CERTIFICATE OF MEDICAL NECESSITY ADDENDUM FOR PROVIGIL (MODAFINIL)

To:

Re:

Treatment:

Reference is made to the Certificate of Medical Necessity. Please be advised the patient has been prescribed modafinil. Modafinil is the first medication in a new class of medications with a unique mechanism of action, categorized as tuberomammillary activators. Although there are many other compounds in this class, no others are yet approved by the FDA. Since modafinil is the only currently available tuberomammillary activator, it must be included in every formulary, and cannot be substituted for medications in a different and unrelated class of agents. The initial DFA approved labeling is excessive daytime sleepiness associated with narcolepsy. The combination of preclinical research, clinical research, peer-reviewed medical literature, presentations at medical meetings, preliminary findings from current research, clinical experience, articles currently in peer review, medical books currently in print and practical psychopharmacology all support a much broader therapeutic efficacy, safety and tolerability beyond the initial FDA labeling. This information is being revised on a daily basis. Currently, there is a broad base of medical information supporting efficacy for a number of indications including deficit syndrome, fatigue, excessive daytime sleepiness, initiative disorders, cognitive impairments, and executive dysfunction associated with a number of medical and psychiatric conditions. The following is some background on the use of modafinil in the treatment of narcolepsy, idiopathic hypersomnia, obstructive sleep apnea, MS fatigue, Parkinson’s disease, depression and attention deficit/hyperactivity disorder.

Background Information on Narcolepsy and Its Available Treatments

Narcolepsy is a chronic neurological disorder characterized by excessive daytime sleepiness. Patients with narcolepsy experience irresistible sleep attacks that can occur at any place and time. These sleep attacks can last from a few seconds to more than an hour. The associated features of narcolepsy include cataplexy, hypnagogic hallucinations, and sleep paralysis. These features represent abnormal intrusions of rapid eye movement (REM) sleep into the waking state. Individuals with narcolepsy may have various combinations of the associated features, but the presence of sleepiness is universal.

Current approaches to the management of narcolepsy combine pharmacological and behavioral therapies. The drug treatment of narcolepsy focuses on the management of two symptoms: excessive daytime sleepiness and cataplexy. Since the 1950s, healthcare providers have used central nervous system (CNS) stimulants such as amphetamine and methylphenidate to treat excessive daytime sleepiness. For approximately the last 30 years, antidepressants have been the mainstay for the management of cataplexy and other REM sleep symptoms.

PROVIGIL is the first non-amphetamine drug in 40 years to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy. PROVIGIL is a new molecular entity that is chemically unrelated to CNS stimulants (e.g., amphetamine and methylphenidate). PROVIGIL has wake-promoting actions like amphetamine and methylphenidate, although its pharmacologic profile is not identical to that of these agents. PROVIGIL appears to exert its major pharmacologic action, “wake promotion,” by selectively affecting the areas of the brain that are believed to regulate normal wakefulness. Therefore, patients receiving PROVIGIL therapy experience normal wakefulness without generalized stimulation usually associated with CNS stimulant therapy.

Background Information on Idiopathic Hypresomnia (IH) and Its Available Treatments

Idiopathic hypersomnia is a diagnosis applied to patients who are excessively sleepy and sleep for long periods of time without feeling refreshed. [1] It is also referred to as non-REM narcolepsy or CNS hypersomnia. [3] The etiology of EDS is patients with IH is unknown. [3]

In comparison with narcolepsy, which is characterized by well-defined clinical, polysomnographic, and immunogenetic features, IH is not well delineated.² The diagnosis of idiopathic hypersomnia is mainly based on clinical features and the absence of associated symptoms such as cataplexy, snoring at night, periodic leg movements, or the patient demonstrating REM sleep in two or more daytime naps on a Multiple Sleep Latency Test.[1,3]

Current treatment approaches, which include pharmacological and behavioral therapies, are similar for both IH and narcolepsy.[i] Central nervous system (CNS) stimulants such as amphetamine and methylphenidate are commonly prescribed to treat EDS in this patient population.^2,4

Rationale for Recommending PROVIGIL Therapy

A number of studies have evaluated the efficacy and safety of modafinil for the treatment of EDS in patients with IH. The results from these studies have demonstrated modafinil significantly and clinically improved EDS associated with IH. [2,3,4] Modafinil was generally well tolerated in this patient population and adverse effects were similar to those observed in narcolepsy patients.

1. Aldrich, MS: Diagnostic aspects of narcolepsy. Neurology 50 (supple. 20): 52-57, 1998.

2. American Sleep Disorders Association: ICSD-International Classification of Sleep Disorders: Diagnostic and Coding Manual, p. 46-49.

3. Billiard, M.: Idiopathic hypersomnia. Neurologic Clinics 14(3): 573-582, 1996.

4. Choo, K.L. and Guilleminault, C.: Narcolepsy and idiopathic hypersomnolence. Clinics in Chest Medicine 19 (1): 169-181, 1998.

5. Laffont, F et al: Effect of modafinil on narcolepsy and idiopathic hypersomnia [abstract P385]. 5th International Congress of Sleep Research, Copenhagen, Denmark, June 28-July 3, 1987.

6. Bastuji H and Jouvet, M.: Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiat 12:695-700, 1988.

7. Schwartz, RL et al: Modafinil in the treatment of idiopathic hypersomnia. Sleep ResOnline 2 (Suppl 1):443, 1999.

Numerous studies that evaluated the use of modafinil for the treatment of residual EDS in patients with OSA/HS (treated with and without CPAP) are presented for your consideration.

Phase 3 Pivotal Study

A 12-week, randomized, double-blind, placebo-controlled, multi-center study was conducted to evaluate the safety and efficacy of PROVIGIL (200 mg or 400 mg administered once daily) in OSA/HS patients (n=327) who were using a stable CPAP regimen with effectiveness.[ii]^,[iii] The results of this study demonstrated significant improvements in sleep latency time and daytime wakefulness as measured by the Maintenance of Wakefulness Test (MWT) and the Epworth Sleepiness Scale (ESS), respectively in patients treated with PROVGIL. Statistically significant improvements were also observed (in both PROVIGIL treatment groups) in overall clinical condition and Quality of Life (vitality and physical composite index domains) as measured by the Clinical Global Impression of Change (CGI-C), and SF-36, respectively. During this study, PROVIGIL was generally well tolerated and did not significantly affect CPAP use. The most commonly reported adverse events included headache, nausea and anxiety.

