Atopic Dermatitis: Clinical Refresh

In this issue: Atopic Dermatitis: Clinical Refresh Asthma Zero Albuterol Refills: 200 Puffs is Enough Safety of Tricyclic Antidepressants in Older Adults Skeletal Muscle Relaxant Quantity Limits FAQ Pharmacy News is produced quarterly for contracted network clinicians and is published under Pharmacy Web pages on MyGroupHealth for Providers. Access the site on onehealthport.com or at kp.org/wa/provider. Feel free to share the newsletter with colleagues. If you would like to be notified when the newsletter is published, or for more information about the articles, contact a Kaiser Permanente Clinical Pharmacist at 509-241-7572 or e mail: goertzen.g@ghc.org. Atopic Dermatitis: Clinical Refresh By Mark Maeda, PharmD Candidate; Edited by Galen Goertzen, PharmD, BCACP Key Points: Atopic dermatitis (AD) is a chronic skin condition that is relatively common and can have a large effect on the quality of life of affected children and adults. The majority of patients with AD will respond to topical therapies such as topical steroids or calcineurin inhibitors (CNIs - tacrolimus and pimecrolimus). Two new agents have recently been released for the treatment of AD: o Crisaborole (Eucrisa TM ) is an expensive topical agent used in the treatment of mild to moderate AD in children and adults. o Dupilumab (Dupixent ) is an extremely expensive injectable medication used in the treatment of moderate to severe AD unresponsive to other agents. Background Atopic dermatitis (or eczema) is a chronic, relapsing, pruritic inflammatory skin disease that affects up to 20% of children and 3% of adults. Dry skin and severe pruritus are the cardinal signs of AD, but the clinical presentation is highly variable. Most patients have a mild course of disease that resolves prior to adulthood. However, a small subset of patients develop severe disease, with widespread lesions that can affect sleep patterns, cause emotional and physical distress, and greatly affect a patient s quality of life. First line therapies recommended for all patients include emollients, topical 1

corticosteroids and/or topical immunomodulators such as topical tacrolimus or pimecrolimus. The vast majority of patients will respond adequately to one of these medications. Systemic therapies, such as cyclosporine, azathioprine, mycophenolate mofetil, and methotrexate have weak evidence supporting their use in severe disease in adults. New Drug Approvals Crisaborole (Eucrisa TM ) Crisaborole is a phosphodiesterase (PDE-4) inhibitor for the treatment of mild to moderate AD. It is a topical ointment applied twice daily and approved for adults and children age 2 and over. It was compared to vehicle in two randomized controlled trials (AD 301 and AD 302) with an endpoint of reducing the Investigator s Static Global Assessment (ISGA) to 0 or 1 AND a reduction of at least two points on a 5 (0-4) point scale. The ISGA tool helps a clinician objectively determine the extent of disease by estimating the percent of body surface area affected as well as assessing the level of erythema, lichenification, edema, and other clinical markers of disease. Crisaborole showed a statistical advantage in achieving this endpoint compared to vehicle (AD 301: 32.8% vs. 25.4%, p = 0.038; AD 302: 31.4% vs. 18.0%, p < 0.001). Crisaborole appears to have an improved short term safety profile when compared to topical corticosteroids and calcineurin inhibitors based on cross trial comparisons. No direct comparisons are available. The most common adverse event and the only one seen in greater than 1% of patients was application site pain. Long term safety is unknown. Place in therapy: Crisaborole seems to be a safe and generally effective product for mild to moderate atopic dermatitis for any patient above the age of two. However, it is approximately ten times as expensive as preferred first line agents such as topical steroids and calcineurin inhibitors so it should be used only in patients who truly cannot tolerate those medications. Coverage criteria: Trial and failure of, or intolerance to a high potency topical steroid (except in sensitive areas such as face or skin folds where low potency steroids are sufficient) AND a topical calcineurin inhibitor (CNI). Dupilumab (Dupixent ) Dupilumab is a human monoclonal antibody that inhibits interleukin-4 and interleukin-13 and is approved for the treatment of moderate to severe AD in adults age 18 and over 2

