Committee Approval Date: February 17, 2015 Next Review Date: January 2016

Medication Policy Manual Policy No: dru209 Topic: Actemra, tocilizumab Date of Origin: March 12, 2010 Committee Approval Date: February 17, 2015 Next Review Date: January 2016 Effective Date: May 1, 2015 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Tocilizumab (Actemra) blocks a chemical in the body called IL-6, a protein involved in the inflammatory process. It is available in intravenous and subcutaneous formulations, and is used to treat diseases that may be caused or worsened by an overactive immune system such as rheumatoid arthritis. dru209.11 Page 1 of 19

Policy/Criteria I. Most contracts require prior authorization approval of tocilizumab (Actemra) prior to coverage. A. Intravenous tocilizumab (Actemra) may be considered medically necessary when criteria 1 and 2 below are met. 1. Alternative Site of Care - for Washington, Oregon, and Idaho commercial, fully insured members only (does not apply to Medicare) Tocilizumab (Actemra) is administered in a non-hospital outpatient setting (also referred to as an alternative site of care ; such as a provider s office, an infusion center, or home infusion), unless both of the following criteria a. and b. below are met: a. All non-hospital outpatient settings are greater than 10 miles further from the member s home than the hospital outpatient setting. AND b. The member s home is not eligible for home infusion services (such as home is not within the service area or is deemed unsuitable for care by the home infusion provider). AND NOTE: Alternative Site of Care criteria will be waived for payment of the first dose, to allow for adequate transition time to arrange for a non-hospital outpatient setting for the infusion. 2. At least one of criterion a. through c. below is met:. a. A diagnosis of juvenile idiopathic arthritis (JIA) and criteria i. and ii. below are met. i. Diagnosis is established by or in consultation with a specialist in rheumatology. AND ii. There is clinical documentation that an oral DMARD (such as methotrexate) was not effective after at least a 6 to 12 week treatment course based on one or more of the assessment components listed in Appendix 1, or that an oral DMARD was not tolerated or all oral DMARDs are contraindicated (see Appendix 4). OR b. A diagnosis of rheumatoid arthritis (RA) and all of criteria i., ii., and iii. below are met. i. Diagnosis is established by or in consultation with a specialist in rheumatology (see Appendix 1). AND dru209.11 Page 2 of 19

ii. AND iii. There is clinical documentation that an oral DMARD (such as methotrexate) was not effective after at least a 6 to 12 week treatment course based on one or more of the assessment components listed in Appendix 2, or that an oral DMARD was not tolerated or all oral DMARDs are contraindicated (see Appendix 4). There is clinical documentation that treatment with infliximab (Remicade) was not effective after at least a 12-week treatment course unless it was not tolerated or is contraindicated. OR c. A diagnosis of systemic juvenile idiopathic arthritis (SJIA; Still s disease) and criteria a, b, and c below are met. i. Diagnosis is established by or in consultation with a specialist in rheumatology. AND ii. There is disease activity for greater than 6 months. AND iii. There is clinical documentation that treatment with at least one oral systemic agent (e.g. methotrexate, corticosteroids) was not effective, not tolerated, or is contraindicated. B. Subcutaneous tocilizumab (Actemra) may be considered medically necessary when all of criteria 1 through 3 below are met. 1. A diagnosis of rheumatoid arthritis (RA) when established by or in consultation with a specialist in rheumatology (see Appendix 1). AND 2. There is clinical documentation that an oral DMARD (such as methotrexate) was not effective after at least a 6 to 12 week treatment course based on one or more of the assessment components listed in Appendix 2, or that an oral DMARD was not tolerated or all oral DMARDs are contraindicated (see Appendix 4). AND 3. There is clinical documentation that treatment with two preferred biologic therapies were each not effective after at least a 12-week treatment course unless each were not tolerated or were contraindicated (see Appendix 3). dru209.11 Page 3 of 19

