==Adalimumab (Humira®)== BCBSF medical coverage guideline

Subject: Adalimumab (Humira®)

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
Related Guidelines Other References Updates    

DESCRIPTION:

Humira® (adalimumab) is a recombinant human IgG1 monoclonal antibody specific for human tumor necrosis factor (TNF). Humira® was created using phage display technology resulting in an antibody with human derived heavy and light chain variable regions and human IgF1:k constant regions. Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system and is purified by a process that includes specific viral inactivation and removal steps. It consists of 1330 amino acids and has a molecular weight of approximately 148 kilodaltons.

Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surfact TNF receptors. Adalimumab also lyses surface TNF expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients and play an in important role in both the pathologic inflammation and the joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques. In plaque psoriasis, treatment with Humira® may reduce the epidermal thickness and infiltration of inflammatory cells. The relationship between these pharmacodynamic activities and the mechanism by which adalimumab exerts its clinical effects is unknown.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte mitration.

POSITION STATEMENT:

REQUIRED: Certificate of Medical Necessity

NOTE: The attached Certificate of Medical Necessity should be completed and submitted with the request for adalimumab, in order to facilitate medical review. To access the certificate of medical necessity, click on the link below, complete the required fields, and print

Adalimumab (Humira®) meets the definition of medical necessity when administered for the following indications (SEE TABLE 1 FOR SPECIFIC CRITERIA):

  • Rheumatoid Arthritis
  • Juvenile Idiopathic Arthritis
  • Psoriatic Arthritis
  • Ankylosing Spondylitis
  • Crohn’s Disease
  • Plaque Psoriasis.

Table 1:

 

   
SPECIFIC CRITERIA FOR HUMIRA® (ADALIMUMAB) THERAPY
1. Rheumatoid Arthritis
  • Patient has a history of beneficial clinical response to adalimumab therapy for rheumatoid arthritis and dosage does not exceed 40 mg every other week if methotrexate is used concomitantly or dosage does not exceed 40 mg weekly if methotrexate is not being used OR
  • Patient is 18 years old or older AND
  • Patient has had an inadequate response to one or more DMARDs (disease modifying antirheumatic drugs). Adalimumab may be used alone OR in combination with methoxate or other DMARDs (Refer to Table 2 under OTHER) AND
  • If methotrexate is used concomitantly, dosage does not exceed 40 mg every other week OR
  • If methrotrexate is not used concomitantly, dosage does not exceed 40 mg weekly.
2. Juvenile Idiopathic Arthritis
  • Patient has a history of beneficial clinical response to adalimumab therapy for juvelile idiopathic arthritis and dosage does not exceed 20 mg every other week if patient weighs less than 30 kg or does not exceed 40 mg every other week if patient weighs more than 30 kg OR
  • Adalimimab is prescribed for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) AND
  • Patient is 4 years of age or older AND
  • Patient has had an inadequate response to one or more DMARDs AND
  • For patients weighing between 15 kg (33 lbs) to <30 kg (66 lbs, dosage does not exceed 20 mg every other week OR
  • For patients weighing >30 kg (66 lbs), dosage does not exceed 40 mg every other week.
3. Psoriatic Arthritis
  • Patient has a history of beneficial clinical response to adalimumab therapy for psoriatic arthritis and dosage does not exceed 40 mg every other week OR
  • Patient is 18 years old or older AND
  • Adalimab is prescribed to reduce the signs and symptoms of psoriatic arthritis as single therapy or in combination with a DMARD AND
  • Dosage does not exceed 40 mg every other week.
4. Ankylosing Spondylitis
  • Patient has a history of beneficial clinical response to adalimumab therapy for ankylosing spondylitis and dosage does not exceed 40 mg every other week OR
  • Patient is 18 years old or older AND
  • Adalimumab is prescribed for reducing signs and symptoms of ankylosing spondylitis in patients when conventional treatment options (e.g., nonsteroidal anti-inflammatory drugs, sulfasalazine, methotrexate) have failed or not indicated AND
  • Dosage does not exceed 40 mg every other week.
5. Crohn’s Disease
  • Patient has a history of beneficial clinical response to adalimumab therapy for Crohn’s disease and dosage does not exceed 40 mg every other week OR
  • Patient is 18 years old or older AND
  • Adalimumab is prescribed for reducing signs and symptoms of moderately to severely active Crohn’s disease and inducing and maintaining clinical remission in adult patients AND
  • Patient has had an inadequate response to conventional therapy or have lost response to or are intolerant to infliximab AND
  • Initial dosing does not exceed 160 mg at week 0, and 80 mg at week 2 AND
  • Maintenance dose does not exceed 40 mg every other week.
6. Plaque Psoriasis
  • Patient has a history of beneficial clinical response to adalimumab therapy for plaque psoriasis and dosage does not exceed 40 mg every other week OR
  • Patient is 18 years old or older AND
  • Adalimumab is prescribed for adult patients with moderate to severe chronic plaque psoriasis AND
  • Patient must have failed to adequately respond to or is intolerant to one of the following phototherapies(unless contraindicated):
  1. psoralens (methoxsalen, trioxsalen) with UVA light (PUVA); OR
  2. UVB with coal tar or dithranol; OR
  3. UVB (standard or narrow-band) AND
  4. Initial dose does not exceed 80 mg at week 0 AND
  5. Maintenance dose does not exceed 40 mg every other week starting at week 1.

NOTE: concomitant use of adalimumab and anakinra is NOTrecommended since serious infections have been seen in clinical studies with concurrent use of anakinra and another TNF-blocking agent with no added benefit.

NOTE: Safety and efficacy of adalimumab in pediatric patients for uses other than juvenile arthritis have not been established.

Adalimumab is considered experimental or investigationalfor all other indications since safety and effectiveness have not been established.

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING IT’S USAGE.

Rheumatoid Arthrtitis

The recommended dose of adalimumab for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection. Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics OR other DMARDsmay be continued during treatment with adalimumab. The dose of adalimumab can be increased to 40 mg per week if methotrexate is not used concomitantly.

Juvenile Idiopathic Arthritis

The recommended dose of adalimumab for patients weighing between 15 kg (33 lbs) to <30 kg (66 lbs) is 20 mg every other week and those weighing >30 kg (66 lbs) the dose is 40mg every other week.

Psoriatic Arthritis

The recommended dose of adalimumab for adult patients with psoriatic arthritis is 40 mg subcutaneously every other week alone or in combination with other disease-modifying anti-rheumaticdrugs.

Ankylosing Spondylitis

The recommended dose of adalimumab for adult patients with ankylosing spondylitis is 40 mg subcutaneously every other week alone or in combination with NSAIDS, glucocorticoids, methotrexate or other DMARDs.

Crohn’s Disease

The recommended dose of adalimumab for adult patients with Crohn’s disease is 160 mg initially at week 0, 80 mg at week 2, followed by a maintenance dose of 40 mg every other week beginning at week 4. Initial dose may be given as 4 injections on 1 day, or divided over 2 days.

Plaque Psoriasis

The recommended dose of adalimumab for adult patients with plaque psoriasis is 80 mg initial dose, followed by 40 mg every other week starting one week after initial dose.

PRECAUTIONS:

 

WARNINGS:
SERIOUS INFECTIONS

Patients treated with adalimumab are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. Reported infections include:

  • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before adalimumab use and during therapy. Treatment for latent infection should be initiated prior to adalimumab use.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.
  • Bacterial, viral and other infections due to opportunistic pathogens.

The risks and benefits of treatment with adalimumab should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

MALIGNANCY

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which adalimumab is a member.

Hepatitis B virus reactivation: Use of TNF blockers, including adalimumab, may increase the risk of reactivation of HBV in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF-blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which also may contribute to HBV reactivation. Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF-blocker therapy. Exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with antiviral therapy in conjunction with TNF-blocker therapy to prevent HBV reactivation. Closely monitor patients who are carriers of HBV and require treatment with TNF blockers for clinical and laboratory signs of active HBV infections throughout therapy and for several months following termination of therapy. In patients who develop HBV reactivation, stop adalimumab and initiate effective antiviral therapy with appropriate supportive treatment. The safety of resuming TNF-blocker therapy after HBV reactivation is controlled is not known. Therefore, exercise caution when considering resumption of adalimumab therapy in this situation and monitor patients closely.

