ADHD Non-Stimulant Medications Step Therapy Program

ADHD Non-Stimulant Medications Step Therapy Program Policy Number: 5.01.596 Last Review: 7/2018 Origination: 07/2014 Next Review: 7/2019 LoB: ACA Policy Blue Cross and Blue Shield of Kansas City (Blue KC) will BCBSKC will provide coverage for brand name non-stimulant when the following criteria are met. The brand name medications affected are: Strattera (atomoxetine capsules Eli Lilly and Company) Intuniv (guanfacine extended-release tablets Shire Pharmaceuticals) Kapvay (clonidine hydrochloride extended-release tablets Shionogi Pharma, generics) When Policy Topic is covered A step therapy program has been developed to encourage use of a Step 1 product prior to a Step 2 product. If the step therapy rule is not met for a Step 2 agent at the point of service, coverage will be determined by the step therapy criteria below. All approvals are provided for 1 year in duration. Note: Generic guanfacine extended-release tablets and generic clonidine extended-release tablets are not included in either Step 1 or Step 2 of this program. Automation: This program looks back for one Step 1 medication in the previous 130 days. If criteria for use of one stimulant medication within the last 130 days (automated) are not met at the point of service, coverage will be determined by the step therapy criteria below. Step 1: generic atomoxetine capsules, stimulant medications (amphetamine and methylphenidate/dexmethylphenidate products) Amphetamines (Note: This is not an all inclusive list.) Amphetamine sulfate tablets (Evekeo ) Amphetamine extended-release orally disintegrating tablets (Adzenys XR-ODT ) Amphetamine extended-release oral suspension (Dyanavel XR, Adzenys ER ) Mixed amphetamine salts [dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine sulfate, amphetamine aspartate] immediate-release tablets (Adderall, generics)/ extended-release capsules (Adderall XR, generics) Dextroamphetamine immediate release tablets (Dexedrine, Zenzedi, generics)/sustained-release capsules (Dexedrine Spansules, generics) Dextroamphetamine sulfate oral solution (ProCentra, generics) Methamphetamine tablets (Desoxyn, generics) Lisdexamfetamine capsules (Vyvanse ) Methylphenidate/dexmethylphenidate (Note: This is not an all inclusive list.) methylphenidate extended-release tablets or capsules (Aptensio XR, Concerta, Metadate CD, Metadate ER, Ritalin LA, Ritalin-SR, generics) methylphenidate immediate release tablets, oral solution, and chewable tablets (Ritalin, Methylin, Methylin Chewable, generics) dexmethylphenidate immediate-release tablets (Focalin, generics)

dexmethylphenidate extended-release capsules (Focalin XR, generics) methylphenidate transdermal system (Daytrana ) methylphenidate extended-release oral suspension (Quillivant XR, QuilliChew ER ) Step 2: Strattera (brand), Intuniv (brand), Kapvay (brand) CRITERIA Exceptions for a Step 2 agent can be made for patients with one of the following conditions/situations: 1. If the patient has tried a Step 1 agent, then authorization for a Step 2 agent may be given. 2. No other exceptions are recommended. When Policy Topic is not covered The use of brand name non-stimulant medications is considered investigational for all other indications. Considerations ADHD non-stimulant medications 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 Attention-deficit hyperactivity disorder (ADHD) is a neurobehavioral disorder that typically begins in childhood and often persists into adulthood. 1 ADHD is characterized by developmentally inappropriate levels of inattention and hyperactivity resulting in functional impairment in academic, family, and social settings. ADHD is the most commonly diagnosed neurobehavioral disorder of childhood. Treatment The American Academy of Pediatrics (AAP) clinical practice guideline for the diagnosis, evaluation, and treatment of ADHD in children and adolescents (2011) indicate that stimulants have the most evidence for efficacy and safety in the treatment of ADHD, and remain the first choice of medication treatment. 