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Nuvigil (armodafinil) and Provigil (modafinil), agents with wake-promoting actions that are similar to

sympathomimetic agents (e.g., amphetamine and methylphenidate), are indicated to improve wakefulness in patients with excessive daytime sleepiness (EDS) associated with narcolepsy; obstructive sleep apnea/hypoapnea syndrome (OSAHS) [approved as adjunctive therapy]; and shift work sleep disorder (SWSD).1-2 _{Armodafinil and modafinil are Schedule IV controlled substances.}

Review of the medical literature notes many other uses of modafinil that are considered off-label or investigational. While armodafinil has not been studied off-label to the same extent as modafinil, it is expected that armodafinil will have similar clinical efficacy for these uses.

Narcolepsy is a disorder characterized by EDS and intermittent manifestations of rapid eye movement (REM) sleep during wakefulness.3 American Academy of Sleep Medicine (AASM) practice parameters for the treatment of narcolepsy, updated in 2007, state that the use of alerting medications often

represents the primary mode of therapy. Modafinil, sodium oxybate, amphetamine, methamphetamine, dextroamphetamine, methylphenidate, and selegiline are effective treatments for EDS associated with narcolepsy.

In OSAHS, armodafinil and modafinil are indicated as an adjunct to standard treatment(s) for the underlying obstruction, such as continuous positive airway pressure (CPAP).1 _{In 2006, the AASM}

authored a review of the medical therapy for OSA.4 _{This review notes that positive airway pressure}

(PAP) is the most uniformly effective therapy, and, to date, this is the only intervention for OSA shown to have favorable impacts on both cardiovascular and neurobehavioral morbidities. However, many patients will either refuse the offer of PAP therapy, or will not tolerate it. Regarding modafinil, the assessment was that modafinil in patients compliant with nasal CPAP, consistently improved subjective and objective sleepiness, quality of life, and vigilance compared with placebo.

SWSD is a form of sleep disturbances that are commonly observed with shift work and the diagnosis, defined by the International Classification of Sleep Disorders,5 _{is based on the following criteria: 1)}

complaint of insomnia or excessive sleepiness temporally associated with a recurring work schedule that overlaps the usual sleep time; 2) symptoms must be associated with the shift work schedule over the course of ≥ 1 month; 3) circadian and sleep-time misalignment as demonstrated by sleep log or actigraphical monitoring (with sleep diaries) for ≥ 7 days; 4) sleep disturbance is not explainable by another sleep disorder, a medical or neurological disorder, mental disorder, medication use or

substance use disorder. Treatment options for SWSD include caffeine, methamphetamine, modafinil, and armodafinil.

Armodafinil and modafinil each have a bolded warning regarding serious rash, including Stevens-Johnson Syndrome.1-2 _{Serious rash requiring hospitalization and discontinuation of treatment has been}

reported in adults and children in association with modafinil therapy. A similar risk of serious rash with Nuvigil cannot be ruled out.2 _{Armodafinil and modafinil are not approved for use in pediatric patients for}

any indication.1-2 _{In clinical trials of modafinil the incidence of rash leading to discontinuation was}

approximately 0.8% (13 per 1,585) in pediatric patients (aged < 17 years).1 _{The rashes included one}

case of possible Stevens-Johnson Syndrome and one case of apparent multi-organ hypersensitivity reaction. No cases were noted in the 380 pediatric patients that received placebo. No serious skin rashes have been reported in adult clinical trials (0 per 4,264) of modafinil.

Rationale

1. Narcolepsy.

Armodafinil and modafinil are FDA-approved for the treatment of EDS associated with narcolepsy. 1-2

2. Excessive sleepiness due to obstructive sleep apea/hypoapnea syndrome (OSAHS) in patients who have tried CPAP.

Armodafinil and modafinil are FDA-approved for the treatment of EDS associated with OSAHS as an adjunct to standard treatment(s) of the underlying obstruction.1-2 _{According to product labeling, a}

maximal effort to treat with CPAP for an adequate period of time should be made prior to initiating treatment with armodafinil or modafinil.

