subcutaneous initially every 4 weeks then every 12 weeks Coverage Criteria: Express Scripts, Inc. monograph dated 02/24/2010

BENEFIT DESCRIPTION AND LIMITATIONS OF COVERAGE ITEM: PRODUCT LINES: COVERED UNDER: DESCRIPTION: CPT/HCPCS Code: Company Supplying: Setting: Humira (adalimumab subcutaneous injection) Commercial HMO/PPO/CDHP HMO/PPO/CDHP: Rx (self-administered) Adalimumab is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor alpha (TNFα). Adalimumab neutralizes the biological activity of TNFα and inhibits binding of TNFα with its receptors. TNF, a naturally occurring cytokine, mediates inflammation and modulates cellular immune responses. Increased levels of TNF are found in the synovial fluid of patients with rheumatoid arthritis (RA), juvenile rheumatoid arthritis (JIA), psoriatic arthritis (PsA), and ankylosing spondylitis. J0135 Abbott Laboratories subcutaneous initially every 4 weeks then every 12 weeks Coverage Criteria: Express Scripts, Inc. monograph dated 02/24/2010 Approval Period: 12 months or as otherwise noted by indication Recommended Authorization Criteria Coverage of adalimumab is recommended in those who meet one of the following criteria: FDA-Approved Indications 1. Adults with rheumatoid arthritis. Approve for 12 months if the patient has tried one DMARD (brand or generic; oral or injectable) for at least 2 months, [this includes patients who have tried other biologic DMARDs for at least 2 months] OR is concurrently receiving MTX. Adalimumab is FDA-approved for moderate or severe active RA in adults and can be used alone or in combination with MTX or other DMARDs. Initiating DMARD therapy with a biologic agent such as adalimumab alone should be rare. Most patients will have received initial therapy with an oral DMARD(s) (e.g., hydroxychloroquine, leflunomide, sulfasalazine, MTX). If MTX is contraindicated, another oral DMARD should be tried. Some patients with important markers of poor prognosis (e.g., functional limitations, rheumatoid factor positivity and/or positive anticyclic citrullinated peptide (CCP) antibodies, extraarticular manifestations of RA [e.g., vasculitis, Sjögren s syndrome, RA lung disease]) or with joint erosions may be started early on biologic agents; patients will be evaluated by a pharmacist and/or physician on a case-by-case basis to determine a coverage recommendation for the client. This criterion is recommended based on the professional opinion of specialized physicians. 2. Juvenile idiopathic arthritis (JIA) or JRA, polyarticular course (regardless of type of onset). Approve for 12 months if the patient has tried MTX or will be 1

starting on adalimumab concurrently with MTX. Approve for 12 months without trying MTX if the patient has an absolute contraindication to MTX (e.g., pregnancy, breast feeding, alcoholic liver disease, immunodeficiency syndrome, blood dyscrasias). Adalimumab is FDA-approved for reducing signs and symptoms of moderately to severely active polyarticular JIA in patients ages 4 and older. The evidence for the effectiveness of DMARDs other than MTX for JRA is weak and no other therapy is the first choice once MTX is ineffective or does not produce an adequate response. Patients with aggressive disease, as determined by the prescribing physician, may be started early on a biologic agent (such as adalimumab); patients will be evaluated by a pharmacist and/or physician on a case-by-case basis to determine a coverage recommendation for the client. (professional opinion of specialist physicians) 3. Psoriatic arthritis (PsA). Approve for 12 months. Adalimumab is FDA-approved for PsA and can be used alone or in combination with DMARDs. In clinical trials, adalimumab was effective in patients with active PsA despite therapy with a NSAID. There are few well-controlled, prospective studies with adequate duration that have evaluated the efficacy of the oral DMARDs. In peripheral arthritis the traditional DMARDs, sulfasalazine, leflunomide, MTX, or cyclosporine, may be effective. For patients with peripheral arthritis who do not respond to a traditional DMARD, one of the TNF inhibitors (etanercept, adalimumab, or infliximab) is equally effective for treatment and also for inhibiting radiographic progression and improving physical function in patients with PsA. Patients with a poor prognosis could use a TNF inhibitor even though they have not failed on a traditional DMARD. The traditional DMARDs have not been shown to prevent the progression of radiographic (structural) damage or to have significant impact on axial disease, dactylitis, or enthesitis in PsA. This is in contrast with the newer biological DMARDs which have shown efficacy