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 clinical practice.
The safety of amphetamine extended-release orally disintegrating tablets has been established from adequate and well-controlled studies of single-entity amphetamine product extended-release (MAS ER) capsules [see Clinical Studies (14)]. The adverse reactions of MAS ER capsules in these adequate and well-controlled studies are described below.
The premarketing development program for MAS ER included exposures in a total of 1,315 participants in clinical trials (635 pediatric patients, 350 adolescent patients, 248 adult patients, and 82 healthy adult subjects). Of these, 635 patients (ages 6 to 12 years) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N=40).
Adverse Reactions Leading to Discontinuation of Treatment
The most frequent adverse reactions leading to discontinuation of MAS ER in controlled and uncontrolled, multiple-dose clinical trials of pediatric patients ages 6 to 12 years (N=595) were anorexia (loss of appetite) (2.9%), insomnia (1.5%), weight loss (1.2%), emotional lability (1%), and depression (0.7%).
In a separate placebo-controlled 4-week study in pediatric patients ages 13 to 17 years with ADHD, five patients (2.1%) discontinued treatment due to adverse events among MAS ER-treated patients (N=233) compared to 0% who received placebo (N=54). The most frequent adverse event leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of MAS ER-treated patients and at a rate at least twice that of placebo) was insomnia (1.3%, n=3).
In one placebo-controlled 4-week study among adults with ADHD with doses 20 mg to 60 mg, 23 patients (12.0%) discontinued treatment due to adverse events among MAS ER-treated patients (N=191) compared to one patient (1.6%) who received placebo (N=64). The most frequent adverse events leading to discontinuation and considered to be drug-related (i.e., leading to discontinuation in at least 1% of MAS ER-treated patients and at a rate at least twice that of placebo) were insomnia (5.2%, n=10), anxiety (2.1%, n=4), nervousness (1.6%, n=3), dry mouth (1.6%, n=3), anorexia (1.6%, n=3), tachycardia (1.6%, n=3), headache (1.6%, n=3), and asthenia (1.0%, n=2).
Adverse Reactions Occurring in Clinical Trials
Adverse reactions reported in a 3-week clinical trial of pediatric patients 6 to 12 years of age and a 4-week clinical trial in pediatric patients 13 to 17 years of age and adults, respectively, treated with MAS ER or placebo are presented in the tables below.
Table 2: Adverse Reactions Reported by 2% or More of Pediatric Patients (6 to 12 years old) Receiving MAS ER with Higher Incidence than on Placebo in a 584-Patient Clinical StudyBody System | Adverse Reaction | MAS ER
(n=374) | Placebo
(n=210) |
General | Abdominal Pain (stomachache) Fever Infection Accidental Injury Asthenia (fatigue) | 14% 5% 4% 3% 2% | 10% 2% 2% 2% 0% |
Digestive System | Loss of Appetite Vomiting Nausea Dyspepsia | 22% 7% 5% 2% | 2% 4% 3% 1% |
Nervous System | Insomnia Emotional Lability Nervousness Dizziness | 17% 9% 6% 2% | 2% 2% 2% 0% |
Metabolic/Nutritional | Weight Loss | 4% | 0% |
Table 3: Adverse Reactions Reported by 5% or More of Pediatric Patients (13 to 17 Years Old) Weighing ≤ 75kg Receiving MAS ER with Higher Incidence than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study*Body System | Preferred Term | MAS ER
(n=233) | Placebo
(n=54) |
General | Abdominal Pain (stomachache) | 11% | 2% |
Digestive System | Loss of Appetite a | 36% | 2% |
Nervous System | Insomnia a | 12% | 4% |
Metabolic/Nutritional | Weight Loss a | 9% | 0% |
* Included doses up to 40 mg |
a Dose-related adverse reactions |
Note: The following reactions did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adolescent patients receiving MAS ER with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting.
Table 4: Adverse Reactions Reported by 5% or More of Adults Receiving MAS ER with Higher Incidence Than Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study*Body System | Preferred Term | MAS ER
(n=191) | Placebo
(n=64) |
General | Headache Asthenia | 26% 6% | 13% 5% |
Digestive System | Dry Mouth Loss of Appetite Nausea Diarrhea | 35% 33% 8% 6% | 5% 3% 3% 0% |
Nervous System | Insomnia Agitation Anxiety Dizziness | 27% 8% 8% 7% | 13% 5% 5% 0% |
Cardiovascular System | Tachycardia | 6% | 3% |
Metabolic/Nutritional | Weight Loss | 10% | 0% |
Urogenital System | Urinary Tract Infection | 5% | 0% |
* Included doses up to 60 mg. |
Note: The following reactions did not meet the criterion for inclusion in Table 4 but were reported by 2% to 4% of adult patients receiving MAS ER with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder (e.g., teeth clenching, tooth infection), emotional lability, libido decreased, somnolence, speech disorder (e.g., stuttering, excessive speech), palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence.
