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MODAFINIL AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Modafinil and armodafinil (R-enantiomer of modafinil) are wakefulness-promoting agents acting as a central nervous system stimulant. They are chemically and pharmacologically unrelated to other CNS stimulants, such as methylphenidate, amphetamine, or pemoline.

Specific Substances

    A) ARMODAFINIL
    1) Armodafinilo
    2) Armodafinilum
    3) CEP-10953
    4) CRL-40982
    5) 2-[(R)-(Diphenylmethyl)sulfinyl]acetamide
    6) CAS 112111-43-0
    MODAFINIL
    1) CEP-1538
    2) CRL-40476
    3) Modafinilo
    4) Modafinilum
    5) 2-[(diphenylmethyl)sulfinyl]acetamide
    6) CAS 68693-11-8

Available Forms Sources

    A) FORMS
    1) Modafinil is available in the US as 100 mg and 200 mg tablets (Prod Info PROVIGIL(R) oral tablets, 2008).
    2) Armodafinil is available in the US as 50 mg, 150 mg, and 250 mg tablets (Prod Info NUVIGIL(TM) oral tablets, 2008).
    B) USES
    1) Modafinil and armodafinil are indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder (Prod Info NUVIGIL(TM) oral tablets, 2008; Prod Info PROVIGIL(R) oral tablets, 2008).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Modafinil and armodafinil are indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder.
    B) PHARMACOLOGY: Modafinil and armodafinil (R-enantiomer of modafinil) are wakefulness-promoting agents acting as a central nervous system stimulant. They are chemically and pharmacologically unrelated to other CNS stimulants, such as methylphenidate, amphetamine, or pemoline.
    C) EPIDEMIOLOGY: Overdose is very rare.
    D) WITH THERAPEUTIC USE
    1) MODAFINIL: COMMON: Headache, anxiety, dizziness, agitation, insomnia, nausea, diarrhea, anorexia, and dry mouth are commonly reported following therapeutic doses of modafinil. INFREQUENT: Tachycardia, Hypertension, chest pain, ECG abnormalities, elevated liver enzyme levels, and oro-facial dyskinesias have infrequently occurred with modafinil therapy. Modafinil is classified as a Schedule IV drug and may cause psychoactive and euphoric effects, with alterations in mood and perception. ARMODAFINIL: Headache, dizziness, nausea, and insomnia have been reported following therapeutic doses of armodafinil.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Effects that have been observed in limited number of exposures include: Nausea, abdominal pain, vomiting, diarrhea, dry mouth, headache, insomnia, excitation, dizziness, anxiety, dyskinesia, dystonia, tremor, dysarthria, tachycardia, erythema, flushing, hypertension, prolonged QTc interval, palpitations, edema, chest pain, and elevated creatine phosphokinase.
    2) SEVERE: Severe hypertension and tachycardia, agitated delirium and hallucinations are possible.
    0.2.20) REPRODUCTIVE
    A) Modafinil is classified as FDA pregnancy category C.
    B) Modafinil administration has resulted in congenital malformations in rats.

Laboratory Monitoring

    A) Monitor vital signs, ECG, and liver enzyme concentrations after significant overdose.
    B) Monitor fluid and electrolyte status in patients with significant vomiting or diarrhea.
    C) Monitor mental status and perform a neurologic exam in symptomatic patients.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Monitor neurologic status. Alterations in heart rhythm and blood pressure may occur. Monitor vital signs. Obtain a baseline ECG and institute continuous cardiac monitoring in patients with tachycardia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise is present. If therapy is required, a short-acting, cardioselective agent such as esmolol is generally preferred.
    C) DECONTAMINATION
    1) PREHOSPITAL: Consider activated charcoal in patients who are awake and able to maintain their airway.
    2) HOSPITAL: Consider activated charcoal after a potentially toxic ingestion and if the patient is able to maintain airway or if airway is protected.
    D) AIRWAY MANAGEMENT
    1) Airway protection may be required in patients with altered mental status.
    E) ANTIDOTE
    1) None
    F) ENHANCED ELIMINATION
    1) There is no information regarding the effectiveness of hemodialysis for enhancing the elimination of modafinil following an overdose ingestion.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic patients with inadvertent ingestions of less than 400 mg can be managed at home.
    2) OBSERVATION CRITERIA: Symptomatic patients, those ingesting 400 mg or more, and those with deliberate overdose should be sent to a healthcare facility for evaluation and treated until symptoms resolve.
    3) ADMISSION CRITERIA: Patients with significant persistent hypertension, tachycardia, severe neurologic symptoms, or dysrhythmias (eg, prolonged QT) should be admitted to the hospital.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected modafinil or armodafinil overdoses, the possibility of multi-drug involvement should be considered.
    I) PHARMACOKINETICS
    1) ARMODAFINIL: Approximately 60% protein-bound; the apparent Vd is approximately 42 L; the apparent terminal half-life is approximately 15 hours. MODAFINIL: Approximately 62% protein-bound; the apparent Vd is approximately 0.9 L/kg; the apparent terminal half-life is 10 to 12 hours.
    J) DIFFERENTIAL DIAGNOSIS
    1) Poisoning with theophylline, herbal remedies, methylxanthines, albuterol, or sympathomimetics.