in well-controlled trials in reducing signs and symptoms of active arthritis, inhibiting the progression of structural damage, and improving physical function in patients with PsA. 4. Ankylosing spondylitis. Approve for 12 months. FDA-approved indication. According to ASAS/European League Against Rheumatism (EULAR) recommendations for ankylosing spondylitis, all patients should have an adequate trial of at least 2 NSAIDs for pain and stiffness. Recommendations for other therapies before receiving adalimumab (or etanercept or infliximab) vary according to the manifestations of the disease, level of current symptoms, clinical findings, etc. According to these recommendations, patients with pure axial manifestations do not have to try traditional DMARDs before anti-tnf agents such as adalimumab; patients with symptomatic peripheral arthritis should have an insufficient response to at least one local corticosteroid injection, if appropriate; patients with persistent peripheral arthritis must have a trial of sulfasalazine; and patients with enthesitis should try appropriate local therapy (corticosteroid injection in selected cases). 5. Plaque psoriasis in patients. Authorization can be given for 12 months for patients who meet all of the following criteria a and b: a. Patient has minimum body surface area (BSA) involvement with plaque psoriasis of 5%. Exceptions can be made to the requirement for 5% BSA involvement in the following instances (i or ii): i. Patients with plaque psoriasis of the palms, soles, head and neck, nails, intertriginous areas or genitalia are not required to have a minimum BSA involvement OR ii. The patient who meets all three of the following conditions is not required to have a minimum BSA involvement: (patient who meet this criteria are not required to meet 5b) 2

Patient has had an inadequate response to 3-month trial of either topical therapy OR localized phototherapy with ultraviolet B (UVB) or oral methoxsalen plus UVA light [PUVA]) for psoriasis and Patient has had an inadequate response to systemic therapy (See d. below) and Patient has significant disability or impairment in physical or mental functioning, according to the treating physician. b. Patient has tried a systemic therapy or phototherapy for 3 months with one of the following agents: MTX, cyclosporine, acitretin (Soriatane ), etanercept, alefacept (Amevive ), infliximab or ustekinumab (Stelara ) or has tried phototherapy with UVB or PUVA for psoriasis. Rarely, a patient may have contraindications to nearly all of these other therapies and patients will be evaluated by a pharmacist and/or a physician on a case-by-case basis to determine a coverage recommendation for the client. Due to its toxicity, adalimumab therapy should be reserved for patients who have not responded well or are intolerant to other standard systemic therapy. In addition, the NSF Clinical Consensus, states that there currently are no prognostic factors that ascertain which therapies will be most efficacious and least toxic.) 6. Crohn s Disease, active (to induce or maintain remission) in adults. Crohn s Disease, active (to induce remission). Approve adalimumab for 12 weeks of therapy in adults if the patient has tried corticosteroids or if corticosteroids are contraindicated or if the patient is currently on corticosteroids (to avoid increasing the dose of the corticosteroid). After 12 weeks (this is following 160 mg at week 0, 80 mg at week 2, and a maintenance dose of 40 mg every other week (EOW) beginning at week 4), patients are evaluated for response and further authorization for maintenance of remission. In patients who do not respond by week 12, additional therapy does not result in significantly more responses. In clinical trials, the first 2 doses of adalimumab were given to induce remission and if patients responded at week 4, then maintenance with EOW adalimumab was started. Crohn s Disease (to maintain remission). If the patient (adult) has received 2 doses of adalimumab to induce remission or has had 12 weeks of therapy with adalimumab (i.e., 160 mg at week 0, 80 mg at week 2, and a maintenance dose of 40 mg EOW) and has had a response to therapy, then authorization is recommended for 12 months. Further authorization is not recommended if there is no response by week 12. In patients who do not respond by week 12, additional therapy does not result in significantly more responses. OR If the patient (adult) has not received adalimumab for induction of remission, then authorize adalimumab for maintenance (i.e., for 12 months) if the patient has tried azathioprine, 6-mercaptopurine, or MTX OR if the patient has tried infliximab (Remicade) or certolizumab pegol (Cimzia ). Patient is already in remission and adalimumab is being used to maintain remission. Adalimumab is FDA-approved for reducing signs and symptoms and inducing and maintaining clinical remission in adults with moderately to severely active Crohn s disease who have had an inadequate response to conventional therapy. Adalimumab is also indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab. Note: Patients with fistulizing Crohn s disease must meet the above criteria for Crohn s 3

