2006 Nov (51): Treatment Guidelines - Drugs for Treatment of ADHD

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Treatment
Guidelines
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from The Medical Letter
Vol. 4 (Issue 51) November 2006
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Tables
Some Drugs for ADHD Page 78
Drug Interactions Page 80
Drugs for Treatment of ADHD
Attention-deficit/hyperactivity disorder (ADHD) is a
disruptive behavior disorder that occurs in 5-7% of
school-age children and has also been estimated to
occur in about 4% of adults. 1
ADHD is characterized by a persistent pattern of frequent,
severe inattention and/or hyperactivity/ impulsivity
that starts before the age of 7, is present in 2 or
more settings (such as home and school), causes significant
impairment in function, and is not caused by
another mental disorder. 2
The drugs approved for treatment of ADHD by the
FDA are listed in the table on page 78. Except for atomoxetine,
they are all stimulants and are classified as
controlled substances by the US Drug Enforcement
Administration (DEA).
STIMULANTS
METHYLPHENIDATE — Methylphenidate (MPH),
the active ingredient in the majority of stimulant medications
prescribed in the US, has been shown to be
effective in reducing ADHD symptoms in both children
and adults. 3,4 MPH is thought to block reuptake
of dopamine into presynaptic neurons in the central
nervous system, increasing its concentration in the
interneuronal space. Most MPH products are racemic
mixtures of d- and l-threo enantiomers; the d-threo
enantiomer is the more pharmacologically active. Two
d-methylphenidate products (Focalin, Focalin-XR)
are currently marketed in the US. MPH is primarily
metabolized extra-hepatically by de-esterification to
an inactive metabolite. About 90% of radiolabeled
MPH can be recovered from urine.
Short-Acting – All immediate-release (IR) MPH formulations
are rapidly absorbed into the systemic circulation;
effects on behavior can be seen within 30
minutes of administration. Plasma concentrations
reach a peak in 1-3 hours, with a mean half-life of
about 3 hours and a duration of action of 3-5 hours.
IR-MPH tablets are now often used concurrently with
long-duration forms either to provide a boost early in
the morning, or to smooth withdrawal in the late afternoon.
When used as the main treatment for ADHD, IR-
MPH can be started at a dose of 5 mg three times a day
for children and 10 mg three times a day for adults. The
dose can be increased in 5-mg increments every 5-7
days, up to a maximum of 20 mg three times daily. Preschool
children generally need a total daily dose of
about 15 mg per day, and school-age children need
about 30 mg per day. 5 Although not FDA-approved,
some older children and adults may require more than
60 mg of MPH per day. Dexmethylphenidate
hydrochloride (Focalin), the d-threo-enantiomer of
MPH, can be given in half the dose of racemic MPH.
EDITOR: Mark Abramowicz, M.D. DEPUTY EDITOR: Gianna Zuccotti, M.D., M.P.H., Weill Medical College of Cornell University
EDITOR, DRUG INFORMATION: Jean-Marie Pflomm, Pharm.D., CONTRIBUTING EDITOR, DRUG INFORMATION: Nina H. Cheigh, Pharm.D.
ADVISORY BOARD: Jules Hirsch, M.D., Rockefeller University; James D. Kenney, M.D., Yale University School of Medicine; Richard B. Kim, M.D.,
University of Western Ontario; Gerald L. Mandell, M.D., University of Virginia School of Medicine; Hans Meinertz, M.D., University Hospital, Copenhagen;
Dan M. Roden, M.D., Vanderbilt University School of Medicine; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York
University School of Medicine
EDITORIAL FELLOWS: Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical School; Eric J. Epstein, M.D., Albert Einstein College of Medicine
SENIOR ASSOCIATE EDITORS: Donna Goodstein, Amy Faucard ASSISTANT EDITORS: Cynthia Macapagal Covey, Tracy Shields
MANAGING EDITOR: Susie Wong PRODUCTION COORDINATOR: Cheryl Brown VP FINANCE & OPERATIONS: Yosef Wissner-Levy
Copyright 2006. The Medical Letter, Inc. (ISSN 1541-2792)
Federal copyright law prohibits unauthorized reproduction by any means and imposes severe fines.
