ADVERSE EVENTS
Hypertension: [See WARNINGS section] In a controlled 4-week outpatient clinical study of adolescents with ADHD, isolated systolic blood pressure elevations ≥15 mmHg were observed in 7/64 (11%) placebo-treated patients and 7/100 (7%) patients receiving ADDERALL XR® 10 or 20 mg. Isolated elevations in diastolic blood pressure ≥ 8 mmHg were observed in 16/64 (25%) placebo-treated patients and 22/100 (22%) ADDERALL XR®-treated patients. Similar results were observed at higher doses.
In a single-dose pharmacokinetic study in 23 adolescents, isolated increases in systolic blood pressure (above the upper 95% CI for age, gender and stature) were observed in 2/17 (12%) and 8/23 (35%), subjects administered 10 mg and 20 mg ADDERALL XR®, respectively. Higher single doses were associated with a greater increase in systolic blood pressure. All increases were transient, appeared maximal at 2 to 4 hours post dose and not associated with symptoms.
The premarketing development program for ADDERALL XR® included exposures in a total of 1315 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) were evaluated in two controlled clinical studies, one open-label clinical study, and two single-dose clinical pharmacology studies (N= 40). Safety data on all patients are included in the discussion that follows. Adverse reactions were assessed by collecting adverse events, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
Adverse events during exposure were obtained primarily by general inquiry and recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of events into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse events.
The stated frequencies of adverse events represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed.
Adverse events associated with discontinuation of treatment: In two placebo-controlled studies of up to 5 weeks duration among children with ADHD, 2.4% (10/425) of ADDERALL XR® treated patients discontinued due to adverse events (including 3 patients with loss of appetite, one of whom also reported insomnia) compared to 2.7% (7/259) receiving placebo. The most frequent adverse events associated with discontinuation of ADDERALL XR® in controlled and uncontrolled, multiple-dose clinical trials of pediatric patients (N=595) are presented below. Over half of these patients were exposed to ADDERALL XR® for 12 months or more.
| Adverse event | % of pediatric patients discontinuing (n=595) |
|---|
| Anorexia (loss of appetite) | 2.9 |
| Insomnia | 1.5 |
| Weight loss | 1.2 |
| Emotional lability | 1.0 |
| Depression | 0.7 |
In a separate placebo-controlled 4-week study in adolescents with ADHD, eight patients (3.4%) discontinued treatment due to adverse events among ADDERALL XR®-treated patients (N=233). Three patients discontinued due to insomnia and one patient each for depression, motor tics, headaches, light-headedness, and anxiety.
In one placebo-controlled 4-week study among adults with ADHD, patients who discontinued treatment due to adverse events among ADDERALL XR ® -treated patients (N=191) were 3.1% (n=6) for nervousness including anxiety and irritability, 2.6% (n=5) for insomnia, 1% (n=2) each for headache, palpitation, and somnolence; and, 0.5% (n=1) each for ALT increase, agitation, chest pain, cocaine craving, elevated blood pressure, and weight loss.
Adverse events occurring in a controlled trial: Adverse events reported in a 3-week clinical trial of pediatric patients and a 4-week clinical trial in adolescents and adults, respectively, treated with ADDERALL XR® or placebo are presented in the tables below.
The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse event incidence rate in the population studied.
Table 1 Adverse Events Reported by More Than 1% of Pediatric Patients Receiving ADDERALL XR® with Higher Incidence Than on Placebo in a 584 Patient Clinical Study
| Body System | Preferred Term | Adderall XR®
(n=374) | Placebo
(n=210) |
|---|
| General | Abdominal Pain (stomachache)
Accidental Injury
Asthenia (fatigue)
Fever
Injection
Viral Infection | 14%
3%
2%
5%
4%
2% | 10%
2%
0%
2%
2%
0% |
| Digestive System | Loss of Appetite
Diarrhea
Dyspepsia
Nausea
Vomiting | 22%
2%
2%
5%
7% | 2%
1%
1%
3%
4% |
| Nervous System | Dizziness
Emotional Lability
Insomnia
Nervousness | 2%
9%
17%
6% | 0%
2%
2%
2% |
| Metabolic/Nutritional | Weight Loss | 4% | 0% |
Table 2 Adverse Events Reported by 5% or more of Adolescents Weighing ≤ 75 kg/165 lbs Receiving ADDERALL XR® with Higher Incidence Than Placebo in a 287 Patient Clinical Forced Weekly-Dose Titration Study*
| Body System | Preferred Term | ADDERALL XR®
(n=233) | Placebo
(n=54) |
|---|
| General | Abdominal Pain (stomachache)
| 11%
| 2%
|
| Digestive System | Loss of Appetite b | 36% | 2% |
| Nervous System | Insomnia b
Nervousness | 12%
6% | 4%
6%a |
| Metabolic/Nutritional | Weight Loss b | 9% | 0% |
a Appears the same due to rounding
b Dose-related adverse events
Note: The following events did not meet the criterion for inclusion in Table 2 but were reported by 2% to 4% of adolescent patients receiving ADDERALL XR with a higher incidence than patients receiving placebo in this study: accidental injury, asthenia (fatigue), dry mouth, dyspepsia, emotional lability, nausea, somnolence, and vomiting.
*Included doses up to 40 mg |
Table 3 Adverse Events Reported by 5% or More of Adults Receiving ADDERALL XR® with Higher Incidence Than on Placebo in a 255 Patient Clinical Forced Weekly-Dose Titration Study*
| Body System | Preferred Term | ADDERALL XR®
(n=191) | Placebo
(n=64) |
|---|
| General | Asthenia
Headache | 6%
26% | 5%
13% |
| Digestive System | Loss of Appetite
Diarrhea
Dry Mouth
Nausea | 33%
6%
35%
8% | 3%
0%
5%
3% |
| Nervous System | Agitation
Anxiety
Dizziness
Insomnia | 8%
8%
7%
27% | 5%
5%
0%
13% |
| Cardiovascular System | Tachycardia | 6% | 3% |
| Metabolic/Nutritional | Weight Loss | 11% | 0% |
| Urogenital System | Urinary Tract Infection | 5% | 0% |
Note: The following events did not meet the criterion for inclusion in Table 3 but were reported by 2% to 4% of adult patients receiving ADDERALL XR® with a higher incidence than patients receiving placebo in this study: infection, photosensitivity reaction, constipation, tooth disorder, emotional lability, libido decreased, somnolence, speech disorder, palpitation, twitching, dyspnea, sweating, dysmenorrhea, and impotence.
*Included doses up to 60 mg. |
The following adverse reactions have been associated with the use of amphetamine, ADDERALL XR ®, or ADDERALL ®:
Cardiovascular: Palpitations, tachycardia, elevation of blood pressure, sudden death, myocardial infarction. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.
Central Nervous System: Psychotic episodes at recommended doses, overstimulation, restlessness, dizziness, insomnia, euphoria, dyskinesia, dysphoria, depression, tremor, headache, exacerbation of motor and phonic tics and Tourette's syndrome, seizures, stroke.
Gastrointestinal: Dryness of the mouth, unpleasant taste, diarrhea, constipation, other gastrointestinal disturbances. Anorexia and weight loss may occur as undesirable effects.
Allergic: Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported.
Endocrine: Impotence, changes in libido.
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