Modafinil (Page 2 of 7)

5.5 Psychiatric Symptoms

Psychiatric adverse reactions have been reported in patients treated with modafinil.

In the adult modafinil controlled trials, psychiatric symptoms resulting in treatment discontinuation (at a frequency ≥0.3%) and reported more often in patients treated with modafinil compared to those treated with placebo were anxiety (1%), nervousness (1%), insomnia (<1%), confusion (<1%), agitation (<1%), and depression (<1%).

Postmarketing adverse reactions associated with the use of modafinil have included mania, delusions, hallucinations, suicidal ideation, and aggression, some resulting in hospitalization. Many, but not all, patients had a prior psychiatric history. One healthy male volunteer developed ideas of reference, paranoid delusions, and auditory hallucinations in association with multiple daily 600 mg doses of modafinil (three times the recommended dose) and sleep deprivation. There was no evidence of psychosis 36 hours after drug discontinuation.

Caution should be exercised when modafinil is given to patients with a history of psychosis, depression, or mania. Consideration should be given to the possible emergence or exacerbation of psychiatric symptoms in patients treated with modafinil. If psychiatric symptoms develop in association with modafinil administration, consider discontinuing modafinil.

5.6 Effects on Ability to Drive and Use Machinery

Although modafinil has not been shown to produce functional impairment, any drug affecting the CNS may alter judgment, thinking or motor skills. Patients should be cautioned about operating an automobile or other hazardous machinery until it is reasonably certain that modafinil therapy will not adversely affect their ability to engage in such activities.

5.7 Cardiovascular Events

In modafinil clinical studies, cardiovascular adverse reactions, including chest pain, palpitations, dyspnea, and transient ischemic T-wave changes on ECG occurred in three subjects in association with mitral valve prolapse or left ventricular hypertrophy. In a Canadian clinical trial, a 35 year old obese narcoleptic male with a prior history of syncopal episodes experienced a 9-second episode of asystole after 27 days of modafinil treatment (300 mg/day in divided doses). Modafinil is not recommended in patients with a history of left ventricular hypertrophy or in patients with mitral valve prolapse who have experienced the mitral valve prolapse syndrome when previously receiving CNS stimulants. Findings suggestive of mitral valve prolapse syndrome include but are not limited to ischemic ECG changes, chest pain, or arrhythmia. If new onset of any of these findings occurs, consider cardiac evaluation. Consider increased monitoring in patients with a recent history of myocardial infarction or unstable angina.

Blood pressure monitoring in short term (≤3 months) controlled trials showed no clinically significant changes in mean systolic and diastolic blood pressure in patients receiving modafinil as compared to placebo. However, a retrospective analysis of the use of antihypertensive medication in these studies showed that a greater proportion of patients on modafinil required new or increased use of antihypertensive medications (2.4%) compared to patients on placebo (0.7%). The differential use was slightly larger when only studies in OSA were included, with 3.4% of patients on modafinil and 1.1% of patients on placebo requiring such alterations in the use of antihypertensive medication. Increased monitoring of heart rate and blood pressure may be appropriate in patients on modafinil. Caution should be exercised when prescribing modafinil to patients with known cardiovascular disease.

6 ADVERSE REACTIONS

The following serious adverse reactions are described elsewhere in the labeling:

  • Serious Rash, including Stevens-Johnson Syndrome [see Warnings and Precautions ( 5.1)]
  • Angioedema and Anaphylaxis Reactions [see Warnings and Precautions ( 5.2)]
  • Multi-organ Hypersensitivity Reactions [see Warnings and Precautions ( 5.3)]
  • Persistent Sleepiness [see Warnings and Precautions ( 5.4)]
  • Psychiatric Symptoms [see Warnings and Precautions ( 5.5)]
  • Effects on Ability to Drive and Use Machinery [see Warnings and Precautions ( 5.6)]
  • Cardiovascular Events [see Warnings and Precautions ( 5.7)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Modafinil has been evaluated for safety in over 3,500 patients, of whom more than 2,000 patients with excessive sleepiness associated with OSA, SWD, and narcolepsy.

Most Common Adverse ReactionsIn placebo-controlled clinical trials, the most common adverse reactions (≥5%) associated with the use of modafinil more frequently than placebo-treated patients were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse reaction profile was similar across these studies.

Table 1 presents the adverse reactions that occurred at a rate of 1% or more and were more frequent in modafinil-treated patients than in placebo-treated patients in the placebo-controlled clinical trials.

Table 1. Adverse Reactions in Pooled Placebo-Controlled Trials* in Narcolepsy, OSA, and SWD
Modafinil tablets (%) (n = 934) Placebo (%) (n = 567)
Headache Nausea Nervousness Rhinitis Back Pain Diarrhea Anxiety Dizziness Dyspepsia InsomniaAnorexia Dry Mouth Pharyngitis Chest Pain Hypertension Abnormal Liver Function Constipation Depression Palpitation Paresthesia Somnolence Tachycardia Vasodilatation Abnormal Vision Agitation Asthma Chills Confusion Dyskinesia Edema Emotional Lability Eosinophilia Epistaxis Flatulence Hyperkinesia Hypertonia Mouth Ulceration Sweating Taste Perversion Thirst Tremor Urine Abnormality Vertigo 341177665555444332222222211111111111111111111 23336551441122111111011000000000000000000000

*Adverse Reactions that occurred in > 1% of modafinil-treated patients (either 200, 300, or 400 mg once daily) and greater incidence than placebo.

Dose-Dependent Adverse Reactions
In the placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of modafinil and placebo, the following adverse reactions were dose related: headache and anxiety.

Adverse Reactions Resulting in Discontinuation of Treatment
In placebo-controlled clinical trials, 74 of the 934 patients (8%) who received modafinil discontinued due to an adverse reaction compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for modafinil than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain, and nervousness (each <1%).

Laboratory Abnormalities
Clinical chemistry, hematology, and urinalysis parameters were monitored in the studies. Mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of modafinil, but not placebo. Few patients, however, had GGT or AP elevations outside of the normal range. Shifts to higher, but not clinically significantly abnormal, GGT and AP values appeared to increase with time in the population treated with modafinil in the placebo-controlled clinical trials. No differences were apparent in alanine aminotransferase (ALT), aspartate aminotransferase (AST), total protein, albumin, or total bilirubin.

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