2-3 Individuals may respond to one stimulant but not to another, and it cannot be predicted which stimulant will be best in an individual. Therefore, if a trial with one group is unsuccessful (poor efficacy or adverse events [AEs]), a trial on a medication from the other group should be undertaken. At least onehalf of the patients whose symptoms fail to respond to one stimulant medication may have a positive response to the alternative medication. The dose of medication should be titrated to achieve maximum benefit with minimum AEs. More than 70% of children and youth with ADHD respond to one of the stimulant medications at an optimal dose when a systematic trial is used. Titration to maximum doses that control symptoms without AEs is recommended instead of titration strictly on a mg-per-kg basis. The 2006 Texas Children s Medication Algorithm for the pharmacotherapy of ADHD 4 and the 2007 American Academy of Child and Adolescent Psychiatry (AACAP) ADHD treatment guidelines 5 recommend stimulants as first line treatment for ADHD followed by a trial of another stimulant if the first stimulant is not effective. 4-5 The Texas Children s Medication Algorithm 4 states that Strattera may be considered in patients after one stimulant trial if the patient experienced severe AEs. According the AACAP guidelines, if patients do not achieve satisfactory treatment response to stimulants or Strattera, use of other medications may be considered. 5 The guidelines indicate that alpha-agonists (guanfacine immediate-release, clonidine) are often used in the treatment of ADHD

even though they were not approved by the Food and Drug Administration (FDA) at the time of publication. However, alpha-agonists (along with other second-line agents) have effect sizes considerably less than those of the first-line agents and comparable with behavioral therapy. Alphaagonists are widely used for ADHD itself, for comorbid aggression, or to combat AEs such as tics or insomnia, although data are lacking. These guidelines also indicate that children with ADHD and a comorbid tic disorder, on average, show a decline in tics when treated with a stimulant. If a patient has treatment emergent tics during a trial of a stimulant, an alternative stimulant or a nonstimulant should be tried. If the patient s ADHD symptoms only respond to a stimulant that induces tics, adding an alpha-agonist is recommended. The Texas Children s Medication Algorithm states that for ADHD an alpha agonist may be used after a trial of two stimulants, Strattera (atomoxetine capsules), bupropion, and a tricyclic antidepressant (TCA). 4 Hence, alpha agonists are the last stage in the algorithm. For ADHD with comorbid tic disorders, stimulant monotherapy is still first-line therapy. However, if tics continue to impair, an alpha agonist may be added. Several stimulants are approved for the treatment of ADHD in adolescents, as well as adults. 6 Strattera is indicated for the treatment of ADHD in children 6 years of age, adolescents, and adults. 7 Limited data are available with Strattera in children < 6 years of age. 8 Overall, studies with Strattera in ADHD have been short term (about 3 to 10 weeks); a 12 month trial in children; an 18 month trial in children and adolescents; and a 97 week open-label study in adults have been published. 9-13 In contrast, the stimulants have been well studied, especially in children with ADHD, and their safety and efficacy for long-term therapy are well established. 14-15 Two alpha agonists are currently approved for the treatment of ADHD: Intuniv (guanfacine extendedrelease tablets) and Kapvay. Both of these agents are approved for use in children and adolescents aged 6 to 17 years. 16-17 No controlled studies have studied Intuniv or Kapvay in children < 6 years of age or adults. The effectiveness of Intuniv and Kapvay for longer-term use (more than 9 weeks and 5 weeks, respectively) has not been systematically evaluated in controlled trials. However, long-term efficacy of Intuniv was assessed in two 24-month open-label extension studies. 18-19 Rationale Comparative Efficacy Intuniv or Kapvay have not been compared to any of the stimulants in head-to-head studies. In total, there are six published studies 20-26 comparing Strattera to a stimulant. More well-designed studies are needed that directly compare Strattera to methylphenidate and amphetamine-type products. A review article (published in 2006) evaluated five of the head-to-head comparison studies between Strattera and stimulants. 21 Overall, there was no difference between Strattera and methylphenidate immediate-release in efficacy as measured by ADHD rating scale total score; methylphenidate osmotic oral release system (OROS) showed significantly greater improvement at Weeks 1 and 2 compared to Strattera and more patients treated with methylphenidate OROS were considered responders; and both Strattera and mixed amphetamine salts (MAS) extended-release (XR) showed significant improvements at endpoint; however, Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scores were significantly better with MAS XR. Tics/Tourette s Syndrome According to product labeling, methylphenidate is contraindicated in patients with motor tics or with a family history or diagnosis of Tourette s syndrome. 27 However, controlled trials have not found that methylphenidate worsens motor tics in children with ADHD with or without Tourette s syndrome. 14,28 In uncontrolled studies with Concerta (methylphenidate extended-release), the cumulative incidence of new onset of tics was 9% after 27 months in one study and 1% in a second study with a treatment period of up to 9 months. 27 In three controlled studies in children with ADHD, the percentage of patients experiencing tics was not significantly different between Concerta (4.0%), methylphenidate