Neurologic effects: Use of TNF-blocking agents, including adalimumab, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease. Exercise caution in considering the use of adalimumab in patients with preexisting or recent-onset CNS demyelinating disorders.

Hematologic effects: Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF-blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., leukopenia, thrombocytopenia), have been reported infrequently with adalimumab. The causal relationship of these reports to adalimumab remains unclear. Advise patients to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., bleeding, bruising, pallor, persistent fever) while on adalimumab. Consider discontinuation of adalimumab therapy in patients with confirmed significant hematologic abnormalities.

Congestive heart failure: Cases of worsening congestive heart failure (CHF) and new-onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with adalimumab. Adalimumab has not been formally studied in patients with CHF; however, in clinical trials of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. Exercise caution when using adalimumab in patients who have heart failure and monitor them carefully.

Autoimmunity: Treatment with adalimumab may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with adalimumab, discontinue treatment.

Immunizations: In a placebo-controlled clinical trial of patients with RA, no difference was detected in antipneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were coadministered with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The clinical significance of this is unknown.

Patients on adalimumab may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving adalimumab. It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating adalimumab therapy.

Immunosuppression: The possibility exists for TNF-blocking agents, including adalimumab, to affect host defenses against infections and malignancies because TNF mediates inflammation and modulates cellular immune responses.

In a study of 64 patients with RA treated with adalimumab, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T and B cells and NK cells, monocyte/macrophages, and neutrophils. The impact of treatment with adalimumab on the development and course of malignancies as well as active and/or chronic infections is not fully understood. The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated.

Immunogenicity: Patients in studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58/1,062) of adult RA patients receiving adalimumab developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate had a lower rate of antibody development than patients on adalimumab monotherapy (1% vs. 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every-other-week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the American College of Rheumatology (ACR) 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of adalimumab is unknown.

In patients with juvenile idiopathic arthritis, adalimumab antibodies were identified in 16% of adalimumab-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared with 26% receiving adalimumab monotherapy.

In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in adalimumab-treated patients was comparable with patients with RA. In patients with psoriatic arthritis, the rate of antibody development in patients receiving adalimumab monotherapy was comparable with patients with RA; however, in patients receiving concomitant methotrexate, the rate was 7% compared with 1% in RA. In patients with Crohn disease, the rate of antibody development was 2.6%. The immunogenicity rate was 8% for plaque psoriasis patients who were treated with adalimumab monotherapy.

The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab in an enzyme-linked immunosorbent assay and are highly dependent on the sensitivity and specificity of the assay. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors, including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to adalimumab with the incidence of antibodies to other products may be misleading.

Latex allergy: The needle cover of the prefilled syringe contains dry rubber (latex), which should not be handled by people sensitive to this substance.

Hypersensitivity reactions: In postmarketing experience, anaphylaxis and angioneurotic edema have been reported rarely following adalimumab administration. If an anaphylactic or other serious allergic reaction occurs, discontinue administration of adalimumab immediately and institute appropriate therapy. In adults in clinical trials of adalimumab, allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, nonspecified drug reaction, urticaria) have been observed in approximately 1% of patients.

Carcinogenesis: Long-term animal studies of adalimumab have not been conducted to evaluate the carcinogenic potential.

Mutagenesis: No clastogenic or mutagenic effects of adalimumab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively.

Fertility impairment: Long-term animal studies of adalimumab have not been conducted to evaluate its effect on fertility.

Children: Safety and effectiveness of adalimumab in children for uses other than juvenile idiopathic arthritis have not been established.

In the juvenile idiopathic arthritis study, adalimumab was shown to reduce signs and symptoms of active polyarticular juvenile idiopathic arthritis in patients 4 to 17 years of age.

Adalimumab has not been studied in children younger than 4 years of age, and there are limited data on adalimumab treatment in children weighing less than 15 kg.

Safety of adalimumab in children was generally similar to that observed in adults, with certain exceptions.

Elderly: A total of 519 RA patients 65 years of age and older, including 107 patients 75 years of age and older, received adalimumab in clinical studies RA-I through RA-IV. No overall difference in effectiveness was observed between these subjects and younger subjects.

The frequency of serious infection and malignancy among adalimumab-treated subjects older than 65 years of age was higher than for those younger than 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population in general, use caution when treating elderly patients.

Monitoring: Closely monitor patients who develop a new infection while undergoing treatment with adalimumab. Monitor patients for signs and symptoms of active TB, including patients who had a negative tuberculin skin test. Monitor heart failure patients carefully. Closely monitor patients who are carriers of HBV and require treatment with TNF blockers for clinical and laboratory signs of active HBV infections throughout therapy and for several months following termination of therapy.

BILLING/CODING INFORMATION:

CPT Coding:

 

96372 Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular

HCPCS Coding:

 

J0135 Adalimumab (Humira®) Injection 20 mg

ICD-9 Diagnoses Codes That Support Medical Necessity:

 

555.0 – 555.9 Crohn’s disease
696.0 Psoriatic arthropathy
696.1 Other psoriasis
714.0 – 714.2 Rheumatoid arthritis
714.30 – 714.33 Juvenile chronic polyarthritis
714.4 Chronic postrheumatic arthropathy
714.81 Other specified inflammatory polyarhtropathies
714.89 Other
714.9 Unspecified inflammatory polyarthropathy
720.0 Ankylosing spondylitis

ICD-10 Diagnoses Codes That Support Medical Necessity: (Effective 10/01/13)

 

K50.00 Crohn’s disease of small intestine without complications
K50.10 Crohn’s disease of large intestine without complications
K50.80 Crohn’s disease of both small and large intestine without complications
K50.90 Crohn’s disease, unspecified, without complications
L40.54 Psoriatic juvenile arthropathy
L40.59 Other psoriatic arthropathy
L40.8 Other psoriasis
M05.00 Felty’s syndrome, unspecified site
M05.10 Rheumatoid lung disease with rheumatoid arthritis of unspecified site
M05.30 Rheumatoid heart disease with rheumatoid arthritis of unspecified site
M05.60 Rheumatoid arthritis of unspecified site with involvement of other organs and systems
M06.1 Adult-onset Still’s disease
M06.4 Inflammatory polyarthropathy
M06.9 Rheumatoid arthritis, unspecified
M08.00 Unspecified juvenile rheumatoid arthritis of unspecified site
M08.3 Juvenile rheumatoid polyarthritis (seronegative
M08.40 Pauciarticular juvenile rheumatoid arthritis, unspecified site
M12.00 Chronic postrheumatic arthropathy [Jaccoud], unspecified site
M45.9 Ankylosing spondylitis of unspecified sites in spine

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

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

DEFINITIONS:

Ankylosing spondylitis: Immobility and consolidation of a vertebral joint caused by inflammation.

Antirheumatic: An agent that relieves or prevents musculoskeletal pain.

Crohn’s diseasse: A chronic granulomatous inflammatory disease of unknown etiology, involving any part of the gastrointestinal tract from mouth to anus, but commonly involving the terminal ileum with scarring and thickening of the bowel wall.

DMARDs: An acronym for disease-modifying antirheumatic drugs.

Psoriatic arthritis: a severe form of arthritis accompanied by inflammation, psoriasis of the skin or nails, and a negative test for rheumatoid factor.

Rheumatic: A term referring to a disorder or condition that causes pain or stiffness in the joints, muscles, or bone of the musculoskeletal system.

Rheumatoid arthritis: An inflammatory disease of the synovium, or lining of the joint, that results in pain, stiffness, and swelling of multiple joints. The inflammation may extend to other joints and cause bone and cartilage erosion, joint deformities, movement problems, and activity limitations.