A open-label extension (n=266 [175 completers]) of this study demonstrated treatment with PROVIGIL (200-400 mg/day) maintained improvements in wakefulness as assessed by the ESS, as well as measures of quality of life, for up to 12 months.[iv] Long-term therapy with PROVIGIL was also well tolerated. Adverse events were mild to moderate; the most frequent emergent adverse events included nervousness, headache, depression and anxiety.

Additional Studies

Summaries of additional studies that evaluated the use of modafinil to improve EDS in OSA/HS patients are presented in Tables 1 and 2.

Table 1: Use of Modafinil in OSA/HS: Cephalon Sponsored Supporting Studies

Study

Design

Treatment

Outcome

Pack et al[v]

Placebo-controlled, double-blind; n=157, OSA/HS, nCPAP-regular users patients

Week 1: Modafinil 200 mg/day;

Weeks 2-4: Modafinil 400 mg/day

Efficacy: Significant improvement in EDS as measured by ESS and MSLT; 68% of patients rated “improved” on CGI-C, compared to 34% in placebo.

Safety: 8 (10%) patients withdrew due to AEs, 1 serious AE unrelated to treatment, common AEs included headache, nervousness, nausea, dizziness and anxiety

Knigshott et al⁴

Placebo-controlled, double-blind, crossover;

n=30, OSA/HS, nCPAP-compliant patients

Modafinil 400 mg/day, 2 week treatment for each with 1 week washout period

Efficacy: Significant improvements in sleep latency as measured by MWT, no significant improvements in ESS, MSLT, cognitive performance or quality of life.

Safety: Generally well tolerated, common AEs: headache, nausea, dry mouth

MSLT=Mean Sleep Latency Test; AE=Adverse Event

Table 2: Use of Modafinil in OSA/HS: Additional Supporting Studies

Study	Design	Treatment	Outcome
Arnulf et al[vi]	Placebo-controlled, randomized, double-blind, crossover; n=6, OSA/HS patients	Modafinil 200 mg; 2 week treatment for each with 1 week washout period	Efficacy: Daytime sleep reduced by 42%, subjective daytime vigilance prolonged by 1 hour, improved long-term memory without modifying nighttime sleep or respiration. Safety: Generally well tolerated, no report of a significant adverse effect.
Cassel et al.[vii]	Placebo-controlled, randomized, double-blind, crossover; n=26, patients with mild to moderate sleep disordered breathing	Modafinil 300 mg, 1 day treatment each over 2 days of study.	Efficacy: Improved vigilance and reduced daytime sleepiness in patients with mild to moderate disordered breathing. Safety: No data reported
Schiza, SE et al[viii]	Placebo-controlled, randomized, double-blind, crossover, n=50, OSA/HS patients receiving CPAP (n=30) and those refused treatment (n=20)	Modafinil (dose not provided) Treatment for 12 weeks	Efficacy: Significant improvement in ESS, MSLT and Mini Mental State in modafinil treated group independent of CPAP use. Safety: Generally well tolerated, no discontinuation due to an AE, no significant change in nighttime sleep and respiration
Bittencourt et al[ix]	7-day single-blind placebo period followed by a placebo-controlled, randomized, double-blind, crossover period; n=20, OSA/HS patients	Modafinil 300 mg administered upon awakening	Efficacy: Significant change from baseline in ESS, visual analog scale for sleepiness and MWT. Increase sleep latency (MWT) was significantly greater for the modafinil group Safety: Generally well tolerated, no discontinuation due to an AE, common AEs: headache, irritability, drowsiness & nausea.
Newcombe et al[x]	Single-dose, placebo-controlled, double-blind, crossover; N=8, Patients with mild OSA and partial sleep deprivation (4-hour restricted sleep)	Modafinil 200 mg	Efficacy: Lower effort to stay awake, general improvement in vigilance observed 2 hours post treatment but not after 6 hours. Impairment of some daytime cognitive performance requires further study Safety: No data reported

MSLT=Mean Sleep Latency Test; AE=Adverse Event

In addition, a 12-week, open-label extension of the study conducted by Pack et al was carried out in 125 patients. The results of this study demonstrated the significant improvements in daytime wakefulness observed with PROVIGIL treatment during the 4-week double-blind study were maintained throughout 12 weeks of open-label treatment.[xi]

The pharmacologic actions of modafinil coupled with the positive findings from these published clinical studies suggest PROVIGIL may be a viable adjunct therapy to CPAP to improve wakefulness in patients with residual EDS associated with OSA/HS.

1. Young, T. et al: The occurrence of sleep-disordered breathing among middle-aged adults. N Eng J Med 328: 1230-1235, 1993.

2. Philipson, EA: Disorders of ventilation. In: Harrison’s Principles of Internal Medicine. 14^th edition, AS Fauci et al eds. (New York, McGraw- Hill, Inc., 1998), pp.1477-1478.

3. Philipson, EA: Sleep Apnea. In: Harrison’s Principles of Internal Medicine. 14^th edition, AS Fauci et al eds.(New York, McGraw-Hill, Inc., 1998), pp.1480-1482.

4. Kingshott, RN et al: Randomized, double-blind, placebo-controlled crossover trial of modafinil in the treatment of residual excessive daytime sleepiness in the sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 163:918-923, 2001.

5. Black, JE et al: Efficacy and safety of modafinil as adjunctive therapy for excessive sleepiness associated with obstructive sleep apnea (abstract 030.J). Sleep 25 (suppl): A22-A23, 2002.

6. Schmidt-Nowara, WW et al: Modafinil improves quality of life in sleepn apnea. (abstact 653.J). Sleep 25 (suppl): A461, 2002.

7. Black, J et al: Modafinil adjunctive therapy improves excessive sleepiness and quality of life in obstructive sleep apnea: A 12-month open-label extension [abstract0680.J]. Sleep 26:A270, 2003.