three times daily (2.3%), and placebo (3.7%) [P = 0.5249]; none of the patients had Tourette s syndrome and those with mild or moderate tics could enroll. 29 Most patients who reported tics during the studies had a prior history of tics. According to product labeling, amphetamines may exacerbate motor and phonic tics and Tourette s syndrome. 30 In a review of seven studies that compared stimulants to placebo or with other medications, there was no increase in tics in children who received stimulants. 31 Studies that compared Strattera with placebo in ADHD did not specify whether patients with motor tics or with a family history or diagnosis of Tourette s syndrome were included or excluded. 32-36 One 18- week, randomized, double-blind, placebo-controlled study 38 enrolled 148 children with ADHD and concurrent Tourette syndrome or chronic motor tic disorder (of mostly mild to moderate severity). The primary objective of the study was to test the hypothesis that Strattera does not worsen tics (noninferiority study design). Both treatment groups decreased tic severity from baseline and Strattera was found to be non-inferior to placebo. In both open label trials that compared Strattera with methylphenidate as well as the controlled trial that compared Strattera with Adderall XR, patients with motor tics or a family history of Tourette s syndrome were excluded; motor and vocal tics were not reported as adverse events. 22-24 Tics are not included as an AE in the product labeling for Strattera. 7 However, there are case reports of children with ADHD who had developed tics on stimulant medications and in whom tics reappeared or were exacerbated on Strattera, 38 and case reports of worsening of tics with Strattera. 39 Practice guidelines for ADHD state that the effects of medication on tics is unpredictable, and the presence of tics before or during medical management of ADHD is not a contraindication to the use of stimulant drugs. 2,7 The 2007 AACAP ADHD treatment guidelines state that Strattera may be considered first-line medication for individuals with ADHD and tics. 2 In treating patients with ADHD and tic disorder, the 2006 Texas Children s Medication Algorithm for the pharmacotherapy of ADHD still recommends first line treatment with a stimulant. 5 However, if tics continue to impair, an alpha agonist may be added to stimulant therapy. Seizures According to a warning in the product labeling, amphetamine and methylphenidate may lower the seizure threshold in patients with a prior history of seizures, in patients with prior electroencephalogram (EEG) abnormalities in absence of seizures, and very rarely, in the absence of history of seizures and no prior EEG evidence of seizures. 27,30 Many studies have reported that methylphenidate is safe in children with active or well-controlled epilepsy and that methylphenidate does not increase the risk of developing seizures in children with ADHD. 40-43 Practice guidelines for ADHD also state that methylphenidate has not caused an increase in seizure frequency or severity when it is added to appropriate anticonvulsant medications. 14 Although amphetamine and methylphenidate are not contraindicated in children with pre-existing epilepsy, it is important to monitor seizure frequency when initiating therapy. 27,30 Strattera has not been systematically evaluated in controlled trials in patients with seizure disorders. During the clinical development program, seizures occurred in 0.2% of children (mean age 10 years). 7 Placebo-controlled efficacy and safety trials with Strattera excluded patients with a history of seizures 32,34 or other serious medical illnesses. 22,33,35-36 Seizures have been reported with Strattera in the postmarketing period. 