II. Administration, Quantity Limitations, and Authorization Period A. Administration 1. RegenceRx does not consider intravenous tocilizumab (Actemra) to be a selfadministered medication. 2. RegenceRx considers subcutaneous tocilizumab (Actemra) to be a selfadministered medication. B. When prior authorization is approved, tocilizumab (Actemra) may be covered in quantities as follows: 1. Intravenous tocilizumab (Actemra) a. Juvenile idiopathic arthritis (JIA) and rheumatoid arthritis (RA) i. Initial Authorization Up to 6 infusions in a 6 month period in a non-hospital outpatient setting, unless waived per criteria I.A.1. above. NOTE: Alternative Site of Care criteria will be waived for payment of the first dose, to allow for adequate transition time to arrange for a non-hospital outpatient setting for the infusion.. ii. Continued Authorization A maximum of 13 infusions in a 1 year period based on a recommended infusion interval of every 4 weeks. b. Systemic juvenile idiopathic arthritis (SJIA) i. Initial Authorization Up to 12 infusions in a 6 month period in a non-hospital outpatient setting, unless waived per criteria I.A.1. above. NOTE: Alternative Site of Care criteria will be waived for payment of the first dose, to allow for adequate transition time to arrange for a non-hospital outpatient setting for the infusion.. ii. Continued Authorization A maximum of 13 infusions in a 1 year period based on a recommended infusion interval of every 4 weeks. iii. Continued Authorization A maximum of 26 infusions in a 1 year period based on a recommended infusion interval of every 2 weeks. 2. Subcutaneous tocilizumab (Actemra) A maximum of 52 syringes in a 1 year period based on a recommended injection interval of weekly. C. Authorization review 1. Intravenous tocilizumab (Actemra) a. Initial authorization shall be reviewed at 6 months. dru209.11 Page 4 of 19

b. Continued authorization or re-authorization (after the initial 6 month period) shall be reviewed at least annually, and clinical documentation indicating that there is disease stability or improvement must be provided. 2. Subcutaneous tocilizumab (Actemra) Authorization may be reviewed at least annually to confirm that current medical necessity criteria are met and that the medication is effective. III. For Washington, Oregon and Idaho commercial, fully insured members only (does not apply to Medicare) Intravenous tocilizumab (Actemra) is considered not medically necessary when administered in a hospital outpatient setting when an alternative site of care (non-hospital outpatient setting) is a treatment option (see Section I. Alternative Site of Care). IV. Tocilizumab (Actemra) is considered investigational when used for all other conditions, including but not limited to: A. Use in combination with another biologic response modifier (see Appendix 3), apremilast (Otezla) or tofacitinib (Xeljanz) B. Conditions other than rheumatoid arthritis (RA) for subcutaneous tocilizumab (Actemra) C. Giant cell arteritis (GCA) D. Multicentric Castleman s disease E. Relapsing polychondritis F. Systemic lupus erythematosus (SLE) Position Statement - There are many treatments for chronic inflammatory conditions that are effective, have known long-term safety profiles, and are recommended by national treatment guidelines. - Non-medical therapies, such as prescribed exercise therapy, physical therapy, weight loss, and smoking cessation are important treatment plan components for patients suffering from many chronic inflammatory conditions. - When a systemic medication therapy is needed to manage a chronic inflammatory condition, generic oral therapies usually offer the best value. - When non-medical therapies and oral medications are inadequate, a biologic medication may be appropriate. - Preferred/formulary biologic medications for the treatment of chronic inflammatory conditions include: adalimumab (Humira), etanercept (Enbrel), infliximab (Remicade), golimumab IV (Simponi Aria) and ustekinumab (Stelara). dru209.11 Page 5 of 19