who have not responded or are not able to take other prescription therapies. It is an injectable product given subcutaneously 300mg every 2 weeks after a 600mg loading dose. Dupilumab was shown to be effective in two 16 week double blind, randomizedcontrolled trials. The primary efficacy endpoint (reduction of ISGA score of at least 2 points or to 0 on a 0-4 scale) was reached in 36-38% of dupilumab patients as compared to 8-10% of placebo patients (p < 0.001). In a 52 week trial 36% of patients treated with dupilumab plus topical corticosteroids (TCS) reached the endpoint compared to 13% with placebo plus TCS (p < 0.0001). Conjunctivitis and injection reaction site reactions occurred more frequently in dupilumab patients compared to placebo in both trials. No drug-related deaths occurred in either trial. Place in therapy: Dupilumab appears to be a very effective agent for the treatment of moderate to severe atopic dermatitis. But since it is a new agent with a new mechanism of action, no long term safety data, and is very expensive it should only be used in patients who have severe disease refractory to other treatments. These patients should be managed by Dermatology or Allergy. Coverage criteria: Documented moderate to severe AD using a validated assessment tool (ISGA, EASI, POEM, or SCORAD) in patients who have had an adequate trial of phototherapy, high potency steroids, topical CNIs and at least one systemic therapy. Table 1. New drug approvals for the treatment of atopic dermatitis (AD) Dosage Form Indication Directions Crisaborole (Eucrisa TM ) Dupilumab (Dupixent ) Topical Ointment 2% (60 g) Mild-Moderate AD Patients 2 years of age Apply a thin layer of crisaborole twice daily to affected areas. Cost 1 tube: $600 ~$38,000 per year *GoodRx.com as of 10/4/17 Subcutaneous Injection 300 mg/2 ml (2 ml) Moderate-Severe AD Patients 18 years of age Initial dose of 600 mg (two 300 mg injections), then 300 mg given every other week. 3

Conclusion For the first time in 15 years we have new agents for the treatment of atopic dermatitis, a disease which can have significant effects on the quality of life of some patients. Both crisaborole and dupilumab appear to be safe and effective and will provide additional options for patients who don t respond or can t tolerate currently available medications. Dupilumab, particularly, may be able to fill a niche in treating patients with severe disease, which can be disabling to a very small subset of AD patients. Return to top of section Asthma Zero Albuterol Refills Endorsed by: Allergy & Asthma, Asthma Oversight Team, Clinical Improvement & Prevention, Pediatrics, Pharmacy, Primary Care, and Pulmonary Clinician FAQ 200 puffs is enough How many doses of medication are in a single canister of albuterol? Each albuterol inhaler contains 200 puffs. How much albuterol is needed in patients with well controlled asthma? Patients with well controlled asthma typically need to use albuterol twice a week or less. Thus, if one uses 2 puffs twice a week that translates to 16 puffs a month or 208 puffs a year. Throw in an asthma exacerbation or two a year and 2 canisters (400 puffs) are enough for well controlled asthmatics. What if my patient is using albuterol prior to exercise? Even here if they exercise all 7 days a week that s 14 puffs a week for exercise plus 4 puffs for asthma symptoms/week so 16 puffs per week. That translates into 72 puffs a month or 864 puffs per year. Thus, 5 canisters (1,000 puffs) should more than suffice even for the rare individual that works out 7 days a week. (But bear in mind, a lot of exercise induced asthma is either uncontrolled persistent asthma or it not asthma at all, e.g., dyspnea due to deconditioning as seen if BMI >30.) 4

What about my patient who needs extra canisters (for school, grandma s house, to keep in the gym bag, etc.)? If we take the exceptionally rare case of someone who exercises 7 days a week and pretreats every time and needs the extra inhaler, they would still only need 5 or 6 canisters per year. And this is a very rare situation. More commonly, 2-3 canisters per year would be adequate in the significant majority of cases, if their asthma is well controlled. Also note the current KPWA formulary quantity limit for albuterol allows patients to receive up to 3 canisters in 90 days before they exceed the health plan refill limit (plus 2 extra canisters per year if extra canisters are needed for different locations such as school). Why does it matter how much albuterol I prescribe to my patients? There is a substantial body of evidence that correlates overuse of albuterol with risk of ED/UC visits, admissions, and even death from asthma. If a patient is using too much albuterol they need help controlling their asthma or their asthma diagnosis needs to be reconsidered (given 30% of adult patients diagnosed with asthma do not actually have asthma). Is it really all that important to give ZERO refills for my asthma patients? In an ideal world, we could just give patients unlimited refills and rely on them to let us know when things get out of control, but we all know that isn t how things work. Limiting albuterol to zero refills is a crude but effective means to keep tabs on our asthma patients. This approach gives us a chance to intervene and help them regain control of their asthma or perhaps discover that they don t even have asthma. What if my patient can t afford to pay for controller meds? See if patients are eligible for the KPWA Medical Financial Assistance program, which covers medically necessary healthcare services, pharmacy services, and medical supplies, in patients whose household income is at or below 300% FPG (Federal Poverty Guidelines) or who have had unusually high medical expenses. Return to top of section Safety of Tricyclic Antidepressants (TCAs) in Older Adults By Beth Arnold, PharmD, BCPP Key Points: All TCAs, including nortriptyline & desipramine, are considered high risk medications in older adults. There is more evidence coming out about the safety of using TCAs in older adults. In older patients, TCAs are associated with memory problems, falls and constipation. 5