7 The postmarketing seizure cases include patients with preexisting seizure disorders and those with identified risk factors for seizures, as well as patients with neither a history of nor identified risk factors for seizures. The exact relationship between Strattera and seizures is difficult to evaluate due to uncertainty about the background risk of seizures in patients with ADHD. Intuniv and Kapvay also have not been evaluated in controlled trials in patients with seizure disorders. During the clinical development programs for Intuniv and Kapvay there were no reports of seizures. 16-17 Cardiovascular (CV) In 2011, the FDA issued safety communications regarding medications used to treated ADHD (stimulants [methylphenidate and amphetamine products] and Strattera) and cardiovascular safety. 44-47 Based on large retrospective cohort studies, the FDA recommendations include: stimulant products

and Strattera should generally not be used in patients with serious heart problems, or for whom an increase in blood pressure or heart rate would be problematic; and, patients treated with ADHD medications should be periodically monitored for changes in heart rate or blood pressure. Methylphenidate products should generally not be used in children or adolescents with known serious structural cardiac abnormalities, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac problems due to reports of sudden cardiac death in association with stimulants. 27 Caution should be used in treating patients with methylphenidate who have underlying medical conditions that might be compromised by increases in blood pressure or heart rate (e.g., preexisting hypertension, heart failure, recent myocardial infarction, or ventricular arrhythmia). Amphetamines are contraindicated in patients with advanced arteriosclerosis, symptomatic CV disease, moderate to severe hypertension, and hyperthyroidism. 30 Strattera is contraindicated in patients with severe CV disorders whose condition would be expected to deteriorate if they experience clinically important increases in blood pressure or heart rate (e.g., 15 to 20 mmhg in blood pressure or 20 beats per minute [bpm] in heart rate). 7 In addition, Strattera should be used with caution in patients with hypertension, tachycardia, or CV or cerebrovascular disease. In pediatric trials, patients on Strattera had a mean increase in heart rate of 5.0 bpm and 9.4 bpm for extensive and poor metabolizers, respectively, and tachycardia was an AE in 0.3% of Strattera patients vs. 0% on placebo. In adult trials, tachycardia was an AE in 1.5% of Strattera patients vs. 0.5% on placebo. In short-term, placebo-controlled clinical trials, the proportions of pediatric and adults patients having an increase in diastolic blood pressure 15 mmhg were 21.5% and 12.6%, respectively, at any one time, and 9.3% and 4.8%, respectively, at endpoint. The proportions of pediatric and adults patients having an increase in systolic blood pressure 20 mmhg were 12.5% and 12.4%, respectively, at any one time, and 4.9% and 4.2%, respectively, at endpoint. The proportions of pediatric and adults patients having an increase in heart rate 20 bpm were 23.4% and 22.4%, respectively, at any one time, and 12.2% and 10.2%, respectively, at endpoint. Orthostatic hypotension and syncope have also been reported in patients taking Strattera; therefore, Strattera should be used with caution in any condition that may predispose patients to hypotension, or conditions associated with abrupt heart rate or blood pressure changes. Intuniv and Kapvay should be used with caution in patients with a history of hypotension, heart block, bradycardia, CV disease, or syncope because it can decrease blood pressure and heart rate. 16-17 These alpha agonists should also be used with caution in patients treated concomitantly with antihypertensives or other drugs that can reduce blood pressure or heart rate or increase the risk of syncope. Patients should be advised to avoid becoming dehydrated or overheated. In the pediatric, short-term, controlled trials with Intuniv, the maximum mean changes from baseline in systolic blood pressure, diastolic blood pressure, and pulse were -5 mmhg, -3 mmhg, and -6 bpm, respectively. 16 Hypotension was reported as an AE for 7% of the Intuniv group vs. 3% of the placebo group. Orthostatic hypotension was reported for 1% and 0% on the Intuniv and placebo groups, respectively. In pediatric patients that completed 5 weeks of treatment in a controlled, fixed-dose, monotherapy trial with Kapvay, the maximum placebo-subtracted mean changes in systolic blood pressure, diastolic blood pressure, and heart rate for the 0.2 and 0.4 mg/day doses were -4.0 and -8.8 mmhg, -4.0 and - 7.3 mmhg, and -4.0 and -7.7 bpm, respectively. 