Range Of Toxicity

    A) TOXICITY: A specific minimum toxic dose of modafinil has not been established, doses of less than 400 mg have not been associated with significant toxicity. In a study of modafinil overdoses (age range, 1.25 to 72 years; mean dose: 939 mg; median dose: 400 mg; range, 25 to 16,100 mg), no major effects or death were reported. ADULTS: Patients have tolerated modafinil doses up to 400 mg/day as a single dose. Ingestion of 4500 mg modafinil by an adult resulted in insomnia, excitation, and tachycardia. CHILDREN: In one study, no significant toxicity was reported in children less than 6 years of age after ingesting less than 400 mg of modafinil. Ingestion of 5 grams of modafinil by a 15-year-old girl resulted in severe headache, nausea, abdominal pain, insomnia, dyskinesia, prolonged QTc interval, and tachycardia.
    B) THERAPEUTIC DOSE: ARMODAFINIL: ADULTS: 150 mg or 250 mg as a single dose orally. CHILDREN: Safety and efficacy of armodafinil administration in children less than 17 years of age has not been established. MODAFINIL: ADULTS: 200 mg orally once daily. CHILDREN: Safety and efficacy of modafinil administration in children less than 16 years of age has not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Modafinil and armodafinil are indicated to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder.
    B) PHARMACOLOGY: Modafinil and armodafinil (R-enantiomer of modafinil) are wakefulness-promoting agents acting as a central nervous system stimulant. They are chemically and pharmacologically unrelated to other CNS stimulants, such as methylphenidate, amphetamine, or pemoline.
    C) EPIDEMIOLOGY: Overdose is very rare.
    D) WITH THERAPEUTIC USE
    1) MODAFINIL: COMMON: Headache, anxiety, dizziness, agitation, insomnia, nausea, diarrhea, anorexia, and dry mouth are commonly reported following therapeutic doses of modafinil. INFREQUENT: Tachycardia, Hypertension, chest pain, ECG abnormalities, elevated liver enzyme levels, and oro-facial dyskinesias have infrequently occurred with modafinil therapy. Modafinil is classified as a Schedule IV drug and may cause psychoactive and euphoric effects, with alterations in mood and perception. ARMODAFINIL: Headache, dizziness, nausea, and insomnia have been reported following therapeutic doses of armodafinil.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE: Overdose effects are anticipated to be an extension of adverse effects observed following therapeutic doses. Effects that have been observed in limited number of exposures include: Nausea, abdominal pain, vomiting, diarrhea, dry mouth, headache, insomnia, excitation, dizziness, anxiety, dyskinesia, dystonia, tremor, dysarthria, tachycardia, erythema, flushing, hypertension, prolonged QTc interval, palpitations, edema, chest pain, and elevated creatine phosphokinase.
    2) SEVERE: Severe hypertension and tachycardia, agitated delirium and hallucinations are possible.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) HYPERTENSION
    a) Hypertension has occurred following therapeutic administration of modafinil and was reversible upon discontinuation of therapy (Prod Info Provigil(R), modafinil, 1999; Wong et al, 1999).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) TACHYCARDIA
    a) Tachycardia was reported after therapeutic administration of modafinil (Wong et al, 1999).
    B) WITH POISONING/EXPOSURE
    1) TACHYCARDIA
    a) Tachycardia was reported following an overdose ingestion of 4500 mg modafinil (Prod Info PROVIGIL(R) oral tablets, 2008; Lyons & French, 1991).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) OCULAR DISTURBANCES
    a) Floating bodies and dry eyes have been infrequently reported with modafinil therapy (Laffont et al, 1994).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Increased heart rate (160 to 170 bpm) was reported in a patient following ingestion of one 800 mg dose of modafinil. The patient's heart rate normalized 2 days after discontinuation of modafinil therapy (Wong et al, 1999).
    b) INCIDENCE: Palpitations were reported in 5 of 24 patients (21%) following therapeutic administration of modafinil during a clinical trial (Wong et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 21-year-old woman experienced tachycardia following an overdose ingestion of 4500 mg modafinil in a suicide attempt (Lyons & French, 1991).
    b) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, tachycardia (mean maximum heart rate 120 beats/min; range 100 to 150 beats/min) was reported in 38 (28%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    c) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, tachycardia (range, 101 to 168 beats/min) was reported in 23 (26.4%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    1) CASE REPORT: Tachycardia (115 beats/min) lasting for 13 hours developed in a 37-year-old woman who presented with agitation, visual hallucinations, marked orofacial dyskinesia, and dysarthria after ingesting 1600 mg of modafinil. Following supportive therapy, she recovered and was discharged 20 hours after ingestion of modafinil (Carstairs et al, 2010).