- No studies have shown that any one biologic medication is more effective than another in the treatment of chronic inflammatory conditions; however, the data for some individual products is of sufficient quality that indirect comparison can be made. * Indirect comparison is made base on the calculated number needed to treat (NNT) which describes the average number of patients that need to be treated for one patient to benefit. * The lower the NNT, the more likely the medication will have a benefit. * Products with similar NNTs can be considered to have comparable efficacy. - When there is no demonstrated difference in safety or efficacy, the medication with the lowest cost often provides the best value for members. - Individual responses and tolerability of biologics are unpredictable and may vary between patients. If one biologic agent provides an inadequate response, another biologic may yet be effective. - Due to the potential for development of antibodies with anti-tnf therapies (see Table 1) which may result in loss of efficacy, clinical practice guidelines generally recommend a trial with no more than two anti-tnf therapies. [1-3] For those who have an inadequate response or intolerance to two anti-tnf therapies, it is reasonable to consider a biologic with an alternative mechanism of action and proven efficacy for the patient s diagnosis [e.g. abatacept (Orencia), tocilizumab (Actemra), rituximab (Rituxan), or ustekinumab (Stelara)]. - All biologics (both anti-tnfs and non-anti-tnfs) carry a risk of severe infections. There is no conclusive evidence that any one biologic option has a superior safety profile. - There is significant variation in recommended dosing across indications for individual medications; therefore, when multiple dosage forms of a biologic agent are available, coverage can be provided for those indications where the dosage form has been evaluated in randomized controlled trials, the dosage form has been proven safe and effective, and for which the dosage form has an established dose. For all other indications, the specific dosage form will be considered investigational. - New technologies and pharmaceuticals allow therapeutic services, such as infusion therapy, to be administered safely, effectively, and much less costly outside of the hospital outpatient setting. Alternative sites of care (such as doctor s offices, infusion centers, and home infusion) are well-established, accepted by physicians, and reduce the overall cost of care. Clinical Efficacy Background - Treatments for rheumatic conditions may include non-medical therapies, medications for the management of symptoms, and medications that modify the disease course such as oral or biologic disease modifying anti-rheumatic drugs (DMARD), including the first-in-class phosphodiesterase 4 (PDE4) inhibitor apremilast (Otezla), and the Janus kinase (JAK) inhibitor, tofacitinib (Xeljanz). dru209.11 Page 6 of 19

- Medications to control inflammation such as nonsteroidal antiinflammatory medications (e.g. ibuprofen, indomethacin, and naproxen) and glucocorticoids (oral or injected into the joint) are effective for the management of symptoms, particularly during the early stages of disease. - Generic, orally administered DMARDs, including methotrexate (MTX), hydroxychloroquine, leflunomide, and sulfasalazine are effective for decreasing symptoms and slowing disease progression, have a proven track record, and have been the standard of care for many years. * Methotrexate (MTX) is considered effective in the treatment of rheumatoid arthritis (RA) and is the standard reference DMARD to which newer oral and biologic DMARDs are compared for efficacy. * Generic oral therapies have known potential risks. The management of these risks is well established. - The biologic agents can also decrease symptoms, help preserve joint functioning, and slow the progression of chronic inflammatory conditions; however, these medications also have significant risks. - There is no comparative safety data within the biologics class that indicates one medication or mechanism of action is safer than alternatives, including anti-tnfs compared to non-anti- TNF medications. - In RA, the best response is seen when MTX is used concomitantly with any of the biologics. Infliximab (Remicade) and golimumab (Simponi, Simponi Aria) have been shown to be effective only when used with MTX. Treatment options other than infliximab (Remicade) or golimumab (Simponi, Simponi Aria) should be considered for patients who cannot take MTX. - Inhibiting PDE4 is a novel mechanism in the treatment of rheumatic conditions. PDE4 is a protein present in immune cells and is associated with inflammation. - JAK inhibition is a novel mechanism in the treatment of rheumatic conditions. JAKs are enzymes that stimulate hematopoiesis and promote immune cell function. Juvenile Idiopathic Arthritis (JIA); Juvenile Rheumatoid Arthritis (JRA) - Several biologic agents have been shown to be effective in the treatment of JIA including: * Abatacept (Orencia) intravenous * Adalimumab (Humira) * Etanercept (Enbrel) * Tocilizumab (Actemra) intravenous - Due to lack of high quality data, the comparative efficacy for these agents in the treatment of JIA is uncertain. Efficacy of tocilizumab (Actemra) in juvenile idiopathic arthritis (JIA); juvenile rheumatoid arthritis (JRA) - The efficacy of intravenous tocilizumab (Actemra) was assessed in one study which included a randomized, double-blind, placebo-controlled phase, in children 2 to 17 years of age with active JIA for at least 6 months who had an inadequate response to, or inability to tolerate, MTX. [4] dru209.11 Page 7 of 19