8. Pack, AI et al: Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med 164:2001.

9. Arnulf, I et al: Modafinil in obstructive sleep apnea-hypopnea syndrome: A pilot study in 6 patients. Respiration 64: 159-161, 1997.

10. Cassell, W et al: Effects of modafinil on vigilance and daytime sleepiness in sleepy patients with mild to moderate sleep disordered breathing [abstract 245.K1]. Sleep 21(suppl): 92, 1998.

11. Schiza, et al: The use of modafinil inpatients with obstructive apnea hypopnea syndrome. A randomized, placebo-controlled, double blind study [abstract 016.J). Sleep 24(suppl): A10-A11, 2001.

12. Bittencourt, LA et al: Modafinil X placebo effects on residual excessive diurnal sleepiness (EDS) in obstructive sleep apnea syndrome (OSAS) patients treated with nasal CPAP [abstract 444.J]. Sleep 24(suppl): A261, 2001.

13. Newcombe, JP et al: Modafinil improves alertness and driving simulator performance in sleep-deprived mild obstructive sleep apnea (OSA) patients [abstract 443.J]. Sleep 24(suppl): A260-A261, 2001.

14. Data on File, Cephalon, Inc.

Background Information on MS fatigue

Multiple sclerosis (MS) is a neurological disorder caused by an inflammatory demyelinating process in the central nervous system (CNS), resulting in muscle weakness, dizziness and vision problems.[xii] Fatigue is one of the most common symptoms of MS, occurring in over 75% percent of patients.^1,[xiii] Fatigue associated with MS may be of profound significance, interfering with a person’s ability to work and function on a daily basis.²

Current pharmacological approaches to the management of MS fatigue include amantadine and pemoline. Although these agents have been evaluated in clinical trials for the management of fatigue associated with MS, statistically significant improvements were not observed, compared to treatment with placebo.[xiv] Additionally, undesirable side effects (e.g. hepatic failure) have been associated with agents such as pemoline.[xv] (Methylphenidate (another CNS stimulant) and selective serotonin reuptake inhibitors (e.g., fluoxetine) have also been used in this patient population.

Rationale for Recommending PROVIGIL Therapy

PROVIGIL is the first non-amphetamine drug indicated to improve wakefulness in patients with EDS associated with narcolepsy. PROVIGIL is chemically unrelated to CNS stimulants (e.g., amphetamine, methylphenidate). PROVIGIL has wake-promoting actions like amphetamine and methylphenidate, although its pharmacologic profile is not identical to that of these agents. In preclinical models, PROVIGIL appears to exert its major pharmacologic action, “wake promotion,” by selectively affecting the areas of the brain that are believed to regulate normal wakefulness. PROVIGIL does not appear to produce frequent CNS (e.g., irritability) or peripheral (e.g., palpitations, hypertension) adverse effects.

CNS stimulants (e.g., methylphenidate) that are effective for the treatment of narcolepsy are also used in patients with MS fatigue. The hypofunctionality of the frontal cortex region of the brain has been implicated in the pathophysiology of fatigue in MS patients. Preclinical studies have shown modafinil, similar to CNS stimulants, activates the frontal cortex region, however, via a non-dopaminergic pathway.

Several clinical studies that describe the use of PROVIGIL in the management of fatigue associated with MS are described below.

Nine-week, Placebo-controlled Study

In a 9-week, single-blind, forced-titration, placebo-controlled study, the safety and efficacy of modafinil for the treatment of MS fatigue were assessed in 72 patients (age range: 18-65 years old).[xvi] Participants had to have a score of £6 on the Kurtzke Extended Disability Status Scale (EDSS) and ³4 on the Fatigue Severity Scale (FSS) at baseline.

The results of this study (Table 1) demonstrated mean scores of measurements of fatigue (FSS, Visual Analog Global Scale of Fatigue, Modified Fatigue Impact Scale were significantly different in the modafinil 200 mg/day treatment group compared to placebo run-in; no significant changes in these parameters were observed in the modafinil 400 mg/day group. Mean Epworth Sleepiness Scale scores for modafinil treatment groups, 200 mg/day or 400 mg/day, were significantly improved compared to baseline suggesting a difference in dose-response profile between fatigue and sleepiness.

Table 1. Fatigue and Sleepiness Scales (Mean Scores)

Scales	Placebo Run-in	Modafinil 200 mg/day	Modafinil 400 mg/day
FSS	5.5	4.7*	5.3
VAFS	4.5	5.4**	4.7
MFIS	44.7	37.7*	42.1
ESS	9.5	7.2*	7.0*

* p <0.001; ** p =0.003

Adverse events during this study were mild to moderate in nature. During the 200 mg/day treatment phase, the most frequent adverse events were headache, nausea, and anxiety. During treatment with 400 mg/day, the most frequent adverse events were asthenia, headache, nausea and nervousness. No serious adverse events were reported; four patients discontinued modafinil treatment (400 mg/day) due to an adverse event.

Other Clinical Studies

Additional clinical studies that evaluated the effects of PROVIGIL in patients with MS are shown in Table 1.

Table 1. Additional Clinical Studies in patients with MS

Study Design	Subjects (n)	Modafinil Dose	Efficacy Results	Safety Profile
12-week, open-label; Kurtzke EDSS£8[xvii]	40	100 mg b.i.d.	Improved fatigue in 85% of patients, some improvement in sleepiness, no significant effects on measures of pain, depression or cognition	4 patients reported AEs (nausea irritability, dizziness, restless legs, epigastric pain)
3-month, open-label; mean Kurtzke EDSS = 3.8 ± 1.5[xviii]	50	100-400 mg/day; mean = 148 ± 61 mg (no patient required 400 mg/day)	Significant improvements in mean ESS and FSS scores: > 85% of patients reported “clear improvement” in fatigue	3 patients discontinued due to AEs: nervousness, restlessness, worsening of pre-existing vertigo
Double-blind, placebo-controlled, crossover; mean Kurtzke EDSS = 3[xix]	60 (goal); 35 (enrolled); 29 completed	100 mg b.i.d.	No statistically significant improvements in measures of fatigue or sleepiness; trends in improvements were observed (this underpowered study was inconclusive)	9% of patients experienced Aes; reports included headache and nausea
Retrospective chart review[xx]	3	200-400 mg/day	Improvements in fatigue in 2 out of 3 patients	AEs included nausea, headache, dry mouth