We are being consistent with guidelines and geriatric experts in minimizing TCA use in the older patient population. There may be individual patients where the benefits outweigh the risks or the patient has failed other alternatives. Our goal is to find the safest option for our older adults. Background In 2015, the American Geriatrics Society (AGS) updated the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. Prior to 2015, the secondary TCAs, nortriptyline & desipramine, were excluded from this list. However, in 2015, all TCAs were added to the list because they are all highly anticholinergic, sedating and can cause orthostatic hypotension. The Beers Committee rated this as a strong recommendation based upon high quality evidence. The exception is low dose doxepin ( 6 mg daily) for sleep. As a result of the Beers criteria update, NCQA added TCAs to the High Risk Medications (HRM) initiative. The TCAs now represent the largest portion of our prescribing on the HRM initiative. Evidence for Risks of TCAs in Older Adults The TCAs are included on the Beers list of drugs with strong anticholinergic properties. This list is based upon several published anticholinergic risk scales that evaluate in vitro or in vivo receptor binding. While nortriptyline and desipramine have less anticholinergic activity than other TCAs, they still have a substantial amount. There is mounting evidence that anticholinergic burden in patients over 65 years of age is linked to an increased risk of cognitive problems. In a prospective cohort study in France that followed cumulative anticholinergic use over 4 years, a 1.4 to 2-fold higher risk of cognitive decline was observed for those who continuously used anticholinergic drugs, but not for those who had discontinued use. The risk of incident dementia was also increased in continuous users compared to patients who discontinued use. In a second prospective cohort study that followed anticholinergic use over 2 years, cognitive decline was greater in patients taking anticholinergic drugs compared to those who were not. In addition, two-year mortality was also greater in patients taking anticholinergic drugs. In a third prospective cohort study with KPWA patients that followed cumulative anticholinergic use over 10 years, there was a trend for increased risk of dementia or Alzheimer s with increasing cumulative anticholinergic dose. There is also evidence that TCAs are associated with an increased risk for falls in patients over 60 years of age, which could potentially lead to fracture, cerebral hemorrhage and loss of independence. In a meta-analysis of studies, the odds ratio for one or more falls was 1.5 (95% CI 1.14-2). 6

Safer Alternatives There are several resources available with recommendations for alternatives to TCAs. There may be individuals where the benefits of continued therapy outweigh the risks or patients have failed other alternatives. In addition, there are certain indications that have limited treatment alternative options (fibromyalgia or GI indications) or the alternatives are also on the Beers list (urology indications). The goal is to find the safest option for our older members. HRM Chart Tool: Safer Alternatives TCA Alternatives: Neuropathic pain TCA Alternatives: Migraine prophylaxis KPWA Clinical Guidelines: Sleep disorders Depression Back pain Talking points for patients In older adults, TCAs are associated with memory problems, dry mouth, falls and constipation. There is more evidence coming out about the safety of using TCAs in older adults. We are being consistent with guidelines and geriatric experts in minimizing TCA use in the older population. Our goal is to find the safest option for our older adults. Return to top of section Skeletal Muscle Relaxant Quantity Limit Frequently Asked Questions What are the quantity limits for skeletal muscle relaxants (SMRs) and who do those limits apply to? The newly established quantity limits are as follows: Cyclobenzaprine 45 tablets per 180 days Methocarbamol 60 tablets for 180 days Orphenadrine 30 tablets per 180 days Metaxalone 60 tablets per 180 days Chlorzoxazone 60 tablets per 180 days These limits apply to all members in commercial (non-medicare) plans who are age 65 and greater. 7