RELATED GUIDELINES:

Etanercept (Enbrel®), 09-J0000-38
Infliximab (Remicade®), 09-J0000-39

Anakinra (Kineret®), 09-J0000-45

Rituximab (Rituxan®), 09-J0000-59

Abatacept (Orencia®), 09-J0000-67

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

Alefacept (Amevive®), 09-J0000-78

Rilonacept (Arcalyst™), 09-J0000-89

Golimumab (Simponi™), 09-J1000-11

Canakinumab (Ilaris®) Injection, 09-J1000-14

Ustekinumab (Stelara™), 09-J1000-16

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

OTHER:

Table 2: DMARDs

 

DMARD Generic Name DMARD Brand Name
Auranofin (oral gold) Ridaura®
Azathioprine Imuran®
Chlorambucil Leukeran®
Cyclophosphamide Cytoxan®
Cyclosporine Neoral, Sandimmune®
Gold sodium thiomalate (injectable gold) Myochrysine®
Hydroxychloroquine sulfate Plaquenil®
Leflunomide Arava®
Methotrexate Rheumatrex®, Trexall®
Minocycline Minocin®
Penicillamine Cuprimine®, Depen®
Sulfasalazine Azulfidine®, Azulfidine EN-Tabs®

REFERENCES:

  1. Abbott Laboratories. Letter, “IMPORTANT DRUG WARNING” dated 11/05/04.
  2. Abbott Laboratories. Press Release. Abbott Seeks U.S. and E.U. Regulatory Approval for Humira® (adalimumab) in Psoriasis. 04/02/07.
  3. American Journal of Respiratory and Critical Care Medicine (2003; 167:603-62).
  4. American Medical Association CPT Coding, 2009 professional edition.
  5. Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD006893. DOI: 10.1002/14651858.CD006893.
  6. Clinical Pharmacology, copyright® 2009.
  7. Cush JJ, Biologic Treatments for Rheumatoid Arthritis. American College of Rheumatology 2006.
  8. DRUGDEX®, accessed 06/24/10.
  9. eHealth MD: Autoimmune Disorders, 2005.
  10. Facts & Comparisons, 4.0, accessed 06/24/10.
  11. Food and Drug Administration (FDA). Orphan designations and approvals list. 2005.
  12. Gordon KB et. al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis. J Am Acad Dermatol 10.1016/j, haad. 05/27/06.
  13. Guidelines for the Management of Rheumatoid Arthritis 2002 Update. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. ARTHRITIS & RHEUMATISM Vol. 46, No. 2, February 2002, pp 328 – 346.
  14. HAYES, Inc. New Drug for Crohn’s Disease Approved. Lansdale, PA: HAYES, Inc. 03/06/07.
  15. HIPAA Space, HCPCS Codes Lookup, Copyright® 2004 – 2010. Accessed 06/29/10.
  16. Humira® Prescribing Information, November 2009.
  17. ICD-9 Data.com. Accessed 06/29/10.
  18. Mease PJ, Gladman DD, Ritchlin CT et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: Results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheum. 2005 Oct; 52(10): 3279-89.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Policy Committee on 07/14/10.

GUIDELINE UPDATE INFORMATION:

 

01/01/05 New Medical Coverage Guideline.
08/15/05 Revised and Updated: Updated description, dosage/administration. Deleted precautions, updated when services are not covered, billing/coding information, and definitions, table 1, references.
11/15/05 Updated when services are covered for psoriatic arthritis, updated ICD-9 codes, definitions, and references.
11/15/06 Scheduled review: added indication of ankylosing spondylitis, added ICD-9 code, corrected CPT-4 coding and updated references.
01/01/07 MCG revised to include Medicare Part D as program exception.
04/15/07 Revision; consisting of adding Crohn’s disease indication and ICD-9 code, related guidelines and definitions.
06/15/07 Review and revision; consisting of reformatting, updating related guidelines and references.
03/15/08 Revision; consisting of adding plaque psoriasis and juvenile idiopathic arthritis (JIA) as covered indications, rewording coverage criteria for Crohn’s disease, updated dosage and administration section, added ICD-9 codes and updated references.
05/15/08 Review and revision; consisting of reformatting, adding a black box warning under “PRECAUTIONS”, adding related guideline and updating references.
09/15/08 Revision of guideline; consisting of adding 3 ICD-9 codes.
01/01/09 Annual HCPCS coding update: deleted code 90772; added code 96372.
09/15/09 Review and revision; consisting of updating references, boxed warning and ICD-9 coding.
04/15/10 Revision; consisting of adding specific continuation criteria.
08/15/10 Review and revision; consisting of adding age criteria to all indications, updated precautions and references.
01/15/11 Revision; consisting of adding ICD-10 codes.
04/01/11 Revision; consisting of adding dosage limitations.

 

Data from: http://mcgs.bcbsfl.com/index.cfm

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Clinical Policy Bulletin: Adalimumab (Humira)

Policy

  1. Aetna considers adalimumab (Humira) medically necessary for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adults 18 years of age or older with moderately to severely active rheumatoid arthritis. According to the Food and Drug Administration (FDA)-approved product labeling, adalimumab can be used alone or in combination with methotrexate or in combination with nonbiologic disease-modifying anti-rheumatic drugs (DMARDs).
  2. Aetna considers adalimumab medically necessary for reducing signs and symptoms of active arthritis in adults with moderate to severely active psoriatic arthritis who have had an inadequate response to two or more nonbiologic disease-modifying antirheumatic drugs (DMARDS).   According to the FDA-approved product labeling, adalimumab can be used alone or in combination with DMARDs.
  3. Aetna considers adalimumab medically necessary for reducing signs and symptoms of members with active ankylosing spondylitis who have an inadequate response to two or more NSAIDs.
  4. Aetna considers adalimumab medically necessary for members with active Crohn’s disease manifested by:
    1. Abdominal pain;
    2. Arthritis;
    3. Bleeding;
    4. Diarheea;
    5. Internal fistulae;
    6. Intestinal obstruction;
    7. Megacolon;
    8. Perianal disease; 
    9. Spondylitis; or
    10. Weight loss.

    When Crohn’s disease has remained active despite treatment with either 6-mercaptopurine, azathioprine, or corticosteroids.

  5. Aetna considers adalimumab medically necessary for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (juvenile rheumatoid arthritis) in persons 4 years of age and older.
  6. Aetna considers adalimumab medically necessary for treatment of adults with moderate to severe chronic plaque psoriasis according to the criteria set forth in CPB 658 – Psoriasis: Biological Therapies.
  7. Aetna considers adalimumab experimental and investigational for all other indications, including any of the following conditions, because the safety and effectiveness of adalimumab for these conditions has not been established:
    • Active infections; or
    • Asthma; or
    • Cellulitis; or 
    • For use in combination with other tumor necrosis-factor blocking agents [(e.g., etanercept (Enbrel) or infliximab (Remicade) or with anakinra (Kineret)]; or
    • Guttate psoriasis; or
    • Osteoarthritis; or
    • Recurrent pregnancy loss; or 
    • Relapsing polychondritis; or
    • Sarcoidosis; or
    • Sciatica; or
    • Ulcerative colitis; or
    • Uveitis.

See also CPB 315 – Enbrel (Etanercept)CPB 341 – Remicade (infliximab), and CPB 595 – Kineret (Anakinra).

BackgroundAdalimumab (Humira) (Abbott Laboratories, North Chicago, IL) is a recombinant human IgG1 monoclonal antibody that acts by inhibiting tumor necrosis factor alpha, an inflammatory protein that, when produced in excess, plays a key role in the inflammatory responses of some autoimmune diseases. Adalimumab has been approved by the U.S. Food and Drug Administration (FDA) for rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn’s disease, plaque psoriasis, and juvenile idiopathic arthritis.