EDSS=Expanded Disability Status Scale; AEs=Adverse Events

Treatment-Induced Fatigue

In a two-week, open-label study, 8 patients who received daily modafinil therapy demonstrated significant decreases in interferon-related fatigue (i.e., fatigue directly occurring on the day following intramuscular injections [“induced patients”]), compared to patients (n=10) whose fatigue was independent of interferon injection timing (“non-induced patients”), and did not receive treatment with modafinil.[xxi]

1. Olek, MJ and Dawson, DM: Multiple sclerosis and other inflammatory demyelinating diseases of the central nervous system. (In) Neurology in Clinical Practice: Principles of Diagnosis and Management. 3^rd Edition WG Bradley et al eds (Boston, Butterworth-Heinemann, 2000), pp. 1431-1465.

2. Fisk, JD et al: The impact of fatigue on patients with MS. Can J Neurol Sci 21:9-14, 1994.

3. Krupp, LB et al: Fatigue in multiple sclerosis. Arch Neurol 45: 435-440, 1988.

4. Cylert^®(Premoline, Abbott Laboratories, Inc.) Physicians’ Desk Reference (Montvale, Medical Economics Co., 2002), pp. 420-421.

5. Rammohan, KW et al: Efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis; a two centre phase 2 study. J Neurol Neurosurg Psychiatry 72:179-183, 2002.

6. Terzoudi, M et al: Fatigue in multiple sclerosis: Evaluation and a new pharmacological approach [abstract P01.100]. Neurology 54 (3): A61-A62, 2000.

7. Zifko, UA et al: Modafinil in treatment of fatigue in multiple sclerosis: Results of an open-label study. J Neurol 249:983-987, 2002.

8. Dowson, A et al: PROVIGIL: A pilot, single-centre, double-blind, placeo-controlled crossover study in the treatment of fatigue in multiple sclerosis. [abstract] Presented at the Eureopean Neurological Society meeting, June 22-26, 2002, Berlin, Germany.

9. Cochran, JW: Effect of modafinil on fatigue associated with neurological illnesses. J Chronic Fatigue Syndrome 8(2): 65-70, 2001.

10. Krupp, LB et al : Reduction of fatigue associated with multiple sclerosis therapy by oral modafinil. [abstract] American Neurological Association, New York, NY, October 13-15, 2002.

Background Information on PD and Its Available Treatments

Parkinson’s Disease is a progressive, neurological disorder caused by a degeneration of dopamine neurons.[xxii] Clinical signs and symptoms of PD include resting tremor, bradykinesia, limb rigidity and postural instability.[xxiii] Sleep abnormalities and fatigue are common complaints of patients with PD.[xxiv] Many patients have difficulty sleeping at night due to depression, persistent tremors and the medications used to treat PD.^2,3 These patients often develop a reversal of sleep-wake patterns, napping excessively during the day.³

The goal in managing PD is to adequately control its accompanying signs and symptoms with medications such as levodopa and dopamine agonists. However, in addition to treating the motor disturbances associated with PD, improving daytime wakefulness and fatigue may contribute to improving a patient’s quality of life.

Rationale for Recommending PROVIGIL Therapy

Several studies that evaluated the use of modafinil for the treatment of EDS and fatigue in patients with PD are presented for your consideration.

Double-Blind, Placebo-Controlled Pilot Study with Open-label Extension

Adler et al evaluated the safety and efficacy of PROVIGIL as adjunctive therapy for the treatment of EDS associated with PD in a randomized, double-blind, placebo-controlled, cross-over study involving 21 patients. [xxv] Patients received either PROVIGIL 200 mg/day or placebo for 3 weeks (period 1), and then received the alternate therapy for 3 weeks (period 2), following a 1-week washout period,. Changes in ESS scores from baseline were compared between treatment groups for period 1 only.

The results from this study demonstrated ESS scores were significantly improved compared to baseline in patients treated with PROVIGIL, compared to placebo. In addition, improvements were reported in 35% of patients receiving PROVIGIL only (1 patient reported improvement in the placebo only group). There was no significant improvement in fatigue (as measured by the modified Fatigue Assessment Inventory) in patients treated with PROVIGIL. Treatment with PROVIGIL did not improve or worsen any other signs of PD.

Following completion of the double-blind period and a one-week wash-out period, 20 patients continued to received PROVIGIL (titrated to 400 mg/day) in an open-label fashion.[xxvi] The results of this study demonstrated significant improvement in ESS (similar to the double-blind period) and Clinical Global Impression of Change scores (both physician- and patient-rated). There were no changes in measurements of fatigue. Adverse events were mild to moderate and included somnolence (n=2) and abnormal dreaming (n=2). There were no significant changes in hemodynamic parameters.

Additional Clinical Studies

Additional clinical studies that evaluated the use of modafinil for the management of symptoms (e.g., EDS, fatigue) associated with PD are presented in Tables 1 and 2.

Table 1. Clinical Studies that evaluated the safety and efficacy of modafinil in patients with PD.

Study Design	Subjects (n)	Modafinil Dose (mg/day)	Efficacy Results	Adverse Events (AE)
2-week, DB/PC Crossover[xxvii]	6	200-400	Improved daytime sleepiness in 2 of 4 pts. (2 pts. withdrawn)	Motor function changes, chest tightness, headache dizziness, palpitations
8-week, OL Prospective; Some CPAP Treatment [xxviii]	18	50-400	Interim analysis (13 pts): Improved fatigue and global clinical condition	Headache, dizziness, nausea, nervousness
1 month, DB, PC, Crossover[xxix]	13	200 mg twice daily	Improved daytime sleepiness; fatigue not improved	No significant adverse events reported
4-week, DB, PC, Crossover[xxx]	12	200	Subjective improvement in daytime sleepiness	Insomnia, constipation, dizziness (n=1 each), dizziness (n=2)
4-week OL[xxxi]	10	Up to 400 Avg=172	Improved daytime sleepiness	Headache, generalized paresthesia, hallucinations (n=1 each)

DB=double blind; PC=placebo controlled

Table 2. Case reports describing the use of modafinil in patients with PD.