3. Excessive sleepiness due to shift work sleep disorder in patients working at least 5 overnight shifts per month.

Armodafinil and modafinil are FDA-approved for the treatment of EDS associated with SWSD.1-2

The primary pivotal trials supporting the use of armodafinil and modafinil in treating SWSD evaluated volunteers who worked a minimum of 5 night shifts per month.

4. Fatigue associated with MS.

Results from clinical trials evaluating the effectiveness of modafinil in the treatment of fatigue associated with MS are equivocal.6-8 _{Modafinil was shown to be effective in treating fatigue}

associated with MS in one open-label6 _{and one randomized, placebo-controlled study.}7 _{In a}

randomized, placebo-controlled, double-blind, 5-week, 115-patient, parallel-group trial8 _modafinil

and placebo both showed similar effectiveness in treating MS fatigue as rated by the Modified Fatigue Impact Scale (baseline score at screening = 63, and decreased to 52.3 for modafinil and 49.2 for placebo on day 35; P < 0.001 for both groups vs. baseline and P = 0.27 between groups). Modafinil is among the most commonly used medications for fatigue associated with MS9 _and,

according to expert opinion, is currently a first-line drug for MS patients. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin, updated in 2007 by the American Academy of Sleep Medicine, state that modafinil may be effective for the treatment of daytime sleepiness due to MS.3 _{Another well-studied agent is amantadine but this drug may have}

tolerability issues in this patient population.8-10 _{Other agents used in MS fatigue include pemoline,}

aspirin, antidepressants (e.g., sertraline, bupropion, fluoxetine, venlafaxine), methylphenidate, and dextroamphetamine; however, these agents are limited by side effect (i.e., pemoline) or have a paucity of clinical data. Although the results with modafinil in clinical trials are heterogeneous, expert opinion considers it to be a first-line anti-fatigue drug for MS patients. While armodafinil has not been studied for this use, expert opinion considers it to be interchangeable with modafinil for this condition.

5. EDS due to myotonic dystrophy.

Trials suggest that modafinil may be useful in treating EDS associated with myotonic dystrophy.11-14 In a randomized, double-blind, placebo-controlled, 14-day, cross-over trial13 modafinil was

evaluated in 40 patients with myotonic dystrophy. Somnolence was reduced in patients receiving modafinil as noted by statistically significant improvements compared with placebo on the ESS scores, and the Stanford Sleepiness Scale. In a randomized, double-blind, crossover trial14 _{in 19}

patients with myotonic dystrophy use of modafinil improved the mean wakefulness scores. Guidelines from the American Academy of Sleep Medicine, published in 2007, state that modafinil may be effective for the treatment of daytime sleepiness due to myotonic dystrophy.3 _While

armodafinil has not been studied for this use, expert opinion considers it to be interchangeable with modafinil for this condition.

6. Attention-Deficit/Hyperactivity Disorder (ADHD) and Attention-Deficit Disorder (ADD) for patients aged < 18 years that have tried two alternative medications for ADHD/ADD from two different classes as follows: methylphenidate products (e.g., methylphenidate,

dexmethylphenidate), amphetamines (e.g., mixed amphetamine salts, dextroamphetamine), atomoxetine, bupropion or tricyclic antidepressants (TCAs; e.g., imipramine, desipramine). Several trials have shown modafinil to be effective for ADHD/ADD in children and adolescents.15-19

In a 9-week, multicenter, randomized, double-blind flexible-dose, controlled trial17 _{children (aged 6}

to 17 years) with ADHD received modafinil (n = 164; titrated to 170 to 425 mg once daily [QD]) or placebo (n = 82). Use of modafinil led to improvements on the ADHD-Rating Scale (RS)-IV (school version) total score at final visit, the primary efficacy variable, compared with placebo (mean

change -15.0 vs. -7.3; P < 0.0001); the benefits commenced at week 1. In another 9-week, randomized, double-blind, flexible-dose study18 _{children with ADHD (aged 6 to 17 years) received}

