Drug Criteria & Outcomes

Dextroamphetamine/amphetamine (Adderall) for ADHD

By Christy L. Collard, PharmD, Pharmacy Practice Resident, Medical University of South Carolina, Charleston

ADHD notes
ADHD is a diagnosis applied to children and adults who consistently display certain characteristic behaviors over a period of time. The most common behaviors fall into three categories: inattention, hyperactivity, and impulsivity.
Inattention: difficulty keeping one’s mind on any one thing; may get bored with a task after only a few minutes; may give effortless, automatic attention to activities and things enjoyed, but deliberate focus and attention to organizing and completing tasks or learning something new is difficult.
Hyperactivity: appearance of always being in motion; inability to sit still (as through a lesson); tend to squirm in seats and roam around rooms; intense feeling of restlessness in adults; attempt to accomplish several things at once, bouncing from one activity to the next.
Impulsivity: inability to curb immediate responses; characterized by reacting before thinking; will blurt out inappropriate comments; difficulty waiting for things they want. 
Adapted from Attention Deficit Hyperactivity Disorder. National Institute of Mental Health, NIH Publication 96-3572, 1996 reprint. May be viewed online at www.nimh.nih.gov/publicat/adhd.cfm#adhd3.

Indications:

Dextroamphetamine/amphetamine (Adderall) by Shire Richwood Inc., of Florence, KY, is indicated for use as a part of a total treatment program, including psychological, educational, social components, for a stabilizing effect in children diagnosed with attention deficit/hyperactivity disorder (ADHD); and for a syndrome of persistent patterns of inattention, hyperactivity, impulsivity, and emotional liability.1,2 It is also indicated for narcolepsy, although there are no published trials to evaluate the drug for this indication.

Pharmacology:

Adderall is an amphetamine product that combines four amphetamine salts: the neutral sulfate salts of dextroamphetamine and amphetamine, dextroamphetamine saccharide, and amphetamine aspartate. Amphetamines are non-catecholamine, sympathomimetic agents, which have a stimulant effect on the central nervous system. Peripheral effects including elevation of systolic and diastolic blood pressure, respiratory stimulation, and weak bronchodilatory effects are also seen with amphetamines. The mechanism of action for the emotional and behavioral modification seen in children is unknown. Additionally, it is unknown how these emotional and behavioral abnormalities relate to the condition of the central nervous system.1,2

Pharmacokinetics:

Dextroamphetamine has an onset of action of two to three hours, achieves peak plasma concentrations in one to three hours, and has a duration of effect of four to 24 hours. Dextroamphetamine has extensive oral bioavailability. Cerebral spinal fluid concentrations of dextroamphetamine reach approximately 80% of plasma concentrations. The volume of distribution for dextroamphetamine is approximately 6 L/kg. It is extensively metabolized by the liver and is 17% to 37% renally eliminated. Dextroamphetamine is dialyzable by hemodialysis and peritoneal dialysis.2 Amphetamine has an onset of action of one to three hours, achieves peak plasma concentrations in two to four hours, and has a duration of effect of up to 10 hours. Amphetamine has good oral bioavailability. Cerebral spinal fluid concentrations of amphetamine reach approximately 80% of plasma concentrations. The volume of distribution for amphetamine is about 3.5 to 6 L/kg. It is primarily liver metabolized, and up to 37% is excreted by the kidney.2

Selected clinical trials:

