Cigna Drug and Biologic Coverage Policy

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1 Cigna Drug and Biologic Coverage Policy Subject Modafinil/ Armodafinil Table of Contents Coverage Policy... 1 General Background... 3 Coding/Billing Information... 6 References... 6 Effective Date... 02/15/2018 Next Review Date... 02/15/2019 Coverage Policy Number Related Coverage Resources Obstructive Sleep Apnea Diagnosis and Treatment Services INSTRUCTIONS FOR USE The following Coverage Policy applies to health benefit plans administered by Cigna Companies. Certain Cigna Companies and/or lines of business only provide utilization review services to clients and do not make coverage determinations. References to standard benefit plan language and coverage determinations do not apply to those clients. Coverage Policies are intended to provide guidance in interpreting certain standard benefit plans administered by Cigna Companies. Please note, the terms of a customer s particular benefit plan document [Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description (SPD) or similar plan document] may differ significantly from the standard benefit plans upon which these Coverage Policies are based. For example, a customer s benefit plan document may contain a specific exclusion related to a topic addressed in a Coverage Policy. In the event of a conflict, a customer s benefit plan document always supersedes the information in the Coverage Policies. In the absence of a controlling federal or state coverage mandate, benefits are ultimately determined by the terms of the applicable benefit plan document. Coverage determinations in each specific instance require consideration of 1) the terms of the applicable benefit plan document in effect on the date of service; 2) any applicable laws/regulations; 3) any relevant collateral source materials including Coverage Policies and; 4) the specific facts of the particular situation. Coverage Policies relate exclusively to the administration of health benefit plans. Coverage Policies are not recommendations for treatment and should never be used as treatment guidelines. In certain markets, delegated vendor guidelines may be used to support medical necessity and other coverage determinations. Coverage Policy Cigna covers modafinil (Provigil ) and armodafinil (Nuvigil ) as medically necessary for any of the following indications: Narcolepsy confirmed by polysomnography (PSG) and Multiple Sleep Latency Test (MSLT) Obstructive sleep apnea / hypopnea syndrome (OSAHS) confirmed by home sleep testing (HST) or PSG AND both of the following: ο Evidence of compliance with standard treatment for OSAHS (for example, CPAP/BPAP, oral appliances, surgery) ο Provigil or Nuvigil is to be used in combination with standard OSAHS therapies Shift work sleep disorder (SWD) Multiple sclerosis related fatigue Modafinil (Provigil ) only: Parkinson s disease related excessive daytime somnolence (EDS) o Provigil is to be used in combination with standard Parkinson s therapy (for example, carbidopalevodopa, pramipexole, ropinirole) Additional specific criteria apply for each drug below: Drug Additional Specific Criteria Nuvigil Documented intolerance to 1 generic formulation of Nuvigil AND Documented intolerance to 1 generic formulation of modafinil Provigil Documented intolerance to 1 generic formulation of Provigil AND Documented intolerance to 1 generic formulation of armodafinil Page 1 of 8

2 Cigna does not cover the use of modafinil (Provigil ) and armodafinil (Nuvigil ) for any other indication including the following because it is considered experimental, investigational or unproven. (This list may not be all-inclusive): Multiple sclerosis- related nocturnal enuresis Under arousal related to traumatic brain injury Fatigue associated with cancer Amyotrophic lateral sclerosis (ALS) Huntington s disease HIV/AIDS Myotonic dystrophy Cognitive impairment associated with cancer Addiction, dependence and/or abstinence (including withdrawal symptoms) associated with substance abuse Symptomatic or adjunctive treatment of bipolar depression Antipsychotic-induced Parkinsonism Attention-deficit hyperactivity disorder (ADHD) Major depressive disorder (MDD) Postpoliomyelitis syndrome-related fatigue When coverage is available and medically necessary, the dosage, frequency, duration of therapy, and site of care should be reasonable, clinically appropriate, and supported by evidence-based literature and adjusted based upon severity, alternative available treatments, and previous response to Provigil (modafinil) or Nuvigil (armodafinil) therapy. Note: Receipt of sample product does not