Adalimumab has been approved by the FDA for reducing signs and symptoms and inhibiting the progression of structural damage in adult patients with moderately to severely active rheumatoid arthritis. Adalimumab can be used alone or in combination with methotrexate or other nonbiolgic DMARDs. The efficacy and safety of adalimumab were assessed in five randomized, double blind studies in 2869 subjects aged 18 years and older with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria.  All subjects had at least 6 tender and 9 swollen joints. Humira was administered subcutaneously in combination with methotrexate or as monotherapy or with other disease modifying anti-rheumatic drugs. Two studies involved 815 patients who had failed to respond to DMARDS; one study involved 619 patients who had an inadequate response to methotrexate. One study assessed 636 patients who were either DMARD-naive or were permitted to remain on their pre-existing rheumatologic therapy. One study evaluated 799 patients with moderately to severely active rheumatoid arthritis of less than 3 years duration who were methotrexate naïve. In all five studies, adalimumab showed significantly greater improvement than placebo in standardized indices of disability and health outcomes from baseline to the end of study. One of the five studies also examined the effect adalimumab on inhibition of disease progression, as detected by X-ray results. Subjects treated with adalimumab and methotrexate showed significantly less radiological progression of disease than subjects treated with methotrexate alone. Subjects treated with adalimumab and methotrexate showed significantly less radiological progression of disease than subjects treated with methotrexate alone.

According to guidelines from the American College of Rheumatology (Saag, et al., 2008), patients with early rheumatology with low or moderate disease activity (in study) were not considered candidates for biologic therapy. The use of anti-TNF agent in combination with methotrexate was recommended if high disease activity was present for less than three months with features of a poor prognosis.

Adverse events from adalimumab include upper respiratory infection, sinusitis, flu syndrome, nausea, and abdominal pain. Cases of tuberculosis and invasive fungal infections have rarely been observed in patients receiving adalimumab.

The recommended dose of adalimumab for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection.

The FDA has approved adalimumab for reducing signs and symptoms of active arthritis in patients with psoriatic arthritis.  The FDA-approved product labeling for Humira states that adalimumab can be used alone or in combination with methotrexate or with DMARDs.  The FDA approval of Humira was based on two multicenter randomized controlled clinical studies evaluating the safety and efficacy of adalimumab compared with placebo in 413 patients with moderate to severely active psoriatic arthritis (greater than 3 swollen and greater than 3 tender joints) who have had an inadequate response to non-steroidal anti-inflammatory drugs (NSAIDS).  In one study (Mease, et al., 2005), 313 patients with moderately to severely active psoriatic arthritis and a history of inadequate response to NSAIDS were randomized to receive 40 mg adalimumab or placebo subcutaneously every other week for 24 weeks.  Study participants had the following forms of psoriatic arthritis: 1) distal interphalangeal (DIP) involvement (n = 23); 2) polyarticular arthritis (absence of rheumatoid nodules and presence of psoriasis) (n = 210); 3) arthritis mutilans (n = 1); 4) asymmetric psoriatic arthritis (n = 77); or 5) ankylosing spondylitis-like (n = 2).  Patients on methotrexate therapy (158 of 313 patients) at enrollment (stable dose of less than or equal to 30 mg/week for greater than 1 month) could continue methotrexate at the same dose.  Study visits were at baseline, weeks 2 and 4, and every 4 weeks thereafter.  The primary efficacy end points were the American College of Rheumatology 20% improvement (ACR20) response at week 12 and the change in the modified total Sharp score of structural damage at week 25.  Secondary end points were measures of joint disease, disability, and quality of life in all patients, as well as the severity of skin disease in those patients with psoriasis involving at least 3% of body surface area.  At week 12, 58% of the adalimumab-treated patients (87 of 151) achieved an ACR20 response, compared with 14% of the placebo-treated patients (23 of 162) (p < 0.001).  At week 24, similar ACR20 response rates were maintained and the mean change in the modified total Sharp score was -0.2 in patients receiving adalimumab and 1.0 in those receiving placebo (p < 0.001).  Similar responses were seen in patients with each of the subtypes of psoriatic arthritis, although few patients were enrolled with the arthritis mutilans and ankylosing spondylitis-like subtypes.  Responses were similar in patients who were or were not receiving concomitant methotrexate therapy at baseline.  Patients with psoriatic involvement of at least three percent body surface area (BSA) were evaluated for Psoriatic Area and Severity Index (PASI) responses.  Among the 69 adalimumab-treated patients evaluated for PASI responses, 59% achieved a 75% PASI improvement response and 42% achieved a 90% PASI improvement response at 24 weeks, compared with 1% of the 69 placebo-treated patients evaluated (p < 0.001).  The investigators reported that disability and quality of life measures were also significantly improved with adalimumab treatment compared with placebo.   

Similar results were seen in an additional, 12-week study in 100 patients with moderate to severe psoriatic arthritis who had suboptimal response to DMARD therapy as manifested by greater than or equal to 3 tender joints and greater than or equal to 3 swollen joints at enrollment.

The manufacturer reported that the rates of adverse events and serious adverse events in clinical trials of adalimumab for psoriatic arthritis submitted for FDA approval were comparable with clinical trials of adalimumab in rheumatoid arthritis. Among patients taking adalimumab, the most common adverse events (those affecting at least 5 percent of patients) were upper respiratory infection, nasopharyngitis, injection site reaction, headache and hypertension. The safety profile of adalimumab in these clinical trials was similar to that observed in the clinical trials of adalimumab for rheumatoid arthritis that were submitted for FDA approval. The FDA-approved product labeling states that the safety and efficacy of adalimumab in pediatric patients has not been established.

The recommended dose of adalimumab for psoriatic arthritis is 40 mg every-other-week by subcutaneous injection, which is also the usual dose used for adalimumab in the treatment of moderate to severe rheumatoid arthritis.

Ankylosing spondylitis (AS) is a form of arthritis known as spondyloarthritis, which is a group of closely linked rheumatic diseases that can cause pain in the spine and joints as well as ligaments and tendons.  Ankylosing spondylitis is an autoimmune disorder in which tumor necrosis factor (TNF)-alpha has been suggested to play a role in its pathogenesis.  A chronic disease, AS primarily affects the spine causing back stiffness and potential deformity over time.  Wendling and Toussirot (2004) noted that anti-TNF represents a major therapeutic advancement in the treatment of AS.  De Keyser and associates (2006) stated that AS is the prototype disease within the spondyloarthropathies, a group of diseases presenting mainly with spondylitis, pauci-articular peripheral arthritis and enthesiopathy.  Non-steroidal anti-inflammatory drugs are the classical cornerstone of medical therapy in these patients; no real DMARD was available, until recently.  Tumor necrosis factor-alpha blocking agents (monoclonal antibodies or soluble receptors) are the first representative drugs, of which the indication has recently been expanded to encompass also patients with AS.  In a 52-week open-label study (n = 15, mean age of 40 years with a range of 19 to 55 years), Haibel and colleagues (2006) reported that adalimumab treatment of active AS resulted in a clear improvement in clinical (reduction of spinal symptom) as well as MRI outcome measurements, similar to that observed with other TNF-alpha blocking agents. 

On July 31, 2006, the FDA granted a supplemental indication for adalimumab – for reducing signs and symptoms in patients with active AS.  This indication was approved by the European Commission in June 2006.  The recommended dosage of adalimumab for AS is 40 mg (subcutaneous injection) every other week.  The approval of adalimumab for the treatment of patients with active AS is based on data from the ATLAS (Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS) trial (n = 315), which was a randomized, placebo-controlled, double-blind, Phase III study conducted in Europe and the United States of patients with AS who had failed to respond to NSAIDs or DMARDs.  Results at 12 weeks showed that 58 % of patients receiving adalimumab achieved and sustained a minimum 20 % reduction in pain and inflammation, as measured via the Assessment in AS (ASAS) International Working Group criteria for evaluating function, pain, patient global assessment, and inflammation.  At week 24, 42 % of adalimumab-treated patients versus 16 % of those receiving placebo achieved a reduction of 50 % or more in disease activity, as evaluated using a patient-assessed composite index for pain, stiffness, and fatigue (Bath AS Disease Activity Index [BASDAI]).  Moreover, approximately 1 of 5 patients achieved partial remission, defined as a value of less than 20 on a 0 to 100 scale in each of the 4 ASAS domains.

