Prior Authorization Guideline

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1 Prior Authorization Guideline Guideline: Enbrel Therapeutic Class: Miscellaneous Therapeutic Agents Therapeutic Sub-Class: Disease-modifying Antirheumatic Drugs Client: 2007 AARP Medicare Rx Inj, 2007 AARP Enhanced Inj, 2007 MAPDEV Inj, 2007EVRCRE Inj, 2007_PBDY Inj, 2007 PDP Standard Inj, 2007_MAPD_S Inj, 2007 SRSPSD Inj, 2007 UMRx Inj, 2007 UMRx Inj - Comp, 2007 UMRx Inj - Extented, 2007_MAPD Inj, 2007 AARP Medicare Rx - Saver Inj, 2007 MPD PHC Inj, 2007 PDP IBT Inj, 2007_MAPD_E Inj, 2007 MAPDLA Inj, 2007 PFFSLC Inj, 2007 UnitedHealth Rx Basic Inj and UHC River Valley (formerly John Deere) Inj Approval Date: 5/17/2005 Revision Date: 8/21/2007 I. BENEFIT COVERAGE Table 1. Formulary status Non-Formulary Products *Subject to Prior Authorization Formulary Products Tier 4 Enbrel (etanercept)* II. INDICATIONS A. FDA Approved Indications 1 1. Rheumatoid Arthritis (RA) Enbrel is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. Enbrel can be initiated in combination with methotrexate (MTX) or used alone. 2. Juvenile Rheumatoid Arthritis (JRA) Enbrel is indicated for reducing signs and symptoms of moderately to severely active polyarticular-course juvenile rheumatoid arthritis in patients who have had an inadequate response to one or more disease modifying anti-rheumatic drugs (DMARDs). 3. Psoriatic Arthritis (PsA) Enbrel is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis. Enbrel can be used in combination with MTX in patients who do not respond adequately to MTX alone.

2 4. Ankylosing Spondylitis (AS) Enbrel is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis. 5. Plaque Psoriasis Enbrel is indicated for the treatment of adult patients (18 years or older) with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy. III. GUIDELINE A. Rheumatoid Arthritis (RA) 1. Initial treatment of rheumatoid arthritis a. Enbrel will be approved based on all of the following criteria: (1) For patients 18 years old with signs of moderate to severe active RA as defined by all of the following: (a) Both of the following: i. At least 6 swollen joints ii. At least 6 tender/painful joints (b) One of the following: i. More than 45 minutes of morning stiffness ii. Elevated erythrocyte sedimentation rate (ESR) unless patient is receiving corticosteroids iii. Elevated C-reactive protein (CRP) unless patient is receiving corticosteroids (2) Prescribed or recommended by a rheumatologist; (3) One of the following: (a) Documented treatment failure, contraindication, or intolerance to methotrexate -OR- (b) Documented treatment failure, contraindication or intolerance to two or more of the following DMARDs for at least 3 months:

3 i. Azathioprine (Imuran ); ii. Cyclosporine (Sandimmune ); iii. Gold Compounds (Aurolate, Myochrysine, Ridaura, Solganal ); iv. Hydroxychloroquine (Plaquenil ); v. Leflunomide (Arava ); vi. Penicillamine (Cuprimine ); vii. Sulfasalazine (Azulfidine ); (4) Verification that patient has been evaluated for tuberculosis and treated accordingly; (5) Enbrel will not be approved for use in combination with anakinira (Kineret) Initial authorization will be approved for 6 months 1, 4 *Refer to contraindications and warning section for list of additional at-risk infections 2. Re-authorization criteria for the treatment of RA a. Enbrel will be approved for continuation of therapy based on one of the following criteria: (1) Both of the following: 8 (a) At least 20% improvement in the tender and swollen joint count; AND (b) At least 20% improvement in three of the following: (i) Patient s global assessment (ii) Physician s global assessment (iii) Patient s assessment of pain (iv) Degree of disability (v) Acute-phase reactant (ESR or CRP) concentration; -OR- (2) Submission of chart documentation demonstrating the clinical equivalent of the above criteria Re-authorization for therapy will be approved for 12 months. Re-evaluation will be requested every year for further determination of coverage B. Juvenile Rheumatoid Arthritis (JRA) 1. Initial treatment of JRA a. Enbrel will be approved for patients with polyarticular-course juvenile rheumatoid arthritis based on all of the following criteria: (1) Patient is at least 4 years of age; 1, c

4 (2) Patient has 5 swollen joints plus pain and/or tenderness; 11,c (3) Prescribed or recommended by a rheumatologist; (4) Documented history of treatment failure (defined as inadequate response or return of symptoms) on non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. naproxen, ibuprofen, tolmetin, etc.) and/or corticosteroids (e.g., prednisone); 1, c (5) Documented treatment failure of one or more DMARDs for at least 3 months: 1 (a) Gold Compounds (Aurolate, Myochrysine, Ridaura, Solganal ) (b) Hydroxychloroquine (Plaquenil ) (c) Penicillamine (Cuprimine ) (d) Sulfasalazine (Azulfidine ) (e) Methotrexate (at dosage of 10 mg/m 2 /wk) (6) Verification that patient has been evaluated for tuberculosis and treated accordingly 5, 7, * (7) Enbrel will not be approved for use in combination with anakinira (Kineret) 1 Initial authorization will be issued for 6 months. *Refer to contraindications and warning section for list of additional at-risk infections 2. Re-authorization criteria for the treatment of JRA a. Enbrel will be approved for continuation of therapy based on one of the following criteria: (1) One of the following: (a) At least 30% improvement (JRA30) from baseline in 3 or more of the following: 1,9,10,11 (i) Physician s global assessment of disease activity; (ii) Patient/parent s global assessment of overall well-being; (iii) Functional assessment as measured by the Childhood Health Assessment Questionnaire (CHAQ); (iv) Number of joints with active arthritis;

