ADVERSE REACTIONS
Modafinil has been evaluated for safety in over 3500 patients, of whom more than 2000 patients with excessive sleepiness associated with primary disorders of sleep and wakefulness were given at least one dose of modafinil. In clinical trials, modafinil has been found to be generally well tolerated and most adverse experiences were mild to moderate.
The most commonly observed adverse events (≥5%) associated with the use of PROVIGIL more frequently than placebo-treated patients in the placebo-controlled clinical studies in primary disorders of sleep and wakefulness were headache, nausea, nervousness, rhinitis, diarrhea, back pain, anxiety, insomnia, dizziness, and dyspepsia. The adverse event profile was similar across these studies.
In the placebo-controlled clinical trials, 74 of the 934 patients (8%) who received PROVIGIL discontinued due to an adverse experience compared to 3% of patients that received placebo. The most frequent reasons for discontinuation that occurred at a higher rate for PROVIGIL than placebo patients were headache (2%), nausea, anxiety, dizziness, insomnia, chest pain and nervousness (each <1%). 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).
Incidence in Controlled Trials
The following table (Table 3) presents the adverse experiences that occurred at a rate of 1% or more and were more frequent in adult patients treated with PROVIGIL than in placebo-treated patients in the principal, placebo-controlled clinical trials.
The prescriber should be aware that the figures provided below cannot be used to predict the frequency of adverse experiences in the course of usual medical practice, where patient characteristics and other factors may differ from those occurring during clinical studies. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. Review of these frequencies, however, provides prescribers with a basis to estimate the relative contribution of drug and non-drug factors to the incidence of adverse events in the population studied.
Table 3. Incidence Of Treatment-Emergent Adverse Experiences In Parallel-Group, Placebo-Controlled Clinical Trials1 With PROVIGIL In Adults With Narcolepsy, OSAHS, and SWSD (200mg, 300mg and 400mg)* Body System
| Preferred Term
| Modafinil
(n = 934) | Placebo
(n = 567) |
|
* Six double-blind, placebo-controlled clinical studies in narcolepsy, OSAHS, and SWSD.
1 Events reported by at least 1% of patients treated with PROVIGIL that were more frequent than in the placebo group are included; incidence is rounded to the nearest 1%. The adverse experience terminology is coded using a standard modified COSTART Dictionary.
Events for which the PROVIGIL incidence was at least 1%, but equal to or less than placebo are not listed in the table. These events included the following: infection, pain, accidental injury, abdominal pain, hypothermia, allergic reaction, asthenia, fever, viral infection, neck pain, migraine, abnormal electrocardiogram, hypotension, tooth disorder, vomiting, periodontal abscess, increased appetite, ecchymosis, hyperglycemia, peripheral edema, weight loss, weight gain, myalgia, leg cramps, arthritis, cataplexy, thinking abnormality, sleep disorder, increased cough, sinusitis, dyspnea, bronchitis, rash, conjunctivitis, ear pain, dysmenorrhea4, urinary tract infection.
2 Elevated liver enzymes.
3 Oro-facial dyskinesias.
4 Incidence adjusted for gender.
|
| Body as a Whole | Headache | 34% | 23% |
| Back Pain | 6% | 5% |
| Flu Syndrome | 4% | 3% |
| Chest Pain | 3% | 1% |
| Chills | 1% | 0% |
| Neck Rigidity | 1% | 0% |
| Cardiovascular | Hypertension | 3% | 1% |
| Tachycardia | 2% | 1% |
| Palpitation | 2% | 1% |
| Vasodilatation | 2% | 0% |
| Digestive | Nausea | 11% | 3% |
| Diarrhea | 6% | 5% |
| Dyspepsia | 5% | 4% |
| Dry Mouth | 4% | 2% |
| Anorexia | 4% | 1% |
| Constipation | 2% | 1% |
| Abnormal Liver Function2 | 2% | 1% |
| Flatulence | 1% | 0% |
| Mouth Ulceration | 1% | 0% |
| Thirst | 1% | 0% |
| Hemic/Lymphatic | Eosinophilia | 1% | 0% |
| Metabolic/Nutritional | Edema | 1% | 0% |
| Nervous | Nervousness | 7% | 3% |
| Insomnia | 5% | 1% |
| Anxiety | 5% | 1% |
| Dizziness | 5% | 4% |
| Depression | 2% | 1% |
| Paresthesia | 2% | 0% |
| Somnolence | 2% | 1% |
| Hypertonia | 1% | 0% |
| Dyskinesia3 | 1% | 0% |
| Hyperkinesia | 1% | 0% |
| Agitation | 1% | 0% |
| Confusion | 1% | 0% |
| Tremor | 1% | 0% |
| Emotional Lability | 1% | 0% |
| Vertigo | 1% | 0% |
| Respiratory | Rhinitis | 7% | 6% |
| Pharyngitis | 4% | 2% |
| Lung Disorder | 2% | 1% |
| Epistaxis | 1% | 0% |
| Asthma | 1% | 0% |
| Skin/Appendages | Sweating | 1% | 0% |
| Herpes Simplex | 1% | 0% |
| Special Senses | Amblyopia | 1% | 0% |
| Abnormal Vision | 1% | 0% |
| Taste Perversion | 1% | 0% |
| Eye Pain | 1% | 0% |
| Urogenital | Urine Abnormality | 1% | 0% |
| Hematuria | 1% | 0% |
| Pyuria | 1% | 0% |
Dose Dependency of Adverse Events
In the adult placebo-controlled clinical trials which compared doses of 200, 300, and 400 mg/day of PROVIGIL and placebo, the only adverse events that were clearly dose related were headache and anxiety.
Vital Sign Changes
While there was no consistent change in mean values of heart rate or systolic and diastolic blood pressure, the requirement for antihypertensive medication was slightly greater in patients on PROVIGIL compared to placebo (See PRECAUTIONS).
Weight Changes
There were no clinically significant differences in body weight change in patients treated with PROVIGIL compared to placebo-treated patients in the placebo-controlled clinical trials.
Laboratory Changes
Clinical chemistry, hematology, and urinalysis parameters were monitored in Phase 1, 2, and 3 studies. In these studies, mean plasma levels of gamma glutamyltransferase (GGT) and alkaline phosphatase (AP) were found to be higher following administration of PROVIGIL, but not placebo. Few subjects, 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 PROVIGIL in the Phase 3 clinical trials. No differences were apparent in alanine aminotransferase, aspartate aminotransferase, total protein, albumin, or total bilirubin.
ECG Changes
No treatment-emergent pattern of ECG abnormalities was found in placebo-controlled clinical trials following administration of PROVIGIL.
Postmarketing Reports
The following adverse reactions have been identified during post-approval use of PROVIGIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of the reporting, or (3) strength of causal connection to PROVIGIL.
Hematologic: agranulocytosis
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