satisfy any criteria requirements for coverage FDA Approved Indication Brand Name Provigil Approved Indication Provigil is indicated to improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnea (OSA), and shift work disorder (SWD). Nuvigil Limitations of Use: In OSA, Provigil is indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating and during treatment with Provigil for excessive sleepiness. Nuvigil is indicated to improve wakefulness in adult patients with excessive sleepiness associated with obstructive sleep apnea (OSA), narcolepsy, or shift work disorder (SWD). Limitations of Use: In OSA, Nuvigil is indicated to treat excessive sleepiness and not as treatment for the underlying obstruction. If continuous positive airway pressure (CPAP) is the treatment of choice for a patient, a maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating Nuvigil for excessive sleepiness. Page 2 of 8

3 FDA Recommended Dosing Brand Name Provigil FDA Recommended Dosing Dosage in Narcolepsy and Obstructive Sleep Apnea (OSA): The recommended dosage of Provigil for patients with narcolepsy or OSA is 200 mg taken orally once a day as a single dose in the morning. Doses up to 400 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that this dose confers additional benefit beyond that of the 200 mg/day dose. Dosage in Shift Work Disorder (SWD): The recommended dosage of Provigil for patients with SWD is 200 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift Nuvigil Dosage in Obstructive Sleep Apnea (OSA) and Narcolepsy: The recommended dosage of Nuvigil for patients with OSA or narcolepsy is 150 mg to 250 mg taken orally once a day as a single dose in the morning. In patients with OSA, doses up to 250 mg/day, given as a single dose, have been well tolerated, but there is no consistent evidence that these doses confer additional benefit beyond that of the 150 mg/day dose. Dosage in Shift Work Disorder (SWD): The recommended dosage of Nuvigil for patients with SWD is 150 mg taken orally once a day as a single dose approximately 1 hour prior to the start of their work shift. Drug Availability Brand Name Provigil Nuvigil Drug Availability Provigil is available as 100 mg or 200 mg capsules. Nuvigil is available as 50 mg, 150 mg, 200 mg or 250 mg capsules. General Background Disease Overview Narcolepsy is a central nervous system disorder, primarily characterized by excessive daytime sleepiness and cataplexy (sudden loss of muscular tone). The pathophysiology of narcolepsy involves intrusion of aspects of REM sleep (e.g., muscle atonia and dreams) into periods of wakefulness. (Billiard, 2011) Obstructive sleep apnea (OSA) is a treatable form of sleep disordered breathing characterized by repetitive episodes of apnea, hypopnea, or respiratory effort related arousals (RERA) during sleep. Apnea may be obstructive, central, or mixed. Polysomnography is the collective process of monitoring and recording physiologic data during sleep. Patients with OSAHS often experience sleep fragmentation due to breathing fluctuations. The change in sleep often causes daytime sleepiness. Continuous positive airway pressure (CPAP) assists in improving oxygenation and indirectly improves sleep. However, some patients continue to experience daytime sleepiness with CPAP therapy. Amphetamines and modafinil have been studied to improve daytime sleepiness in the patients with OSAHS. (Young, 2004) Patients diagnosed with OSA receive education regarding the pathophysiology of OSA and the impact of lifestyle modifications, including weight loss, reduced alcohol consumption, especially at bedtime, and lateral sleeping position (vs. supine). While such noninvasive measures are encouraged, particularly in the obese or those with very poor sleep hygiene, OSA does not usually resolve with these measures alone. Potential treatment options for OSA include treatment with positive airway pressure (PAP), the use of oral appliances, and surgical interventions. Treatment decisions are based on condition severity, the presence of comorbidities and complicating factors, and the patient s tolerance and response to treatment. (Young, 2004) Page 3 of 8

