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.
Clinical Studies Experience
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 reactions, results of physical examinations, vital signs, weights, laboratory analyses, and ECGs.
Adverse reactions 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 reactions without first grouping similar types of reactions into a smaller number of standardized event categories. In the tables and listings that follow, COSTART terminology has been used to classify reported adverse reactions.
The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse event of the type listed.
Adverse Reactions Leading To 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 reactions (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 reactions leading to discontinuation of ADDERALL XR in controlled and uncontrolled, multiple-dose clinical trials of children (N=595) were anorexia (loss of appetite) (2.9%), insomnia (1.5%), weight loss (1.2%), emotional lability (1%), and depression (0.7%). Over half of these patients were exposed to ADDERALL XR for 12 months or more.
In a separate placebo-controlled 4-week study in adolescents with ADHD, five patients (2.1%) discontinued treatment due to adverse events among ADDERALL XR-treated patients (N=233) compared to none 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 ADDERALL XR-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 ADDERALL XR-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 ADDERALL XR-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 Controlled Trials
Adverse reactions reported in a 3-week clinical trial of children and a 4-week clinical trial in adolescents and adults, respectively, treated with ADDERALL XR or placebo are presented in the tables below.
Table 1 : Adverse Reactions Reported by 2% or More of Children (6-12 Years Old) Receiving ADDERALL XR with Higher Incidence Than on Placebo in a 584-Patient Clinical Study
|Body System||Preferred Term||ADDERALL
|General||Abdominal Pain (stomachache)||14%||10%|
|Digestive System||Loss of Appetite||22%||2%|
Table 2 : Adverse Reactions Reported by 5% or More of Adolescents (13-17 Years Old) 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
|General||Abdominal Pain (stomachache)||11%||2%|
|Digestive System||Loss of Appetite b||36%||2%|
|Nervous System||Insomnia b||12%||4%|
|Metabolic/Nutritional||Weight Loss b||9%||0%|
|*Included doses up to 40 mg
a Appears the same due to rounding
b Dose-related adverse reactions
Note: The following reactions 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.
Table 3 : Adverse Reactions 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
|Digestive System||Dry Mouth||35%||5%|
|Loss of Appetite||33%||3%|
|Urogenital System||Urinary Tract Infection||5%||0%|
|*Included doses up to 60 mg.
a Appears the same due to rounding
Note: The following reactions 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 (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.
[see WARNINGS AND PRECAUTIONS]
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 with ADHD, 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.
Adverse Reactions Associated With The Use Of Amphetamine, ADDERALL XR, Or ADDERALL
The following adverse reactions have been associated with the use of amphetamine, ADDERALL XR, or ADDERALL:
Palpitations. There have been isolated reports of cardiomyopathy associated with chronic amphetamine use.
Central Nervous System
Psychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea, dermatillomania, paresthesia (including formication).
Vision blurred, mydriasis.
Unpleasant taste, constipation, other gastrointestinal disturbances.
Urticaria, rash, hypersensitivity reactions including angioedema and anaphylaxis. Serious skin rashes, including Stevens-Johnson Syndrome and toxic epidermal necrolysis have been reported.
Impotence, changes in libido, frequent or prolonged erections.