Study Design	Subjects (n)	Modafinil Dose (mg/day)	Efficacy Results	Adverse Events (AE)
Retrospective Chart Review[xxxii]	3	200-400	Improved fatigue	Nausea, dry mouth, increased frequency of hallucinations (1 pt)
Case Report[xxxiii]	1	400	Improved daytime sleepiness	No reported AEs
Case Report[xxxiv]	1	100	Improved daytime sleepiness; decreased nighttime sleep and daytime naps	No reported AEs (Restlessness and agitation with 200 mg)

1. Riley, DE and Lang, AE: Movement Disorders. In Neurology in Clinical Practice. 3^rd edition, WG Bradley et al eds. (MA, Butterworth-Heinemann, Inc.,2000), pp. 1891-1899.

2. Hauser, R and Zesiewicz: Parkinson’s Disease. 3^rd edition (Coral Springs, Florida, Merit Publishing, 2000).

3. American Sleep Disorders Association: ICSD-International Classification of Sleep Disorders: Diagnostic and Coding Manual, p. 240, 1997.

4. Adler, CH et al: Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Movement Disorders 18(3):287-293, 2003.

5. Adler, CH et al: An open-label extension study of modafinil for the treatment of daytime sleepiness in patients with Parkinson’s disease. [abstract 341.N]. Sleep 25:A251-252, 2002.

6. McKee, L et al: Modafinil in hypersomnolence complicating Parkinson’s Disease. [Abstract]. 9^th Meeting- European Neurological Society, 1999.

7. Hauser, RA et al: Evaluation and treatment of fatigue in Parkinson’s Disease. [Abstract P06.015]. Neurology 58 (suppl 3):A433, 2002.

8. Ondo, WG et al: Excessive daytime sleepiness in Parkinson’s Disease: A double-blind, placebo-controlled parallel design study of modafinil. [Abstract P06.016]. Neurology 58 (suppl 3):A433-434, 2002.

9. Hogl, B et al: Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: A double-blind, randomized, crossover, placebo-controlled polygraphic trial. Sleep 25 (8): 905-909, 2002.

10. Nieves, AV and Lang, AE: Treatment of excessive daytime sleepiness in patients with Parkinson’s disease with modafinil. Clinical Neurophamacology 25 (2):111-114, 2002.

11. Cochran, JW: Effect of modafinil on fatigue associated with neurological illnesses. J Chronic Fatigue Syndrome 8(2): 65-70, 2001.

12. Rabinstein, A et al: Modafinil for the treatment of excessive daytime sleepiness in Parkinson’s disease: a case report. Parkinsonism and Related Disorders 7:287-288, 2001

13. Happe, S et al: Successful treatment of excessive daytime sleepiness in Parkinson’s disease with modafinil. J Neurol 248:632-634, 2001

Background Information on Depression and Its Available Treatments

Depression is a chronic disorder characterized by depressed mood, diminished interest for pleasure and daily activities, significant weight gain or weight loss, reduced ability to concentrate or think, fatigue or loss of energy, and the onset of chronic insomnia or hypersomnia.[xxxv] Most patients with depression experience disrupted sleep patterns.[xxxvi] Sleep studies using polysomnography, have shown one third of patients with major depressive disorders have decreased rapid eye movement (REM) latency and increased density of REM epoch.¹ Short REM latency has been reported in patients with narcolepsy.¹

Current pharmacological treatment approaches for the management of depression include tricyclic antidepressants (eg, amitriptyline), selective serotonin reuptake inhibitors (eg, fluoxetine), serotonin/norepinephrine reuptake inhibitors (eg, venlafaxine), atypical antidepressants, and monoamine oxidase inhibitors.¹ Many patients who receive antidepressant therapy and do not fully respond to the treatment, may require other medications including central nervous system (CNS) stimulants (e.g., methylphenidate) for adjunct therapy.[xxxvii]^,4

Rationale for Recommending PROVIGIL Therapy

PROVIGIL is the first non-amphetamine drug indicated to improve wakefulness in patients with EDS associated with narcolepsy. PROVIGIL is chemically unrelated to CNS stimulants (e.g., amphetamine and methylphenidate). PROVIGIL has wake-promoting actions like amphetamine and methylphenidate, although its pharmacologic profile is not identical to that of these agents. In preclinical models, PROVIGIL appears to exert its major pharmacologic action, “wake promotion,” by selectively affecting the areas of the brain that are believed to regulate normal wakefulness. PROVIGIL does not appear to produce frequent CNS (e.g., irritability) or peripheral (e.g., palpitations, hypertension) adverse effects.

A number of studies suggest CNS stimulants (e.g., methylphenidate), that are commonly used in narcolepsy, may also be useful as adjunct therapy in patients who are partial- or non-responders to antidepressant therapy. Several studies that evaluated the use of modafinil in patients with depression are described below for your consideration.

Double-Blind, Placebo-Controlled Study

A 6-week, double-blind, placebo-controlled, multi-center pilot study was conducted in 136 patients who met the DSM-IV criteria for major depression, and who had an incomplete response to their antidepressant therapy.[xxxviii]^{,[xxxix],[xl]} Patients who were receiving an antidepressant therapy for at least 6 weeks were randomized to receive either placebo or PROVGIL (between 100 mg/day and 400 mg/day). Efficacy evaluations included the following: Hamilton Rating Score for Depression (HAM-D [overall depression]), Epworth Sleepiness Scale (ESS [subjective sleepiness]), Fatigue Severity Scale (FSS [fatigue]), Clinical Global Impression of Change (CGI-C [overall clinical condition]) and SF-36 (health-related quality of life).

The results from this study showed treatment with PROVIGIL lowered HAM-D scores (mean change from baseline: 7 points). However, there were no statistically significant differences between the PROVIGIL and placebo groups. Similarly, there were improvements on the retardation subscale of the HAM-D (assessing energy and concentration) from baseline in patients receiving modafinil. However, these changes were not significantly different from those in the placebo group.