- Patients treated with tocilizumab (Actemra) experienced significantly fewer disease flares compared to placebo-treated patients (26% [21/82] versus 48% [39/81]; adjusted difference in proportions -21%, 95% CI: -35%, -8%). [4] Rheumatoid Arthritis (RA) - Several biologic and newer oral agents have been shown to be effective in the treatment of RA including the following: * Abatacept (Orencia) intravenous and subcutaneous * Adalimumab (Humira) * Anakinra (Kineret) * Etanercept (Enbrel) * Certolizumab pegol (Cimzia) * Golimumab (Simponi, Simponi Aria) * Infliximab (Remicade) * Rituximab (Rituxan) * Tocilizumab (Actemra) intravenous and subcutaneous * Tofacitinib (Xeljanz) - All of these agents, with the exception of tocilizumab (Actemra) subcutaneous and tofacitinib (Xeljanz) have high quality data in the treatment of RA (see Table 1) and, therefore, can be indirectly compared based on their calculated NNTs (see Table 2). - With the exception of anakinra (Kineret), and those products without high quality data, the efficacy of these agents in the treatment of RA is similar. Efficacy of tocilizumab (Actemra) in rheumatoid arthritis (RA) - Both intravenous and subcutaneous tocilizumab (Actemra) are effective in the treatment of RA in patients who have had an inadequate response to MTX or other oral DMARDs, as well as in patients who have had an inadequate response to anti-tnf therapies. [4-10] - The recommended dose of tocilizumab (Actemra) intravenous (with or without a concomitant oral DMARD) is 4 mg/kg administered every four weeks as a one hour infusion. [4] * The dose of tocilizumab (Actemra) may be increased to 8 mg/kg every 4 weeks depending on clinical response. * Individual doses exceeding 800 mg per infusion are not recommended. * Individual doses exceeding 8 mg/kg or administration more often than every 4 weeks has not been determined to be safe or effective, and are considered investigational. - The recommended dose of subcutaneous tocilizumab (Actemra) is based on weight. [4] * For patients weighing less than 100 kg, the recommended dose of subcutaneous tocilizumab (Actemra) is 162 mg every other week followed by an increase to every week based on clinical response. * For patients weighing 100 kg, the recommended dose of subcutaneous tocilizumab (Actemra) is 162 mg every week. dru209.11 Page 8 of 19

- The safety and efficacy of tocilizumab (Actemra) as initial therapy for RA or subcutaneous tocilizumab (Actemra) in conditions other than RA have not been established. Systemic Juvenile Idiopathic Arthritis (SJIA) - Several biologic agents have been shown to be effective in the treatment of SJIA including: * Anakinra (Kineret) * Canakinumab (Ilaris) * Tocilizumab (Actemra) intravenous - Due to lack of high quality data, the comparative efficacy for these agents in the treatment of SJIA is uncertain. Efficacy of tocilizumab (Actemra) in systemic juvenile idiopathic arthritis (SJIA) - A Phase III randomized, double-blinded study (TENDER) evaluated the use of intravenous tocilizumab (Actemra) in 112 patients aged 2-17 years with a diagnosis of SJIA/Still's disease for longer than 6 months with a history of an inadequate response to treatment with NSAIDs and/or glucocorticoids. [11] * Patients were randomized to receive either tocilizumab (Actemra) 8 mg/kg or 12 mg/kg infused every 2 weeks, or placebo for 12 weeks. * At the end of 12 weeks, significantly more patients who received tocilizumab (Actemra) achieved a juvenile idiopathic arthritis (JIA) ACR30 response plus absence of fever than did patients receiving placebo infusions (85% vs 24% respectively, p < 0.0001). - The use of tocilizumab (Actemra) in the management of patients with SJIA has been endorsed by published consensus guidelines. [1] Other Conditions Tocilizumab (Actemra) has been studied in a variety of other conditions. Due to lack of published data, lack of high quality data, or lack of positive data these conditions are considered investigational. Details of select investigational uses are reported below. Giant Cell Arteritis (GCA) - No randomized controlled trials have been published evaluating the use of tocilizumab (Actemra) in the treatment of GCA; data is limited to small case series. [12-17] Multicentric Castleman s Disease - A number of case reports have been published describing the successful use of tocilizumab (Actemra) in the treatment of patients with multicentric Castleman's disease. However, no randomized, clinical trials were identified that evaluated the clinical safety and efficacy of tocilizumab (Actemra) in this disorder. [18-22] dru209.11 Page 9 of 19