4 Pharmacology Provigil and Nuvigil have wake-promoting actions similar to sympathomimetic agents including amphetamine and methylphenidate, although their pharmacologic profile is not identical to that of the sympathomimetic amines. The specific mechanism(s) through which either drug supports wakefulness is not known. Armodafinil (R-modafinil) has pharmacological properties similar to those of modafinil (a mixture of R- and S-modafinil), to the extent tested in animal and in vitro studies. The R- and S-enantiomers have similar pharmacological actions in animals. (Clinical Pharmacology 2015) Guidelines European Federation of Neurological Societies (EFNS) The EFNS recommends diagnosis of narcolepsy by first interviewing the patient and a full night polysomnography, directly followed by a multiple sleep latency test (MSLT). A follow up polysomnography would be warranted only if the patient has worsening symptoms or other symptoms occur, but not for the purposes of evaluating response to treatment. Modafinil is recommended for narcolepsy symptoms of excessive daytime sleepiness and irresistible episodes of sleep, but is not suggested for symptoms of poor sleep. The EFNS does mention, however, that some patients do report modafinil ameliorates poor sleep. (Billiard, 2011) American Academy of Neurology (AAN) The American Academy of Neurology state modafinil should be considered for patients to improve their subjective perception of excessive daytime somnolence. The guidelines note that patients who are treated with modafinil may experience an improvement in sleep perception without an actual improvement in objective sleep measurements. (Zesiewicz, 2010) The etiology of Parkinson s disease excessive daytime somnolence (EDS) may be the result of disease process, medications, or other sleep disorders. Two studies assessed the therapeutic efficacy of modafinil in the treatment of EDS in patients with Parkinson s disease EDS. These studies found that modafinil improved EDS on a subjective level using the Epworth Sleepiness Score (ESS), however, there was no objective improvement in EDS as measured by the maintenance of wakefulness test or Multiple Sleep Latency Test. (Adler et al 2003, Hogl et al 2002) American Academy of Sleep Medicine (AASM) The American Academy of Sleep recommends modafinil for the treatment of residual excessive daytime sleepiness in OSA patients who have sleepiness despite effective PAP treatment and who are lacking any other identifiable cause for their sleepiness. (AASM, 2009) The AASM suggests several modalities for treating circadian rhythm sleep disorders (CRSD). Suggested methods to treat shift work disorder include nonpharmaceutical approaches such as planning a sleep schedule and light exposure. Pharmaceutical treatments proposed include scheduled melatonin, hypnotics, stimulants and alerting agents such as modafinil. The AASM mentions that modafinil may be an option for daytime sleepiness due to Parkinson s disease, multiple sclerosis, myotonic dystrophy or idiopathic hypersomnia. However, supporting data in idiopathic hypersomnia are limited to case reports, retrospective series, and one small randomized trial. The organization is silent on the use of armodafinil. (Mayer, 2015 Morgenthaler 2008, Zesiewicz 2011) American Psychiatric Association (APA) The APA published clinical practice guidelines in 2010 for the treatment of patients with major depressive disorder. The APA guidelines address many elements associated with treating major depressive disorder including augmentation therapy in patients who do not respond to initial therapy and potential treatments for side effects associated with antidepressant medications. Modafinil is mentioned in both aforementioned areas. The APA provides several recommendations, with varying levels of supporting evidence, for augmenting therapy in patients who have not responded fully to treatment. Modafinil is identified as a strategy with less evidence for efficacy and is provided a categorical rating equivalent to the lowest level of clinical confidence possible for a recommendation. (Gelenberg, 2010) Department of Veterans Affairs (VA) / Department of Defense (DOD) The VA/DoD published clinical practice guidelines in 2016 for the treatment of patients with major depressive disorder. The VA/DoD guidelines address many aspects of treating major depressive disorder including the use of augmentation agents. Neither modafinil nor armodafinil are mentioned in the clinical practice guidelines. (VA/DoD, 2016) Page 4 of 8

