Download Attention Deficit/Hyperactivity Disorder: Case

CONTINUING EDUCATION
Attention Deficit/Hyperactivity Disorder:
Case-Based Therapeutic Update
by Ashley Khan, PharmD
June 2, 2014 (expires June 2, 2017)
Activity Type: Knowledge-based
To earn continuing education credit:
ACPE Program 207-000-14-006-H01-P
207-000-14-006-H01-T
Upon successful completion of this article, the pharmacist should be
able to:
1. Describe the pathophysiology of attention deficit/hyperactivity disorder
(ADHD) and the clinical signs and symptoms.
2. Identify notable differences in ADHD between children and adults, and
address differing perceptions of the disorder in girls and boys.
3. Select appropriate treatment options for patients from standard and new
regimens, and discuss patient counseling conversations that could address knowledge gaps about dietary and alternative treatments for ADHD.
4. Identify the risks for potential abuse and the signs of such abuse in pediatric and adult populations. In this context, interpret the latest research
about true abuse risks that could guide patient counseling.
5. Detail the drug interactions possible in outpatient populations, especially
those that have clinically relevant consequences in patients with mental
health disorders.
Upon successful completion of this article, the pharmacy technician
should be able to:
1. D
escribe the pathophysiology of attention deficit/hyperactivity disorder
(ADHD) and the clinical signs and symptoms.
2. Identify notable differences in ADHD between children and adults, and
address differing perceptions of the disorder in girls and boys.
3. D
iscuss how OTC and dietary supplement purchases are influenced by
seeking dietary and alternative treatments for ADHD.
4. Identify the risks for potential abuse and the signs of such abuse in pediatric and adult populations and bring to the attention of a pharmacist.
5. Identify common drug interactions possible in patients taking prescription
drugs to treat ADHD.
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continuing pharmacy education. NCPA has assigned 1.5 contact hours (0.15 CEU) of continuing
education credit to this article. Eligibility to receive continuing education credit for this article
expires three years from the month published.
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www.americaspharmacist.net45
As a highly diagnosed DSM-5 mental health disorder,
attention deficit/hyperactivity disorder afflicts both children
and adults as a chronic, treatable condition. However,
within-class treatment options and dosages vary considerably because of patient tolerability, safety concerns, and
efficacy differences. Additionally, new treatment options
and recurring evaluations of medication abuse, safety, and
treatment durations continue to change how clinicians
view ADHD treatment options. A review of current literature and therapy approaches is warranted periodically to
update practitioners about best practices.
OVERVIEW
The Centers for Disease Control and Prevention estimates
that approximately 11 percent of children between the ages
of 4 and 17 suffer from ADHD. The American Academy of
Pediatrics cites it as the most common psychiatric disorder
in children and adolescents. Approximately 4 percent of
adults also carry the diagnosis, and the prevalence is rising
in all age groups. As researchers gain a better understanding of this neurobehavioral disorder, diagnostic criteria and
treatment recommendations continue to evolve, and new
medications are being introduced within established treatment classes. Stimulants remain a mainstay of treatment
for ADHD, and concerns about their abuse continue to be
a source of debate among the public and researchers alike.
Questions also linger about the effectiveness of alternative therapies and dietary modifications. As patients and
families rely more on the Internet and less on physicians
for health information, pharmacists have an opportunity to
provide education and reliable resources and promote safe
and optimal use of medications for the long-term treatment
of this chronic disorder.
PATHOGENESIS AND RISK FACTORS
Although the precise mechanisms underlying ADHD
remain unclear, an imbalance in catecholamine activity in
several regions of the brain is believed to play a critical role.
Reduced activity of the neurotransmitters norepinephrine
and dopamine in several brain regions appear to impair
mental and emotional functioning in patients with ADHD.
Neuroimaging studies note structural differences in
particular brain regions of patients with ADHD. Relative to
those of people without ADHD, variations exist in the size,
thickness, and symmetry of areas within the prefrontal
cortex, cerebellum, and caudate nucleus. The imaging also
indicates that children with ADHD have less activity in and
less development of the basal ganglia, prefrontal cortex,
and cerebellum. The prefrontal cortex plays a significant
role in executive functioning; it mediates decision making,
organization, attention, and social behavior. The basal
ganglia, which includes the caudate nucleus, interacts with
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the prefrontal cortex and responds primarily to dopamine.
