Canoui-Poitrine F, Revuz JE, et al. Combination therapy with clindamycin and rifampicin for hidradenitis suppurativa: a series of 116 consecutive patients. Dermatology. 2009;219(2): Giardina A, Ferrante A, Ciccia F, et al. One year study of efficacy and safety of infliximab in the treatment of patients with ocular and neurological Behcet s disease refractory to standard immunosuppressive drugs. Rheumatol Int 2011;31: Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis Mar;75(3): Gottlieb A, Korman NJ, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 2. Psoriatic arthritis: overview and guidelines of care for treatment with an emphasis on the biologics. J Am Acad Dermatol May;58(5): doi: /j.jaad 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 Sep 22;9(9):e Hsu S, Papp KA, Lebwohl MG, et al. Consensus guidelines for the management of plaque psoriasis. Arch Dermatol 2012;148(1): Inflectra (infliximab-dyyb) [package insert]. Pfizer Laboratories Div Pifzer Inc. New York (NY): July Ingram JR, Woo PN, Chua SL, et al. Interventions for hidradenitis suppurativa. Cochrane Database Syst Rev Oct 7;(10):CD Ixifi (infliximab-qbtx) [package insert]. Pfizer Laboratories Div Pifzer Inc. New York (NY): December Levy-Clarke G, Jabs DA, Read RW, et al. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology Mar;121(3): e3.