17 Bradycardia was reported as an AE for 4% of the Kapvay 0.4 mg/day group, and 0% for both the Kapvay 0.2 mg/day and placebo groups. Comorbid Anxiety Anxiety disorders reportedly occur in up to one third of patients with ADHD. 2 There are data showing treatment with Strattera, either as monotherapy or in combination with a selective serotonin receptor antagonist (SSRI), significantly reduces ADHD and anxiety symptom scores. 48-49 Initial reports showed an increased placebo response rate, a greater incidence of side effects, and smaller improvements on cognitive tests in children with ADHD and comorbid anxiety disorder treated with methylphenidate. 14 However, more recent controlled studies do not support these findings. 14-15,50 There are data from recent controlled trials showing improvement in anxiety symptoms as well as

ADHD symptoms in children treated with methylphenidate. 14-15,51 Treatment guidelines state that the contraindication of anxiety disorder in the methylphenidate prescribing information has not been supported by data from recent randomized, controlled trials which actually showed children with comorbid anxiety disorder to improve on methylphenidate. 4-5,14 Anxiety is not listed as a contraindication, warning, or precaution in amphetamine product labeling. A trial with a stimulant is one of the first-line treatment options in this patient population. If the stimulant improves ADHD symptoms but the anxiety symptoms remain, an SSRI or other anti-anxiety medication should be added. 14 In a recently published small, double-blind, placebo-controlled study there was no improvement in residual anxiety symptoms when the SSRI fluvoxamine was added to existing methylphenidate therapy compared to placebo. 52 As a result of this study, the 2007 AACAP ADHD treatment guidelines 5 now state that using Strattera for the treatment of ADHD with comorbid anxiety is a viable alternative approach to the practice of first treating with a stimulant and then adding an SSRI if necessary. In treating patients with ADHD and comorbid anxiety, the 2006 Texas Children s Medication Algorithm for the pharmacotherapy of ADHD recommends either first treating the ADHD with a stimulant and then adding an SSRI to treat residual anxiety symptoms or treating with Strattera initially; either approach is considered acceptable as initial treatment. 4 References: 1. National Survey of Children s Health (NSCH). Data Resource Center for Child and Adolescent Health. Available at: http://childhealthdata.org/learn/nsch. Accessed on: February 21, 2014. 2. American Academy of Pediatrics. ADHD: Clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128:1007-1022. 3. American Academy of Pediatrics. Supplemental Information. Implementing the key action statements: an algorithm and explanation for process of care for the evaluation, diagnosis, treatment, and monitoring of ADHD in children and adolescents. Pediatrics. Published online: October 16, 2011. Available at: http://pediatrics.aappublications.org/content/suppl/2011/10/11/peds.2011-2654.dc1.full. Accessed on February 21, 2014. 4. Pliszka SR, Crismon L, Hughes CW, et al. The Texas children s medication algorithm project: revision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2005;45(6):642-657. 5. American Academy of Child and Adolescent Psychiatry. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921. 6. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2013. Available at http://www.clinicalpharmacology-ip.com/default.aspx. Accessed on: February 21, 2014. Search terms: amphetamine, methylphenidate, and lisdexamfetamine. 7. Strattera capsules [prescribing information]. Indianapolis, IN: Eli Lilly and Company; February 20, 2014. 8. Kratochvil CJ, Vaughan BS, Stoner JA, et al. A double-blind, placebo-controlled study of atomoxetine in young children with ADHD. Pediatrics. 2011;127:e862-e868. 9. Michelson D, Buitelaar JK, Danckaerts M, et al. Relapse prevention in pediatric patients with ADHD treated with atomoxetine: a randomized, double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 2004;43:896-904. 10. Buitelaar JK, Michelson D, Danckaerts M, et al. A randomized, double-blind study of continuation treatment for attention-deficit/hyperactivity disorder after 1 year. Biol Psychiatry. 2007;61:694-699. 11. Wilens TE, Newcorn JH, Kratochvil CJ, et al. Long-term atomoxetine treatment in adolescents with attention-deficit/hyperactivity disorder. J Pediatr. 2006;149:112-9. 12. Kratochvil CJ, Wilens TE, Greenhill LL, et al. Effects of long-term atomoxetine treatment for young children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2006;45(8):919-927.