Swanson and colleague3 conducted a randomized, double-blind, cross-over study involving 30 children with ADHD. The study was designed to evaluate four different doses of Adderall (5 mg, 10 mg, 15 mg, 20 mg) administered orally. Patients were eligible for participation if they met the following inclusion criteria: age 7 to 14 years, DSM-IV diagnosis of ADHD, and a history of a clinically significant response to usual doses of methylphenidate (5 mg to 20 mg, administered orally in two to three divided doses). Patients were not eligible to participate in this study if they had any of the following: blood pressure readings outside the 95th percentile (according to age and gender), a WISC-III IQ rating of less than 80, abnormal physical exam, current use of nonstimulant medication for the treatment of ADHD, a comorbid disorder, or a history of aggressive behavior serious enough to prohibit participation in ordinary classroom activities. Participants were evaluated over a seven-week period, which allowed six weeks for medications and an extra week to reschedule any missed weeks. For each week, seven identical capsules were provided, to be administered one capsule each morning. Capsules contained placebo, Adderall in doses of 5 mg, 10 mg, 15 mg, and 20 mg, or methylphenidate (dose determined by the subject’s clinical history). All doses were administered orally. Patients were scheduled to participate in classroom, playground, and laboratory activities and were evaluated during these activities by the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) scale, the National Institute of Mental Health Collaborative Multisite Treatment Study of Children with ADHD impairment scale (MTA), and the permanent product (PERMP) measure of performance rating. Side effects of Adderall were also assessed using the MTA 10-item Stimulant Side Effect (SSE) scale. The SSE uses a four-point rating scale: not at all, just a little, pretty much, or very much.3

The study participants did not experience any serious or unusual side effects during the trial, and the measures of common psychostimulant side effects (e.g., insomnia, anorexia) were reported no more frequently than with placebo for most treatment weeks. Adderall-treated subjects showed improved behavior. There was a dose-dependent improvement in SKAMP and PERMP scores for the Adderall treatments. The duration of effect appeared to be dose-dependent, as well. Time to peak effect was shorter on average for methylphenidate (1.88 hours) at an average oral dose of 12.5 mg than for the Adderall 5 mg, 10 mg, 15 mg, and 20 mg doses (1.5, 2.6, 2.6, and 3.0 hours, respectively). The duration of effect was shorter, on average, for methylphenidate (3.98 hours) at an average oral dose of 12.5 mg, compared to the Adderall 5 mg, 10 mg, 15 mg, and 20 mg doses (3.52, 4.83, 5.44, and 6.4 hours, respectively). These data support that the use of Adderall is a treatment option for children affected with ADHD.3

Pliska and colleagues4 conducted a three-week, randomized, double-blind, placebo-controlled, parallel-group study of Adderall involving 58 children diagnosed with ADHD. Children were evaluated three times daily using the Inattention/ Overactivity With Aggression (IOWA) scale by both teachers (morning and afternoon) and parents (evening). Side effects of treatment were assessed using the Multi-Modality Treatment of ADHD side effects scale. Doses of methylphenidate and Adderall were started at 5 mg, administered orally, for children weighing less than 60 pounds and 10 mg, administered orally, for children weighing more than 60 pounds. Week One dosing occurred once daily in the morning. For patients showing improvement for morning, afternoon, and evening with Adderall, the dosing was continued at the daily dose in the morning for Week Two. For patients who did not show improvement on either the morning or afternoon evaluation, the daily Adderall dose was doubled for Week Two. For patients who showed improvement in the morning and afternoon evaluations, but not in the evening evaluation, a second dose was added after school for Week Two. For the third week, if afternoon scores remained impaired, a noon dose was added, and for those patients who showed impaired evening scores, an after-school dose was added. For methylphenidate, the dosing algorithm was similar except that a noon dose could be added for Week Two. The patients receiving placebo adhered to either the Adderall or methylphenidate algorithm.4

The average daily doses of methylphenidate and Adderall were 25.2 +/- 13.6 mg and 12.5 +/- 4.1 mg, respectively. Several adverse effects (stomach ache and sadness/tearfulness) were more common in the Adderall treatment group compared to the placebo group. Adderall did not have a statistically different side effect profile when compared to methylphenidate. Adderall showed improvement in the IOWA morning and evening evaluations compared to methylphenidate (p < 0.5). It should be noted that the results of this study are limited due to the possibility of underdosing of the methylphenidate group. The average daily dose of methylphenidate in this study was 0.43 mg/kg. The known required dose of methylphenidate is 0.3 to 0.8 mg/kg.4