5 National Comprehensive Cancer Network (NCCN) The NCCN published clinical practice guidelines in 2017 for the treatment of cancer related fatigue. The NCCN guidelines address the treatment of cancer related fatigue associated with many stages of cancer treatment including during active treatment, post-treatment, and end of life care. Modafinil is mentioned on several occasions throughout the guidelines however its use is not recommended for the treatment of cancer related fatigue during any stage of cancer treatment. (Berger, 2017) Clinical Efficacy FDA Approved Indications Modafinil was compared to placebo in 6 published trials of wakefulness in narcolepsy where all patients were required to have objectively documented excessive daytime sleepiness. Therapeutic response to modafinil was superior to placebo, with little difference in adverse effects, in all clinical trials. No significant difference in efficacy was detected between modafinil 200 mg and 400 mg in the majority of clinical trials. Modafinil demonstrated superior efficacy for improving daytime wakefulness in patients with OSAHS compared to placebo in 3 published clinical trials. Patients suffering from SWD showed greater alertness and quality of life with modafinil therapy compared to placebo in 2 abstracts. (Cephalon, 2015) Armodafinil was studied in one 12 week trial of improving wakefulness in narcolepsy. Patients received either 150 mg or 250 mg of armodafinil or placebo. Both active drug regimens demonstrated a statistically significant enhanced ability to remain awake compared to placebo. The 250 mg dosage regimen produced a greater magnitude of effect. Armodafinil showed a statistically significant improvement in the ability to remain awake, as compared to placebo in 2 trials of patients with OSAHS, who received either 150 mg or 250 mg of armodafinil. No difference in efficacy was detected between the two dosing regimens. Patients experiencing SWD showed a statistically significant prolongation in time to sleep onset compared to placebo in one 12 week trial. Patients with all conditions were reported to have improvement in their overall clinical condition. (Cephalon, 2017) Experimental, Investigational, Unproven Uses Case series, randomized controlled trials, systematic reviews, and/or meta-analysis have investigated Provigil/ Nuvigil for numerous conditions/indications, including multiple sclerosis- related nocturnal enuresis (Carrieri, 2007), under arousal related to traumatic brain injury (Jha, 2008), fatigue associated with cancer (Jean-Pierre, 2010), amyotrophic lateral sclerosis (Rabkin, 2009), Huntington s disease (Blackwell, 2008), HIV/AIDS (Rabkin, 2010), myotonic dystrophy (Orlikowski, 2009), Cognitive impairment associated with cancer (Boele, 2013), addiction, dependence and/ or abstinence (including withdrawal symptoms) associated with substance abuse (Joos, 2013), symptomatic or adjunctive treatment of bipolar depression (Frye, 2007), antipsychotic-induced Parkinsonism (Lohr, 2013) and fatigue associated with fibromyalgia (Schwartz, 2010). Studies in adults, adolescents and children have shown improvement in attention-deficit hyperactivity disorder (ADHD) symptoms, and various studies report the efficacy of modafinil similar to dextroamphetamine. In 2000, a phase III study conducted by Cephalon, Inc demonstrated no benefit in decreasing ADHD symptoms in adults when modafinil was compared to placebo. Cephalon, Inc submitted an NDA for pediatric ADHD in 2005, which led to review of safety data by the FDA Advisory Committee. Despite modafinil s ability to treat ADHD in children and adolescents, safety signals such as a possible incident of Stevens-Johnson syndrome, psychiatric adverse reactions and lab abnormalities resulted in the drug not receiving approval for this indication. Further safety data was requested by the FDA. Cephalon, Inc is no longer seeking a pediatric ADHD indication. (Biederman et al 2006, Goez et al 2012, Greenhill et al 2006, Swanson et al 2006, Clinical Pharmacology 2014) Fatigue and sleepiness are common symptoms in major depressive disorder (MDD) patients. These symptoms can result in early discontinuation of treatment which may lead to inadequate treatment. Adjunct therapy to antidepressant therapy may be useful and also improve the Hamilton Rating Scale for Depression (HAM-D). This may be particularly important in patients who are non-responders or only partial responders to antidepressant therapy. Randomized controlled trials with modafinil have demonstrated limited short term benefit (for example, 2 weeks) for wakefulness and fatigue in these patients. In a few studies, an improvement in Clinical Global Impression of change (CGI-c) was noted to favor modafinil, however, there was no statistically significant differences noted with modafinil treatment versus placebo for HAM-D scores. In a multi-center randomized controlled trial, no significant differences were found between modafinil and placebo for daytime sleepiness measured by the rate of change in the Epworth Sleepiness Scale (ESS) score from baseline to week 6 in patients with primary MDD initiating SSRI treatment (n = 72). In addition, the mean end point ESS scores were not statistically significantly between placebo and modafinil. In addition, modafinil was not statistically Page 5 of 8