As part of the limbic system, it influences emotions and
reward learning. The cerebellum contributes to cognitive
functions such as attentiveness, although it is primarily
known for its role in motor control.
Among the causative factors of ADHD, genetics may account for up to 75 percent of all cases. The disorder has a
strong hereditary component; children with parents or siblings with ADHD are more likely to develop it. To date, most
studies on genetic risk have focused on the role of the
particular genes that influence the action of dopamine in
the brain. Another 10-15 percent of cases may be attributed
to a wide variety of early environmental insults. Prenatal and perinatal exposure to drugs, alcohol, or nicotine
through maternal abuses has been tied to the development
of ADHD. Low birth weight for any reason may possibly be
linked to the disorder as well. Other insults during the early
postnatal period, such as head trauma, brain hypoxia, and
lead poisoning, also increase the risk of developing ADHD.
CLINICAL FEATURES AND DIAGNOSIS
ADHD develops in childhood, regardless of age at diagnosis, and the disease is characterized in children or adults
by symptoms of inattention and/or hyperactivity and impulsivity that persist for at least six months. The symptoms
must be significant enough to negatively affect functioning
or development in both social and academic or occupational settings. The disorder can be further classified into three
subtypes according to the specific symptoms exhibited:
predominantly hyperactive/impulsive, predominantly inattentive, or combined.
Diagnosis of ADHD and the subtype in all patients is based
on an assessment of nine specific symptoms of hyperactivity-impulsivity and nine symptoms of inattention. Symptoms
of hyperactivity and impulsivity, particularly in children, include fidgeting or squirming; leaving one’s seat or running
and climbing about inappropriately; being unable to remain
quiet; talking excessively; blurting out responses and interrupting others; and having difficulty waiting one’s turn. Inattention, though less obvious than hyperactive disturbances,
is an equal contributor to diagnosis. Inattention presents
as failure to focus on tasks or details; poor listening and
organization skills; failure to complete activities; avoidance
of tasks that require prolonged mental effort; forgetfulness;
and problems with misplacing items and getting distracted
by external stimuli. Table 1 lists these diagnostic criteria according to the latest edition of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-5), released in 2013.
To reflect new research and help clinicians better diagnose ADHD in patients of all ages, the DSM-5 includes
America’s PHARMACIST | June 2014
Table 1. DSM-5 Diagnostic Criteria for Attention Deficit/Hyperactivity Disorder
(A)A persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development,
as characterized by (1) and/or (2). For patients under age 17 years, six or more symptoms of (1) and/or six or more
symptoms of (2) must have persisted for at least six months. For patients age 17 years and older, at least five
symptoms from a single category are required.
(1)Inattention:
a.Often fails to give close attention to details or makes
careless mistakes in schoolwork, at work or during other
activities
b.Often has difficulty sustaining attention in tasks or play
activities
c.Often does not seem to listen when spoken to directly
d.Often does not follow through on instructions and fails to
finish schoolwork, chores, or duties in the workplace
e.Often has difficulty organizing tasks and activities
f.Often avoids, dislikes, or is reluctant to engage in tasks that
require sustained mental effort
g.Often loses things necessary for tasks or activities
h.Is often easily distracted by extraneous stimuli
i.Is often forgetful in daily activities
(2)Hyperactivity-Impulsivity:
a.Often fidgets with or taps hands or feet or squirms in seat
b.Often leaves seat in situations when remaining seated is
expected
c.Often runs about or climbs in situations where it is
inappropriate
d.Often unable to play or engage in leisure activities quietly
e.Is often “on the go,” acting as if “driven by a motor”
f.Often talks excessively
g.Often blurts out an answer before a question has been
completed
h.Often has difficulty waiting his or her turn
i.Often interrupts or intrudes on others
(B)Several inattentive or hyperactive-impulsive symptoms were present prior to age 12 years.