77

Some Drugs for ADHD
Duration Pediatric Dosage Adult Dosage
Drug Forms of Action Start/Typical Start/Typical Cost 1
STIMULANTS 2
Dexmethylphenidate
Focalin (Novartis) 2.5, 5, 10 mg tabs 5-6 h 2.5 mg AM/5 mg AM 5 mg AM/20 mg AM $25.20
Focalin XR 3 5, 10, 15, 20 mg caps 12 h 5 mg AM/10 mg AM 5 mg AM/20 mg AM 102.00
Methylphenidate
short-acting 3-5 h 5 mg tid/10 mg tid 10 mg bid/20 mg tid
generic 5, 10, 20 mg tabs 38.70
Ritalin (Novartis) 5, 10, 20 mg tabs 79.20
Methylin (Mallinckrodt) 5, 10, 20 mg tabs 28.80
Methylin Chewable Tablets 2.5, 5, 10 mg tabs 81.00
(Alliant)
Methylin Oral Solution 5 mg/5 mL, 94.50
(Alliant) 10 mg/5 mL 4
intermediate-acting
3-8 h
generic 20 mg tabs 5 20 mg AM/40 mg AM 20 mg AM/80 mg AM 54.60
Ritalin SR (Novartis) 20 mg tabs 5 112.80
Metadate ER (Celltech) 10, 20 mg tabs 5 10 mg bid/30 mg AM 10 mg bid/80 mg AM 54.90
Methylin ER (Mallinckrodt) 10, 20 mg tabs 5 49.80
long-acting
8-12 h
Metadate CD (Celltech) 10, 20, 30, 40, 10 mg AM/30 mg AM 20 mg AM/80 mg AM 76.80
50, 60 mg tabs
Ritalin LA 3 (Novartis) 10, 20, 30, 40 mg 10 mg AM/30 mg AM 10 mg AM/80 mg AM 89.70
caps
Concerta (Alza) 18, 27, 36, 54 mg 10-12 h 18 mg AM/36 mg AM 18 mg AM/72 mg AM 111.90
tabs 5
Daytrana (Noven/Shire) 12.5, 18.75, 25, 10-12 h 10 mg patch on 9hrs, 10 mg patch on 9hrs 141.60
37.5 cm 2 off 15hrs/ off 15hrs/
transdermal patch 6 30 mg patch on 9hrs, 60 mg patch on 9hrs,
off 15hrs
off 15hrs
Dextroamphetamine
short-acting 4-6 h 5 mg bid/10 mg bid 5 mg bid/15 mg bid
generic 3 5, 10 mg tabs 32.40
Dextrostat 3 (Shire) 5, 10 mg tabs 27.60
Dexedrine 3 (GSK) 5 mg tabs 67.20
long-acting 6-8 h 5 mg AM/15 mg AM 5 mg AM/30 mg AM
generic 3 5, 10, 15 mg caps 33.30
Dexedrine Spansules 3 (GSK) 5, 10, 15 mg caps 62.70
Amphetamine Mixed Salts
short-acting 4-6 h 5 mg bid/10 mg bid 5 mg bid/15 mg bid
generic 3 5, 7.5, 10, 12.5, 66.60
15, 20, 30 mg tabs
Adderall 3 (Shire) 5, 7.5, 10, 12.5, 5 mg bid/10 mg bid 5 mg bid/10 mg bid 138.00
15, 20, 30 mg tabs
long-acting
8-10 h
Adderall XR 3 (Shire) 5, 10, 15, 20, 25, 5 mg AM/30 mg AM 5 mg AM/60 mg AM 113.10
30 mg caps
NON-STIMULANTS
Atomoxetine
Strattera (Lilly) 10, 18, 25, 40, 24 h 0.5 mg/kg/d once or 40 mg once/ 129.00 7
60, 80, 100 mg caps divided bid/ 80 mg once or
1.2 mg/kg/d once or divided bid
divided bid
1. Cost for 30 days' treatment with the typical pediatric dosage, based on most recent data (August 30, 2006) from retail pharmacies nationwide available from
Wolters Kluwer Health.
2. All are classified by the DEA as Schedule II controlled substances.
3. Should not be taken with antacids or other drugs that decrease gastric acidity.
4. Available in bottles containing 500 mL.
5. Must be swallowed whole, not crushed or chewed.
6. The four patch sizes deliver 10, 15, 20, 30 mg over 9 hours, respectively. Daytrana is supplied in sealed trays containing 10 or 30 patches in individual pouches.