5 (v) Number of joints with limited range of motion; (vi) Erythrocyte sedimentation rate (ESR) during the first year and as C-reactive protein (CRP) thereafter. -OR- (2) Submission of chart documentation demonstrating the clinical equivalent of the above criteria. Re-authorization for therapy will be issued for12 months. Re-evaluation will be requested every year for further determination of coverage. C. Psoriatic Arthritis (PsA) 1. Initial treatment of psoriatic arthritis (PsA) a. Enbrel will be approved based on all of the following criteria: (1) For patients 18 years old who have active disease as defined by all the following: 1,12 (a) At least 3 swollen joints; AND (b) At least 3 tender/painful joints; AND (c) One of the following: 19 i. Presence of plaque psoriasis with a qualifying target skin lesion at least 2 cm in diameter; OR ii. A documented history of psoriasis; OR iii. Nail changes consistent with psoriasis (e.g., pitting, ridging, onycholysis) (2) Prescribed or recommended by a rheumatologist; (3) One of the following (a) Documented treatment failure, contraindication, or intolerance to methotrexate -OR- (b) Documented treatment failure, contraindication or intolerance to two or more of the following DMARDs for at least 3 months 12 (i) Azathioprine (Imuran ) (ii) Cyclosporine (Sandimmune, Neoral, Gengraf ) (iii) Gold compounds (Aurolate, Myochrysine, Riduara, Solganal ) (iv) Hydroxychloroquine (Plaquenil ) (v) Leflunomide (Arava ) (vi) Penicillamine (Cuprimine ) (vii) Sulfasalazine (Azulfidine )

6 (4) Verification that patient has been evaluated for tuberculosis and treated accordingly; 5,7, * (5) Enbrel will not be approved for use in combination with anakinira (Kineret); 1 Initial authorization will be issued for 6 months *Refer to contraindications and warning section for list of additional at-risk infections 2. Re-authorization criteria for treatment of psoriatic arthritis a. Enbrel will be approved for continuation of therapy based on one of the following criteria: (1) Both of the following: 5 (a) At least 20% improvement in the tender and swollen joint count; AND (b) At least 20% improvement in three of the following: (i) Patient s global assessment. (ii) Physician s global assessment (iii) Patient s assessment of pain (iv) Degree of disability (v) Acute-phase reactant (ESR or CRP) concentration -OR- (2) Submission of chart documentation demonstrating the clinical equivalent of the above criteria. Re-authorization for therapy will be issued for 12 months. Re-evaluation will be requested every year for further determination of coverage. D. Plaque Psoriasis 1. Initial treatment of chronic moderate to severe plaque psoriasis a. Enbrel will be approved based on all of the following criteria: (1) Diagnosis of moderate to severe chronic (>6 months) plaque psoriasis in 1, 13,14 patients 18 years of age involving a minimum body surface of 10%; 1, 13,14 (2) Failure or intolerance to both of the following conventional therapies: (a) Phototherapy with at least one of the following, unless contraindicated or unavailable to the patient: (i) Ultraviolet Light B (UVB) used alone or in combination with topical or systemic treatments; OR

7 (ii) Pulse Dye Laser; OR (iii) Psoralen and exposure to ultraviolet light A (PUVA); OR (iv) Photochemotherapy (b) Systemic therapy with at least one of the following: (i) Methotrexate (Rheumatrex, Trexall ); OR (ii) Cyclosporine (Sandimmune, Neoral, Gengraf ); OR (iii) Acitretin (Soriatane ); OR (iv) Hydroxyurea (Hydrea ); OR (v) Sulfasalazine (Azulfidine ); OR (vi) 6-thioguanine (Purinethol ); OR (vii) Mycophenolate (Cellcept ) (3) Prescribed or recommended by a dermatologist; (4) Verification that patient has been evaluated for tuberculosis and treated accordingly; 5,7,* Authorization for therapy for maximum dose of 50 mg SC twice weekly (3 to 4 days apart) will be issued for 3 months 1 *Refer to contraindications and warning section for list of additional at-risk infections 2. Re-authorization criteria for chronic moderate to severe plaque psoriasis a. Enbrel will be approved for continuation of therapy based on the following criteria: (1) One of the following: (a) Patient has achieved a scoring of minimal or clear by static Physician Global Assessment (spga) -OR- (b) Documentation of clinical improvement from the ongoing therapy with Enbrel (2) Enbrel dosage is 50 mg per week (see dosing section) Re-authorization will be issued for 12 months E. Ankylosing Spondylitis (AS) 1. Initial treatment of ankylosing spondylitis 1, 14