(C)Several inattentive or hyperactive-impulsive symptoms are present in 2 or more settings.
(D)There is clear evidence that symptoms interfere with, or reduce the quality of, social, academic, or occupational
functioning.
(E)The symptoms do not occur exclusively during the course of schizophrenia or another psychotic disorder and are not
better explained by another mental disorder.
Presentation Subtypes
Combined:
Both Criterion A1 and Criterion A2 are met for the past 6 months
Predominantly inattentive
Criterion A1 is met but Criterion A2 is not met for the past 6
months
Predominantly hyperactive-impulsive
Criterion A2 is met but Criterion A1 is not met for the past 6
months
Adapted from DSM-5
substantial updates for two criteria. One key diagnostic
change pertains to the time of symptom onset. Through
the release of DSM-IV, diagnosis focused on symptom
presentation before age 7 years. Now, the DSM-5 extends
the time period for symptom identification to before age
12. The updated DSM-5 also makes a distinction between the number of symptoms needed for diagnosis for
children and older patients. Six of nine symptoms from
at least one of the two groups (inattention or hyperactivity-impulsivity) must be present for children to be diagnosed with ADHD. However, in older adolescents (age 17
and older) and adults, only five symptoms in a given group
are required.
The DSM-5 provides a better framework for clinicians
to assess patients of any age who may have ADHD; it
acknowledges ADHD as a chronic condition that requires
long-term care. Roughly two-thirds of patients diagnosed
as children endure residual symptoms into adulthood. As
more research supports this persistence of symptoms,
more attention is being directed at recognizing adults
with ADHD. The medical community now acknowledges
that these individuals do not necessarily “grow out” of
this disorder and require continued treatment. Moreover,
although a new diagnosis in adults is less common, it can
also occur as a result of earlier diagnostic delays and can
still be treated at any age.
www.americaspharmacist.net47
Table 2. Summary of FDA-Approved Medications for the Treatment of ADHD
Stimulants
Methylphenidate-based Drugs
Amphetamine-based Drugs
Brand Names
MPH: Ritalin, Methylin; Ritalin-SR,
Metadate ER; Ritalin LA, Metadate CD;
Concerta; Quillivant XR; Daytrana;
DMPH: Focalin, Focalin XR
Mixed amphetamine salts: Adderall,
Adderall XR; DAMPH: Dextrostat,
Procentra, Dexedrine Spansule;
LDX: Vyvanse
Generic Availability
Yes for all except Quillivant XR and
Daytrana
Yes for all except Vyvanse
Formulations
IR products: tablet, chewable tablet,
oral solution; ER products: tablet, capsule,
oral suspension, transdermal patch
IR products: tablet, oral solution;
ER products: capsule
FDA Approvals for ADHD
Children ages 6-17 years and adults,
except transdermal MPH, which is only
approved for children ages 6-17 years
Mixed amphetamine salts and IR DAMPH
tablets: children ages 3-17 years and
adults; IR DAMPH solution: children ages
6-17 years; ER DAMPH and LDX: children
ages 6-17 years and adults
Recommended Initial Daily Dose
MPH: 10 mg - 20 mg; OROS tablet: 18 mg;
DMPH: 5 mg
Mixed amphetamine salts: Ages 3 to 5:
2.5 mg; Ages 6-17: 5 mg - 10 mg; Adults:
20 mg; DAMPH: Ages 3 to 5: 2.5 mg; Ages
6-17: 5 mg - 10 mg; Adults: 10 mg; LDX:
30 mg
Maximum Daily Dose
MPH: Labeled: 60 mg; Off-label: 100 mg
if over 50 kg; OROS tablet: Labeled: 54
mg; Off label: 72 mg if adolescents/adults;
DMPH: IR products—Labeled: 20 mg; Offlabel: 50 mg; ER products—Labeled: 30 mg
(children), 40 mg (adults); Off-label: 50 mg
Mixed amphetamine salts: IR
products—40 mg, rarely up to 60 mg; ER
products—Labeled: 30 mg; Off-label: 60 mg
if over 50 kg; DAMPH: 40 mg, rarely up to
60 mg; LDX: 70 mg
Dose Adjustments
Weekly as needed
Administration Considerations
All: Take in the morning and/or early
afternoon; ER Products: Wax matrix
tablets and OROS tablets must be taken
whole, but all other oral ER products can
be opened and contents sprinkled over
applesauce; Patch: store in pouch. Once
tray opened, use within 2 months; once
an individual patch has been removed
from pouch and protective liner, use
immediately. Do not refrigerate or freeze.