Narcolepsy:

The Food and Drug Administration approved Adderall for the indication of narcolepsy without any pivotal trials. In addition, Shire Richwood Inc., was unable to provide any information on the use of Adderall in narcolepsy.5

Adverse reactions:

The most common adverse effects experienced by patients taking Adderall are cardiovascular in nature and include palpitations, tachycardia, and blood pressure elevation. More serious adverse effects of cardiomyopathy have been reported in isolated cases associated with the long-term use of amphetamines.1,2 Reported central nervous system effects include stimulant effects such as overstimulation, restlessness, dizziness, insomnia, and euphoria. Dyskinesia, dysphoria, tremor, and headache have also been reported. Some patients may experience an exacerbation of motor tics, phonetic tics, and Tourette’s syndrome or psychotic episodes while taking this product.1,2 Gastrointestinal effects include dry mouth, unpleasant taste, diarrhea, and constipation. Anorexia and weight loss can also be seen with stimulant medication use.1,2 Allergic effects include urticaria, and reported endocrine effects include changes in libido and impotence.1,2

Pregnancy/lactation:

Adderall is rated as a Pregnancy Category C.1,2 There are no adequate, well-controlled human studies of Adderall in pregnant women to date. It is noted that there have been case reports of malformations in infants born to a mothers who took amphetamine products during pregnancy. There has been one case report of structural abnormalities in an infant born to a mother who took Adderall and lovastatin during the first trimester of pregnancy. Severe congenital bony deformity, tracheoesophageal fistula, and anal atresia were seen in this infant. For dextroamphetamine and amphetamine alone, several cases have been reported in which various malformations have occurred. Such malformations include cardiac deformities, exencephalia, and limb reduction defects.2,6 Only in cases where the benefits justify the potential fetal risk, should amphetamines be administered in pregnant women. In addition, mothers taking amphetamines should be advised to abstain from breastfeeding, as amphetamines are excreted in human breast milk.1,2,6,7

Contraindications:

Adderall is contraindicated in patients who have a known hypersensitivity to sympathomimetic amines. Patients who suffer from advanced arteriosclerosis, symptomatic cardiovascular disease, moderate to severe hypertension, hyperthyroidism, or glaucoma should not use this product. In addition, use of Adderall is contraindicated in patients who experience agitated states or with a history of drug abuse. Adderall is contraindicated during or within 14 days following the administration of monoamine oxidase inhibitors, as a hypertensive crisis may result.1,2

Warnings:

Clinical experience suggests that, in psychotic children, administration of amphetamines may exacerbate symptoms of behavior disturbance and thought disorder. There are insufficient data to determine whether chronic administration of amphetamines may be associated with growth inhibition. Therefore, growth should be monitored during treatment with the drug. Adderall may impair the patient’s ability to operate machinery or vehicles, and patients should be advised of this risk.1,2

Dosage and administration:

Dosage of amphetamines should be individualized, and the lowest effective dosage should be administered. Doses should be administered in the morning, if possible. Late-night doses should be avoided because insomnia may result. No dosage adjustments are recommended for patients experiencing renal or hepatic insufficiency. Adderall does not have any geriatric dosage recommendations or recommendations for children younger than 3 years of age.1,2

For children 3 to 5 years of age, the recommended starting dose of Adderall is 2.5 mg daily, administered orally. Daily dosage may be adjusted at weekly intervals in increments of 2.5 mg (until the desired response is obtained). For children 6 years of age and older, the recommended starting dose is 5 mg daily. Alternatively, the dose may be divided twice daily. Daily dosage may be adjusted at weekly intervals in increments of 5 mg until the desired response is obtained. Only in rare instances is it necessary to prescribe a total daily dose of 40 mg or greater. The first dose of Adderall should be administered upon waking, and additional doses may be administered at intervals of four to six hours. If possible, treatment with Adderall should be interrupted occasionally, to assess whether behavioral symptoms persist and to evaluate whether continued therapy is necessary.1