modafinil 170-425 mg QD (n = 128) or placebo (n = 66). Significant reductions (P < 0.0001) in ADHD-RS-IV total scores at both school and home were noted with modafinil therapy. Fifty-two percent of patients given modafinil versus 18% given placebo were classified as responders on the Clinical Global Impression of Improvement (CGI-I) (P < 0.0001). In a randomized, double-blind, placebo-controlled, fixed-dose study19 _{modafinil (340-425 mg QD), given for 7 weeks, in 190}

children (aged 6 to 17 years) also improved ADHD symptoms as demonstrated by reductions in ADHD-RS-IV school version (total score) at the final visit (change from baseline of -17.2 for

modafinil vs. -8.2 for placebo; P < 0.001). Modafinil is not considered a first- or second-line therapy in the treatment of ADHD/ADD in children per clinical practice guidelines/parameters or reviews.20-24

The American Academy of Pediatrics (AAP) clinical practice guidelines for the treatment of school-aged children with ADD/ADHD lists methylphenidate and amphetamine as first-line treatment and TCAs and bupropion as second-line treatment.20,23 _{The 2007 American Academy of Child and}

Adolescent Psychiatry practice parameters for the assessment and treatment of children and adolescents with AD/HD state that around 65-75% of children with ADHD respond to either

methylphenidate or dextroamphetamine and nearly 85% will respond if both stimulants are tried.21

Modafinil is not listed as a first-line, second-line, or alternative therapy. The Texas Children’s Medication Algorithm Project considers stimulant medications (methylphenidate and

amphetamines) as first-line treatment, with other agents to try after two stimulants have failed including atomoxetine, bupropion, a tricyclic antidepressant, and an alpha agonist.24 _Although

modafinil appears effective comparative studies with first-line ADHD agents are needed and long-term safety and efficacy are not established. While armodafinil has not been studied for this use, expert opinion considers it to be interchangeable with modafinil for this condition.

7. Adjunctive/augmentation treatment for depression in adults when the patient is concurrently receiving other medication therapy for depression (e.g., selective serotonin reuptake

inhibitors [SSRIs]).

Various trials have used scales involving fatigue measurement to determine the effects of modafinil augmentation in patients with major depressive disorder or for sedation/sleepiness due to

antidepressant therapy or the disease state.25-31 Some of the trials, which included retrospective analysis26,31, open-label27-28 studies, and double-blind, placebo-controlled trials29-30, revealed that modafinil may have benefits in depressed patients. In an 8-week, placebo-controlled study30

involving 311 patients with MDD considered partial responders to stabilized SSRI therapy, modafinil 200 mg QD as adjunctive therapy improved the clinical condition as assessed by CGI-improvement scores compared with placebo (P = 0.02). In a 12-week, open-label extension study27 of 245 patients who had completed an 8-week double-blind study of modafinil found that the agent continued to improve patients overall clinical condition and reduced fatigue and excessive sleepiness when given to augment SSRI therapy in patients with depression. Limited data have investigated modafinil as monotherapy for depression.32 _{While armodafinil has not been studied for}

this use, expert opinion considers it to be interchangeable with modafinil for this condition. 8. Excessive daytime sleepiness in Parkinson’s disease (PD).

EDS occurs frequently (20-50%) in PD patients and can be due to the disease state or due to use of dopamingeric drugs.33 _{Double-blind, randomized, controlled trials}34-36_{, an open-label trial}37_{, and}

case reports38 _{have studied modafinil in EDS associated with PD and many patients were receiving}

PD medication (e.g., pramipexole, levodopa-carbidopa, bromocriptine, amantadine, tolcapone, entacapone, ropinirole). A double-blind, placebo-controlled crossover study34 _{in 21 patients with PD}

and an ESS score ≥ 10 received placebo and modafinil (200 mg QD) for three weeks, separated by a washout week. ESS scores were decreased by 3.4 points when modafinil was given compared with a 1.0 increase with placebo (P = 0.039). Another double-blind, randomized, crossover trial35 _in