7. Cost of 30 60-mg capsules.
Treatment Guidelines from The Medical Letter • Vol. 4 (Issue 51) • November 2006
78

Drugs for Treatment of ADHD
Methylin is a short-acting MPH branded generic that
has been formulated in chewable tablets and an oral
solution for young children who have difficulty swallowing
tablets or capsules. Peak plasma concentrations
of MPH are achieved within 1-2 hours with the
chewable tablets; high-fat meals delay the peak by 1
hour. No large-scale clinical trials using these formulations
have been published.
Long-Acting – Despite the effectiveness of IR-MPH,
its 3-5 hour duration of action usually requires mid-day
dosing in school, which children may find disruptive or
stigmatizing. The short duration of action also requires
administration by non-family adults when children
participate in after-school programs. Long-duration
MPH preparations with once-daily dosing have therefore
become the mainstay of clinical practice.
Single-Pulse (Ritalin-SR, Metadate ER, Methylin
ER) – Single-pulse, sustained-release MPH formulations
use a wax matrix to prolong release. They have a
slower onset of action than IR-MPH and a duration of
action of up to 8 hours, but some clinicians have found
their duration of action to be highly variable and view
these drugs as less effective in practice than immediate-release,
beaded double-pulse, or osmotic-release
MPH (OROS-MPH) preparations. Many clinicians
prescribe single-pulse formulations twice daily, and
some add an immediate-release tablet in the morning.
Beaded Double-Pulse (Ritalin LA, Focalin XR,
Metadate CD) – Beaded MPH products use an extended-release
formulation with a bi-modal release mechanism.
With Ritalin LA and Focalin XR, half the dose
is in immediate-release beads and half in enteric-coated,
delayed-release beads. Metadate CD contains 30%
immediate-release beads and 70% delayed-release
beads. In young children who have difficulty swallowing
pills, the capsules can be opened and the beads
sprinkled into a small amount of cold applesauce or
vanilla ice cream to disguise the bitter taste.
Osmotic-Release (Concerta; OROS-MPH) – The
Concerta tablet uses an osmotic delivery system to
extend the duration of action of MPH to up to 12
hours. 6,7 The tablet is coated with IR-MPH for immediate
action. The rest of the dose is delivered by an osmotic
pump that gradually releases the drug over a 10-hour
period, producing slightly ascending MPH serum concentrations.
Taken once daily, serum concentrations are
similar to those produced by taking IR-MPH three times
daily, but with less variation. 8 The tablets themselves are
excreted intact in the stool.
Three double-blind, randomized clinical trials have
compared OROS-MPH to IR-MPH in children with
ADHD; the results show that the reductions in ADHD
symptoms that occur with once-daily doses of OROS-
MPH match those achieved with multiple doses of IR-
MPH. 9,10,11 Studies in adolescents have also demonstrated
effectiveness with OROS-MPH. 12 In one small
study in 6 patients, OROS-MPH taken once daily in
the morning was more effective in reducing ADHDinduced
driving impairments in the evening than IR-
MPH taken three times daily. 13
Transdermal (Daytrana) – Transdermal MPH appears
to be as effective as other long-duration MPH preparations,
but adverse effects such as anorexia, insomnia,
and tics have occurred more frequently with the patch
formulation. Mild skin reactions are common. 14 After
application of the transdermal patch, MPH is steadily
absorbed and reaches peak concentrations in serum
after 7-9 hours. Chronic dosing with the patch results in
higher peak MPH levels than with equivalent doses of
OROS-MPH. The duration of MPH action for a 9-hour
wear period is about 11.5 hours. A double-blind, placebo-controlled
crossover study conducted in a laboratory
classroom showed significantly lower ADHD symptom
scores and higher math test scores with the MPH
patch compared to a placebo patch during postdose
hours 2 through 12. 15 One advantage of the patch formulation
is that it can be removed early in patients who
have a problem with insomnia.
AMPHETAMINES — Like MPH, amphetamines
used to treat ADHD are available as either the d-isomer,
dextroamphetamine (Dexedrine, Dextrostat), or
in racemic forms, which are mixtures of d- and l-
amphetamine (Adderall, Adderall XR).
Dextroamphetamine – Dextroamphetamine has been as
effective as MPH in decreasing overactivity, impulsivity
and inattention in children with ADHD. Some children
unresponsive to MPH may respond to dextroamphetamine,
and vice versa. Absorption of dextroamphetamine
is rapid; plasma concentrations reach a peak 3 hours after
oral administration. Taking the drug with ascorbic acid or
fruit juice tends to decrease absorption of amphetamine,
while alkalinizing agents such as sodium bicarbonate
tend to increase absorption. Acidification of the urine
increases amphetamine excretion.
