Topical Immunomodulator Step Therapy Program

Topical Immunomodulator Step Therapy Program Policy Number: 5.01.557 Last Review: 8/2017 Origination: 7/2013 Next Review: 8/2018 Policy Blue Cross and Blue Shield of Kansas City (Blue KC) BCBSKC will provide coverage for topical immunomodulators when the following criteria are met. The topical immunomodulators affected are: Elidel (pimecrolimus cream) Protopic (tacrolimus ointment) Generic tacrolimus ointment When Policy Topic is covered This step therapy program has been developed to encourage the use of a topical corticosteroid (brand or generic) prior to pimecrolimus cream or tacrolimus ointment. If the step therapy rule is not met, coverage will be determined by prior authorization criteria. Automation: This program uses one topical steroid (brand or generic) in the previous 130 days as a surrogate marker. Step 1: topical corticosteroids (brand or generic) Step 2: tacrolimus ointment, Protopic, Elidel Criteria 1. If the patient has tried one prescription topical corticosteroid (brand or generic), then authorization for a Step 2 agent may be given. 2. Authorization for a Step 2 agent may be given if the patient has a dermatologic condition on or around the face, eyes/eyelids, axilla, or genitalia Topical corticosteroids may cause skin atrophy. The risk for this adverse event increases when these agents are used on thinner skin, in areas such as the face or skin folds. 5 Topical immunomodulators have not been found to cause skin atrophy. 1,5 The 2014 American Academy of Dermatology (AAD) Guidelines of Care for the Management of AD indicate that topical immunomodulators are effective for acute and chronic AD treatment, especially in patients with AD in sensitive areas (e.g., face, genitalia, skin folds), steroid-refractory AD, steroid-induced atrophy, or a history of long-term uninterrupted topical steroid use. 3. Authorization for a Step 2 agent may be given if the patient has steroid-induced rosacea. Preliminary reports indicate 7 to 10 days of therapy with topical tacrolimus (extemporaneously compounded) is effective for steroid-induced rosacea when combined with avoidance of all other topical therapy including topical corticosteroids. 10-11 In one small (n = 18), investigator-blind, split-face study, topical pimecrolimus (formulation not specified) was effective in treating steroid-induced rosacea. 12 In another small (n = 35), open-label study, topical pimecrolimus (formulation not specified) was effective

in treating steroid-induced rosacea. 13 The American Acne & Rosacea Society (AARS) consensus guidelines on the management of rosacea (2014) state that both tacrolimus ointment and Elidel cream have been used in the treatment of patients with steroid-induced rosacea. 14 When used in combination with steroid discontinuation, these agents have been observed to reduce erythema and other rosacea symptoms. 4. No other exceptions are recommended. When Policy Topic is not covered The use of topical immunomodulators is considered investigational for all other indications. Considerations Topical immunomodulators require prior authorization through the Clinical Pharmacy Department. This Blue Cross and Blue Shield of Kansas City policy Statement was developed using available resources such as, but not limited to: Food and Drug Administration (FDA) approvals, Facts and Comparisons, National specialty guidelines, Local medical policies of other health plans, Medicare (CMS), Local providers Description of Procedure or Service Atopic Dermatitis (AD) AD is a genetically transmitted, chronic inflammatory skin disease that affects 10% to 20% of children and 1% to 3% of adults. 1 Pruritis, scratching, and chronic and/or relapsing eczematous lesions are major hallmarks of the disease. In infants and young children, there is a characteristic pattern of involvement of the face, neck, and extensor skin surfaces. In older children and adults, the skin lesions often involve lichenification and are usually localized to the flexural folds of the extremities. The diagnosis of AD is based on clinical presentation rather than results of diagnostic testing. The effective management of AD involves a combination of trigger avoidance, measures to restore skin barrier function (e.g., emollients), and anti-inflammatory medications (e.g., topical corticosteroids, Protopic, and Elidel). Protopic and Elidel are topical calcineurin inhibitors (immunomodulators) indicated as second-line therapy for the short-term and non-continuous chronic treatment of AD in non-immunocompromised patients who have failed to respond adequately to other topical prescription treatments, or when those treatments are not advisable. 2-3 Protopic is indicated for moderate to severe AD while Elidel is indicated for mild to moderate AD. Protopic 0.03% ointment and Elidel are indicated in adults and children aged 2 years. Although there are data documenting the Protopic 0.1% strength s safety and efficacy in children, this product is not approved for use in pediatric patients. Neither Protopic nor Elidel are indicated for use in children < 2 years of age; however, both agents have been studied in this patient population. 1 Based on concerns of the potential carcinogenicity (skin cancer and lymphomas) that may be associated with using a topical immunomodulator continuously over a prolonged period of time, a Black Box Warning was added to Elidel and Protopic product labeling. 2-3 There have been no empirical data to date definitively linking Elidel and Protopic to an increased cancer risk in humans and a causal relationship has not been established. 2-5 A case-control study of nearly 300,000 patients with AD did not demonstrate an increased risk of lymphoma in patients who received therapy with a topical calcineurin inhibitor. 1 There are data in three different animal species which demonstrated that the risk of cancer increased as the amount of drug given increased and that immunosuppressant use in transplant patients has led to an increase in cancer incidence. 2-3 Data reviewed also included a small number of reports of cancers in children and adults. The Food and Drug Administration (FDA) Pediatric Advisory Committee expressed concern over the widespread off-label use of these agents as first-line treatment and in children 2 years of age. 6 The FDA emphasized that these agents should be used only as directed and as indicated and only after other eczema treatments have failed to work. The