Relapsing Polychondritis - No randomized controlled trials have been published evaluating the use of tocilizumab (Actemra) in the treatment of relapsing polychondritis; data is limited to small case series. [23,24] Systemic Lupus Erythematosus (SLE) - A small preliminary study assessing the use of tocilizumab (Actemra) in patients with SLE found promising signs of response, but larger, controlled studies will be needed to establish the efficacy and safety in this population. [25] Safety Summary - All biologic and non-biologic DMARDs have an adequate track record of clinical experience ( 3 years) with the exception of tofacitinib (Xeljanz), vedolizumab (Entyvio) and golimumab (Simponi Aria); however, the compound golimumab has been available as Simponi since 2009. - All biologics (both anti-tnfs and non-anti-tnfs) carry a risk of severe infections. There is no conclusive evidence that any one biologic option has a superior safety profile. - Apremilast (Otezla) has a short track record of clinical experience (< 1 year) in the U.S. for the treatment of PsA. It has been approved in Europe for the treatment of Behçet s disease since August 2013. - Immune suppression and subsequent increased risk of infection or malignancy is a potential risk with all biologic and non-biologic DMARDs. Serious infections such as tuberculosis and fungal infections should be considered prior to starting any of these therapies. - Branded DMARDs are not recommended to be given concomitantly, should be used with caution when given concomitantly with other immunosuppressive therapies, and may interfere with live vaccines. Safety of tocilizumab (Actemra) - Due to risk of decreased platelets and white blood cells, liver damage, and severe infusionrelated reactions, the use of tocilizumab (Actemra) should be reserved for patients who have had an inadequate response to, or have not tolerated, anti-tnf therapies such as adalimumab (Humira), etanercept (Enbrel), or infliximab (Remicade). - Treatment with tocilizumab (Actemra) was associated with neutropenia in clinical trials. It is not recommended to initiate tocilizumab (Actemra) treatment in patients with a low neutrophil count [i.e. absolute neutrophil count (ANC) < 2,000/mm 3 ] and if the on-treatment ANC falls below 500/mm 3, treatment should be discontinued. [4] - Treatment with tocilizumab (Actemra) was also associated with a reduction in platelet counts in clinical trials. It is not recommended to initiate tocilizumab (Actemra) treatment in patients with a platelet count below 100,000/mm 3 and if the on-treatment platelet count falls below 50,000/mm 3, treatment should be discontinued. [4] dru209.11 Page 10 of 19

- Treatment with tocilizumab (Actemra) was associated with transaminase elevations during clinical trials. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with tocilizumab (Actemra). It is not recommended to initiate tocilizumab (Actemra) treatment in patients with elevated transaminases [ALT or AST > 1.5x the upper-limit of normal (ULN)] and if the ontreatment ALT or AST rises above 5x ULN, treatment should be discontinued. [4] - The most common adverse reactions (incidence 5%) reported with tocilizumab (Actemra) include upper respiratory tract infections, nasopharyngitis, headache, hypertension, and increased ALT. [4] - Other serious adverse reactions with tocilizumab (Actemra) include serious infections, reactivation of tuberculosis, and gastrointestinal perforation. [4] - Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with infusion of tocilizumab (Actemra). In the postmarketing setting, events of clinically significant hypersensitivity and anaphylaxis, including events with a fatal outcome, have occurred in patients treated with a range of doses of tocilizumab (Actemra), with or without concomitant arthritis therapies. Events have occurred in patients who received premedication. [4] Alternative Site of Care - Use of an alternative site of care, including non-hospital outpatient infusion centers and home infusion services, is an accepted standard medical practice. These alternative sites of care offer high-quality services for patients and reduce the overall cost of care, as compared to a hospital-based infusion center. - All medications infused outside of a hospital setting (at an alternative site of care) have undergone an evaluation for safe infusion and development of infusion standards, including adverse drug reaction (ADR) management and reporting algorithms. - For use of an alternative site of care, every patient undergoes a patient assessment during the intake process by the infusion provider, which includes evaluation of individual clinical assessment parameters. These parameters may include, but are not limited to, previous tolerance of products (such as IVIG), assessment of kidney function, risk factors for developing thromboembolic events, and venous access. - For use of home infusion services, an assessment is conducted to determination whether or not the home is a safe, appropriate site of care, with adequate support for infusion in the home. - Because these alternative site of care providers need time to arrange for assessment and coordinate the first dose of each new medication, the first dose of infused medications may be covered in a hospital-based infusion center, if needed, to allow adequate time for a seamless transition of care. This may include arranging for delivery of medications and/or patient education, such as for self-administration of medications such as subcutaneous immune globulin (SCIG). dru209.11 Page 11 of 19