6 significant compared to placebo for secondary outcome measures of proportion of subjects achieving response for ESS score, Fatigue Severity Scale (FSS) score, Hamilton Depression Rating Scale or Montgomery-Asberg Depression Rating Scale (MADRS) score. These results suggest only a short-term benefit for wakefulness and fatigue in patients with MDD receiving adequate SSRI treatment. (Dunlop et al 2007, DeBattista et al 2003, Fava et al 2005, Clinical Pharmacology 2015) Results of controlled studies and meta analyses do not indicate improvement in symptoms of postpoliomyelitis syndrome-related fatigue as compared to placebo, therefore, use in this condition is not supported by evidence. (Chan, 2006) Coding/Billing Information Note: Modafinil and armodafinil are typically covered under pharmacy benefit plans. Certain prescription drugs require an authorization for coverage to ensure that appropriate treatment regimens are followed. Medical drug coding and diagnosis codes, however, are generally not required for pharmacy claims submissions, therefore, this section is not in use. References 1. Adler CH et al. Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson s Disease. Mov Disord 2003 March; 18(3): AASM. Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical Guideline for the Evaluation, Management and Long-term Care of Obstructive Sleep Apnea in Adults. Journal of Clinical Sleep Medicine. J Clin Sleep Med Jun 15; 5(3): Berger AM, Mooney K, Banerjee C, et al. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Cancer-Related Fatigue. Version Biederman J, Swanson J, Wigal S et al. A comparison of once-daily and divided doses of modafinil in children with attention-deficit/hyperactivity disorder: a randomized, double-blind, and placebo-controlled study. J Clin Psychiatry May;67(5): Billiard M, Davilliers Y, Dolenc-Groselj L. Management of Narcolepsy in adults. In: Gilhus N, Barnes M, Branin M, editor(s). European handbook of neurological management. 2 nd ed. Vol 1. Oxford (UK): Wiley- Blackwell P Blackwell AD, Paterson NS, Barker RA, et al. The effects of modafinil on mood and cognition in Huntington's disease. Psychopharmacology (Berl) Jul;199(1): Boele, F, Douw L, de Groot M et al. The effect of modafinil on fatigue, cognitive functioning, and mood in primary brain tumor patients: a multicenter randomized controlled trial. Neuro Oncol Oct;15(10): Brain Trauma Foundation; American Association of Neurological Surgeons; Congress of Neurological Surgeons; Joint Section on Neurotrauma and Critical Care, AANS/CNS, Carney NA, Ghajar J. Guidelines for the management of severe traumatic brain injury. Introduction [published correction appears in J Neurotrauma. 2008;25(3): ]. J Neurotrauma. 2007;24(suppl 1):S1-S2. 9. Brioschi A, Gramigna S, Werth E, et al. Effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients. Eur Neurol. 2009;62(4): Carrieri PB, de Leva MF, Carrieri M, Buongiorno M. Modafinil improves primary nocturnal enuresis in multiple sclerosis. Eur J Neurol. 2007;14(3). 11. Cephalon Inc. Nuvigil (armodafinil) package insert. Frazer, PA. Cephalon Inc. February Cephalon Inc. Provigil (modafinil) package insert. Frazer, PA. Cephalon Inc. January Chan KM, Strohschein FJ, Rydz D, Allidina A, Shuaib A, Westbury CF. Randomized controlled trial of modafinil for the treatment of fatigue in postpolio patients. Muscle Nerve. 2006;33(1): Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; URL: Updated October Dean A, Sevak R, Monterosso J et al. Acute modafinil effects on attention and inhibitory control in methamphetamine-dependent humans. J Stud Alcohol Drugs Nov;72(6): DeBattista C, Doghramji K, Menza MA, et al; Modafinil in Depression Study Group. Adjunct modafinil for the short-term treatment of fatigue and sleepiness in patients with major depressive disorder: a preliminary double-blind, placebo-controlled study. J Clin Psychiatry. 2003;64: Page 6 of 8