The onset of action of dextroamphetamine occurs
within one hour of ingestion, and its duration of action
is up to 5 hours, somewhat longer than that of MPH.
Twice-daily administration is needed to extend the
treatment throughout the school day, and children may
dislike taking the second dose in school.
Mixtures – Adderall and Adderall XR are mixtures of
amphetamine salts. Adderall XR is a double-pulse cap-
Treatment Guidelines from The Medical Letter • Vol. 4 (Issue 51) • November 2006
79

Drugs for Treatment of ADHD
sule formulation that contains both immediate-release
and extended-release beads. There is no evidence that
these mixed amphetamine salts offer any advantage
over MPH or dextroamphetamine, but some patients
respond to one and not to another.
Some older children say that stimulants make them
feel less spontaneous and less comfortable in their
social interactions. Drug holidays during weekends
and vacations may be helpful, particularly in making
up for weight loss and slow growth.
ADVERSE EFFECTS — Adverse events frequently
reported during use of any stimulant include delayed
sleep onset, headache, decreased appetite and weight
loss. Infrequent adverse events include emotional
lability and either new onset or an increase in the frequency
of tics. Tactile and visual hallucinations can
occur. Stimulants can slow growth and possibly lower
the convulsive threshold. They should be used with
great care in patients with a history of mania, psychosis,
drug dependence or alcoholism.
The most common adverse events leading to discontinuation
of treatment with stimulants have been motor or
vocal tics, anorexia, insomnia and tachycardia.
Some Drug Interactions*
Reports of 20 cases of sudden unexpected death (14
children and 6 adults) and 12 cases of stroke in patients
taking Adderall XR led Health Canada to suspend sales
of the drug. 16 That decision was later reversed. The
FDA decided that the number of sudden deaths was no
greater than expected among the large number of people
taking the drug, but because 5 of the children who
died had structural heart defects, a warning against
using any stimulant in such patients was added.
Routine ECGs and echocardiograms are not indicated
before starting stimulants in a patient who has an unremarkable
history and physical examination. Patients
with pre-existing heart disease should be referred to a
Comments and
Interacting Drugs Effects Probable Mechanism Recommendations
METHYLPHENIDATE:
Carbamazepine Possible decreased Possibly increased metabolism May require methylphenidate dose
(Tegretol) methylphenidate effect increase
Clonidine (Catapres) ECG abnormalities and sudden Mechanism unknown; cause and effect Monitor blood pressure and pulse
death
not established
MAO inhibitors and Hypertensive crisis Increased release of norepinephrine Should not be used concurrently or
linezolid (Zyvox)
within 2 weeks of each other
Phenobarbital Possible phenobarbital toxicity Decreased metabolism Monitor phenobarbital concentrations
Phenytoin (Dilantin) Possible phenytoin toxicity Decreased metabolism Monitor phenytoin concentrations
Sympathomimetics Increased blood pressure and Additive Monitor clinical status
heart rate
Tricyclic antidepress- Possible increase in TCA serum Inhibition of TCA metabolism Monitor clinical status and TCA serum
ants (TCAs) concentrations concentrations; reported with
imipramine and desipramine
Warfarin (Coumadin) Increased anticoagulant effect Decreased metabolism Monitor INR
AMPHETAMINES:
Acetazolamide Increased amphetamine effect Urinary alkalinization decreases Monitor clinical status; could occur
(Diamox) amphetamine excretion with other drugs that increase
urine PH
Antacids Increased amphetamine effect Urinary alkalinization decreases Monitor clinical status; reported with
amphetamine excretion
sodium bicarbonate
MAO inhibitors and Increased amphetamine effect; Decreased amphetamine metabolism Should not be used concurrently
linezolid (Zyvox) hypertensive crisis or within 2 weeks of each other
Sympathomimetics Increased blood pressure and Additive Monitor clinical status
heart rate
Tricyclic antidepress- Increased cardiovascular effects Additive Monitor clinical status
ants (TCAs)
ATOMOXETINE:
Albuterol Increased blood pressure and Additive Reported with IV albuterol; could
heart rate
occur with other systemically
administered B 2 agonists
Fluoxetine (Prozac) Increased atomoxetine effect Decreased atomoxetine metabolism; Atomoxetine dose reduction or slow
inhibition of CYP2D6
titration may be needed
MAO inhibitors and Severe atomoxetine toxicity, Increased brain monoamine Should not be used concurrently or
linezolid (Zyvox) possibly fatal concentrations within 2 weeks of each other
Paroxetine (Paxil) Increased atomoxetine effect Decreased atomoxetine metabolism; Atomoxetine dose reduction or slow
inhibition of CYP2D6
titration may be needed
Quinidine Increased atomoxetine effect Decreased atomoxetine metabolism; Atomoxetine dose reduction or slow
inhibition of CYP2D6
titration may be needed
*See The Medical Letter’s Adverse Drug Interactions Program for references and additional interactions.
