Adderall XR Capsules
"The US Food and Drug Administration (FDA) has approved the amphetamine Dyanavel XR (Tris Pharma Inc), a once-daily extended-release oral liquid, for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children aged 6 years "...
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 XR
|General||Abdominal Pain (stomachache)||14%||10%|
|Digestive System||Loss of Appetite||22%||2%|
|Metabolic/ Nutritional||Weight Loss||4%||0%|
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
|Body System||Preferred Term||ADDERALL XR
|General||Abdominal Pain (stomachache)||11%||2%|
|Digestive System||Loss of Appetiteb||36%||2%|
|Metabolic/ Nutritional||Weight Lossb||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 notmeet 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%|
|Metabolic/ Nutritional||Weight Loss||10%||0%|
|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%) placebotreated 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:
Central Nervous System
Psychotic episodes at recommended doses, overstimulation, restlessness, irritability, euphoria, dyskinesia, dysphoria, depression, tremor, tics, aggression, anger, logorrhea, dermatillomania, paresthesia (including formication), and bruxism.
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.
Musculoskeletal and Connective Tissue Disorders
Read the Adderall XR (amphetamine, dextroamphetamine mixed salts) Side Effects Center for a complete guide to possible side effects
Agents That Increase Blood Levels Of Amphetamines
MAOI antidepressants slow amphetamine metabolism. This slowing potentiates amphetamines, increasing their effect on the release of norepinephrine and other monoamines from adrenergic nerve endings; this can cause headaches and other signs of hypertensive crisis. A variety of toxic neurological effects and malignant hyperpyrexia can occur, sometimes with fatal results. Do not administer ADDERALL XR during or within 14 days following the administration of monoamine oxidase inhibitors [see CONTRAINDICATIONS].
Gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) increase absorption of amphetamines. Co-administration of ADDERALL XR and gastrointestinal alkalinizing agents, such as antacids, should be avoided. Urinary alkalinizing agents (acetazolamide, some thiazides) increase the concentration of the non-ionized species of the amphetamine molecule, thereby decreasing urinary excretion. Both groups of agents increase blood levels and therefore potentiate the actions of amphetamines.
Agents That Lower Blood Levels Of Amphetamines
Gastrointestinal acidifying agents (e.g., guanethidine, reserpine, glutamic acid HCl, ascorbic acid) lower absorption of amphetamines. Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine salts) increase the concentration of the ionized species of the amphetamine molecule, thereby increasing urinary excretion. Both groups of agents lower blood levels and efficacy of amphetamines.
Agents Whose Effects May Be Reduced By Amphetamines
Amphetamines may reduce the cardiovascular effects of adrenergic blockers.
Amphetamines may counteract the sedative effect of antihistamines.
Amphetamines may antagonize the hypotensive effects of antihypertensives.
Amphetamines inhibit the hypotensive effect of veratrum alkaloids.
Amphetamines may delay intestinal absorption of phenobarbital.
Amphetamines may delay intestinal absorption of phenytoin.
Amphetamines may delay intestinal absorption of ethosuximide.
Agents Whose Effects May Be Potentiated By Amphetamines
Amphetamines may enhance the activity of tricyclic antidepressants or sympathomimetic agents; d-amphetamine with desipramine or protriptyline and possibly other tricyclics cause striking and sustained increases in the concentration of d-amphetamine in the brain; cardiovascular effects can be potentiated.
Amphetamines potentiate the analgesic effect of meperidine.
Amphetamines may enhance the adrenergic effect of norepinephrine.
Agents That May Reduce The Effects Of Amphetamines
Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines.
Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines.
The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate.
Agents That May Potentiate The Effects Of Amphetamines
Norepinephrine may enhance the adrenergic effect of amphetamine.
In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.
Proton Pump Inhibitors (PPI)
PPIs act on proton pumps by blocking acid production, thereby reducing gastric acidity. When ADDERALL XR (20 mg single-dose) was administered concomitantly with the proton pump inhibitor, omeprazole (40 mg once daily for 14 days), the median Tmax of d-amphetamine was decreased by 1.25 hours (from 4 to 2.75 hours), and the median Tmax of l-amphetamine was decreased by 2.5 hours (from 5.5 to 3 hours), compared to ADDERALL XR administered alone. The AUC and Cmax of each moiety were unaffected. Therefore, co-administration of ADDERALL XR and proton pump inhibitors should be monitored for changes in clinical effect.
Drug/Laboratory Test Interactions
Amphetamines can cause a significant elevation in plasma corticosteroid levels. This increase is greatest in the evening. Amphetamines may interfere with urinary steroid determinations.
Drug Abuse And Dependence
ADDERALL XR is a Schedule II controlled substance.
Abuse And Dependence
Amphetamines have been extensively abused. Tolerance, extreme psychological dependence, and severe social disability have occurred. There are reports of patients who have increased the dosage to levels many times higher than recommended. Abrupt cessation following prolonged high dosage administration results in extreme fatigue and mental depression; changes are also noted on the sleep EEG. Manifestations of chronic intoxication with amphetamines may include severe dermatoses, marked insomnia, irritability, hyperactivity, and personality changes. The most severe manifestation of chronic intoxication is psychosis, often clinically indistinguishable from schizophrenia.
Read the Adderall XR Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/21/2016
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