8 a. Enbrel will be approved based on all of the following criteria: (1) Diagnosis of ankylosing spondylitis based on the modified New York criteria as follows: 1,15,16 (a) Radiologic criterion: Sacroiliitis (> grade II bilaterally or grade III-IV unilaterally) confirmed by X-ray of the pelvis (b) At least two of the following clinical criteria: (i) Low back pain and stiffness for > 3 months that improves with exercise but is not relieved by rest; OR (ii) Limitation of motion of the lumbar spine in both the sagittal and frontal planes; OR (iii) Limitation of chest expansion relative to normal values correlated for age and sex (2) One of the following: (a) Evidence of active disease as defined by two BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) scores > 4 (scale 0-10); scores must be obtained at least one month apart. 16 -OR- (b) Documented evidence of active disease (3) Prescribed or recommended by a rheumatologist; (4) Documented treatment failure contraindication, or intolerance to two or more NSAIDs for at least 3 months 15,16 (5) One of the following (except in axial disease): 15 (a) For patients with symptomatic peripheral arthritis, documented treatment failure, contraindications, or intolerance to at least one local corticosteroid injection and sulfasalazine (Azulfidine ) up to 3 g/day (or maximum tolerated dose) for 4 months; OR (b) For patients with symptomatic enthesitis, documented treatment failure, contraindications or intolerance to appropriate local corticosteroid injection; OR

9 (c) For patients with persistent peripheral arthritis, documented treatment failure, contraindication, or intolerance to sulfasalazine (Azulfidine) up to 3 g/day (or maximum tolerate dose) for 4 months; (6) Verification that patient has been evaluated for tuberculosis and treated accordingly 1,15,* Initial authorization will be issued for 6 months *Refer to contraindications and warning section for list of additional at-risk infections 2. Re-authorization criteria for the treatment of ankylosing spondylitis a. Enbrel will be approved for continuation of therapy based on one the following criteria: (1) A positive response to therapy defined by a 50% relative change or absolute change of 2 (scale 0-10) in BASDAI score from baseline 15 -OR- (2) Documentation of clinical improvement from on going therapy with Enbrel Re-authorization will be issued for 1 year IV. CONTRAINDICATIONS AND WARNINGS 1 A. Contraindications 1. Hypersensitivity B. Warnings Enbrel should not be administered to patients with sepsis or known hypersensitivity to Enbrel or any of its components. 1. Infections In post-marketing reports, serious infections and sepsis, including fatalities, have been reported with the use of Enbrel. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections. Rare cases of tuberculosis (TB) have been observed in patients treated with TNF antagonist, including Enbrel. Patients who develop a new infection while undergoing treatment with Enbrel should be monitored closely. Administration of Enbrel should be discontinued if a patient develops a serious infection or sepsis. Treatment with Enbrel should not be initiated in patients with active infections, including chronic or localized infections. Physicians should exercise caution when considering the use of Enbrel in patients with a history of recurring infections or with infections, such as advanced or poorly controlled diabetes.

10 In a 24-week study of concurrent Enbrel and Anakinra therapy, the rate of serious infections in the combination arm (7%) was higher than Enbrel alone (0%). The combination of Enbrel and Anakinra did not result in higher ACR response rates compared to Enbrel alone. Concurrent therapy with Enbrel and Anakinra is not recommended. 2. Neurological Events Treatment with Enbrel and other TNF blockers has been associated with rare cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status change and some associated with permanent disability. Cases of transverse myelitis, optic neuritis, multiple sclerosis, and new onset or exacerbation of seizure disorder have been observed with Enbrel therapy. The casual relationship to Enbrel therapy remains unclear. Prescribers should exercise caution when considering Enbrel in patients with pre-existing or recent onset CNS demyelinating disorder. 3. Hematologic Events Rare reports of pancytopenia and aplastic anemia, some with fatal outcome, have been reported in patients treated with Enbrel. The casual relationship to Enbrel remains unclear. No high risk groups have been identified but caution should be exercised in patients with a significant history of hematologic abnormalities. Enbrel should be discontinued in patients with confirmed significant hematologic abnormalities. 4. Malignancies In clinical trials with all TNF blocking agents, more cases of lymphomas were observed compared to those on placebo. This is 3-folder higher increase in incidence than the expected general population. Patients with RA or psoriasis, especially in those with highly active disease, may be at a higher risk (up to several fold) for the development of lymphoma, the potential role of TNF blocking therapy in the development of malignancies is not known. V. DOSING 1 Adult Rheumatoid Arthritis (RA) Ankylosing Spondylitis (AS) Psoriatic Arthritis (PsA) Adult Plaque Psoriasis Juvenile Rheumatoid Arthritis (4 to 17 years of age) 50 mg SC once weekly 50 mg SC once weekly 50 mg SC once weekly 50 mg SC twice weekly (3 to 4 days apart) for 3 months followed by reduction to a maintenance dose of 50 mg once weekly. 0.8 mg/kg/week (maximum 50 mg/week) VI. AVAILABILITY 1