ATLAS also explored the impact of adalimumab on enthesitis, a primary pathology in AS that is characterized by inflammation of the ligaments attachment to the bone.  At week 24, the mean change in the enthesitis symptom score as indexed by Maastricht Ankylosing Spondylitis Enthesitis Score (MASES) in patients treated with adalimumab showed significant reduction.  MASES is an index that assesses enthesitis in certain locations, such as the rib cage, lower back, and Achilles tendons.

The British Society for Rheumatology (BSR, 2006) has stated that “there is evidence to support the use of adalimumab as a treatment for adult patients with active AS, who have had an inadequate response to non-steroidal anti-inflammatory drugs and conform to the current BSR guideline for the use of anti-TNF-? drugs in AS.” The BSR statement notes that “[w]hilst there have not been any direct comparisons between anti-TNF-α drugs in AS, adalimumab appears to be as effective as any other licensed agents.”

Adalimumab has also been shown in clinical trials to be effective for moderate to severe Crohn’s disease. Colombel, et al. (2007) reported on the results of a controlled clinical trial which demonstrated that adalimumab was effective in maintenance of response and remission in patients with moderate to severe Crohn’s disease. In this clinical study, patients received open-label induction therapy with adalimumab 80 mg at study initiation followed by 40 mg two weeks later. Four weeks following study initiation, patients who responded to adalimumab were stratified by response (decrease in Crohn’s Disease Activity Index greater than or equal to 70 points from baseline) and randomized to three treatment groups: placebo, adalimumab 40 mg every other week, or adalimumab 40 mg weekly. Patients were followed for 56 weeks. Coprimary end points were the percentages of randomized responders who achieved clinical remission (Crohn’s Disease Activity Index score less than 150) at weeks 26 and 56. The investigators reported that the percentage of randomized responders in remission was significantly greater in the groups receiving adalimumab weekly and every other week compared to the placebo group at week 26 (47%, 40%, and 17%, respectively; p <  0.001) and at week 56 (41%, 36%, and 12%, respectively; p <  0.001).  There were no significant differences in efficacy between adalimumab administered weekly and every other week. The investigators noted that adalimumab was well tolerated; more patients receiving placebo discontinued treatment because of an adverse event (13.4%) than those receiving adalimumab (4.7% and 6.9% in the adalimumab weekly and every other week groups, respectively). The investigators concluded that, among patients who responded to adalimumab, both weekly and every other week adalimumab was significantly more effective than placebo in maintaining remission in moderate to severe Crohn’s disease through 56 weeks.

Hanauer, et al. (2006) reported that adalimumab was shown in a controlled clinical trial to be superior to placebo for induction of remission in patients with moderate to severe Crohn’s disease.  A total of 299 patients with moderate to severe Crohn’s disease naive to anti-tumor necrosis factor (TNF) therapy were randomized to receive subcutaneous injections at study initiation and two weeks later with adalimumab 40 mg/20 mg, 80 mg/40 mg, or 160 mg/80 mg or placebo. The primary endpoint was demonstration of a significant difference in the rates of remission (defined as a Crohn’s Disease Activity Index score <150 points) at four weeks after study initiation among the 80 mg/40 mg, 160 mg/80 mg, and placebo groups. The investigators found that the rates of remission at the fourth week in the adalimumab 40 mg/20 mg, 80 mg/40 mg, and 160 mg/80 mg groups were 18% (p = 0.36), 24% (p = 0.06), and 36% (p = 0.001), respectively, and 12% in the placebo group. The investigators reported that adalimumab was well tolerated, noting that adverse events occurred at similar frequencies in all four treatment groups except injection site reactions, which were more common in adalimumab-treated patients. The investigators concluded that adalimumab was superior to placebo for induction of remission in patients with moderate to severe Crohn’s disease naive to anti-TNF therapy. The investigators stated that the optimal induction dosing regimen for adalimumab in this study was 160 mg at initiation of therapy followed by 80 mg two weeks later.

Colombel et al (2009) compared outcomes of induction dosing followed by continuous adalimumab treatment with those of induction dosing with re-initiation of adalimumab (in the event of clinical deterioration) for patients with moderate-to-severe Crohn’s disease who participated in the Crohn’s Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM). In the CHARM trial, all patients received open-label induction therapy with adalimumab 80 mg and 40 mg at weeks 0 and 2, respectively. In total, 778 patients were randomized at week 4 to one of three groups: (i) placebo after initial induction doses (followed by re-initiation of adalimumab therapy); (ii) continuous maintenance treatment with adalimumab 40 mg every other week (e.o.w.); and (iii) continuous maintenance treatment with adalimumab 40 mg every week. At/after week 12, patients receiving placebo with flare or non-response could re-initiate open-label adalimumab 40 mg e.o.w., and patients receiving continuous blinded adalimumab therapy could switch to open-label 40 mg e.o.w. Patients in all groups could switch to weekly therapy with continued flare/non-response. In the previously published primary analysis, results for only those patients who had responded at week 4 (decrease in Crohn’s Disease Activity Index (CDAI) of greater than or equal to 70 points, referred to as “randomized responders”) and remained on blinded therapy were analyzed. In this analysis, data from all randomized patients were analyzed based on original randomized treatment using an intention-to-treat analysis, regardless of whether they subsequently switched to open-label therapy. Disease activity, clinical remission, number of flares, Inflammatory Bowel Disease Questionnaire (IBDQ) score, number of Crohn’s disease-related surgeries, and hospitalization incidence were compared between the continuous and induction only/reinitiation adalimumab groups. Results for all outcome measures were superior for both continuous groups compared with the induction only/re-initiation group. On the basis of median CDAI and IBDQ results, patients in both continuous treatment groups achieved statistically significantly greater improvements versus the induction only/re-initiation group (p < 0.05). At week 56, a significantly greater percentage of patients who had received continuous adalimumab (51 % for e.o.w. and 49 % for weekly) were in clinical remission versus the induction only/re-initiation group (38 %, p < 0.05). Continuous adalimumab therapy was also associated with fewer flares and fewer Crohn’s disease-related surgeries (p < 0.05). Patients in both continuous adalimumab groups had significantly lower risks of Crohn’s disease-related and all-cause hospitalizations than did patients in the induction only/re-initiation group (p < 0.05). The authors concluded that for patients with active Crohn’s disease, continuous treatment with adalimumab was more effective than a strategy of induction dosing followed by re-initiation of adalimumab with clinical deterioration for maintenance of clinical remission, improved quality-of life outcomes, reduced flares, and a decrease in number of surgeries and risk of hospitalization.

Adalimumab has been approved by the FDA for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis (JIA) in patients four years of age and older. In the United States, JIA is commonly referred to as juvenile rheumatoid arthritis (JRA). JIA is the most common chronic rheumatic disease in children with onset before age 16. Typical symptoms include stiffness when awakening, limping, and joint swelling. Any joint can be affected and inflammation may limit the mobility of the affected joints. Polyarticular JIA is a form of arthritis affecting 5 or more joints, usually in a symmetrical fashion. While it was once believed that most children eventually outgrow JIA, it is now known that between 25 and 70 percent of children with JIA will still have active disease into adulthood.