disease, active (to induce or maintain remission), since adalimumab is not FDAapproved for fistulizing Crohn s disease. Other Uses with Supportive Evidence 7. Patient has already been started on adalimumab. Approve for any indication except Crohn s disease. (professional opinion of specialist physicians) For adults or adolescents 15 years of age with Crohn s disease, approve if the patient has had two doses for induction of remission and has responded by week 4 (standard induction dosing in adults for adalimumab is 160 mg at week 0 and then 80 mg at week 2 and is followed at week 4 with maintenance dosing) OR Approve if the patient with Crohn s disease has already received adalimumab, is already in remission, and is continuing therapy for maintenance of remission. Patients who are not in remission for Crohn s disease must meet the criteria #6 above for induction of remission. Level of evidence: 2. 8. Undifferentiated spondylarthritis (undifferentiated arthritis). Approve for 12 months. In a double-blind study conducted at 2 centers in Germany, 46 patients with active axial spondylarthritis without radiographically defined sacroiliitis were randomized to placebo or adalimumab 40 mg EOW for 12 weeks followed by an open-label extension for up to week 52. All patients in the open-label extension received adalimumab EOW. Patients were refractory to treatment with NSAIDs and had baseline BASDAI 4. The adalimumab dosage was increased to every week in 10 patients who did not attain ASAS 40 response after 12 weeks of therapy. At week 12 an ASAS 40 response (primary endpoint) was attained by 54.5% of the patients on adalimumab compared to 12.5% with placebo (P = 0.004 vs. placebo). Efficacy was maintained at week 52. In the entire study group of 46 patients, 50% attained an ASAS 40 response at week 52. Of note, trials with ankylosing spondylitis include patients who have radiographic changes in the sacroiliac joints which are the consequences of previous inflammation and may take years to become evident. Level of evidence: 1. 9. Crohn s Disease, active (to induce or maintain remission) in adolescents. Crohn s Disease, active (to induce remission). Approve adalimumab for 12 weeks of therapy in adolescents aged 15 to < 18 years, if the patient has tried infliximab (Remicade) AND if the patient has tried corticosteroids or if corticosteroids are contraindicated or if the patient is currently on corticosteroids (to avoid increasing the dose of the corticosteroid). After 12 weeks (this is following an induction dose at week 0 and at week 2 followed by a maintenance dose EOW beginning at week 4), patients are evaluated for response and further authorization for maintenance of remission. In adults who do not respond by week 12, additional therapy does not result in significantly more responses. In clinical trials in adults, the first 2 doses of adalimumab were given to induce remission and if patients responded at week 4, then maintenance with EOW adalimumab was started. Crohn s Disease (to maintain remission). If the patient (adolescent aged 15 to < 18 years) has received 2 doses of adalimumab to induce remission or has had 12 weeks of therapy with adalimumab (i.e., induction dose at week 0 and at week 2, and a maintenance dose EOW) and has had a response to therapy, then authorization is recommended for 12 months. Further authorization is not recommended if there 4

is no response by week 12. In adults who do not respond by week 12, additional therapy does not result in significantly more responses. OR If the patient (adolescent aged 15 to < 18 years) has not received adalimumab for induction of remission, then authorize adalimumab for maintenance (i.e., for 12 months) if the patient has tried azathioprine, 6-mercaptopurine, or MTX OR if the patient has tried infliximab (Remicade). Patient is already in remission and adalimumab is being used to maintain remission. Note: there is no information on Cimzia in children. Adalimumab is FDA-approved in adults with moderately to severely active Crohn s disease who have had an inadequate response to conventional therapy and in these patients if they have lost response to or are intolerant to infliximab. Infliximab is FDAapproved in pediatric patients 6 years of age with Crohn s disease. Limited information is available on the use of adalimumab in children with Crohn s disease and published information mostly includes adolescents who have lost response to infliximab or are intolerant to infliximab. Note: Patients with fistulizing Crohn s disease must meet the above criteria for Crohn s disease, active (to induce or maintain remission), since adalimumab is not FDAapproved for fistulizing Crohn s disease. 