Regarding ESS and FSS scores, significantly improvements were observed in the modafinil group as early as 1 and 2 weeks, respectively, compared to placebo. Although these improvements were maintained throughout the study, changes from baseline at final visit were not statistically significant, compared to placebo. No significant between-group differences were observed for overall clinical condition and quality of life as assessed by the CGI-C and SF-36, respectively.

PROVIGIL was generally well tolerated and the most common adverse events were headache, nervousness and insomnia (similar to placebo-treated patients).

Additional Studies

Additional information including open-label studies and case reports that evaluated the use of PROVIGIL for the management of symptoms associated with depression is presented in Tables 1 and 2, respectively.

Table 1. Open-label Studies

Study Design	Subjects (n)	Modafinil (mg/day)	Efficacy Results	Safety Profile
4-week, open-label, prospective study; adjunctive use in patients w/partial response to AD[xli]	11	200	Significant improvements in measures of depression (HAM-D), mood and overall clinical condition; generally observed within 1 week of treatment	No AEs reported
Open-label, prospective study, adjunctive use in patients with ongoing lethargy and/or apathy[xlii]	27	200-400	Significant improvements in residual symptoms as measured by Global Assessment of Functioning scores	Headache was most commonly reported AE; two patients withdrew due to AE
4-week, open-label, adjunctive use in patients with incomplete response to AD.[xliii]	24	100-400	Significant improvements in the following: HAM-D, Beck Depression Inventory, Fatigue Symptom Inventory and Fatigue Analog Scale; 14 of 20 “completers” considered themselves as “much improved” or “very much improved”; No significant improvements on cognitive batteries.	Generally well tolerated; most common AE was headache; 4 patients discontinued due to AE.
6-week, open-label, adjunctive use initiated at onset of AD treatment [xliv]	18	200	Significant improvements in HAM-D 31 scores (n=14 completers) within 1 week of therapy and throughout study; 60% of patients met HAM-D criterion for remission by week 6. Significant improvements in ESS and FSS scores.	Well tolerated; 3 patients discontinued due to AE.

AD=antidepressants; AE=adverse event

Table 2. Case Reports

Study Design	Subjects (n)	Modafinil (mg/day)	Efficacy Results	Safety Profile
Retrospective chart review; adjunctive use in patients w/partial response to AD[xlv]	7	100-200	Improvements in HAM-D scores, measures of overall well-being and fatigue generally observed within 1-2 weeks of therapy	Generally well tolerated, no reports of significant side effects, abuse or sleep disturbances
Retrospective chart review; adjunctive use in patients w/partial response to AD[xlvi]	78	Avg. dose=249	Significant improvements in measures of depression (Carroll Depression Rating Scale) & overall clinical condition	Generally well tolerated; one report of worsening of pre-existing tremors
Case report; adjunctive use in patient w/residual sleepiness with AD[xlvii]	1	200	Subjective and objective improvements in daytime sleepiness; improved depressive symptoms (HAM-D)	No AEs reported
Case report; used as monotherapy in patient w/partial response to AD[xlviii]	1	200	Significant improvement in HAM-D scores (from 19 to 0) over a 5-month period	One side effect: dry mouth
Retrospective chart review; adjunctive use in patients w/partial response to AD[xlix]	5	Not reported	4 patients had improvements as assessed by CGI-C and HAM-D (avg. improvement was 29% over 33 days)	One patient reported anxiety and tremor, no cardiovascular problems reported

Bipolar Disorder

Several of the studies described above, which evaluated the use of PROVIGIL as adjunct therapy in patients with depression included a subset of patients with bipolar disorder.^8,9,15 In these three studies, patients were categorized as follows: bipolar disorder/depressed type (n=3), bipolar depression (n=13), and bipolar disorder type I /depressed (n=4) . As noted, the results of these studies demonstrated PROVIGIL was an effective adjunct to antidepressants, however, no specific efficacy or safety evaluation of this subset of patients (i.e., bipolar) was described.

Seasonal Affective Disorder

In an 8-week, open-label study, thirteen patients (12 were evaluated for efficacy; 9 completed) with SAD received PROVIGIL (100 mg/day in am, or 200 mg/day as a split dose) as monotherapy (n=6), or as adjunctive therapy (n=6) with antidepressants.[l] The results of this study demonstrated treatment with PROVIGIL significantly reduced fatigue and improved wakefulness as measured subjectively by the Fatigue Severity Scale and Epworth Sleepiness Scale, respectively, compared to baseline. Symptoms of depression and overall clinical condition were also improved. The most common adverse events included headache, dry mouth, and dyspepsia.

The pharmacological actions of modafinil (improved wakefulness) coupled with the preliminary positive findings from these clinical studies suggest PROVIGIL may be a viable therapeutic option for the treatment of certain symptoms associated with depression.

1. Grief, Reactive Depression, Endogenous Depression and Manic-Depressive Disease. In: Principles of

Neurology. 6^th edition, RD Adams et al, eds. (New York, McGraw-Hill, Inc., 1997), pp.1531-1543.

2. DeBattista, C et al: Modafinil as adjunctive in treatment of fatigue and hypersomnia in major depression
abstract NR532, Poster Presentation]. American Psychiatric Association annual meeting, New Orleans, LA, May 2001.

3. Feighner, JP et al: Combined MAOI, TCA and direct stimulant therapy of treatment-resistant depression. J Clin
Psychiatry 48(6): 206-209, June 1985.

4. Data on file (Protocol C1538a/412/DP/US), Cephalon, Inc.

5. Doghramji, K et al: Adjunct modafinil for fatigue and wakefulness in MDD. [abstract 18] Presented at the Annual Meeting of the American Psychiatric Association, Philadelphia, PA, May 19-23, 2002.

6. Menza, MA et al: Effect of adjunct modafinil on energy and concentration in depressed patients. [abstract 111] Presented at the Annual Meeting of the American Psychiatric Association, Philadelphia, PA, May 19-23, 2002.

7. Kogeorgos, J: Modafinil as augmentation of antidepressant therapy. [abstract P.1.101] J of Eur College of Neuropsychopharm 12(3): S211, 2002.