Drug-drug interactions:

Gastrointestinal acidifying agents (e.g., fruit juice, vitamin C) may lower absorption of Adderall. Conversely, gastrointestinal alkalinizing agents (e.g., sodium bicarbonate) may increase amphetamine absorption.1,2 Amphetamines delay gastrointestinal absorption of ethosuxamide.1,2 Urinary acidifying agents (e.g., ammonium chloride, sodium acid phosphate, methenamine) may increase urinary excretion of amphetamines by increasing the ionized species concentration of amphetamines. Conversely, urinary alkalinizing agents (e.g., acetazolamide, thiazides) may increase the non-ionized species concentration of amphetamines, resulting in decreased urinary excretion of amphetamines.1,2

Amphetamines delay the intestinal absorption of phenobarbital and phenytoin, and co-administration may result in a synergistic anticonvulsant action. In cases of propoxyphene overdose, fatal convulsions may occur due to the potentiation of CNS stimulation with amphetamines. Amphetamines inhibit adrenergic blockers and the hypotensive effects of veratrum alkaloids. The hypotensive effects of antihypertensive agents and the sedative effect of antihistamine agents may be antagonized by amphetamine use. Lithium may inhibit the anorectic and stimulatory effects of amphetamines. Haloperidol may inhibit the CNS stimulant effects of amphetamines by blocking dopamine receptors. Similarly, chlorpromazine may inhibit the CNS stimulant effects of amphetamines by blocking dopamine and norepinephrine receptors. The analgesic effect of meperidine may be increased with amphetamine use. Amphetamines may potentiate the adrenergic effects seen with norepinephrine. Tricyclic antidepressant agents may have enhanced activity when used with amphetamines. Monoamine oxidase inhibitor agents slow the metabolism of amphetamines.1,2

Drug-laboratory test interactions:

Adderall use can result in elevated serum corticosteroid levels, with the greatest increase occurring in the evening. Additionally, Adderall can interfere with urinary determinations of steroids.1

Dosage forms available:

Adderall is available in four strengths (5 mg, 10 mg, 20 mg, 30 mg) in the form of an oral tablet.1,8

Potential for medication errors:

"Adderall" has the potential to be confused with "Inderal."8 Inderal is a brand-name product containing propranolol, a beta adrenergic antagonist.

Discussion:

Clinical data support the efficacy of Adderall in the behavioral management of children with ADHD, and it appears to be comparable in efficacy, safety, and side effects to methylphenidate.3,4 However, it should be noted that these trials may be flawed in their comparisons of Adderall to methylphenidate, and these results may be skewed in favor of Adderall.

References:

1. Adderall package insert. Florence, KY: Shire Richmond, Inc.; 1998 July.

2. Gelman CR, Rumack BH, Hutchinson TA, eds. DRUGDEX System. Micromedex Inc., Englewood, CO; 2000.

3. Swanson JM, Wigal S, Greenhill LL, et al. Analog classroom assessment of Adderall in children with ADHD. Journal of the American Academy of Child & Adolescent Psychiatry 1998; 37(5):519-25.

4. Pliska SR, Browne RG, Olvera RL, Wynne SK. A double-blind, placebo-controlled study of Adderall and methylphenidate in the treatment of attention-deficit/hyperactivity disorder. Journal of the American Academy of Child & Adolescent Psychiatry 2000; 39(5):619-26.

5. Personal Communication, Darlene Parker, Shire Richwood Inc., 7900 Tanners Gate Drive, Suite 200, Florence, KY 41042, (800) 536-7878, Nov. 16, 2000.

6. Hall AH, ed. REPRORISK System. Micromedex Inc., Englewood, CO; 2000.

7. Briggs GG, Freeman RK, Yaffe SJ, eds. Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 5th ed. Baltimore: Williams & Wilkins; 1998.

8. Cardinale V, ed. Drug Topics Red Book 2000. Montvale, NJ: Medical Economics Co. Inc.; 2000.