    2) CASE REPORT: A 24-year-old woman developed tachycardia (168 beats/min) and hypertension (BP 168/131 mm Hg) after ingesting 400 mg modafinil instead of her usual dose of 200 mg. She recovered following supportive therapy (Carstairs et al, 2010).
    d) CASE REPORT: Tachycardia (140 beats/min) developed in a 19-year-old man who also experienced agitated delirium and hypertension (150/93 mmHg) after ingesting 6 grams of modafinil. Following 48 hours of supportive care, he recovered completely (Spiller et al, 2009).
    e) CASE REPORT: Tachycardia developed in a 15-year-old girl who also experienced severe headache, nausea, abdominal pain, prolonged QTc interval, insomnia, and dyskinesia after ingesting 5 grams of modafinil in a suicide attempt. She recovered following supportive care (Neuman et al, 2009).
    B) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) CASE REPORT: Hypertension (160/115 mmHg) occurred in a patient after ingestion of a single 800 mg dose of modafinil. The patient's blood pressure normalized 2 days after cessation of modafinil therapy (Wong et al, 1999).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, hypertension (mean systolic and diastolic pressures 159 and 93 mmHg, respectively) was reported in 6 (4%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    b) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, hypertension was reported in 6 (6.9%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    1) CASE REPORT: A 24-year-old woman developed tachycardia (168 beats/min) and hypertension (BP 168/131 mm Hg) after ingesting 400 mg modafinil instead of her usual dose of 200 mg. She recovered following supportive therapy (Carstairs et al, 2010).
    c) CASE REPORT- Hypertension (150/93 mmHg) developed in a 19-year-old man who also experienced agitated delirium and tachycardia (140 beats/min) after ingesting 6 grams of modafinil. Following 48 hours of supportive care, he recovered completely (Spiller et al, 2009).
    C) CHEST PAIN
    1) WITH THERAPEUTIC USE
    a) Chest pain and tightness have infrequently occurred with modafinil therapy (Laffont et al, 1994).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, chest pain was reported in 6 (4%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    b) CASE SERIES: In a retrospective chart review of modafinil exposures (n=87) reported to the California Poison Control system over an 11-year period, a 65-year-old man developed chest pain after ingesting modafinil 800 mg instead of acetaminophen (Carstairs et al, 2010).
    D) PALPITATIONS
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, palpitations was reported in 2 (2.3%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    E) EDEMA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, edema was reported in 1 (1.1%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdose. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    F) ELECTROCARDIOGRAM ABNORMAL
    1) WITH THERAPEUTIC USE
    a) ECG abnormalities, including transient ischemic T-wave changes, have been reported following therapeutic administration of modafinil, particularly in patients with mitral valve prolapse or left ventricular hypertrophy (Prod Info PROVIGIL(R) oral tablets, 2008; Wong et al, 1999). Administration of modafinil is NOT recommended in patients with a history of left ventricular hypertrophy or those with a history of dysrhythmias, ECG changes, or chest pain associated with CNS stimulant use.
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Prolonged QTc interval (457 and 460 milliseconds on 2 different measurements) developed in a 15-year-old girl who also experienced severe headache, nausea, abdominal pain, tachycardia, insomnia, and dyskinesia after ingesting 5 grams of modafinil in a suicide attempt. She recovered following supportive care (Neuman et al, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) WITH THERAPEUTIC USE
    a) MODAFINIL
    1) Headache (dose-related) was reported in 34% of patients receiving modafinil (200 mg, 300 mg, or 400 mg/day; n=934) compared with 23% of patients receiving placebo (n=567) during 6 clinical trials evaluating adults with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder (Prod Info PROVIGIL(R) oral tablets, 2008).
    2) INCIDENCE: Headache was reported in 11 of 24 patients (34%) following therapeutic administration of modafinil during a clinical trial (Wong et al, 1999).
    b) ARMODAFINIL
    1) Headache was reported in 11%, 16%, and 28% of patients on placebo, armodafinil 150 mg, and armodafinil 250 mg, respectively, in patients with narcolepsy in a 12-week, multicenter, randomized, double-blind, placebo-controlled study (n=196). In general, headache was considered mild or moderate in severity, occurred within the first 2 weeks of therapy, and was transient (Harsh et al, 2006).