11 Enbrel is available as a single-use pre-filled syringe or single-use prefilled SureClick auto injector in a carton containing four pre-filled syringes/auto injectors. Each pre-filled syringe/autoinjector contains 0.98ml of 50mg/ml of Enbrel with a 27 gauge, ½-inch needle. VII. BACKGROUND A. Description 1 Enbrel binds specifically to TNF and blocks its interaction with cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune response. It plays an important role in the inflammatory processes of RA, JRA, AS, and plaque psoriasis. B. Clinical Studies 1. Rheumatoid Arthritis a. Enbrel monotherapy in RA Moreland et al (1999) compared the efficacy of twice-weekly subcutaneous (SC) injections of etanercept 10 mg or 25 mg to placebo in a randomized, double-blind 6- month clinical trial. A total of 234 patients with active RA who had an inadequate response to DMARDs were enrolled; 76 patients received etanercept 10 mg twice weekly, 78 patients received etanercept 25 mg twice weekly, and 80 patients received placebo. 2 Patients were required to have an inadequate response to one to four DMARDs, and were also required to complete a DMARD washout period. No DMARDs were allowed during the study. The patients were primarily female (78%), with a mean age of 52, and mean duration of disease of 12 years. Primary efficacy end points were ACR20 and ACR50 at 3 and 6 months. Etanercept significantly reduced disease activity in a dose-related fashion. The 25 mg dose was significantly more effective than the 10 mg dose in producing ACR20 responses at 3 months (62% vs. 45%, respectively; p=0.036) and in producing ACR50 responses at 3 months (41% vs. 13%, respectively; p<0.001) and 6 months (40% vs. 24%, respectively; p=0.032). At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved an ACR20 response (p<0.001). At 6 months, 59% of the 25 mg group and 11% of the placebo group achieved an ACR20 response (p<0.001); 40% and 5%, respectively, achieved an ACR50 response (p< 0.01). Significantly more etanercept recipients achieved an ACR70 (15% in the 25 mg group, 9% in the 10 mg group and 1% in the placebo group, p<0.031 for each etanercept group compared with the placebo). All components of the HAQ substantially improved over baseline in both etanercept groups compared with placebo (p<0.05). Etanercept was well tolerated, with no dose-limiting toxic effects. b. Enbrel in combination with MTX for RA Weinblatt et al (1999) conducted a 24-week, trial to determine whether the addition of etanercept to MTX therapy would provide additional benefit to patients who had persistent RA despite receiving MTX. 3 Eighty-nine patients with persistently active RA despite at least 6 months of MTX therapy at a stable dose of 15 to 25 mg per week were randomized to receive either etanercept 25 mg (n=59) or placebo (n=30) SC twice weekly while continuing to receive MTX. The mean duration of RA was 13 years, with subjects comprised mainly of women. At 24 weeks, 71% of the patients receiving etanercept-mtx and 27% of those receiving placebo-mtx met the primary endpoint, ACR20 criteria

12 (p<0.001); 39% of the patients receiving etanercept-mtx and 3% of those receiving placebo-mtx met the ACR50 criteria (p<0.001). c. Rheumatoid Arthritis disease progression prevention 2. JRA Bathon et al (2000) treated 632 patients with either twice-weekly SC etanercept 10 or 25 mg (n=208 and n=207, respectively) or weekly oral MTX at a mean dose of 19 mg/week (n=217) for 12 months to assess the efficacy of etanercept in reducing disease activity and preventing joint damage in patients with early active RA. 4 In this 12-month active-controlled study, adult patients who had had RA for no more than 3 years, had no important concurrent illnesses, and had not been treated with MTX were enrolled. At baseline, 87% of patients had erosions and 79% had joint-space narrowing. The mean age of patients for the three groups was 50 years, and 75% of the subjects were women. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. In comparison to patients who received MTX, patients who received the 25 mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20%, 50%, and 70% improvement in disease activity during the first six months (p<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the MTX group (p=0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (p=0.002). Among patients who received the 25 mg dose of etanercept, 72% had no increase in the erosion score, as compared with 60% of patients in the MTX group (p=0.007). The group receiving etanercept 25 mg also had fewer adverse events (p=0.02) and fewer infections (p=0.006) than the group that was treated with MTX. The safety and efficacy of Enbrel were assessed in a two-part study in 69 children with polyarticular-course JRA who had a variety of JRA onset types. 1,11 Patients ages 4 to 17 years with moderately to severely active polyarticular-course JRA refractory to or intolerant of methotrexate were enrolled; patients remained on a stable dose of a single NSAID and/or prednisone ( 0.2 mg/kg/day or 10 mg maximum). In part 1, all patients received 0.4 mg/kg (maximum 25 mg per dose) Enbrel SC twice weekly. In part 2, patients with a clinical response at day 90 were randomized to remain on Enbrel or receive placebo for four months and assessed for disease flare. Responses were measured using the JRA Definition of Improvement (DOI) 10, defined as 30% improvement in at least three of six and 30% worsening in no more than one of the six JRA core set criteria, including active joint count, limitation of motion, physician and patient/parent global assessments, functional assessment, and ESR. Disease flare was defined as 30% worsening in three of the six JRA core set criteria and 30% improvement in not more than one of the six JRA core set criteria and a minimum of two active joints. In part 1 of the study, 51 of 69 (74%) patients demonstrated a clinical response and entered part 2. In par 2, 6 of 25 (24%) patients remaining on Enbrel experienced a disease flare compared to 20 of26 (77%) patients receiving placebo (p = 0.007). From the start of part 2, the median time to flare was 116 days for patients who received Enbrel and 28 days for patients who received placebo. Each component of the JRA core set criteria worsened in the arm that received placebo and remained stable or improved in the arm that continued on Enbrel. 3. Psoriatic Arthritis The safety and efficacy of Enbrel were assessed in a randomized, double-blind, placebocontrolled study in 205 patients with psoriatic arthritis. 1 Patients were between 18 and 70