Common Adverse Reactions
Decreased appetite, weight loss, headache, insomnia, mood lability, GI upset, and tics;
Rare: serious cardiac events, sudden death
Storage
Store at room temperature, and protect from light.
Safety Information
Avoid use in patients with tics or cardiac conditions
All: Take in the morning and/or early
afternoon; ER Products: Capsules can
be opened and contents sprinkled over
applesauce. LDX: Tablets can be dissolved
in water
MPH: methylphenidate; DMPH: dexmethylphenidate; DAMPH: dextroamphetamine; LDX: lisdexamfetamine; IR: immediate-release;
ER: extended-release; yo: years old
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America’s PHARMACIST | June 2014
Selective Norepinephrine Reuptake
Inhibitors
Alpha-2 Adrenergic Agonists
Atomoxetine
Clonidine
Guanfacine
Strattera
Kapvay
Intuniv
No
No
No
IR capsule
ER tablet
ER tablet
Children ages 6 years and older and adults
Children ages 6-17 years, as monotherapy or adjunct to stimulants
Patients up to 70 kg: 0.5 mg/kg
Patients > 70 kg: 40 mg
0.1 mg
1 mg
1.4 mg/kg
0.4 mg
4 mg
Can increase dose after the first 3-4 days
of therapy; then increase every 2-4 weeks
as needed
Weekly as needed; must taper dose when discontinuing
Swallow capsules whole
Initially, take at bedtime. Tablets cannot be crushed, chewed, or broken.
Decreased appetite, headache, insomnia,
GI upset, and dry mouth
Dry mouth, somnolence, dizziness, headache, constipation, and hypotension
Increased risk of suicidal ideation in
pediatric patients
ER and IR formulations are not interchangeable on a mg:mg basis; retitrate if switching
between the two
www.americaspharmacist.net49
Some special consideration should be given to how adults
present with ADHD. As patients grow older, they typically
suffer from less hyperactivity but experience more inattention and impulsivity. However, when adults do exhibit
signs of hyperactivity, those symptoms are often less
overt than in their younger counterparts. These features,
coupled with disorganization, are especially detrimental to
home and work life for adults. Statistically, these symptoms are manifested in higher rates of car accidents, job
turnover, and divorce, as well as lower income. In a 2008
multinational study, ADHD was associated with 143.8
million lost days of productivity, defined by a combination of missed days and reduced quality and quantity of
performance on the job.
Clinicians face additional challenges when assessing
adults, because an accurate childhood history is required
for the diagnosis. Clinicians must also consider medical
and psychiatric comorbidities, such as traumatic brain
injury, seizures, dementia, learning disabilities, and substance abuse disorders. If these or other psychiatric morbidities remain uncontrolled, they may mimic or worsen
the symptoms of ADHD. Any urgent psychiatric conditions
or active substance abuse should be addressed first before
directing full attention to the management of ADHD.
ADHD is often accompanied by comorbid psychiatric
conditions, many of which have overlapping symptoms.
Approximately 80 percent of adults with ADHD have at
least one coexisting condition, many of which are psychiatric in nature. An estimated 30-50 percent of patients
have suffered from depression; 40-60 percent anxiety; and
50 percent, substance abuse. Other common psychiatric
comorbidities seen in adult ADHD patients include bipolar
disorder and antisocial personality disorder. In children,
anxiety disorders, sleep disorders, autism, learning disabilities, and oppositional-defiant disorder may coexist with
ADHD. As many as 14 percent of children with ADHD are
also diagnosed with oppositional-defiant disorder, in which
aggression and antisocial behavior become prominent.