    2) Headache appeared to be dose-related in patients taking armodafinil for narcolepsy and shift work sleep disorder. Headache occurred in 23% (n=198) of patients receiving armodafinil 250 mg and in 14% (n=447) of patients receiving armodafinil 150 mg compared to 9% of patients receiving placebo in a controlled clinical trials (Prod Info NUVIGIL(TM) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, headache was reported in 9 (7%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    b) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, headache was reported in 8 (9.2%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    c) CASE REPORT: Severe headache developed in a 15-year-old girl who also experienced nausea, abdominal pain, tachycardia, prolonged QTc interval, insomnia, and dyskinesia after ingesting 5 grams of modafinil in a suicide attempt. She recovered following supportive care (Neuman et al, 2009).
    B) CENTRAL STIMULANT ADVERSE REACTION
    1) WITH THERAPEUTIC USE
    a) Insomnia, anxiety, excitation, agitation, and dizziness may occur with high-dose modafinil therapy (Prod Info PROVIGIL(R) oral tablets, 2008; Broughton et al, 1997; Besset et al, 1996; Lyons & French, 1991).
    b) INCIDENCE: Insomnia and anxiety were reported in 21% of patients (n=24) following therapeutic administration of modafinil during a clinical trial (Wong et al, 1999).
    c) Insomnia occurred in 5% (n=645) of patients receiving armodafinil (250 mg and 150 mg) compared to 1% of patients receiving placebo (n=445) in clinical trials (Prod Info NUVIGIL(TM) oral tablets, 2007). Insomnia appeared to be dose-related in patients taking armodafinil for narcolepsy and shift work sleep disorder. Insomnia occurred in 6% (n=198) of patients receiving armodafinil 250 mg and in 4% (n=447) of patients receiving armodafinil 150 mg compared to 1% of patients receiving placebo in controlled clinical trials (Prod Info NUVIGIL(TM) oral tablets, 2007).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Insomnia and excitation were reported in a 21-year-old female following an intentional modafinil overdose ingestion of 4500 mg (Prod Info Provigil(R), modafinil, 1999; Lyons & French, 1991).
    b) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, insomnia (24%), agitation (20%), increased anxiety (18%), and hyperactivity (2%) were reported in patients (n=137; mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    c) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, agitation (n=14; 16.1%), anxiety (n=11; 12.6%), dysarthria (n=2; 2.3%), and insomnia (n=4; 4.6%) were reported in patients (n=87; mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    1) CASE REPORT: A 37-year-old woman developed agitation, visual hallucinations, marked orofacial dyskinesia, dysarthria, and tachycardia after ingesting 1600 mg of modafinil. Following supportive therapy, she recovered and was discharged 20 hours after ingestion of modafinil (Carstairs et al, 2010).
    d) CASE REPORT- A 19-year-old man presented with agitated delirium, tachycardia, and hypertension after ingesting 6 grams of modafinil. Following 48 hours of supportive care, he recovered completely (Spiller et al, 2009).
    e) CASE REPORT: Insomnia developed in a 15-year-old girl who also experienced severe headache, nausea, abdominal pain, tachycardia, prolonged QTc interval, and dyskinesia after ingesting 5 grams of modafinil in a suicide attempt. She recovered following supportive care (Neuman et al, 2009).
    C) DYSKINESIA
    1) WITH THERAPEUTIC USE
    a) Oro-facial dyskinesias following modafinil therapy are infrequent, with an incidence of 2% during a phase III clinical trial (n=365) (S Sweetman , 2002; Prod Info Provigil(R), modafinil, 1999).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: Dyskinesia developed in a 15-year-old girl who also experienced severe headache, nausea, abdominal pain, tachycardia, prolonged QTc interval, and insomnia after ingesting 5 grams of modafinil in a suicide attempt. She recovered following supportive care (Neuman et al, 2009).
    b) CASE REPORT: A 37-year-old woman developed agitation, visual hallucinations, marked orofacial dyskinesia, dysarthria, and tachycardia after ingesting 1600 mg of modafinil. Following supportive therapy, she recovered and was discharged 20 hours after ingestion of modafinil (Carstairs et al, 2010).
    D) DYSTONIA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, dystonia was reported in 7 (5%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    b) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, dystonia was reported in 6 (6.9%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    E) TREMOR
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, tremor was reported in 6 (4%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    b) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, tremor was reported in 6 (6.9%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    F) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) ARMODAFINIL
    1) Dizziness was reported in 0%, 8%, and 3% of patients on placebo, armodafinil 150 mg, and armodafinil 250 mg, respectively, in patients with narcolepsy in a 12-week, multicenter, randomized, double-blind, placebo-controlled study (n=196). In general, dizziness was considered mild or moderate in severity, occurred within the first 2 weeks of therapy, and was transient (Harsh et al, 2006).