The approval of adalimumab for JIA was based on the results of a 48-week study and a subsequent open-label extension evaluating the efficacy and safety of adalimumab in children with JIA. The 48-week Phase III study included 171 children (four to 17 years of age) with polyarticular JIA. In the first part of this study, two groups of children – those taking methotrexate (MTX) and those not taking MTX – received open-label adalimumab (up to a maximum of 40 mg) every other week for 16 weeks. Patient responses were measured using the American College of Rheumatology Pediatric (ACR Pedi) 30 score, which represents a 30% or greater improvement in JIA signs and symptoms. Children who showed a positive clinical response (n= 133) entered the second part of the study and were randomized to receive adalimumab or placebo for an additional 32 weeks or until disease flare. A flare was defined as a worsening of 30% or more in at least three of the six ACR Pedi response variables, a minimum of two active joints, and no more than one indicator improving by 30%.In the second part of this study, significantly fewer children receiving adalimumab demonstrated disease flare compared to children on placebo, both without MTX (43% versus 71%) and with MTX (37% versus 65%). Additionally, more children treated with adalimumab continued to show ACR Pedi 30/50/70 responses at week 48 compared to placebo. At the conclusion of the 48-week study or at the time of disease flare during the double-blind phase, children could enter the open-label extension period. Efficacy and safety were assessed at routine intervals throughout the study. ACR Pedi responses were maintained for up to two years in children who received adalimumab throughout the study. Upon initiation of treatment with adalimumab, the most common adverse reactions that occurred were injection site pain and injection site reaction (19% and 16%, respectively). In general, adverse reactions in children were similar in frequency and type to those seen in adult patients. Severe adverse reactions reported in the clinical trial in JIA included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia and appendicitis. Serious infections were observed in 4% of children within approximately two years of initiation of treatment with adalimumab and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. Recommended dosing in JIA is based upon weight. For children 15 kg (33 lbs) to less than 30 kg (< 66 lbs), recommended dose is 20 mg by injection every other week. For children 30 kg (66 lbs) and greater, recommended dose is 40 mg by injection every other week.

Adalimumab has been approved by the FDA for the treatment for adults with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate.  According to the FDA-approved labeling, adalimumab should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician. Chronic plaque psoriasis is an autoimmune disease characterized by inflammed, scaly skin lesions known as plaques, which may crack and bleed. While psoriasis can occur in people of all ages, it typically appears in patients between the ages of 15 and 35 years. Approximately 25% of persons with chronic plaque psoriasis exhibit moderate to severe disease. Up to 30 percent of psoriasis patients develop psoriatic arthritis. Treatment may include topical agents, phototherapy or oral or injectable medications.

The FDA approval of adalimumab for chronic plaque psoriasis was based on two pivotal trials, REVEAL and CHAMPION, showing that approximately 3 out of 4 patients achieved 75% clearance or better at week 16 of treatment versus placebo. Both studies evaluated the efficacy and safety of HUMIRA in clearing skin in moderate to severe adult plaque psoriasis patients versus placebo. In addition, CHAMPION compared a biologic medication to methotrexate, a standard systemic treatment for psoriasis.  In each trial, reduction in disease activity was determined by the Psoriasis Area and Severity Index (PASI) and Physician’s Global Assessment (PGA).  In REVEAL, a 52-week trial, the short-term and sustained clinical efficacy and safety of adalimumab were evaluated in 1212 patients with moderate to severe chronic plaque psoriasis. Patients experienced a significant reduction in the signs and symptoms of their disease at 16 weeks when treated with adalimumab. Specifically, 71% of patients receiving adalimumab achieved PASI 75 compared to 7% of patients receiving placebo at week 16.  At week 16, 62% of adalimumab-treated patients achieved a PGA score of clear or minimal compared to 4% of placebo-treated patients. In CHAMPION, a 16-week study evaluating 271 psoriasis patients, adalimumab-treated patients experienced a significant reduction in the signs and symptoms of their disease compared with methotrexate or placebo-treated patients. Seventy-eight percent of patients treated with adalimumab (n=99) achieved a PASI 75 response, compared to 19% of patients treated with placebo (n= 48).  Seventy-one percent of patients treated with adalimumab achieved a PGA score of clear or minimal at 16 weeks of treatment, compared with 10% of placebo-treated patients. The safety profile of adalimumab in the plaque psoriasis clinical trials was reported to be similar to that seen in adalimumab clinical trials for rheumatoid arthritis. The most commonly reported adverse events in adalimumab psoriasis trials were upper respiratory tract infection, nasopharyngitis (inflammation of the nose and pharynx), headache, sinusitis and arthralgia. In clinical studies of plaque psoriasis, patients are treated with an initial 80 mg dose of adalimumab (two 40 mg injections) followed by one adalimumab injection (40 mg) one week later. After that, a maintenance dose of 40 mg  was administered every other week.

Adalimumab has not been proven to be effective for ulcerative colitis. In an open-label study, Peyrin-Biroulet et al (2007) assessed the effectiveness of adalimumab induction therapy in patients with ulcerative colitis who previously responded to infliximab and then lost response or became intolerant. A total of 10 patients with ulcerative colitis were enrolled in a 4-week trial. Patients received a loading dose of 160 mg adalimumab at week 0 followed by 80 mg at week 2. The primary outcome measure was clinical improvement at week 4, as defined by a decrease in clinical activity index (CAI) of more than 4. Four of 10 patients (40 %) benefited from subsequent adalimumab therapy; 1 patient achieved remission (CAI less than 4) and 3 had clinical improvement at week 4. 6 patients had no response (60 %); 2 of 6 (33.3 %) subsequently underwent colectomy. This was accompanied by a decrease in median CRP concentration from 16.8 mg/ml at baseline to 3.85 mg/ml at week 4, excluding 2 patients who underwent colectomy after two infusions of adalimumab. Among the 6 patients with severe colitis (CAI greater than 12) at baseline, none achieved remission and only 1 patient had clinical improvement at week 4. The authors concluded that the small advantage of adalimumab in patients with mild to moderate ulcerative colitis and lost response or intolerance to infliximab needs to be confirmed in randomized, double-blind, placebo-controlled trials.  Furthermore, in a Cochrane review on TNF-alpha blocking agents for induction of remission in ulcerative colitis, Lawson et al (2006) did not mention the use of adalimumab.

In a pilot study (n = 12), Magnano et al (2007) examined if adalimumab can safely improve symptoms of erosive/inflammatory osteoarthritis (EOA).  Patients greater than 45 years of age with EOA of the hands defined by greater than or equal to 2 tender and greater than or equal to 2 swollen joints (distal inter-phalangeal, proximal inter-phalangeal, first carpo-metacarpal) despite non-steroidal anti-inflammatory drug therapy were eligible.  Patients were excluded for autoimmune arthritis, recent disease modifying anti-rheumatic drug use, prior use of anti-TNF therapy, infection, malignancy, or poorly controlled medical conditions.  All patients received adalimumab 40 mg every other week for 12 weeks.  Safety was assessed 4 weeks after the final dose.  Primary endpoints included safety and ACR response.  Patients were predominantly female with a mean age of 60 years and 12 years of arthritis.  All subjects completed the study and safety follow-up.  Adverse events were mild without necessitating discontinuation of study drug.  After 12 weeks, there was a statistically significant improvement in the number of swollen joints compared to baseline (p < 0.01).  One patient achieved an ACR20 response and 42 % achieved an OMERACT-OARSI response.  Although these investigators detected no statistically significant improvement in the number of tender joints, grip strength, disability, pain, or global disease assessments, trends suggested modest improvement in all efficacy measures.  The authors concluded that the findings of this small open-label study of patients with EOA demonstrated that adalimumab was well-tolerated.  Treatment with adalimumab for 3 months did not significantly improve the signs and symptoms of EOA and most patients did not achieve an ACR20.  Trends suggested improvement and individual patients had some benefit.  Factors limiting interpretation of this study include the lack of a control group, outcomes chosen, number of patients treated, and the duration of treatment.

Cutaneous sarcoidosis may be a chronic disease with important morbidity requiring aggressive therapy.  The effectiveness of different anti-TNF-α treatments in refractory cutaneous and systemic sarcoidosis has been reported previously.  Thielen et al (2009) reported the first patient with chronic cutaneous sarcoidosis who responded to dose escalation of anti-TNF-α agents that have been ineffective at the standard dosage, illustrating that the optimal dosing regimen has still to be defined for this indication before considering difficult-to-treat patients as non-responders.  This case report also illustrated that the fusion protein etanercept, even used at a high dosage, may be less effective for the treatment of cutaneous sarcoidosis than the monoclonal antibodies infliximab and adalimumab.