13 years of age and had active psoriatic arthritis ( 3 swollen joints and; 3 tender joints) in one or more of the following forms: (1) distal interphalangeal (DIP) involvement (N = 104); (2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis; N = 173); (3) arthritis mutilans (N = 3); (4) asymmetric psoriatic arthritis (N = 81); or (5) ankylosing spondylitis-like (N = 7). Patients also had plaque psoriasis with a qualifying target lesion 2 cm in diameter. Patients on MTX therapy at enrollment (stable for 2 months) could continue at a stable dose of: 25 mg/week MTX. Doses of 25 mg Enbrel or placebo were administered SC twice a week during the initial 6-month double-blind period of the study. Patients continued to receive blinded therapy in an up to 6-month maintenance period until all patients had completed the controlled period. Following this, patients received open-label 25 mg Enbrel twice a week in a 12-month extension period. Compared to placebo, treatment with Enbrel resulted in significant improvements in measures of disease activity. Among patients with psoriatic arthritis who received Enbrel, the clinical responses were apparent at the time of the first visit (4 weeks) and were maintained through 6 months of therapy. At 6 months, the ACR 20/50/70 responses were achieved by 50%, 37%, and 9%, respectively, of patients receiving Enbrel, compared to 13%, 4%, and 1 %, respectively, of patients receiving placebo. The skin lesions of psoriasis were also improved with Enbrel, relative to placebo, as measured by percentages of patients achieving improvements in the Psoriasis Area and Severity Index (PASI). Responses increased over time, and at 6 months, the proportions of patients achieving a 50% or 75% improvement in the PASI were 47% and 23%, respectively, in the Enbrel group (N = 66), compared to 18% and 3%, respectively, in the placebo group (N = 62). 4. Ankylosing Spondylitis (AS) The safety and efficacy of Enbrel were assessed in a randomized, double-blind, placebocontrolled study in 277 patients with active AS. 1 Patients were between 18 and 70 years of age and had AS, defined by the modified New York Criteria for AS. Patients were to have evidence of active disease based on values of 30 on a unit Visual Analog Scale (VAS) for the average of morning stiffness duration and intensity, and 2 of the following 3 other parameters: a) patient global assessment, b) average of nocturnal and total back pain, and c) the average score on the Bath Ankylosing Spondylitis Functional Index (BASFI). Patients with complete ankylosis of the spine were excluded from study participation. Patients taking hydroxychloroquine, sulfasalazine, methotrexate, or prednisone ( 10 mg/day) could continue these drugs at stable doses for the duration of the study. Doses of 25 mg Enbrel or placebo were administered SC twice a week for 6 months. The primary measure of efficacy was a 20% improvement in the Assessment in Ankylosing Spondylitis (ASAS) response criteria. Compared to placebo, treatment with Enbrel resulted in improvements in the ASAS and other measures of disease activity. At 12 weeks, the ASAS 20/50/70 responses were achieved by 60%, 45%, and 29%, respectively, of patients receiving Enbrel, compared to 27%, 13%, and 7%, respectively, of patients receiving placebo (p , Enbrel vs. placebo). Similar responses were seen at week 24. Responses were similar between those patients-receiving concomitanttherapies at baseline and those who were not. 5. Plaque Psoriasis Leonardi et al (2003) conducted a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 study in adults with chronic stable plaque psoriasis involving 10% of the body surface area (BSA), a minimum of PASI of 10 and who received or were candidates for systemic anti-psoriatic therapy or phototherapy. Patients (n=672) were randomized to receive placebo or Enbrel at a low dose (25mg once weekly), a medium dose (25mg twice weekly), or a high dose (50mg twice weekly). After 12 weeks, patients in the placebo group began double-