15 patients with PD and an ESS score ≥ 10 showed similar positive benefit with modafinil in ESS scores, which were also better compared with placebo (P = 0.011). In contrast, a double-blind, placebo-controlled, 4-week, parallel-designed trial36 _{failed to show benefit of modafinil (200-400}

point decrease, respectively; P = 0.28). However, a review addressing EDS and PD recommended modafinil along with other agents such as bupropion and dextroamphetamine, although published data with the latter are limited.39 _{Guidelines from the American Academy of Sleep Medicine,}

published in 2007, state that modafinil may be effective for the treatment of daytime sleepiness due to Parkinson’s disease.3 _{While armodafinil has not been studied for this use, expert opinion}

considers it to be interchangeable with modafinil for this condition. References

1. Provigil [package insert]. Frazer, PA: Cephalon, Inc.; August 2007. 2. Nuvigil™ _{tablets [package insert]. Frazer, PA: Cephalon, Inc.; July 2008.}

3. Morgenthaler TI, Kapur VK, Brown T, et al, for the Standard of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. An American Academy of Sleep Medicine Report. Sleep. 2007;30(12):1705-1711.

4. Veasey SC, Guilleminault C, Strohl KP, et al. Medical therapy for obstructive sleep apnea: a review by the medical therapy for obstructive sleep apnea task force of the standards of practice committee of the American Academy of Sleep Medicine. Sleep. 2006;29(8):1036-1044.

5. Schwartz JRL, Roth T. Shift work sleep disorder. Burden of illness and approaches to management. Drugs. 2006;66(18):2357-2370.

6. Zifko UA, Rupp M, Schwarz S, et al. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol. 2002;249:983-987.

7. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two center phase 2 study. J Neurol Neurosurg

Psychiatry. 2002;72:179-183.

8. Stankoff B, Waubant E, Confavreux C, et al. Modafinil for fatigue in MS. Neurology. 2005;64:1139-1143.

9. MacAllister WS, Krupp LB. Multiple-sclerosis-related fatigue. Phys Med Rehabil Clin N Am. 2005;16:483-502.

10. Krupp LB. Fatigue in multiple sclerosis. Definition, pathophysiology and treatment. CNS Drugs. 2003;17(4):225-234.

11. Damian MS, Gerlach A, Schmidt F, et al. Modafinil for excessive daytime sleepiness in myotonic dystrophy. Neurology. 2001;56:794-796.

12. Wintzen AR, Lammers GJ, van Dijk JG. Does modafinil enhance activity of patients with myotonic dystrophy? A double-blind, placebo-controlled, crossover study. J Neurol. 2007;254:26-28. 13. MacDonald JR, Hill JD, Tarnopolsky MA. Modafinil reduces excessive somnolence and enhances

mood in patients with myotonic dystrophy. Neurology. 2002;59(12):1876-1880.

14. Talbot K, Stradling J, Crosby J, Hilton-Jones D. Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy. Neuromuscul Disord. 2003;13(5):357-364.

15. Boellner SW, Early CQ, Arora S. Modafinil in children and adolescents with attention-deficit/hyperactivity disorder: a preliminary 8-week, open-label study. Curr Med Res Opin. 2006;22(12):2457-2465.

16. Biederman J, Swanson JM, Wigal SB, for the modafinil ADHD Study Group. 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. 2006;67:727-735. 17. Biederman J, Swanson JM, Wigal SB, et al. Efficacy and safety of modafinil film-coated tablets in

children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study. Pediatrics. 2005;116(6):e777-e784.

18. Greenhill LL, Biederman J, Boellner SW, 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. 2006;45(5):1-9.

19. Swanson JM, Greenhill LL, Lopez FA, 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. 2006;67(1):137-147.

20. American Academy of Pediatrics. Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical practice guideline: treatment of school-aged child with attention-deficit/hyperactivity disorder. Pediatrics. 2001;108:1033-1044.

21. 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.

22. Wolraich ML, Wibbelsman CJ, Brown TE, et al. Attention-deficit/hyperactivity disorder among adolescents: a review of the diagnosis, treatment and clinical implications. Pediatrics. 2005;115:1734-1746.