13. Adler LA, Spencer TJ, Milton DR, et al. Long-term, open-label study of the safety and efficacy of atomoxetine in adults with attention-deficit/hyperactivity disorder: an interim analysis. J Clin Psychiatry. 2005;66:294-299. 14. Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry. 2002;41(2 Suppl):26S-49S. 15. The MTA Cooperative Group. A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD. Arch Gen Psychiaty. 1999;56:1073-1086. 16. Intuniv extended-release tablets [prescribing information]. Wayne, PA: Shire US Inc; August 2013. 17. Kapvay extended-release tablets, oral [prescribing information]. Atlanta, GA: Shionogi Pharma, Inc.; February 2013. 18. Biederman J, Melmed RD, Patel A, et al. Long-term, open-label extension study of guanfacine extended release in children and adolescents with ADHD. CNS Spectr. 2008;13:1047-1055. 19. Sallee FR, Lyne A, Wigal T, McGough JJ. Long-term safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009;19:215-226. 20. Yildiz O, Sismanlar SG, Memik NC, Karakaya I, Agaoglu B. Atomoxetine and methylphenidate treatment in children with ADHD: the efficacy, tolerability and effects on executive function. Child Psychiatry Hum Dev. 2011;42:257-269. 21. Gibson A, Bettinger TL, Patel NC, Crismon ML. Atomoxetine versus stimulants for treatment of attention deficit/hyperactivity disorder. Ann Pharmacother. 2006;40(6):1134-42. 22. Wigal SB, Wigal TL, McGough JJ, et al. A laboratory school comparison of mixed amphetamine salts extended release (Adderall XR ) and atomoxetine (Strattera ) in school-aged children with attention deficit/hyperactivity disorder. J Atten Disord. 2005;9(1):275-89. 23. Kratochvil CJ, Heiligenstein JH, Dittmann R, et al. Atomoxetine and methylphenidate treatment in children with ADHD: a prospective, randomized, open-label trial. J Am Acad Child Adolesc Psychiatry. 2002;41:776-784. 24. Kemner JE, Starr HL, Ciccone PE, Hooper-Wood CG, Crockett RS. Outcomes of OROS methylphenidate compared with atomoxetine in children with ADHD: a multicenter, randomized prospective study. Adv Ther. 2005;22(5):498-512. 25. Newcorn JH, Kratochvil CJ, Allen AJ, et al. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry. 2008;165:721-730. 26. Sangal RB, Owens J, Allen AJ, et al. Effects of atomoxetine and methylphenidate on sleep in children with ADHD. Sleep. 2006;29(12):1573-1585. 27. Concerta extended release tablets [prescribing information]. Titusville, NJ: Janssen Pharmaaceuticals, Inc.; December 2013. 28. Roessner V, Robatzek M, Knapp G, Banaschewski T, Rothenberger A. First-onset tics in patients with attention-deficit/hyperactivity disorder: impact of stimulants. Dev Med Child Neurol. 2006;48:616-621. 29. Palumbo D, Spencer T, Lynch J, et al. Emergence of tics in children with ADHD: impact of oncedaily OROS methylphenidate therapy. J Child Adolesc Psychopharmacol. 2004;14:185-194. 30. Adderall XR extended release capsules [prescribing information]. Newport, KY: Shire US Inc.; December 2013. 31. Jadad AR, Boyle M, Cunningham C, et al. Treatment of attention deficit/hyperactivity disorder. Evidence Report/Technology Assessment No. 11. Rockville, MD: Agency for Healthcare Research and Quality; 1999. AHRQ Pub. No. 00-E005. 32. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. Pediatrics. 2001;108(5):E83. 33. Michelson D, Allen AJ, Busner J, et al. Once-daily atomoxetine treatment for children and adolescents with attention deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatr. 2002;159:1896-1901.