14 blind treatment with Enbrel 25mg BIW treatment. The primary endpoint was the proportion of patients with an improvement of at least 75% in the psoriasis area-andseverity index (PASI) at week 12. At week 12, there was an improvement from baseline of 75% or more in the PASI in 4% of placebo compared to 14%, 34% and 49% in the low-dose, medium-dose and high-dose Enbrel group, respectively, (p<0.001 for all 3 comparisons with the placebo group). The clinical responses continued to improve with longer treatment. At week 24, there was at least a 75% improvement in the PASI in 25% of the low-dose group, 44% in the medium-dose group and 59% high-dose group and 33% in the original placebo group who had begun receiving Enbrel after week 12, a response that was consistent with the medium-dose Enbrel group at week 12 (34%). The responses as measured by improvement in the PASI were paralleled by improvement in global assessments by physician and patients and in quality-of-life measures (p<0.001 for all 3 comparisons with the placebo group). Enbrel was well tolerated with adverse events and infections occurring in similar proportions of patients in each group during the study at week 12. Due to the crossover from placebo to medium-dose Enbrel at week 12, safety comparison could not be made. Papp et al (2005) assessed the efficacy and safety of Enbrel in chronic plaque psoriasis after dose reduction in a 24-week, phase III, multicenter, randomized, double-blind, parallel-group trial. 14 The study had a 2 part design: in the initial 12 week period, patients were randomized to placebo (n=193), Enbrel 25mg BIW (n=196) or 50 mg BIW in a double-blinded manner; during the second 12-week period, all patients received Enbrel 25mg BIW. Inclusion criteria were similar to the above plaque psoriasis study. The primary efficacy endpoint was a 75% or greater improvement from baseline in PASI (PASI 75) at week 12. Five hundred and eightythree patients were randomized and received at least one dose of study drug. At week 12, a PASI 75 was achieved by 49% of patients in the Enbrel 50 mg BIW, 34% in the 25 mg BIW and 3% in the placebo group (p< for each Enbrel group compared with placebo). At week 24 a PASI 75 was achieved in 54% of patients whose dose was reduced from 50 to 25 mg BIW, 45% in the continuous 25 mg BIW group and 28% in the placebo group followed by 25 mg BIW. Statistically significant differences were seen between each active group and placebo at week 12 in the PASI 50, PASI 90 response and the achievement of a clear or almost clear assessment on the spga. The response of Enbrel was dose dependent. At week 12, the differences between Enbrel 50 and 25 mg BIW group was statistically significant (p=0.004). PASI response rates at week 24 were sustained or improved compared with those at week 12. At week 24, a PASI 75 was achieved by 54% of patients in the group following a dose reduction from 50 to 25 mg BIW, by 45% of patients after continuous treatment with 25 mg BIW and by 28% in the placebo group that received 25 mg BIW after week 12. Of the patients who achieved a PASI 75 at week 12, 77% maintained the PASI 75 response at week 24, and 97% maintained at least a PASI 50 at week 24 after dose reduction. One-third of the patients who had not achieved a PASI 75 response at week 12 on the high dose did so by week 24 despite dose reduction. C. National Guidelines 1. Ankylosing Spondylitis a. International ASAS Consensus Statement (2006) 15 First update of the international ASAS consensus statement for the use of anti-tnf agents in patients with ankylosing spondylitis.

15 (1) Diagnosis: Patients normally fulfilling modified New York Criteria for definitive ankylosing spondylitis Radiological criterion: Sacroiliitis (> grade II bilaterally or grade III-IV unilaterally) Clinical criteria (two of the following three): low back pain and stiffness for > 3 months that improves with exercise but is not relieved by rest; limitation of motion of the lumbar spine in both the sagittal and frontal planes or limitation of chest expansion relative to normal values correlated for age and sex (2) Disease activity: Active disease for > 4 weeks, and BASDAI > 4 (on a scale of 0-10). The BASDAI and the expert opinion should be recorded at two different times about one month apart. (3) Failure of standard treatment: All patients must have had adequate trials of at least two NSAIDs. An adequate therapeutic trial is defined as: (a) Treatment for > 3 months at maximal recommended or tolerated antiinflammatory dose unless contraindicated (b) Treatment for < 3 months where treatment was withdrawn because of intolerance, toxicity, or contraindications. (c) Patients with symptomatic peripheral arthritis must have had adequate therapeutic trial of both NSAIDs and sulfasalazine (d) Patients with symptomatic enthesitis must have had an adequate therapeutically trial local steroid injections unless contraindicated (4) Assessment of response: (a) Responder criteria: A 50% relative change or absolute change of 2 (scale of 0-10) and expert opinion (b) Time of evaluation: between 6 and 12 weeks b. British Society for Rheumatology (BSR) Guideline for Prescribing TNF-α Blockers in Adults with Ankylosing Spondylitis (2004) 16 Treatment guideline for use of TNF blocking agents includes: (1) A definite diagnosis of ankylosing spondylitis as defined by the modified New York criteria (2) Evidence of active disease as defined by BASDAI 4 and spinal pain VAS 4, both of which are recorded on two occasions at least four weeks apart without any change of treatment (3) Criteria for withdrawal of therapy: Development of severe adverse effects, or inefficacy as indicated by failure to improve BASDAI score by 50% or to fall by 2 units, and/or for the spinal pain VAS to reduce by 2 units after 3 months of therapy. (4) Response to treatment is defined as: Reduction of BASDAI to 50% of the pretreatment value or a fall of 2 units AND reduction of the spinal pain VAS by 2 units. (5) Response to therapy should be accessed between 6 and 12 weeks after initiation of treatment. If the response criteria are not met, a second assessment should be made at 12 weeks. Treatment should not be stopped because of ineffectiveness within 12 weeks. (6) Failure to maintain the original response leads to repeat assessment after 6 weeks; failure to maintain response on both occasions leads to cessation or change of treatment. 2. Rheumatoid Arthritis a. International Consensus Statement on Biological Agents for Treatment of Rheumatic Diseases (2004) 17