Tables and Appendices Table 1. Summary of Evidence Quality by Indication for Select Disease Modifying Anti- Rheumatic Drugs (DMARD) Generic (brand) [Original FDA-approval Date] infliximab (Remicade) [8/1998] etanercept (Enbrel) [11/1998] adalimumab (Humira) [12/2002] certolizumab pegol (Cimzia) [4/2008] golimumab (Simponi) [4/2009] golimumab (Simponi Aria) [7/2013] Route/Site of Administration IV/HCP SC/Pat SC/Pat SC/Pat SC/Pat IV/HCP Mechanism of action TNF antagonist (anti- TNF) TNF antagonist (anti- TNF) TNF antagonist (anti- TNF) TNF antagonist (anti- TNF) TNF antagonist (anti- TNF) rituximab (Rituxan) [11/1997] IV/HCP B-lymphocyte depleter anakinra (Kineret) [11/2001] canakinumab (Ilaris) [6/2009] tocilizumab (Actemra) [1/2010] tocilizumab (Actemra) [10/2013] ustekinumab (Stelara) [9/2009] natalizumab (Tysabri) [11/2004] vedolizumab (Entyvio) [5/2014] abatacept (Orencia) [12/2005] abatacept (Orencia) [12/2011] tofacitinib (Xeljanz) [11/2012] SC/Pat SC/Pat IV/HCP SC/Pat SC/Pat, HCP IL-1 receptor antagonist IL-1β receptor antagonist IL-6 receptor antagonist IL-12, -23 receptor antagonist Rheumatoid Arthritis Psoriatic Arthritis Ankylosing Spondylitis Juvenile Idiopathic Arthritis Systemic Juvenile Idiopathic Arthritis Chronic Plaque Psoriasis Crohn s Disease Ulcerative Colitis a x x x a a x x x x x x x IV/HCP Integrin inhibitor x IV/HCP Integrin inhibitor x x IV/HCP SC/Pat T-lymphocyte inhibitor PO/Pat JAK inhibitor x x x apremilast (Otezla) [3/2014] PO/Pat PDE-4 inhibitor b HCP = healthcare provider administered; IL = interleukin; IV = intravenous; JAK = Janus kinases; Pat = patient (self) administered; PDE = phosphodiesterase; PO = oral; SC = subcutaneous; TNF = tumor necrosis factor; = FDA-approved indication and high confidence data; x = FDAapproved indication and less than high confidence data; = not FDA-approved, but specifically recommended by clinical practice guidelines a Refers to data for induction therapy only. Data for maintenance therapy is less than high confidence. b =FDA approved, but evidence has not undergone complete appraisal dru209.11 Page 12 of 19

Table 2. Summary of Likelihood of Symptom Improvement with Select Disease Modifying Anti- Rheumatic Drugs (DMARDs) a Condition Description of symptom improvement Medication abatacept (Orencia) adalimumab (Humira) anakinra (Kineret) apremilast (Otezla) certolizumab pegol (Cimzia) etanercept (Enbrel) golimumab (Simponi) infliximab (Remicade) natalizumab (Tysabri) rituximab (Rituxan) tocilizumab (Actemra) tofacitinib (Xeljanz) ustekinumab (Stelara) vedolizumab (Entyvio) Ankylosing Spondylitis At least a 20% improvement in ASAS NNT = 4 (Range 3-4) Psoriatic Arthritis At least a 20% improvement in ACR criteria Rheumatoid Arthritis At least a 20% improvement in ACR criteria NNT = 4 (Range 3-4) (Range 2-4) Chronic Plaque Psoriasis At least a 75% improvement in PASI Crohn s Disease Remission based on the CDAI Ulcerative Colitis Remission based on the Mayo score (Range 2-4) Initial NNT = 7 (Range 5-8) Ongoing Initial NNT = 11 Ongoing NNT = 7 NNT = 4 (Range 3-4) NNT = 6 (Range 4-8) NNT = 4 (Range 3-4) (Range 2-4) (Range 2-4) NNT = 4 (Range 3-5) (Range 2-4) at this time at this time (Range 2-4) (Range 2-4) Initial Ongoing Initial Ongoing NNT = 4 (Range 3-5) NNT = 4 (Range 4-5) (Range 2-4) Initial Ongoing Initial Ongoing ACR = American College of Rheumatology; ASAS = Assessment in Ankylosing Spondylitis International Working Group Criteria; PASI = Psoriasis Area Severity Index a In select conditions. Likelihood of symptom improvement relative to placebo after three to six months of treatment based on number needed to treat (NNT). An NNT represents the average number of patients that need to be treated for one patient to benefit and can be calculated only where there is high confidence data. dru209.11 Page 13 of 19