prescribing information for both products was updated to clarify that these drugs are recommended for use as second-line therapy for the short-term and non-continuous treatment in nonimmunocompromised patients. Elidel and Protopic should be used for short periods of time and patients should use only the minimum amount necessary to control symptoms. Rationale According to the 2012 Joint Task Force (American Academy of Allergy, Asthma, and Immunology [AAAAI], the American College of Allergy, Asthma, and Immunology [ACAAI], and the Joint Council of Allergy, Asthma, and Immunology [JCAAI]) AD practice parameter, topical corticosteroids are appropriate for the vast majority of patients. 1 The 2014 American Academy of Dermatology (AAD) Guidelines of Care for the Management of AD also indicate that topical steroids are the mainstay of therapy for AD in both adults and children. 5 The intensity of management and treatment of AD is dictated by the severity of illness. 1 Clinicians should use a multifaceted approach that includes skin hydration, topical anti-inflammatory medications, antipruritic therapy, antibacterial measures, and elimination of exacerbating factors. Moisturizers should be recommended as first-line therapy. If AD is not controlled by moisturizers alone, a topical corticosteroid should be used. 1,5 Low-potency corticosteroids are recommended for maintenance therapy, while intermediate- and high-potency corticosteroids should be used for the treatment of exacerbation over short periods of time. 1 Potent fluorinated corticosteroids should not be used on the face, eyelids, genitalia, and intertriginous areas or in young infants; a low-potency corticosteroid preparation is generally recommended for these areas. Ultrahigh-potency corticosteroids should only be used for very short periods (1 to 2 weeks) and in nonfacial, non-skinfold areas. The Joint Task Force guidelines note that Protopic should be considered for AD that is unresponsive to low-potency topical steroids. 1 Protopic, unlike topical glucocorticoids, is not atrophogenic and has a greater therapeutic margin of safety than medium-strength corticosteroids for facial and eyelid eczema. Studies have demonstrated that Protopic 0.1% ointment has the strength of a mid-potency topical corticosteroid and should be considered first-line therapy for facial eczema where treatment with corticosteroids is limited to low-potency corticosteroids due to safety concerns. According to guidelines, Elidel decreases the number of AD flares, reduces the need for corticosteroids, does not cause skin atrophy, and controls pruritus. The AAD guidelines also confirm that the topical immunomodulators are effective for acute and chronic AD treatment, especially in patients with steroidrefractory AD, AD in sensitive areas (e.g., face, genitalia, skin folds), steroid-induced atrophy, and longterm uninterrupted topical steroid use. 5 Furthermore, the AAD guidelines recommend intermittent use of a topical immunomodulator as maintenance therapy (two to three times per week) to help prevent relapses in areas that commonly flare. In this setting, the topical immunomodulators are more effective treatment than emollients alone and also reduce the need for topical corticosteroids. Off-Label Use There is widespread off-label use of the topical immunomodulators in several dermatologic conditions. In these conditions, topical immunomodulators are used when patients have failed standard therapy or in patients with contraindications to standard therapy agents. Data on the use of the topical immunomodulators are available in patients with lichen planus, cutaneous lupus erythematosus (CLE), psoriasis, and vitiligo, as well as numerous other rare dermatologic conditions. 4,7-9 In these conditions, topical corticosteroids remain first line-therapy, with tacrolimus and Elidel utilized as second-line therapy when patients have failed primary treatment. References 1. Schneider L, Tilles S, Lio P, et al. Atopic dermatitis: a practice parameter update 2012. J Allergy Clin Immunol. 2013;131:295-299. 2. Elidel cream [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals North American LLC; March 2014. 3. Protopic ointment [prescribing information]. Northbrook, IL: Astellas Pharma US, Inc.; May 2012. 4. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis. J Am Acad Dermatol. 2009;60:643-659.

5. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis. Section 2: management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116-132. 6. FDA Talk Paper. FDA issues public health advisory informing health care providers of safety concerns associated with theuse of two eczema drugs, Elidel and Protopic. March 10, 2005. 7. Davari P, Hsiao HH, Fazel N. Mucosal lichen planus: an evidence-based treatment update. Am J Clin Dermatol 2014;15(3):181-195. 8. Winkelmann RR, Kim GK, Del Rosso JQ. Treatment of cutaneous lupus erythematosus: review and assessment of treatment benefits based on Oxford Centre for Evidence-Based Medicine criteria. J Clin Aesthet Dermatol. 2013;6(1):27-38. 9. Taieb A, Alomar A, Bohm M, et al. Guidelines for the management of vitiligo. The European Dermatology Forum consensus. Brit J Dermatol. 2013;168(1):5-19. 10. Ruzicka T, Assmann T, Lebwohl M. Potential future dermatological indications for tacrolimus ointment. Eur J Dermatol. 2003;13:331-342. 11. Goldman D. Tacrolimus ointment for the treatment of steroid-induced rosacea: a preliminary report. J Am Acad Dermatol. 2001;44:995-998. 12. Lee DH, Li K, Suh DH. Pimecrolimus 1% cream for the treatment of steroid-induced rosacea: an 8-week split-face clinical trial. Br J Dermatol. 2008;158(5):1069-1076. 13. Chu CY. An open-label pilot study to evaluate the safety and efficacy of topically applied pimecrolimus cream for the treatment of steroid-induced rosacea-like eruption. J Eur Acad Dermatol Venereol. 2007;21:484-490. 14. Del Rosso JQ, Thiboutot D, Gallo R. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 5: a guide on the management of rosacea. Cutis. 2014;93(3):134-8. Other References Utilized Siegfried EC, Jaworski JC, Hebert AA. Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice. Am J Clin Dermatol. 2013;14:163-178. Billing Coding/Physician Documentation Information Topical immunomodulators are considered a pharmacy benefit Additional Policy Key Words Policy Number: 5.01.557 Policy Implementation/Update Information 08/2013 New Policy titled Topical Immunomodulator Step Therapy Program 08/2015 Annual Review- updated References; no changes in policy statement 12/2015 Added generic tacrolimus ointment 08/2016 Annual Review- updated References; no changes in policy statement 08/2017 Annual review- no changes to policy statement State and Federal mandates and health plan contract language, including specific provisions/exclusions, take precedence over Medical Policy and must be considered first in determining eligibility for coverage. The medical policies contained herein are for informational purposes. The

medical policies do not constitute medical advice or medical care. Treating health care providers are independent contractors and are neither employees nor agents Blue KC and are solely responsible for diagnosis, treatment and medical advice. No part of this publication may be reproduced, stored in a retrieval system or transmitted, in any form or by any means, electronic, photocopying, or otherwise, without permission from Blue KC.