Treatment Guidelines from The Medical Letter • Vol. 4 (Issue 51) • November 2006
80

Drugs for Treatment of ADHD
cardiologist before starting stimulant treatment. Known
cardiac problems that require special caution in using
stimulants include postoperative tetralogy of Fallot,
coronary artery abnormalities and obstructive subaortic
stenosis. Hypertension, syncope (especially during exercise),
arrhythmias or chest pain may be signs of hypertrophic
cardiomyopathy, which has been associated with
sudden unexpected death in patients taking stimulants.
Contraindications – Clinical conditions that can be
exacerbated by stimulant treatment include psychosis,
mania, Tourette syndrome and closed-angle glaucoma.
NON-STIMULANTS
ATOMOXETINE – A selective norepinephrine reuptake
inhibitor, atomoxetine (Strattera) was the first
drug to be approved by the FDA to treat ADHD in both
children and adults. 17 It is neither a controlled substance
nor a stimulant.
Pharmacokinetics – Atomoxetine is rapidly absorbed,
with peak serum concentrations occurring within 1
hour without food and in

Drugs for Treatment of ADHD
once a day in children with attention-deficit/hyperactivity disorder.
Pediatrics 2001; 108:883.
10. J Swanson et al. Development of a new once-a-day formulation of
methylphenidate for the treatment of attention-deficit/hyperactivity
disorder: proof-of-concept and proof-of-product studies. Arch Gen
Psychiatry 2003; 60:204.
11. WE Pelham et al. Once-a-day Concerta methylphenidate versus threetimes-daily
methylphenidate in laboratory and natural settings.
Pediatrics 2001; 107:E105.
12. TE Wilens et al. Multisite controlled study of OROS methylphenidate
in the treatment of adolescents with attention-deficit/hyperactivity
disorder. Arch Pediatr Adolesc Med 2006; 160:82.
13. DJ Cox et al. Impact of methylphenidate delivery profiles on driving
performance of adolescents with attention-deficit/hyperactivity disorder:
a pilot study. J Am Acad Child Adolesc Psychiatry 2004; 43:269.
14. Transdermal methylphenidate (Daytrana) for ADHD. Med Lett Drugs
Ther 2006 48:49.
15. JJ McGough et al. A randomized, double-blind, placebo-controlled,
laboratory classroom assessment of methylphenidate transdermal system
in children with ADHD. J Atten Disord 2006; 9:476.
16. Adderall. Med Lett Drugs Ther 2005; 47:28.
17. Atomoxetine (Strattera) for ADHD. Med Lett Drugs Ther 2003; 45:11.
18. SB Wigal et al. A laboratory school comparison of mixed amphetamine
salts extended release (Adderall XR) and atomoxetine (Strattera) in
school-aged children with attention deficit/hyperactivity disorder. J
Atten Disord 2005; 9:275.
19. Drug interactions. Med Lett Drugs Ther 2003; 45:46.
20. New indications for modafinil (Provigil). Med Lett Drugs Ther 2004;
46:34.
21. JS Ballon and D Feifel. A systematic review of modafinil: potential
clinical uses and mechanisms of action. J Clin Psychiatry 2006; 67:554.
22. SR Pliszka et al. Comparative effects of methylphenidate and mixed
salts amphetamine on height and weight in children with attentiondeficit/hyperactivity
disorder. J Am Acad Child Adolesc Psychiatry
2006; 45:520.
Coming Soon in Treatment Guidelines:
Surgical Prophylaxis – December 2006
Eye Disorders – January 2007
Coming Soon in The Medical Letter:
Posaconazole (Noxafil) for Fungal Infections
Rasagiline (Azilect) for Parkinson’s Disease
Transdermal Fentanyl (Ionsys) for Pain
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Treatment Guidelines from The Medical Letter • Vol. 4 (Issue 51) • November 2006
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