    2) ARMODAFINIL: In patients diagnosed with narcolepsy and shift work sleep disorder, dizziness occurred in 5% (n=645) of patients receiving armodafinil (250 mg and 150 mg) compared to 2% of patients receiving placebo (n=445) in clinical trials (Prod Info NUVIGIL(TM) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, dizziness developed in 18% of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    b) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, dizziness developed in 5 (5.7%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA
    1) WITH THERAPEUTIC USE
    a) MODAFINIL
    1) Nausea was reported in 11% of patients receiving modafinil (200 mg, 300 mg, or 400 mg/day; n=934) compared with 3% of patients receiving placebo (n=567) during 6 clinical trials evaluating adults with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder (Prod Info PROVIGIL(R) oral tablets, 2008).
    b) ARMODAFINIL
    1) Nausea was reported in 0%, 14%, and 7% of patients on placebo, armodafinil 150 mg, and armodafinil 250 mg, respectively, in patients with narcolepsy in a 12-week, multicenter, randomized, double-blind, placebo-controlled study (n=196). In general, nausea was considered mild or moderate in severity, occurred within the first 2 weeks of therapy, and was transient (Harsh et al, 2006).
    2) Nausea appeared to be dose-related in patients taking armodafinil for narcolepsy and shift work sleep disorder. Nausea occurred in 9% (n=198) of patients receiving armodafinil 250 mg and in 6% (n=447) of patients receiving armodafinil 150 mg compared to 3% of patients receiving placebo in controlled clinical trials (Prod Info NUVIGIL(TM) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, nausea was reported in 11 (8%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    b) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, stomach upset/nausea was reported in 4 (4.6%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    c) CASE REPORT: Nausea developed in a 15-year-old girl who also experienced severe headache, abdominal pain, tachycardia, prolonged QTc interval, insomnia, and dyskinesia after ingesting 5 grams of modafinil in a suicide attempt. She recovered following supportive care (Neuman et al, 2009).
    B) VOMITING
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, vomiting was reported in 4 (3%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    C) DIARRHEA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, diarrhea was reported in 3 (2%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    D) APTYALISM
    1) WITH THERAPEUTIC USE
    a) Dry mouth was frequently reported with modafinil therapy and the incidence appeared to be directly proportional to the dose of modafinil (Broughton et al, 1997; Laffont et al, 1994).
    b) MODAFINIL: Dry mouth was reported in 4% of patients receiving modafinil (200 mg, 300 mg, or 400 mg/day; n=934) as compared with 2% of patients receiving placebo (n=567) during 6 clinical trials evaluating adults with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder (Prod Info PROVIGIL(R) oral tablets, 2008).
    2) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective multi-poison center chart review of patients from 11 states, dry mouth was reported in 9 (7%) of 137 patients (mean age 22 years; range 1 to 82 years) after modafinil overdoses. Mean and median ingested doses (known for 108 patients) were 1031 and 400 mg, respectively (range, 50 to 7000 mg) (Spiller et al, 2009).
    E) ABDOMINAL PAIN
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: Abdominal pain developed in a 15-year-old girl who also experienced severe headache, nausea, tachycardia, prolonged QTc interval, insomnia, and dyskinesia after ingesting 5 grams of modafinil in a suicide attempt. She recovered following supportive care (Neuman et al, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) Elevated liver enzyme levels have been infrequently reported following modafinil therapy (Prod Info PROVIGIL(R) oral tablets, 2008).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ERYTHEMA
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, erythema was reported in 2 (2.3%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).
    B) FLUSHING
    1) WITH POISONING/EXPOSURE
    a) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, flushing was reported in 2 (2.3%) of 87 patients (mean age 29.9 years; range 1.25 to 72 years) after modafinil overdoses. Mean and median ingested doses were 939 and 400 mg, respectively (range, 25 to 16,100 mg) (Carstairs et al, 2010).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT- Elevated creatine phosphokinase (54,158) was reported in a 19-year-old man who presented with agitated delirium, tachycardia (140 beats/min), and hypertension (150/93 mmHg) after ingesting 6 grams of modafinil. Following 48 hours of supportive care, he recovered completely (Spiller et al, 2009).