Appendix 1: American College of Rheumatology (ACR) Classification Criteria for Establishing the Diagnosis of Rheumatoid Arthritis (RA) [26,27] Diagnosis of RA requires the presence of at least 4 of 7 criteria below: 1. Morning stiffness in and around joints lasting more than 1 hour. 2. Arthritis in at least 1 area in a wrist or proximal interphalangeal (PIP) joint (hands or fingers) for > 6 weeks. 3. Simultaneous swelling or fluid accumulation in 3 or more joints for > 6 weeks. 4. Symmetric (bilateral joint) involvement for > 6 weeks. 5. Presence of rheumatoid nodules. 6. Positive serum rheumatoid factor. 7. Radiographic changes typical of RA (erosion or unequivocal bony decalcification in or adjacent to the involved joint) on hand and wrist present. Appendix 2: American College of Rheumatology (ACR) Assessment Components for Improvement in Rheumatoid Arthritis (RA) [28] - Tender joint count. - Swollen joint count. - Patient's assessment of pain. - Patient's global assessment of disease activity. - Physician's global assessment of disease activity. - Patient's assessment of physical function. - Acute phase reactant measures (erythrocyte sedimentation rate or C-reactive protein levels.) dru209.11 Page 14 of 19

Appendix 3: Select Biologic Response Modifiers - Actemra, tocilizumab - Cimzia, certolizumab pegol - Enbrel, etanercept* - Entyvio, vedolizumab - Humira, adalimumab* - Kineret, anakinra - Orencia, abatacept - Remicade, infliximab* - Rituxan, rituximab - Simponi, golimumab - Simponi Aria, golimumab* - Stelara, ustekinumab - Tysabri, natalizumab * Preferred/formulary medications for rheumatologic conditions Appendix 4: Select List of Oral Disease Modifying Anti-rheumatic Drugs (DMARD) Oral DMARDS for Rheumatic Conditions azathioprine (Imuran) cyclosporine (Gengraf, Neoral, Sandimmune) hydroxychloroquine (Plaquenil) leflunomide (Arava) methotrexate (oral, injectable) mycophenolate (CellCept, Myfortic) sulfasalazine (Azulfidine) dru209.11 Page 15 of 19

Cross References Cimzia, certolizumab dru160 Enbrel, etanercept dru035 Entyvio, vedolizumab dru356 Humira, adalimumab dru081 Kineret, anakinra dru049 Orencia, abatacept dru129 Rituxan, rituximab dru214 Simponi, golimumab dru183 Stelara, ustekinumab dru193 Tysabri, natalizumab dru111 Xeljanz, tofacitinib dru289 dru209.11 Page 16 of 19

Codes Number Description CPT 96365 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour 96366 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); each additional hour (List separately in addition to code for primary procedure) (Use 96366 in conjunction with 96365, 96367) 96367 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); additional sequential infusion, up to 1 hour (List separately in addition to code for primary procedure) (Use 96367 in conjunction with 96365, 96374, 96409, 96413 if provided as a secondary or subsequent service after a different initial service is administered through the same IV access. Report 96367 only once per sequential infusion of same infusate mix) 96368 Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); concurrent infusion (List separately in addition to code for primary procedure) (Use 96368 in conjunction with 96365, 96366, 96413, 96415, 96416. Report 96368 only once per encounter) HCPCS J0129 Injection, abatacept, 10 mg, for intravenous use J0135 J0717 J1438 J1602 J1745 J2323 J3262 J3357 J9310 Injection, adalimumab, 20 mg (to be used only when drug is given under direct supervision of a physician) Injection, certolizumab pegol, 1 mg (to be used only when drug is given under direct supervision of a physician) Injection, etanercept, 25 mg and 50 mg (to be used only when drug is given under direct supervision of a physician) Injection, golimumab, 1 mg, for intravenous use Injection, infliximab, 10 mg Injection, natalizumab, 1 mg Injection, tocilizumab, 1 mg, for intravenous use Injection, ustekinumab, 1 mg Injection, rituximab, 100 mg dru209.11 Page 17 of 19

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