7 17. Dunlop BW, Crits-Christoph P, Evans DL, et al. Coadministration of modafinil and a selective serotonin reuptake inhibitor from the initiation of treatment of major depressive disorder with fatigue and sleepiness: a double-blind, placebo-controlled study. J Clin Psychopharmacol 2007;27: Farbu E, Gilhus NE, Barnes MP, et al. EFNS guideline on diagnosis and management of post-polio syndrome. Report of an EFNS task force. Eur J Neurol. 2006;13(8): Fava M, Thase ME, DeBattista C, et al. A multicenter, placebo-controlled study of modafinil augmentation in partial responders to selective serotonin reuptake inhibitors with persistent fatigue and sleepiness. J Clin Psychiatry 2005;66: Frye M, Grunze H, Suppes T et al. A placebo-controlled evaluation of adjunctive modafinil in the treatment of bipolar depression. Am J Psychiatry Aug;164(8): Gelenberg AJ, Freeman MP, Markowitz JC, et al. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3 rd ed. Arlington (VA): American Psychiatric Association; 2010 Oct. 22. Goez H, Scott O, Nevo N et al. Using the test of variables of attention to determine the effectiveness of modafinil in children with attention-deficit hyperactivity disorder (ADHD): a prospective methylphenidatecontrolled trial. J Child Neurol Dec;27(12): Greenhill L, Biederman J, Boellner S et al. A randomized, double-blind, placebo-controlled study of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry May;45(5): Hogl et al. Modafinil for the treatment of daytime sleepiness in Parkinson s Disease: a double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 2002: 25(8): Jean-Pierre P, Morrow G, Roswe J et al. A phase 3 randomized, placebo-controlled, double-blind, clinical trial of the effect of modafinil on cancer-related fatigue among 631 patients receiving chemotherapy: a University of Rochester Cancer Center Community Clinical Oncology Program Research base study. Cancer Jul 15;116(14): Jha A, Weintraub A, Allshouse A, et al. A randomized trial of modafinil for the treatment of fatigue and excessive daytime sleepiness in individuals with chronic traumatic brain injury. J Head Trauma Rehabil. 2008;23(1): Joos L, Goudriaan AE, Schmaal L, et al. Effect of modafinil on cognitive functions in alcohol dependent patients: a randomized, placebo-controlled trial. J Psychopharmacol Nov;27(11): Kaiser PR, Valko PO, Werth E, et al. Modafinil ameliorates excessive daytime sleepiness after traumatic brain injury. Neurology. 2010;75(20): Lange R, Volkmer M, Heesen C, Liepert J. Modafinil effects in multiple sclerosis patients with fatigue. J Neurol. 2009;256(4): Lohr J, Liu L, Caligiuri M et al. Modafinil improves antipsychotic-induced parkinsonism but not excessive daytime sleepiness, psychiatric symptoms or cognition in schizophrenia and schizoaffective disorder: a randomized, double-blind, placebo-controlled study. Schizophr Res Oct;150(1): Lou JS, Dimitrova DM, Park BS, et al. Using modafinil to treat fatigue in Parkinson disease: a double-blind, placebo-controlled pilot study. Clin Neuropharmacol. 2009;32(6): Mayer G, Benes H, Young P, et al. Modafinil in the treatment of idiopathic hypersomnia without long sleep time a randomized, double-blind, placebo-controlled study. J Sleep Res Feb;24(1): Morgenthaler TI, Kapur VK, Brown T, et al; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin [published correction appears in Sleep. 2008;31(2):table of contents]. Sleep. 2007;30(12): Orlikowski D, Chevert S, Quera-Salva M et al. Modafinil for the treatment of hypersomnia associated with myotonic muscular dystrophy in adults: a multicenter, prospective, randomized, double-blind, placebocontrolled, 4-week trial. Clin Ther Aug;31(8): Rabkin JG, Gordon PH, McElhiney M, et al. Modafinil treatment of fatigue in patients with ALS: a placebocontrolled study. Muscle Nerve Mar;39(3): Rabkin JG, McElhiney MC, Rabkin R, et al. Modafinil treatment for fatigue in HIV/AIDS: a randomized placebo-controlled study. J Clin Psychiatry Jun;71(6): Swanson J, Greenhill L, Lopez F et al. Modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation. J Clin Psychiatry Jan;67(1): Swartz TL, Siddiqui UA, Raza S, et al. Armodafinil for fibromyalgia fatigue. Ann Pharmacother Jul- Aug;44(7-8): Page 7 of 8

8 39. VA/DoD clinical practice guideline for the management of major depressive disorder. Management of Major Depressive Disorder Working Group. Washington (DC): Department of Veterans Affairs, Department of Defense; 2016 Apr. 173 p. 40. Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. Jama. Apr ;291(16): Zesiewicz TA, Sullivan KL, Arnulf I, et al; Quality Standards Subcommittee of the American Academy of Neurology. Practice Parameter: treatment of nonmotor symptoms of Parkinson disease: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2010;74(11): Cigna Companies refers to operating subsidiaries of Cigna Corporation. All products and services are provided exclusively by or through such operating subsidiaries, including Cigna Health and Life Insurance Company, Connecticut General Life Insurance Company, Cigna Behavioral Health, Inc., Cigna Health Management, Inc., QualCare, Inc., and HMO or service company subsidiaries of Cigna Health Corporation. The Cigna name, logo, and other Cigna marks are owned by Cigna Intellectual Property, Inc Cigna. Page 8 of 8