Reproductive

    3.20.1) SUMMARY
    A) Modafinil is classified as FDA pregnancy category C.
    B) Modafinil administration has resulted in congenital malformations in rats.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) RATS - An increase in resorption, hydronephrosis, and skeletal variations occurred in rats following maternal administration of modafinil at a dose of 200 mg/kg/day (approximately 10 times the maximum recommended daily dose of 200 mg on a mg/m(2) basis) (Prod Info Provigil(R), modafinil, 1999).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Modafinil is classified as FDA pregnancy category C (Prod Info Provigil(R), modafinil, 1999).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether modafinil is excreted in human milk; however, breastfeeding is not recommended due to potential risk to the infant (Prod Info Provigil(R), modafinil, 1999).

Genotoxicity

    A) ARMODAFINIL: There was no evidence of genotoxicity or mutagenicity in the following tests: In vitro bacterial reverse mutation assay in human lymphocytes and an in vitro chromosomal aberration assay in human lymphocytes (Prod Info NUVIGIL(R) oral tablets, 2015).
    B) MODAFINIL: There was no evidence of genotoxicity or mutagenicity in the following tests: A series of in vitro (ie, bacterial reverse mutation, mouse lymphoma tk, chromosomal aberration in human lymphocytes, cell transformation in BALB/3T3 mouse embryo cells) assays and in vivo (mouse bone marrow micronucleus) assays (Prod Info PROVIGIL(R) oral tablets, 2015; Prod Info NUVIGIL(R) oral tablets, 2015).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor vital signs, ECG, and liver enzyme concentrations after significant overdose.
    B) Monitor fluid and electrolyte status in patients with significant vomiting or diarrhea.
    C) Monitor mental status and perform a neurologic exam in symptomatic patients.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor liver enzyme concentrations after significant overdose.
    4.1.4) OTHER
    A) OTHER
    1) MONITORING
    a) Monitor vital signs, including blood pressure and pulse rate, in symptomatic patients.
    2) ECG
    a) An ECG should be obtained in symptomatic patients, particularly in cases of pre-existing cardiovascular dysfunction.

