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.                 

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

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*

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*

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.

DRUG ABUSE AND DEPENDENCE

ADDERALL XR® is a Schedule II controlled substance.

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.

Acidifying agents -Gastrointestinal acidifying agents (guanethidine, reserpine, glutamic acid HCl, ascorbic acid, etc.) lower absorption of amphetamines.

Urinary acidifying agents -These agents (ammonium chloride, sodium acid phosphate, etc.) 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.

Adrenergic blockers -Adrenergic blockers are inhibited by amphetamines.

Alkalinizing agents -Gastrointestinal alkalinizing agents (sodium bicarbonate, etc.) 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.

Antidepressants, tricyclic -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.

MAO inhibitors -MAOI antidepressants, as well as a metabolite of furazolidone, 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.

Antihistamines -Amphetamines may counteract the sedative effect of antihistamines.

Antihypertensives -Amphetamines may antagonize the hypotensive effects of antihypertensives.

Chlorpromazine -Chlorpromazine blocks dopamine and norepinephrine receptors, thus inhibiting the central stimulant effects of amphetamines, and can be used to treat amphetamine poisoning.

Ethosuximide -Amphetamines may delay intestinal absorption of ethosuximide.

Haloperidol -Haloperidol blocks dopamine receptors, thus inhibiting the central stimulant effects of amphetamines.

Lithium carbonate -The anorectic and stimulatory effects of amphetamines may be inhibited by lithium carbonate.

Meperidine -Amphetamines potentiate the analgesic effect of meperidine.

Methenamine therapy -Urinary excretion of amphetamines is increased, and efficacy is reduced, by acidifying agents used in methenamine therapy.

Norepinephrine -Amphetamines enhance the adrenergic effect of norepinephrine.

Phenobarbital -Amphetamines may delay intestinal absorption of phenobarbital; co-administration of phenobarbital may produce a synergistic anticonvulsant action.

Phenytoin -Amphetamines may delay intestinal absorption of phenytoin; co-administration of phenytoin may produce a synergistic anticonvulsant action.

Propoxyphene -In cases of propoxyphene overdosage, amphetamine CNS stimulation is potentiated and fatal convulsions can occur.

Veratrum alkaloids -Amphetamines inhibit the hypotensive effect of veratrum alkaloids.

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.

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