8. Markovitz, PJ and Wagner, S: An open-label trial of modafinil augmentation in patients with partial response to antidepressant therapy [Letter]. J of Clinical Psychopharmacology 23(2):1-3, 2003.

9. DeBattista, C et al: Modafinil as adjunctive in treatment of fatigue and hypersomnia in major depression [abstract NR532, Poster Presentation]. American Psychiatric Association annual meeting, New Orleans, LA, May 2001.

10. Hassman, H et al: Modafinil combined with SSRI enhances the degree and rate of benefit in major depression [abstract NR410]. Annual Meeting of American Psychiatric Association, San Francisco, CA, May 17-22, 2003.

11. Menza, MA et al: Modafinil augmentation of antidepressant treatment in depression. J Clin Psych 61(5):378-381, 2000.

12. Nasr, S. J.: Adjunctive use of modafinil in a psychiatric practice [Poster Presentation]. Meeting of Biology Psychiatry, Philadelphia, PA, May 16 –18, 2002.

13. Holder, G et al: Reduction of daytime sleepiness in a depressive patient during adjunct treatment with modafinil [Letter]. Journal of Psychiatric Research 36:49-52, 2002.

14. Kaufman, KR et al: Modafinil monotherapy in depression. EurPsychiatry 17:167-9, 2002.

15. Schwartz, TL et al: Modafinil in the treatment of depression with severe comorbid medical illness [Letter]. Psychosomatics 43 (3):336-337,2002.

16. Lundt, L: Modafinil improves wakefulness and reduces fatigue in patients with seasonal affective disorder/winter depression: An open-label study [abstract 0963.Q]. Sleep 26: A382, 2003.

Background Information on ADHD and Its Available Treatments

Attention Deficit/Hyperactivity Disorder is a diagnosis applied to children and adults who consistently display certain characteristic behaviors over a period of time. The most common core features include inattention, distractibility, impulsivity, and hyperactivity.[li] ADHD affects approximately 2% to 9%-- of school age children.¹ Up to 60%- of children continue to have significant symptoms and behaviors that persist throughout adulthood and impacts their lives on various fronts including job performance, and family and social relationships.¹

Current approaches to the management of symptoms associated with ADHD include the use of central nervous system (CNS) stimulants (e.g., methylphenidate , dextroamphetamine, and pemoline) and antidepressant medications (e.g., bupropion, venlafaxine, and mirtazapine).^1,[lii] These treatments have a 70 to 90 percent response rate, but may produce undesirable side effects.²

Rationale for Recommending PROVIGIL Therapy

CNS stimulants (e.g., methylphenidate) that are effective for the treatment of narcolepsy are also indicated for ADHD. The hypofunctionality of the frontal cortex region of the brain has been implicated in the pathophysiology of ADHD symptoms. Preclinical studies have shown modafinil, similar to stimulants, activates the frontal cortex region, however, via a non-dopaminergic pathway. Several clinical studies that evaluated the effectiveness and safety profile of PROVIGIL in patients with ADHD are presented for your consideration.

Adult Clinical Studies

1) Taylor and Russo conducted a double-blind, placebo-controlled, three-period, crossover study in 22 adult patients (aged 18 to 59) to compare the effects of modafinil with dextroamphetamine (d-AMP) in the treatment of ADHD symptoms.[liii] ADHD subtypes of study patients included: inattentive (n=11), hyperactive-impulsive (n=2), mixed (n=9). The mean daily dose of modafinil was 207 mg (maximum 400 mg). The results of this study indicated both modafinil and d-AMP improved DSM-IV ADHD symptom scales (both inattention and hyperactivity sub-scores) and Controlled Oral Word Association Test performances, compared to placebo. Copeland Symptom Checklist for Adult Attention Deficit Disorder scores were improved in the modafinil treatment group only. Modafinil was generally well tolerated; the most common adverse events included insomnia, irritability, muscle tension, and anorexia.

2) A double-blind, placebo-controlled clinical trial was conducted in 113 adult patients with ADHD. In this study, the effect of modafinil (100 mg/day or 400 mg/day) on symptoms of ADHD (as measured by the DSM-IV ADHD rating scale) was not different than that of placebo.[liv] Modafinil was generally well tolerated in this study.

3) In a case report, two patients (ages 17 and 21) reported significant improvements in clinical symptoms (e.g. improved concentration) while receiving modafinil (200-400 mg/day) for up to 4 months of observation.[lv] No adverse events were reported during treatment with modafinil.

Pediatric Clinical Studies

1) In a four-week, double-blind, placebo-controlled, 248 children and adolescents (aged 6 to 13 years) with ADHD (symptoms included both hyperactivity and inattentiveness) were evaluated to determine the efficacy and safety of four modafinil dosing regimens. In this study, children who weighed <30 kg received 300 mg/day administered once daily (in am) or as a split dose (100/200 mg [am and midday] or 200/100 mg [am and midday]); children who weighed ≥30 kg received 400 mg/day as a split dose.[lvi]

The results of a sub-analysis (n=198; 400 mg/day group not included) of this study demonstrated modafinil 300 mg/day administered once daily or as a split dose (200/100 mg) significantly improved symptoms of ADHD as assessed by the teacher-completed DSM-IV ADHD Rating Scale. Symptoms of ADHD were also significantly improved in the 300 mg/day single dose group as assessed by the parent-completed DSM-IV ADHD Rating Scale and the parent version of the Connors’ ADHD Scales (Total and ADHD Index). Modafinil was generally well tolerated; the most frequently reported adverse events included insomnia, abdominal pain, anorexia, cough, fever and rhinitis.

2) In a 4-week analog classroom study, forty eight children (aged 6-13) with ADHD were treated with placebo or modafinil (100, 200, 300 or 400 mg/day [only children ≥30 kg] and evaluated for symptoms of ADHD.[lvii] The results of this study demonstrated improvements on the parent-completed DSM-IV ADHD Rating Scale in the 300 and 400 mg/day groups. Adverse events that occurred more frequently in the modafinil group than in the placebo group included abdominal pain and headache.

