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 al^4	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)