Patel (2009) stated that sarcoidosis is an inflammatory disorder characterized by the presence of non-caseating granulomas in affected organs.  The presence of CD4-positive T lymphocytes and macrophages in affected organs suggests an ongoing immune response.  Systemic corticosteroids remain the mainstay of treatment, but therapy is often limited by adverse effects.  This is the first report of the use of adalimumab in a patient with systemic sarcoidosis with bone marrow involvement.  The patient was a 42-year-old African-American man with a medical history significant for hypertension and diabetes mellitus presented with anemia and thrombocytopenia of 2-month duration.  He underwent physical examination, bone marrow aspiration and biopsy, chest X-ray, acid-fast bacilli stain, computed tomography with contrast, and additional laboratory tests; and was diagnosed with systemic sarcoidosis with splenomegaly and bone marrow involvement.  Drug therapy included prednisone, which had to be discontinued owing to adverse effects, and adalimumab.  The author concluded that this is the first report describing the use of adalimumab in a patient with systemic sarcoidosis with bone marrow involvement.  Tumor necrosis factor antagonism with adalimumab was effective and well-tolerated in this patient and may be considered as a treatment option for similar cases.

Antoniu (2010) noted that sarcoidosis is a granulomatous disease with various organ manifestations in which TNF-α has been demonstrated to play a major pathogenic role.  Conventional therapies are not always able to minimize TNF-α-driven inflammation and other approaches should be used.  The author reviewed TNF-α roles in sarcoid inflammation and granuloma formation based on the literature published in the last 20 years and the therapies able to target it specifically or non-specifically in sarcoidosis were discussed.  In some subsets of sarcoidosis with more rapid progession and/or therapeutic refractoriness TNF-α plays a more prominent role in disease pathogenesis, and its blockade might represent an appropriate therapeutic approach.

In a multi-center, double-blind, randomized, controlled trial, Genevay and colleagues (2010) evaluated the effectiveness of adalimumab in patients with radicular pain due to lumbar disc herniation.  Patients with acute (less than 12 weeks) and severe (Oswestry Disability index greater than 50) radicular leg pain and imaging-confirmed lumbar disc herniation were randomized to receive as adjuvant therapy either 2 subcutaneous injections of adalimumab (40 mg) at 7-day interval or matching placebo.  The primary outcome was leg pain, which was recorded every day for 10 days and at 6 weeks and 6 months based on a visual analog scale (0 to 100).  Of the 265 patients screened, 61 were enrolled (adalimumab = 31) and 4 were lost to follow-up.  Over time, the evolution of leg pain was more favorable in the adalimumab group than in the placebo group (p < 0.001).  However, the effect size was relatively small and at last follow-up the difference was 13.8 (95 % confidence interval; -11.5 to 39.0).  In the adalimumab group, twice as many patients fulfilled the criteria for “responders” and for “low residual disease impact” (p < 0.05) and fewer surgical discectomies were performed (6 versus 13, p = 0.04).  The authors concluded that the addition of a short course of adalimumab to the treatment regimen of patients suffering from acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures.  Limitations of this study include small sample sizes, inability to determine the sufficient dose and best route of administration for TNF-α inhibitors in radiculopathy because of disk herniation, or to identify subgroups of patients most likely to respond to this treatment.  More studies are needed to ascertain the adequate dose and the best route of administration of TNF-α inhibitors, elucidating the effective therapeutic role of TNF-α inhibitors in this disease and determining the dosage, times and route of administration, as well as evaluating the possible occurrence of harmful events, as serious infections or adverse cardiovascular events, as seen in patients with rheumatoid arthritis treated with biological drugs.

The FDA-approved product labeling for Humira includes a black box warning about the risk of serious infections with adalimumab. The labeling states that patients treated with Humira are at increased risk of developing serious infections that may lead to hospitalizations or death. Most patients who developed these infections were taking concomitant immunosuppresents such as methotrexate or corticosteroids. The labeling states that Humira should be discontinued if a patient develops a serious infection or sepsis.

The labeling states that tuberculosis (TB), invasive fungal infections, and other opportunistic infections, have been observed in patients receiving adallimumab. The labeling notes that some of these infections have been fatal.

Active tuberculosis including reactivation of latent tuberculosis has been reported in patients taking Humira. Patients with tuberculosis have frequently presented with disseminated or extrapulmonary disease. Anti-TB treatment of patients with latent TB infection reduces the risk of reactivation in patients receiving adalimumab. However, active TB has developed in patients receiving adalimumab whose screening for latent TB infection was negative. The labeling recommends that patients should be evaluated for TB risk factors and be tested for latent TB prior to initiationg adalimumab and during therapy. According to the product labeling, when TB skin testing is performed, an induration size of 5 mm or greater should be considered positive, even if the patient was previously vaccinated with Bacille Calmette-Guerin (BCG). Treatment of latent TB should be initiated prior to therapy with adalimumab. The labeling recommends that physicians should monitor patients receiving adalimumab for signs and symptoms of active TB, including patients who tested negative for latent TB.

Invasive fungal infections, including histoplasmosis, coccidiodomyocosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis, have been reported in patients taking Humira. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. The labeling states that empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness.

Bacterial, viral and other infections due to opportunistic infections have been reported. The labeling recommends that the risks and benefits of treatment with Humira should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Humira, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

The labeling states that cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Humira has not been formally studied in patients with CHF; however, in clinical studies in CHF of another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. The labeling recommends to exercise caution when using Humira in patients who have heart failure, and to monitor patients with heart failure carefully.

Appendix

Information about the Psoriasis Area and Severity Index (PASI) and the Physicians’ Global Assessment (PGA) is available from the following reference (Feldman & Krueger, 2005): http://ard.bmj.com/cgi/content/full/64/suppl_2/ii65

 
CPT Codes / HCPCS Codes / ICD-9 Codes
HCPCS codes covered if selection criteria are met:
J0135 Injection, adalimumab, 20 mg
S9359 Home infusion therapy, anti-tumor necrosis factor intravenous therapy; (e.g., Infliximab); administrative services, professional pharmacy services, care coordination, and all necessary supplies and equipment (drugs and nursing visits coded separately), per diem
Other HCPCS codes related to the CPB:
J1438 Injection, etanercept, 25 mg (code may be used for Medicare when drug administered under the direct supervision of a physician, not for use when drug is self-administered)
J1600 Injection, gold sodium thiolamate, up to 50 mg
J1745 Injection, infliximab, 10 mg
J7500 Azathioprine, oral, 50 mg
J7501 Azathioprine, parenteral, 100 mg
J7502 Cyclosporine, oral, 100mg
J7515 Cyclosporine, oral, 25 mg
J7516 Cyclosporine, parenteral, 250 mg
J8530 Cyclophosphamide; oral, 25 mg
J8610 Methotrexate; oral, 2.5 mg
J9070 Cyclophosphamide, 100 mg
J9250 Methotrexate sodium, 5 mg
J9260 Methotrexate sodium, 50 mg
ICD-9 codes covered if selection criteria are met:
555.0 – 555.9 Regional enteritis [active Crohn’s disease with listed manifestations]
696.0 Psoriatic arthropathy [moderately to severely active in adults and failed two or more nonbiologic DMARDS]
696.1 Other psoriasis [moderate to severe chronic plaque psoriasis]
714.0 – 714.2 Rheumatoid arthritis [moderately to severely active in adults]
714.30 – 714.33 Juvenile chronic polyarthritis [severely active]
720.0 Ankylosing spondylitis [active and failed two or more NSAIDS]
ICD-9 codes not covered for indications listed in the CPB (not all-inclusive):
001.0 – 139.8 Infectious and parasitic diseases [active]
363.00 – 363.22 Focal chorioretinitis and focal retinochoroiditis, and other and unspecified forms of chorioretinitis and focal retinochoroiditis
364.00 – 364.3 Acute and subacute iridocyclitis, chronic iridocyclitis, certain types of iridocyclitis,, and unspecified iridocyclitis
376.01 Orbital cellulitis
493.00 – 493.92 Asthma
528.3 Cellulitis and abscess of oral soft tissues, excluding lesions specific for gingiva and tongue
556.0 – 556.9 Ulcerative colitis
629.81 Habitual aborter without current pregnancy
634.00 – 634.92 Spontaneous abortion
646.30 – 646.31
646.33
Habitual aborter
681.00 – 681.9 Cellulitis and abscess of finger and toe
682.0 – 682.9 Other cellulitis and abscess
696.1 Other psoriasis and similar disorders [guttate]
715.00 – 715.99 Osteoarthritis and allied disorders
724.3 Sciatica
733.99 Other disorders of bone and cartilage [relapsing polychondritis]
V13.21 Personal history of pre-term labor
V23.41 Pregnancy with history of pre-term labor
V23.49 Pregnancy with other poor obstetric history
Other ICD-9 codes related to the CPB:
560.9 Unspecified intestinal obstruction [with active Crohn’s disease]
569.81 Other specified disorders of intestine [fistula or megacolon with active Crohn’s disease]
713.1 Arthropathy associated with gastrointestinal conditions other than infections [with active Crohn’s disease]