16 Tumor necrosis factor (TNF) blockers have shown effective for the treatment of rheumatoid arthritis in methotrexate naïve patients (category A, D evidence); however, the use of TNF blocking agents as the first DMARD for the treatment of rheumatoid arthritis should, at present, be limited in considering emerging data on long-term safety, effectiveness, and economic factor. TNF blocking agents may be considered as the initial DMARD in some patients (category A, D evidence). When used in adequate doses and sufficiently frequent dosing regimens, TNF blocking agents should lead to significant, documented improvement within 12 weeks for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and juvenile rheumatoid arthritis (category A evidence). If documented significant improvement occurs, treatment should be continued. If patients show no response to TNF blocking agents at their maximum approved dose, treatment should be discontinued in 12 weeks. If an incomplete response occurs, increasing the dose or reducing the dosing interval may provide additional benefits in rheumatoid arthritis (category B evidence). Categories of Evidence: Category A evidence: based on evidence from at least one randomized controlled trial or on the meta-analyses of randomized controlled trials. Category B evidence: based on evidence from at least one controlled trial without randomization or at least one other type of experimental study or on extrapolated recommendations from randomized controlled trials or meta-analyses. Category D evidence: based on expert committee reports or opinions or clinical experience or respected authorities, or both, or extrapolated recommendations from randomized controlled trials, meta-analyses, non-randomized controlled trials, experimental studies, or non-experimental descriptive studies. b. American College of Rheumatology (ACR) (2002) 5 All patients with RA are candidates for DMARD therapy. Although NSAIDS and glucocorticoids may alleviate symptoms, joint damage may continue to occur and progress. DMARDs have the potential to reduce or prevent joint damage, preserve joint integrity and function, and ultimately, reduce the total costs of health care and maintain economic productivity of the patient with RA. The initiation of DMARDs should not be delayed beyond 3 months for any patient with established diagnosis who, despite adequate treatment with NSAIDs, has ongoing joint pain, significant morning stiffness or fatigue, active synovitis, persistent elevations of ESR or CRP level or radiographic joint damage. For any untreated patients with persistent synovitis and joint damage, DMARD treatment should be started promptly to prevent or slow further damage. DMARDs commonly used in RA include hydroxychloroquine, sulfasalazine, methotrexate, leflunomide, etanercept and infliximab. Less frequently used DMARDs are azathioprine, penicillamine, gold salts, minocycline, and cyclosporine. Based on considerations of safety, convenience, and cost, most rheumatologists select hydroxychloroquine or sulfasalazine first, but for patients with very active disease or with indicators of a poorer prognosis, MTX or combination therapy is preferred. The ACR Subcommittee recommends a trial of methotrexate as monotherapy or as a component of combination therapy in patients whose treatment has not yet included methotrexate. Many rheumatologists select MTX as the initial DMARD because of its favorable efficacy and toxicity profile, low cost and established track record in the

17 treatment of RA. MTX has become the standard by which new DMARDs are evaluated. Randomized clinical trials have established efficacy in RA, particularly in patients with severe disease. Longitudinal studies and randomized controlled trials show that MTX retards the progression of radiographic erosions. For patients in whom methotrexate is contraindicated or has failed to achieve satisfactory disease control either because of lack of efficacy (in doses up to 25 mg/week) or intolerance, treatment with biologic agents or DMARDs, either alone or in combination, is recommended. The ACR recommends assessment of tuberculosis risk prior to initiation of a TNFalpha antagonist due to postmarketing surveillance which yielded reports of sepsis, tuberculosis, atypical mycobacterial infections, fungal infections, opportunistic infections, demyelinating disorders and aplastic anemia. 3. Psoriatic Arthritis a. British Society for Rheumatology (2004) 12 Standards Guidelines Audit Working Group (SGAWA): Guideline for anti- TNF-α therapy in psoriatic arthritis In psoriatic arthritis it is important to tailor the treatment to the severity of the disease. Pharmacologic therapies include: First-line treatment is NSAIDs. Many patients with PsA respond well to NSAIDS alone. No evidence for superiority of any one NSAID in PsA. Persistent monoarthritis is often improved by intra-articular corticosteroid injections. Triamcinolone hexacetonide is used due to minimization of systemic absorption leading to maximized local effect. Pharmacologic therapies may be instituted by a specialist: Patients with severe articular disease commonly need combined treatment with NSAIDs and DMARDs. Antimalarials, such as hydroxychloroquine, may be used in mild to moderate disease. Gold salts are rarely, if ever, used today, because of its multiple toxicities. MTX and leflunomide, either alone or in combination, have been shown to be effective, as has sulfasalazine. Cyclosporine may be considered for those who have not responded to other DMARDs. Anti-TNF-α therapy is recommended for patients with active psoriatic arthritis who had failed an adequate trial of at least two of the standard DMARDs individually or in combination. An adequate therapeutic trial is defined as: Treatment for at least 6 months, of which at least 2 months is at standard target dose (unless significant intolerance or toxicity limits the dose). Treatment for < 6 months, where treatment is withdrawn because of drug intolerance or toxicity. When treatment is withdrawn because of intolerance or toxicity after >2 months therapy, at least 2 months should have been at therapeutic doses. VIII. DEFINITIONS A. American College of Rheumatology (ACR) response criteria 8