23. Brown RT, Amler RW, Freeman WS, et al. Treatment of attention-deficit/hyperactivity disorder: overview of the evidence. Pediatrics. 2005;115e:e749-e757.

24. Pliszka SR, Crismon ML, Hughes CW, et al, and the Texas Consensus Conference Panel on Pharmacotherapy of Childhood Attention-Deficit/Hyperactivity Disorder. The Texas Children’s Medication Algorithm Project: Revision of the Algorithm for Pharmacotherapy of Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2006;45(6):642-57.

25. Lam JY, Freeman MK, Cates ME. Modafinil augmentation for residual symptoms of fatigue in patients with a partial response to antidepressants. Ann Pharmacother. 2007;41:1005-1012. 26. Nasr S. Modafinil as adjunctive therapy in depressed outpatients. Ann Clin Psychiatry.

2004;16:113-138.

27. Thase ME, Fava M, DeBattista C, et al. Modafinil augmentation of SSRI therapy in patients with major depressive disorder and excessive sleepiness and fatigue: a 12-week, open-label extension study. CNS Spectr. 2006;11(2):93-102.

28. DeBattista C, Lembke A, Solvason HB, et al. A prospective trial of modafinil as an adjunctive treatment of major depression. J Clin Psychopharmacol. 2004;24(1):87-90.

29. DeBattista C, Coghramji K, Menza MA, et al for the 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(9):1057-1064.

30. Fava M, Thase ME, DeBattista C. 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(1):85-93.

31. Fava M, Thase ME, Debattista C, et al. Modafinil augmentation of selective serotonin reuptake inhibitor therapy in MDD partial responders with persistent fatigue and sleepiness. Ann Clin

Psychiatry. 2007;19(3):153-159.

32. Price SC, Taylor FB. A retrospective chart review of the effects of modafinil on depression as monotherapy and as adjunctive therapy. Depress Anxiety. 2005;21:149-153.

33. Arnulf I. Excessive daytime sleepiness in parkinsonism. Sleep Med Rev. 2005;9(3):185-200. 34. Adler CH, Caviness JN, Hentz JG, Lind M. Randomized trial of modafinil for treating subjective

daytime sleepiness in patients with Parkinson’s disease. Mov Disord. 2003;18(3):287-293.

35. Hogl B, Saletu M, Brandauer E, 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):905-909.

36. Ondo WG, Fayle R, Atassi F, Jankovic J. Modafinil for daytime somnolence in Parkinson’s disease: double-blind, placebo-controlled parallel trial. J Neurol Neurosurg Psychiatry. 2005;76:1636-1639. 37. Nieves AV, Lang AE. Treatment of excessive daytime sleepiness in patients with Parkinson’s

disease with modafinil. Clin Neuropharmacol. 2002;25(2):111-114.

38. Happe S, Pirker W, Sauter C, et al. Successful treatment of excessive daytime sleepiness in Parkinson’s disease with modafinil. J Neurol. 2001;248:632-634.

39. Rye DB. Excessive daytime sleepiness and unintended sleep in Parkinson’s disease. Curr Neurol

and Neurosci Rep. 2006;6:169-176.

Billing Coding/Physician Documentation

Information

N/A Provigil and Nuvigil are considered a pharmacy benefit.

Additional Policy Key Words

Policy Number: 5.01.534

Policy Number:

5.01.534

Related

Topics

N/A

Policy

Implementation/Update

Information

09/2010 New policy titled Provigil / Nuvigil 08/2011

08/2012 08/2013 08/2014

Policy reviewed, no changes made Policy reviewed, no changes made Policy reviewed, no changes made Policy reviewed – no changes made

This Medical Policy is designed for informational purposes only and is not an authorization, an

explanation of benefits, or a contract. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there is any exclusion or other benefit limitations applicable to this service or supply. Medical technology is constantly changing and Blue Cross and Blue Shield of Kansas City reserves the right to review and revise medical policy. This information is

proprietary and confidential and cannot be shared without the written permission of Blue Cross and Blue Shield of Kansas City.