The above policy is based on the following references:

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  2. Den Broeder AA, Creemers MC, van Gestel AM, van Riel PL. Dose titration using the Disease Activity Score (DAS28) in rheumatoid arthritis patients treated with anti-TNF-alpha. Rheumatology (Oxford). 2002;41(6):638-642.
  3. den Broeder AA, Joosten LA, Saxne T, et al. Long term anti-tumour necrosis factor alpha monotherapy in rheumatoid arthritis: Effect on radiological course and prognostic value of markers of cartilage turnover and endothelial activation. Ann Rheum Dis. 2002;61(4):311-318.
  4. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial. Arthritis Rheum. 2003;48(1):35-45.
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  25. Russo C, Polosa R. TNF-alpha as a promising therapeutic target in chronic asthma: A lesson from rheumatoid arthritis. Clin Sci (Lond). 2005;109(2):135-142.
  26. De Keyser F, Van den Bosch F, Mielants H. Anti-TNF-alpha therapy in ankylosing spondylitis. Cytokine. 2006;33(5):294-298.
  27. Haibel H, Rudwaleit M, Brandt HC, et al.  Adalimumab reduces spinal symptoms in active ankylosing spondylitis: Clinical and magnetic resonance imaging results of a fifty-two-week open-label trial. Arthritis Rheum. 2006;54(2):678-681.
  28. Abbott Laboratories. Abbott’s Humira (adalimumab) receives FDA approval for treatment of ankylosing spondylitis. Press Release. Abbott Park, IL: Abbott; July 31, 2006. Available at: http://www.abbott.com/global/url/pressRelease/en_US/60.5:5/ Press_Release_0340.htm. Accessed September 1, 2006.
  29. British Society for Rheumatology (BSR). British Society for Rheumatology (BSR) Statement on Adalimumab for Ankylosing Spondylitis. London, UK: BSR; August 2006.
  30. National Horizon Scanning Centre (NHSC). Adalimumab (Humira) for moderate to severely active Crohn’s disease – horizon scanning review. Birmingham, UK: NHSC; 2005.
  31. National Horizon Scanning Centre (NHSC). Adalimumab (Humira) for moderate to severe chronic plaque psoriasis – horizon scanning review. Birmingham, UK: NHSC; 2006.
  32. Pichon Riviere A, Augustovski F, Alcaraz A, et al. Etanercept, infliximab and adalimumab for the treatment of rheumatoid arthritis [summary]. Report IRR No. 79. Buenos Aires, Argentina; Institute for Clinical Effectiveness and Health Policy (IECS); 2006.
  33. Colombel JF, Sandborn WJ, Rutgeerts P,et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn’sdDisease: The CHARM Trial. Gastroenterology. 2007;132(1):52-65.
  34. Chen Y-F, Jobanputra P, Barton P, et al. A systematic review of the effectiveness of adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis in adults and an economic evaluation of their cost-effectiveness. Health Technol Assess. 2006;10(42):1-248.
  35. National Horizon Scanning Centre (NHSC). Adalimumab (Humira) for juvenile idiopathic arthritis: Horizon Scanning Technology Briefing. Birmingham, UK: NHSC; 2007.
  36. Lawson MM, Thomas AG, Akobeng AK. Tumour necrosis factor alpha blocking agents for induction of remission in ulcerative colitis. Cochrane Database Syst Rev. 2006;(3):CD005112.
  37. U.S. Food and Drug Administration (FDA). FDA approves new treatment for Crohn’s disease. FDA News. Rockville, MD: FDA; February 27, 2007. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01572.html. Accessed September 13, 2007.
  38. Peyrin-Biroulet L, Laclotte C, Roblin X, Bigard MA. Adalimumab induction therapy for ulcerative colitis with intolerance or lost response to infliximab: An open-label study. World J Gastroenterol. 2007;13(16):2328-2332.
  39. McLeod C, Bagust A, Boland A, et al. Adalimumab, etanercept and infliximab for the treatment of ankylosing spondylitis: A systematic review and economic evaluation. Health Technol Assess. 2007;11(28):1-158
  40. Boudreau R, Blackhouse G, Goeree R, Mierzwinski-Urban M. Adalimumab, alefacept, efalizumab, etanercept, and infliximab for severe psoriasis vulgaris in adults: Budget impact analysis and review of comparative clinical- and cost-effectiveness. Technology Report No. 97. Ottawa, ON: Canadian Agency for Drugs and Technologies in Health (CADTH); 2007.
  41. Behm BW, Bickston SJ. Tumor necrosis factor-alpha antibody for maintenace of remission in Crohn’s disease. Cochrane Database Syst Rev. 2008;(1):CD006893.
  42. Abbott Laboratories. Abbott receives FDA approval for Humira (adalimumab) for polyarticular juvenile idiopathic arthritis. Press Release. Abbott Park, IL: Abbott Laboratories: February 22, 2008.
  43. Abbott Laboratories. Abbott’s Humira (adalimumab) receives FDA approval for moderate to severe chronic plaque psoriasis. Press Release. Abbott Park, IL: Abbott Laboratories; January 18, 2008.
  44. Abbott Laboratories. Humira (adalimumab) injection, solution for subcutaneous use. Prescribing Information. Abbott Park, IL: Abbott Laboratories; revised February 2008. Available at: http://www.rxabbott.com/pdf/humira.pdf. Accessed February 26, 2008.
  45. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: A randomized, controlled phase III trial. J Am Acad Dermatol. 2008;58(1):106-115.
  46. Revicki D, Willan MK, Saurat JH, et al. Impact of adalimumab treatment on health-related quality of life and other patient-reported outcomes: Results from a 16-week randomized controlled trial in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2008;158(3):549-557.
  47. Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 2005;64:ii65-ii68. Available at: http://ard.bmj.com/cgi/content/full/64/suppl_2/ii65. Accessed March 7, 2008.
  48. Magnano MD, Chakravarty EF, Broudy C, et al. A pilot study of tumor necrosis factor inhibition in erosive/inflammatory osteoarthritis of the hands. J Rheumatol. 2007;34(6):1323-1327.
  49. Seymour MW, Home DM, Williams RO, Allard SA. Prolonged response to anti-tumour necrosis factor treatment with adalimumab (Humira) in relapsing polychondritis complicated by aortitis. Rheumatology (Oxford). 2007;46(11):1738-1739.
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  51. National Institute for Health and Clinical Excellence (NICE). Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis. NICE Technology Appraisal Guidance 130. London, UK: NICE; October 2007.
  52. Pichon-Riviere A, Augustovski F, Garcia Marti S, et al. Etanercept, infliximab and adalimumab for the treatment of rheumatoid arthritis [summary]. IRR No. 148. Buenos Aires, Argentina: Institute for Clinical Effectiveness and Health Policy (IECS); 2008.
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  57. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Comparison of two adalimumab treatment schedule strategies for moderate-to-severe Crohn’s disease: Results from the CHARM trial. Am J Gastroenterol. 2009;104(5):1170-1179.
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Data from: http://www.aetna.com/cpb/medical/data/600_699/0655.html