18 The ACR20 response criterion is defined as a 20 % improvement in swollen and tender joint count and 20 % improvement in three of the outcome measures listed below: 1. Physician's global assessment 2. Patient's global assessment 3. Pain 4. Functional status or physical disability 5. Acute phase reactant (erythrocyte sedimentation rate or C-reactive protein) The ACR50 and 70 responses are defined as a 50 % and a 70 % response, respectively, in the aforementioned criteria. B. American College of Rheumatology cores set of disease activity measures for RA 18 The core set of disease activity measures consists of the following: 1. Tender joint count 2. Swollen joint count 3. Patient s assessment of pain 4. Patient s global assessment of disease activity 5. Physician s global assessment of disease activity 6. Patient s assessment of physical function 7. Laboratory evaluation of acute-phase reactants (ESR and/or CRP). C. Radiographic grading system in ankylosing spondylitis Grade II: evidence or erosion and sclerosis 2. Grade III: erosion sclerosis and early ankylosis 3. Grade IV: total ankylosis D. Static Physician s Global Assessment (spga) in plaque psoriasis. 1 A six-point scale system where 0 indicates no psoriasis (clear of disease) and higher scores indicating more severe disease are as follows: 1. Zero (0) is clear of psoriasis 2. One (1) is almost clear of psoriasis 3. Two (2) is mild to moderate psoriasis 4. Three (3) is moderate psoriasis 5. Four (4) is moderate to severe psoriasis 6. Five (5) is severe disease IX. REFERENCES 1. Enbrel Prescribing Information. Amgen and Wyeth Pharmaceuticals; June Moreland, L, Schiff, M, Baumgartner, S, et al. Etanercept therapy in rheumatoid arthritis. Ann Intern Med 1999;130: Weinblatt M, Kremer J, Bankhurst A, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. NEJM 2005;340: Bathon J, Martin R, Fleischman R, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. NEJM 2000;343: American College of Rheumatology (ACR): Guidelines for the management of Rheumatoid Arthritis. American College of Rheumatology Subcomittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum.2002 update; 46(2):

19 6. Pavy S. Constantin A, Pham T, et al. Methotrexate therapy for rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinions. Joint Bone Spine 2006; [Epub ahead of print]: Ledingham J, Deighton C, on behalf of the British Society of Rheumatology Standards, Guidelines and Audit Working Group (SGAWG). Update on the British Society for Rheumatology guidelines for prescribing TNF-alpha blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001). Rheumatol 2005; 44: Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum. 1995; 38(6): Bulletin on the Rheumatic Diseases for evidence-based management of rheumatic disease, a publication of the arthritis foundation: Use of etanercept in children. Bulletin on the Rheumatic Dis 2000; 49 (12): Giannini H, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997; 40(7): Lovell DJ, Giannini H, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med. 2000; 342(11): Kyle S, Chandler D, Griffiths EM, et al. Guideline for anti-tnf-α therapy in psoriatic arthritis. Rheumatology. 2005; 44(3): Leonardi GL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. NEJM 2003; 349: Papp KA, Tyring S, Lahfa M, et al. A global phase III randomized controlled trial of etanercept in psoriasis: safety, efficacy, and effect of dose reduction. Br J Dermatol. 2005;152: Braun J, Davis J, Dougados M, Sieper J, Linden SVD, Heijde DVD, for the ASAS working group. First update of the international ASAS consensus statement for the sue of anti-tnf agents in patients with ankylosing spondylitis. Ann Rheum Dis. 2006;65: British Society for Rheumatology (BSR) Guideline for Prescribing TNFα Blockers in Adults with Ankylosing Spondylitis. London: BSR; 2004 July: Furst DE, Breedveld FC, Kadlden JR, et al. Updated consensus statement on biological agents, specifically tumor necrosis factor α (TNF α) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases. Ann Rheum Dis. 2004; 63 (Suppl II): ii2-ii Felson D, Anderson JJ, Boers M, et al. The American College of Rheumatology preliminary core sets of disease activity measures for rheumatoid arthritis clinical trials. Arthritis & Rheumatism 1993; 36(6): Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment for psoriatic arthritis. Arthritis Rheum. 2004; 50(4): X. ENDNOTES a. The safety and efficacy of Enbrel for the treatment of adult RA were assessed in 4 randomized, double-blinded, controlled studies. Study subjects were 18 years old with active moderate to severe RA as defined by ACR criteria. 1-4 Methotrexate is used by most rheumatologists as the first line disease-modifying antirheumatic drug for patients with RA. This choice rests on the good effectiveness and safety profile of the drug, its low cost, and the availability of long-term follow-up data on RA patients given methotrexate. In addition, recent data indicate that methotrexate can produce substantial survival benefits by reducing cardiovascular mortality in patients with RA. 6 The recommended starting dosage for MTX in patients with RA should not be less than 10 mg/week and increase at 6 weeks interval to a maximum of 20 mg/week based on disease severity, patient related factors, and tolerance. 6

20 b. In the study for JRA, the study population were patients ages 4 to 17 years of age with moderately to severe active JRA refractory to or intolerant of MTX, on a stable dose of NSAIDs and/or prednisone. 1 This Prior Authorization Guideline represents the recommendation of Prescription Solutions Pharmacy and Therapeutics (P&T) Committee. It is based upon the P&T Committee s review of the available evidence as of the date of drafting or revision of this Prior Authorization Guideline. It is subject to updating from time to time, based upon changes in scientific knowledge and information. This Prior Authorization Guideline is intended as a resource for making coverage decisions for Health Plan members, but it does not replace an individualized case-by-case review and medical necessity determination for each Health Plan member. Copyright 2007 by Prescription Solutions. All rights reserved. This Prior Authorization Guideline is intended for use by Prescription Solutions and Health Plan employees and applicable contracted providers and practitioners only. The information contained in this Prior Authorization Guideline is confidential and proprietary to Prescription Solutions and shall not be used, reproduced, or transferred in whole or in part without Prescription Solutions prior written consent.