Why are these quantity limits being put in place? SMRs are indicated for the short term relief of muscle spasm associated with acute, painful musculoskeletal conditions. There is data showing that they are efficacious in the short term 2-3 weeks maximum but there is no data showing that they are effective for chronic management of any musculoskeletal conditions. SMRs have strong sedative and anticholinergic effects which can lead to serious safety concerns in elderly patients. They are considered to be medications to avoid by the American Geriatric Association and the Beers criteria. Why is there a different quantity allowed for each SMR? The quantity limit for each drug is based on allowing a 15 day supply. For cyclobenzaprine, which is given every 8 hours or three times a day a 15 day supply would be 45 tablets. Methocarbamol is usually given four times daily or every 6 hours so 60 tablets are allowed for it. How do SMRs work? The term muscle relaxant is actually a misnomer since none of these medications actually have any kind of muscle relaxing effect. Although we don t know their exact mechanism of action, their effects seem to be mediated through their strong sedative action. What are the safety concerns with SMRs in patients over the age of 65? SMRs have very strong anticholinergic and sedative effects. These adverse reactions lead to an increased risk of fall and problematic cognitive effects. A retrospective study conducted by Kaiser Permanente of Southern California found that risk of injury leading to hospitalization, emergency department visit or urgent care visit was significantly increased in patients over the age of 65 who were taking SMRs compared to those who were not. When do these quantity limits take effect? New starts on SMRs implementation date is October 1 st, 2017 Patients established on chronic SMRs implementation date is January 1 st, 2018 Can patients pay cash for these medications if they so choose? If the physician chooses to continue to prescribe the medication and the patient chooses to pay cash (instead of using their pharmacy benefit) they will be allowed to do so. We would discourage this use due to the aforementioned safety concerns but will not block this use. Cyclobenzaprine and methocarbamol are not particularly expensive. Do you need to taper patients off of chronic skeletal muscle relaxants? Generally patients taking muscle relaxants do not need to be tapered off of their medication. (Tizanidine, baclofen & carisoprodol are exceptions to that rule.) However, if a patient has been taking an SMR consistently for a long period of time a gradual decrease over a period of a couple of weeks might make the patient more comfortable and less fearful. My patient has been taking an SMR for years now and has not had any problems. Why can t they continue? As people age they process and metabolize medications differently than they did when they were younger. Some of the changes you see might be gradual and subtle and not easily attributed to medications. Also, anticholinergic effects in particular can be cumulative, meaning the longer you take them the stronger the effects they cause, particularly on memory and cognition. One of the biggest concerns with SMRs and other medications with strong anticholinergic effects is that long term use seems to be associated with an increased risk of dementia and Alzheimer s. 8

Why do these quantity limits only apply to patients age 65 and over? As noted above, the sedative and anticholinergic effects seen with chronic muscle relaxant use can increase fall risk as well as risk of dementia. These problems are particularly problematic in older patients. Why isn t there similar quantity limits for tizanidine and baclofen? Are they safer options for older patients? There is no evidence to support the long-term use of tizanidine and baclofen for the treatment of low back pain or other common musculoskeletal conditions. Neither of these medications are listed as high risk medications by the Beers criteria, but both also have risks associated with their use, particularly in patients greater than age 65. The evidence for use of tizanidine and baclofen are limited to the treatment of spasticity due to spinal cord injury, including multiple sclerosis. Therefore, they are NOT recommended for long term treatment of low back pain, and should not be seen as a safer option than SMRs for treatment of common musculoskeletal conditions, particularly in patients greater than age 65. For more information on treating KPWA patients with lower back pain please refer to the Back Pain guideline on the KPWA provider website. Return to top of section References: 1. https://www.fda.gov/safety/medwatch/safetyinformation/safetyalertsforhumanmedicalproducts/ucm454 141.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery 2. https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm10614 8.htm 3. https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm10629 0.htm 4. https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadviso rycommittee/ucm383191 5. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or ibuprofen for arthritis. N Engl J Med. 2016; 375:2519-29. Doi:10.1056NEJMoa1611593 6. UpToDate: Atopic dermatitis (eczema): Pathogenesis, clinical manifestations, and diagnosis 7. Eucrisa [package insert]. Palo Alto, CA: Anacor Pharmaceuticals; 2016. 8. Dupilumab [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals/Sanofi-Aventis; March 2017. 9. Paller AS, Tom WL, Lebwohl MG et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol 2016;75:494-503 10. Simpson EL, Bieber T, Guttman-Yassky E. et al. Two phase 3 trials of Dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016;375(24):2235-2348 11. Blauvelt A, debruin-weller M, Gooderham M et al. Long term management of moderate-to-severe atopic dermatitis with Dupilumab and concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomized, double-blinded, placebo-controlled, phase 3 trial. Lancet 2017;389:2287-2303 12. AGS 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2015. DOI: 10.1111/jgs.13702. 13. Carriere I, Fourrier-Reglat A, et al. Drugs with anticholinergic properties, cognitive decline and dementia in an elderly general population. Arch Intern Med 2009;169(14):1317-1324. 9

14. Fox C, Richardson K, et al. Anticholinergic medication use and cognitive impairment in the older populations: the medical research council cognitive function and ageing study. J Am Geriatr Soc 2011. DOI: 10.1111/j.1532-5415.2011.03491.x 15. Gray et al. Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA Intern Med. 2015;175 (3):401-407. 16. Leipzig RM, Cumming RG, Tinetti ME. Drugs and falls in older people: a systematic review and metaanalysis: psychotropic drugs. J Am Geriatr Soc 1999;47(1):30-9. 17. Spence MM, Shin PJ, Lee EA, Gibbs NE. Risk of injury associated with skeletal muscle relaxant use in older adults. Ann Pharmacother 2013;47:993-8 10