10. Uveitis (noninfectious) in children or adults. Approve for 12 months if patient has tried topical (ophthalmic) or systemic corticosteroids, MTX, etanercept, infliximab, mycophenolate mofetil, or cyclosporine. Adalimumab has been effective in a small number of children with chronic uveitis (either with rheumatic disease (JIA) or idiopathic) refractory to other therapies. Adalimumab was also effective in the management of refractory uveitis in adults and allowed the dose of concomitant immunosuppressives to be reduced. Further long-term studies are needed. Level of evidence: 4. 11. Uveitis or other systemic manifestations of Behcet s disease in adults. Approve for 12 months if patient has tried topical (ophthalmic) or systemic corticosteroids, azathioprine, interferon alfa, MTX, etanercept, infliximab, mycophenolate mofetil, or cyclosporine. In 3 cases, adalimumab was effective in controlling uveitis in adults with Behcet s disease who were in remission after receiving infliximab. In another case series, 6 adults with Behcet s disease [uveitis (2), central nervous system disease (2), colitis (1), and severe oral ulcers and arthritis (1)] in whom immunosuppressive therapy had failed, adalimumab was effective. These patients had received prior therapy with infliximab which had been discontinued after complete response or acceptable improvement. EULAR recommendations for the management of Behcet disease include either infliximab or cyclosporine in combination with azathioprine and corticosteroids for refractory eye involvement. For gastrointestinal or parenchymal involvement, TNFα antagonists have been used in resistant and complicated case. More study is needed with adalimumab. Level of evidence: 4. 12. Sarcoidosis, cutaneous. Approve for 12 months if patient has tried corticosteroids and immunosuppressive agents (MTX, azathioprine, cyclosporine, chlorambucil) or infliximab, or chloroquine. Well-controlled studies are not available for any therapies. Adalimumab has been effective in case reports of patients who were refractory to standard therapy. A randomized, placebo-controlled trial is underway using adalimumab for cutaneous sarcoidosis. Level of evidence: 5. 13. Pyoderma gangrenosum. Approve for 12 months if patient has tried one other systemic therapy (e.g., intralesional injections of corticosteroids or cyclosporine [for localized pyoderma gangrenosum]; systemic corticosteroids or immunosuppressants 5

such as azathioprine, 6-mercaptopurine, cyclosporine, cyclophosphamide, chlorambucil, infliximab). In 4 case reports, adalimumab was effective in treating pyoderma gangrenosum. Additional studies are needed. Level of evidence: 5. 14. Hidradenitis suppurativa. Approve for 12 months if the patient has tried one other therapy (e.g., intralesional or oral corticosteroids, antibiotics, isotretinoin). In case reports, adalimumab has been effective in treating hidradenitis suppurativa that was refractory to other therapies. Level of evidence: 5. Exclusions Coverage of adalimumab is not recommended in the following circumstances: 1. Adalimumab should not be given in combination with anakinra or abatacept. Serious infections were seen with concurrent use of etanercept (a tumor necrosis factor (TNF)-blocking agent) and anakinra with no added benefit. Similar toxicities may also occur from combination therapy with anakinra and other TNF-blocking agents such as adalimumab. Increased rates of serious adverse events, including serious infections, have been reported with concomitant administration of TNF blocking agents and abatacept and there was no significant increased efficacy over using the TNF blocking agent alone. 2. Children with Crohn s disease who are less than 15 years of age. Safety and efficacy in pediatric patients have not been established. A phase 3 clinical trial is underway in children with Crohn s disease. Limited information is published on the use of adalimumab in children, mostly adolescents, who could not tolerate infliximab or who lost response to infliximab. 