3) Rugino and Copley conducted an open-label study to evaluate the effects of once-daily dosing of modafinil (100-400 mg/day) on clinical features of ADHD in 15 children (age range: 5-15 years old).[lviii] The average duration of treatment was 4.6 weeks. The results from this study demonstrated significant improvements in patients’ clinical response from baseline as assessed by validated efficacy measures (e.g., Conners’ Parent and Teaching Rating Scale-Revised, ADHD Rating Scale-IV). Modafinil was generally well tolerated, side effects were mild and included delayed onset of sleep, light-headedness and headache. Four patients discontinued the study; one withdrawal was due to an adverse event (night awakening with tremor) that was completely resolved upon medication withdrawal.

4) A 6-week, double-blind, placebo-controlled study was conducted in 24 children who met the DSM-IV criteria for ADHD.[lix] The results of this study indicated patients treated with modafinil showed significant improvements on the Test of Variables of Attention (TOVA) scores, as well as improvements in several other rating scale sub-scores, compared to placebo. One patient discontinued due to emesis, which resolved completely upon discontinuation of therapy.

1. Wilens, TE et al: Pharmacology of adult attention deficit/hyperactivity disorder: A review. J Clin Psychopharmacol 15 (4): 270-270, 1995.

2. Rugino, TA and Copley, TA: Effects of modafinil in children with attention-deficit/hyperactivity disorder: An open-label study. J Am Acad Child Adolesc Psychiatry 40 (2): 230-235, 2001.

3. Taylor, F and Russo, J: Efficacy of modafinil compared to dextroamphetamine for the treatment of attention-deficit-hyperactivity disorder in adults. J Child Adolesc Psychopharmacol 10(4): 311-320, 2000.

4. Press Release 7/31/02, Cephalon Inc.

5. Norton, J: Use of modafinil in attention deficit/hyperactivity disorder. Primary Psychiatry 9(9):48-49, 2002.

6. Biederman, J: Modafinil improves ADHD symptoms in children in a randomized, double-blind, placebo-controlled study [abstract 36]. Presented at the Annual Meeting of the American Psychiatric Association, San Francisco, CA, May 17-22, 2003.

7. Swanson, JM: Modafinil in children with ADHD: A randomized, placebo-controlled study [abstract 44]. Presented at the Annual Meeting of the American Psychiatric Association, San Francisco, CA, May 17-22, 2003.

8. Rugino, TA and Copley, TA: Effects of modafinil in children with attention-deficit/hyperactivity disorder: An open-label study. J Am Acad Child Adolesc Psychiatry 40(2): 230-235, 2001.

9. Rugino, TA et al: Modafinil in children with ADHD: A double-blind, placebo-controlled study. [abstract 77] Presented at the Annual Meeting of the American Psychiatric Association, Philadelphia, PA, May 19-23, 2002.

More recently there have been additional sources in regard to the efficacy of modafinil. These articles include, but are not limited to:

Stahl SM. Essential Psychopharmacology; Neuroscientific Basis and Practical Applications. 3^rd ed. Cambridge, UK; University of Cambridge; 2004

The Journal of Clinical Psychiatry; Volume 64 2003 Supplement 14

Contains seven articles which support the use of modafinil:

Introduction: Optimizing Wakefulness in Patients with Fatigue and Executive Dysfunction. Stephen M. Stahl

Primary Care Commentary: Fatigue and Executive Dysfunction in the Primary Care Setting. Larry Culpepper

Brain Circuits Determine Destiny in Depression: A Novel Approach to the Psychopharmacology of Wakefulness, Fatigue, and Executive Dysfunction in Major Depressive Disorder. Stephen M. Stahl, Lishu Zhang, Cristina Damatarca, and Meghan Grady

Role of Executive Function in Late-Life Depression. George S. Alexopoulos

Treatment Strategies for Sleep Disturbance in Patients with Depression. Karl Doghramji

Symptoms of Fatigue and Cognitive/Executive Dysfunction in Major Depressive Disorder Before and After Antidepressant Treatment. Maurizio Fava

Role of Executive Function in ADHD. James M. Swanson

Other articles include:

Pediatr Neurol. 2003 Aug;29(2):136-42.

Background Information on Narcolepsy and Its Available Treatments

Background Information on Idiopathic Hypresomnia (IH) and Its Available Treatments

Phase 3 Pivotal Study

Additional Studies

Background Information on MS fatigue

Other Clinical Studies

1. Olek, MJ and Dawson, DM: Multiple sclerosis and other inflammatory demyelinating diseases of the central nervous system. (In) Neurology in Clinical Practice: Principles of Diagnosis and Management. 3rd Edition WG Bradley et al eds (Boston, Butterworth-Heinemann, 2000), pp. 1431-1465.

2. Fisk, JD et al: The impact of fatigue on patients with MS. Can J Neurol Sci 21:9-14, 1994.

Background Information on PD and Its Available Treatments

Double-Blind, Placebo-Controlled Pilot Study with Open-label Extension

Additional Clinical Studies

Study Design

Study Design

Background Information on Depression and Its Available Treatments

Double-Blind, Placebo-Controlled Study

Adult Clinical Studies

Pediatric Clinical Studies

1. Olek, MJ and Dawson, DM: Multiple sclerosis and other inflammatory demyelinating diseases of the central nervous system. (In) Neurology in Clinical Practice: Principles of Diagnosis and Management. 3rd Edition WG Bradley et al eds (Boston, Butterworth-Heinemann, 2000), pp. 1431-1465.

2. Fisk, JD et al: The impact of fatigue on patients with MS. Can J Neurol Sci 21:9-14, 1994.

1. Olek, MJ and Dawson, DM: Multiple sclerosis and other inflammatory demyelinating diseases of the central nervous system. (In) Neurology in Clinical Practice: Principles of Diagnosis and Management. 3^rd Edition WG Bradley et al eds (Boston, Butterworth-Heinemann, 2000), pp. 1431-1465.

1. Olek, MJ and Dawson, DM: Multiple sclerosis and other inflammatory demyelinating diseases of the central nervous system. (In) Neurology in Clinical Practice: Principles of Diagnosis and Management. 3^rd Edition WG Bradley et al eds (Boston, Butterworth-Heinemann, 2000), pp. 1431-1465.