Methods

    A) CHROMATOGRAPHY
    1) High-performance liquid chromatography methods with liquid-liquid and solid-phase extractions have been described for determination of modafinil and its metabolites in human plasma. The limits of detection of modafinil and its metabolites, using these methods, ranged from 0.01 to 0.04 mg/L and 0.02 to 0.04 mg/L, respectively. The limits of quantitation of modafinil and its metabolites ranged from 0.10 to 0.13 mg/L and 0.11 to 0.14 mg/L, respectively (Gorman, 1999; Burnat et al, 1998; Moachon & Matinier, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with significant persistent hypertension, tachycardia, severe neurologic symptoms, or dysrhythmias (eg, prolonged QT) should be admitted to the hospital.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic patients with inadvertent ingestions of less than 400 mg can be managed at home. (Carstairs et al, 2010).
    B) CHILDREN: In a retrospective multi-poison center chart review of patients from 11 states, no significant toxicity was reported in children less than 6 years of age after ingesting less than 400 mg of modafinil. The authors suggested that ingestions of 200 mg or less of modafinil by small children may be safely observed outside of the healthcare facility (Spiller et al, 2009).
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Symptomatic patients, those ingesting 400 mg or more, and those with deliberate overdose should be sent to a healthcare facility for evaluation and treated until symptoms resolve.

Monitoring

    A) Monitor vital signs, ECG, and liver enzyme concentrations after significant overdose.
    B) Monitor fluid and electrolyte status in patients with significant vomiting or diarrhea.
    C) Monitor mental status and perform a neurologic exam in symptomatic patients.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) MONITORING OF PATIENT
    1) Monitor vital signs, ECG, and liver enzyme concentrations after significant overdose.
    2) Monitor fluid and electrolyte status in patients with severe vomiting or diarrhea.
    3) Monitor mental status and perform a neurologic exam in symptomatic patients.
    B) TACHYARRHYTHMIA
    1) TACHYCARDIA SUMMARY
    a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
    b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    c) ESMOLOL/ADULT LOADING DOSE
    1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010).
    d) ESMOLOL/ADULT MAINTENANCE DOSE
    1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010).
    2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010).
    3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
    e) CAUTION
    1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010).

Enhanced Elimination

    A) LACK OF INFORMATION
    1) There is no information regarding the effectiveness of hemodialysis for enhancing the elimination of modafinil following an overdose ingestion.

Range Of Toxicity

Summary

    A) TOXICITY: A specific minimum toxic dose of modafinil has not been established, doses of less than 400 mg have not been associated with significant toxicity. In a study of modafinil overdoses (age range, 1.25 to 72 years; mean dose: 939 mg; median dose: 400 mg; range, 25 to 16,100 mg), no major effects or death were reported. ADULTS: Patients have tolerated modafinil doses up to 400 mg/day as a single dose. Ingestion of 4500 mg modafinil by an adult resulted in insomnia, excitation, and tachycardia. CHILDREN: In one study, no significant toxicity was reported in children less than 6 years of age after ingesting less than 400 mg of modafinil. Ingestion of 5 grams of modafinil by a 15-year-old girl resulted in severe headache, nausea, abdominal pain, insomnia, dyskinesia, prolonged QTc interval, and tachycardia.
    B) THERAPEUTIC DOSE: ARMODAFINIL: ADULTS: 150 mg or 250 mg as a single dose orally. CHILDREN: Safety and efficacy of armodafinil administration in children less than 17 years of age has not been established. MODAFINIL: ADULTS: 200 mg orally once daily. CHILDREN: Safety and efficacy of modafinil administration in children less than 16 years of age has not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) ARMODAFINIL
    1) The usual therapeutic dose is 150 mg or 250 mg as a single dose orally in the morning (Prod Info NUVIGIL(TM) oral tablets, 2008).
    B) MODAFINIL
    1) The usual therapeutic dose is 200 mg orally once daily (Prod Info PROVIGIL(R) oral tablets, 2010).
    7.2.2) PEDIATRIC
    A) ARMODAFINIL
    1) Safety and efficacy of armodafinil administration in children less than 17 years of age has not been established (Prod Info NUVIGIL(TM) oral tablets, 2008).
    B) MODAFINIL
    1) Safety and efficacy of modafinil administration in children less than 16 years of age has not been established (Prod Info PROVIGIL(R) oral tablets, 2010).