3. Osteoarthritis. In an open-label trial in 12 patients with moderate to severe erosive/inflammatory osteoarthritis of the hands despite therapy with NSAIDs, 12 weeks of therapy with adalimumab 40 mg EOW did not significantly improve signs and symptoms (number of tender joints, grip strength, disability, pain, or global disease assessment). Trends suggested modest improvement. Long-term, placebo-controlled trials that have a specific efficacy outcome for hand or generalized osteoarthritis are needed. 4. Ulcerative colitis. In a 4-week open-label study conducted at 2 centers in France, 10 adults with ulcerative colitis who had lost response or became intolerant to infliximab received adalimumab 160 mg at week 0 and 80 mg at week 2. Disease activity was assessed using the ulcerative colitis clinical activity index (CAI) with scores > 12 indicating severe disease and 4 to 12 representing mild to moderate activity. The primary outcome was a decrease in the CAI score of > 4 at week 4. Other concurrent therapies for ulcerative colitis were allowed. In the 6 patients with severe ulcerative colitis, no remissions resulted and only one patient had clinical improvement. One patient with mild to moderate disease achieved remission. A randomized placebocontrolled trial is needed to determine if adalimumab has a place in the therapy of ulcerative colitis. 6. Intra-articular injection. Large placebo- or corticosteroid-controlled trials are needed to determine which patients might benefit from intra-articular injection and if this therapy is safe and effective. 7. Recurrent spontaneous pregnancy loss (RSPL). In a retrospective analysis, TNF inhibitors (etanercept [n = 3] or adalimumab [n = 14]) were used in combination with 6

intravenous immune globulin (IVIG) and anticoagulants plus low dose aspirin in patients with recurrent spontaneous abortion. The authors concluded that the addition of IVIG or a TNF inhibitor plus IVIG to the anticoagulant regimen appears to improve live birth rates compared to therapy with anticoagulants alone. Further prospective clinical trials are needed. According to guidelines from the American College of Obstetricians and Gynecologists, recommended therapy for preventing recurrent early (< 15 weeks of gestation) pregnancy loss does not include IVIG. At the time of these guidelines were written anti- TNF agents were not being studied for this indication. Patients with a positive test for lupus anticoagulant or anticardiolipin antibodies should be treated with heparin and low dose aspirin during the next pregnancy attempt. The American Society for Reproductive Medicine also concluded after reviewing 5 randomized controlled trials which assessed IVIG treatment for RSPL, that IVIG is not effective for primary RSPL. For secondary (indicates an antecedent pregnancy) RSPL, there was a higher percentage of successful pregnancies with IVIG, but the number of patients was not sufficient to rule out a chance finding. They concluded that IVIG as a treatment for RSPL is experimental and should only be used in a randomized clinical trial setting. 8. In vitro fertilization (IVF). In an observational study, use of adalimumab and IVIG improved IVF outcome in young infertile women who were < 38 years of age with Th1/Th2 cytokine elevations who had > 2 IVF embryo transplant failures. In group I, 41 patients used both IVIG and adalimumab; in group II, 23 patients used IVIG; in group III, 6 patients used adalimumab alone; and in group IV, 5 patients did not use either IVIG or adalimumab. Patient groups were formed partly through self selection and partly through differences in initial work up and history. Patients who received adalimumab had two 40 mg doses at 2-week intervals and about 2 to 3 weeks after the second injection, a second Th1/Th assay was done. If the Th1/Th2 was still increased, 2 more dose of adalimumab were given. All patients received enoxapirin daily during their treatment cycles and 75 mg of aspirin daily. The implantation rate (number of gestational sacs per embryo transferred, with an average of two embryos transferred by cycle) was 59% (group I), 47% (group II), 31% (group III), and 0% (group IV). The respective clinical pregnancy rates (fetal heart activity per IVF cycle started) were 80%, 57%, 50%, and 0%. The respective live birth rates were 73%, 52%, 50%, and 0%. These improvements were significant for group I vs. group IV and for group II vs. group IV. Well controlled trials in a larger, well defined group of patients are needed. 9. Other indications. Exceptions not recommended. 10. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available. APPROVAL: ENDORSED BY: Pharmacy & Therapeutics Committee Original Date: Reviewed: 5/19/2010 APPROVED BY: Date 7