34. Biederman J, Heiligenstein JH, Faries DE, et al. Efficacy of atomoxetine versus placebo in schoolage girls with attention-deficit/hyperactivity disorder. Pediatrics. 2002;110:e75. 35. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults with ADHD: two randomized, placebo-controlled studies. Biol Psychiatry. 2003;53:112-120. 36. Kelsey DK, Sumner CR, Casat CD, et al. Once-daily atomoxetine treatment for children with attention-deficit/hyperactivity disorder, including an assessment of evening and morning behavior: a double-blind, placebo-controlled trial. Pediatrics. 2004;114:e1-8. 37. Allen AJ, Kurlan RM, Gilbert DL, et al. Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders. Neurology. 2005;65:1941-1949. 38. Lee TS, Lee TD, Lombroso PJ, et al. Atomoxetine and tics in ADHD. J Am Acad Child Adolesc Psychiatry. 2004;43:1068-1069. 39. Feldman PD, Ruff DD, Allen AJ. Atomoxetine and tics in ADHD. J Am Acad Child Adolesc Psychiatry. 2005;44:405-406. 40. Schubert R. Attention deficit disorder and epilepsy. Pediatr Neurol. 2005;32:1-10. 41. Gucuyener K, Erdemoglu AK, Senol S, et al. Use of methylphenidate for attention-deficit hyperactivity disorder in patients with epilepsy or electroencephalographic abnormalities. J Child Neurol. 2003;18:109-112. 42. Tan M, Appleton R. Attention deficit and hyperactivity disorder, methylphenidate, and epilepsy. Arch Dis Child. 2005;90:57-59. 43. Aldenkamp AP, Arzimanoglou A, Reijs R, Van Mil S. Optimizing therapy of seizures in children and adolescents with ADHD. Neurology. 2006;67(Suppl 4):S49-S51. 44. FDA Drug Safety Communication: Safety review update of medications used to treat attentiondeficit/hyperactivity disorder (ADHD) in children and young adults. November 1, 2011. Available at: http://www.fda.gov/drugs/drugsafety/ucm277770.htm. Accessed on February 21, 2014. 45. FDA Drug Safety Communication: Safety review update of medications used to treat attentiondeficit/hyperactivity disorder (ADHD) in adults. December 12, 2011. Available at: http://www.fda.gov/drugs/drugsafety/ucm279858.htm. Accessed on February 21, 2014. 46. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306:E1-E11. 47. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;356:1896-1904. 48. Kratochvil CJ, Newcorn JH, Arnold E, et al. Atomoxetine alone or combined with fluoxetine for treating ADHD with comorbid depressive or anxiety symptoms. J Am Acad Child Adolesc Psychiatry. 2005;44(9):915-924. 49. Geller D, Donnelly C, Lopez F, et al. Atomoxetine treatment for pediatric patients with attentiondeficit/hyperactivity disorder with comorbid anxiety disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(9):1119-1127. 50. Diamond IR, Tannock R, Schachar RJ. Response to methylphenidate in children with ADHD and comorbid anxiety. J Am Acad Child Adolesc Psychiatry. 1999;38(4):402-409. 51. Abikoff H, McGough J, Vitiello B, et al. Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2005;44(5)418-427. 52. Abikoff H, McGough J, Vitiello B, et al. Sequential pharmacotherapy for children with comorbid attention-deficit/hyperactivity and anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2005;44(5):418-427. 53. Berigan TR. Atomoxetine used adjunctively with selective serotonin reuptake inhibitors to treat depression. Prim Care Companion J Clin Psychiatry. 2004;6:93-94. 54. Carpenter LL, Milosavljevic N, Jordan JD, Schecter JM, Tyrka AR, Price LH. Augmentation with open-label atomoxetine for partial or nonresponse to antidepressants. J Clin Psychiatry. 2005;66:1234-1238. 55. Michelson D, Adler LA, Amsterdam JD, et al. Addition of atomoxetine for depression incompletely responsive to sertraline: a randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2007;68:582-587. 56. Shatkin JP. Atomoxetine for the treatment of pediatric nocturnal enuresis. J Child Adolesc Psychopharmacol. 2004 Fall;14(3):443-447.

57. Berigan T. The use of atomoxetine adjunctively in fibromyalgia syndrome. Can J Psychiatry. 2004;49:499-500. Billing Coding/Physician Documentation Information N/A Brand name non-stimulant medications are considered a pharmacy benefit. Additional Policy Key Words Policy Number: 5.01.596 Policy Implementation/Update Information 07/2014 New Policy titled ADHD Non-Stimulant Medications Step Therapy Program 07/2015 Annual Review- no changes 07/2016 Annual Review- no changes 07/2017 Annual Review- no changes 07/2018 Annual review no changes 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.