Maximum Tolerated Exposure

    A) Patients have tolerated modafinil doses up to 400 mg/day as a single dose (Prod Info PROVIGIL(R) oral tablets, 2010).
    B) In a retrospective poison center study, no significant toxicity was reported in children less than 6 years of age after ingesting less than 400 mg of modafinil (Spiller et al, 2009).
    C) CASE SERIES: In a retrospective chart review of modafinil exposures reported to the California Poison Control system over an 11-year period, tachycardia, agitation, anxiety, headache, hypertension, dystonia/tremor, dizziness, dysarthria, insomnia, stomach upset/nausea, erythema/flushing, dysarthria, hallucinations, palpitations, chest pain, and edema were reported in patients (n=87; mean age, 29.9 years; range, 1.25 to 72 years) after modafinil overdoses (mean dose: 939 mg; median dose: 400 mg; range, 25 to 16,100 mg). Overall, no major effects or death were reported; moderate (mean dose, 1922 mg; range, 400 to 8000 mg), minor (mean dose, 995 mg; range, 25 to 16100 mg), and no effects (mean dose, 411 mg; range, 50 to 1200 mg) were reported in 11, 54, and 22 patients, respectively. Doses of less than 400 mg were not associated with significant toxicity (Carstairs et al, 2010).
    1) CASE REPORT: A 37-year-old woman developed agitation, visual hallucinations, marked orofacial dyskinesia, dysarthria, and tachycardia after ingesting 1600 mg of modafinil. Following supportive therapy, she recovered and was discharged 20 hours after ingestion of modafinil (Carstairs et al, 2010).
    2) CASE REPORT: A 24-year-old woman developed tachycardia and hypertension after ingesting 400 mg modafinil instead of her usual 200 mg dose. She recovered following supportive therapy (Carstairs et al, 2010).
    D) CASE REPORT: Ingestion of 5 grams of modafinil by a 15-year-old girl resulted in severe headache, nausea, abdominal pain, insomnia, dyskinesia, prolonged QTc interval, and tachycardia. She recovered following supportive care (Neuman et al, 2009).
    E) CASE REPORT - A 21-year-old woman intentionally ingested 4500 mg of modafinil and subsequently developed insomnia, excitation, and tachycardia (Lyons & French, 1991).
    F) Modafinil doses of 400 mg or greater have been associated with insomnia, euphoria, excitation, headaches, dizziness, nausea, dry mouth, tachycardia, and hypertension (Wong et al, 1999; Broughton et al, 1997; Lyons & French, 1991).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Armodafinil, an alpha1-adrenoceptor agonist, is the R enantiomer of modafinil (Boyd & Castan, 2006). The exact mechanism that armodafinil produces wakefulness is unknown. The wake-promoting actions of armodafinil are similar to that of sympathomimetic amines despite differences in their pharmacologic profiles (Prod Info NUVIGIL(TM) oral tablets, 2008).
    B) The mechanism of action of modafinil is uncertain (Prod Info Modafinil, 99). The pharmacological profile of modafinil differs from that of sympathomimetic amines (Prod Info Modafinil, 99). The CNS-activating actions of modafinil, methylphenidate, and amphetamine were studied in cats given doses of each medication that produced equivalent wakefulness (Prod Info Modafinil, 99). CNS-activation with methylphenidate and with amphetamine was widespread; however, CNS-activation with modafinil occurred in discrete brain regions (Prod Info Modafinil, 99), suggesting a more specific wakefulness-promoting effect with modafinil (Prod Info Modafinil, 99). Modafinil does not show alpha-adrenergic agonist activity in vitro or in animal studies; however, the wakefulness induced by modafinil can be attenuated by prazosin, an alpha1-adrenergic antagonist (Prod Info Modafinil, 99). Modafinil does not bind to norepinephrine, serotonin, dopamine, gamma-aminobutyric acid (GABA), adenosine, histamine H3, melatonin, or benzodiazepine receptors, nor does it inhibit monoamine oxidase (MAO)-B or phosphodiesterases II through V (Prod Info Modafinil, 99).

Physicochemical

Physical Characteristics

    A) Modafinil is a white to off-white crystalline powder that is insoluble in water and cyclohexane and slightly soluble in methanol and acetone (Prod Info Provigil(R), modafinil, 1999).

Molecular Weight

    A) 273.36 (Prod Info Provigil(R), modafinil, 1999)

References

General Bibliography

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