Symptom presentation can also differ along gender lines.
Boys are more likely than girls to be diagnosed with ADHD
of either type. Boys are more likely to have the combined
type, whereas girls are usually diagnosed with the predominantly inattentive type. The CDC estimates that the maleto-female ratio is 4:1 for the predominately hyperactive-impulsive type and 2:1 for the predominantly inattentive type
of ADHD. However, it is unclear whether this disparity is a
function of biology, diagnostic oversight, or both factors.
To elucidate the relationship between gender and ADHD,
researchers are beginning to evaluate how hormonal
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and genetic differences influence ADHD symptoms and
compensatory responses, self-perception, and societal attitudes. A 2004 U.S. survey of children with ADHD, as well
as parents and teachers, suggests that girls with ADHD
respond differently to societal demands as they attempt
to manage their disorder. In part, because of the expectations of women in the American culture, girls with ADHD
ultimately suffer from lower self-esteem in their efforts to
cope. Society’s frequent mislabeling and misperceptions of
behavior in girls often precipitates their emotional deterioration. This impairment in females is further compounded
by the higher rates of diagnosis during adolescence, a
time when puberty and social pressures pose exceptional
challenges. Girls with ADHD are more likely to experience
depression, be rejected by their peers, and perform worse
in school. As girls transition from adolescence into adulthood, those same difficulties persist unless the disorder is
accurately diagnosed and effectively treated.
Diagnostic accuracy may now improve with use of the Neuropsychiatric EEG-Based Assessment Aid (NEBA) System.
Approved by the Food and Drug Administration in July 2013,
its purpose is to help health care providers confirm a diagnosis of ADHD or support the decision for additional testing
in children ages 6-17 years. This noninvasive test calculates
the ratio of theta to beta wave frequencies in the brain,
which has been shown to be higher in ADHD patients than
in others. Diagnostic confirmation by the NEBA System can
help ensure that treatment is appropriately prescribed.
TREATMENT APPROACH
A multimodal approach remains the mainstay of treatment
for all patients. Multimodal therapy encompasses a wide
variety of treatments, such as psychoeducation, schoolbased interventions, family counseling, and pharmacotherapy. Treatment can be individualized to best suit the needs
of the child and family or of the adult patient.
However, cognitive and behavior therapies are often less
accessible to patients (http://www.helpguide.org/mental/
adhd _ add _ therapy _ supplement.htm). In some cases,
families cannot afford these therapies, or regions may
have limited availability and resources for programs. In
other instances, the time commitment needed for the
success of behavioral therapies pose challenges. Consequently, medications become a central player in the
management of ADHD. Just over two-thirds of children
diagnosed with ADHD take medications to treat the disorder. Adolescents are more likely than younger children to
take medications, and boys are almost three times more
likely than girls to receive prescription therapy. The majority of adults with ADHD also report taking medications to
manage the condition.
America’s PHARMACIST | June 2014
The 2011 practice guidelines from the American Academy
of Pediatrics (AAP) offer updated treatment recommendations for children ages 4-18 years. Like the DSM-5, the AAP
practice guidelines acknowledge that ADHD is a chronic
condition; this consideration is reflected in some of the
recommendations. Although these guidelines are limited to
pediatric patients, clinicians generally agree that applying
the same principles to adults is appropriate.
The AAP makes a few distinctions in the specific therapy
recommendations for children depending on their age. For
children the ages of 4-5 years (considered preschool age),
behavior therapy is the initial treatment. After approximately three months, if the behavioral interventions are
unsuccessful and symptoms remain moderate or severe,
then clinicians may prescribe methylphenidate. If behavior
therapy is unavailable, the decision to start a medication at
an early age is based on the risks and benefits to the child.
For children ages 6-11 years (elementary school age), the
guidelines indicate that clinicians can prescribe FDA-approved drugs for ADHD or initiate behavior therapy; a
combination of both is preferred. Finally, for patients aged
12-17 years, clinicians are encouraged to prescribe FDA-approved drugs for ADHD, after obtaining consent from the
both the parent and the adolescent. Clinicians may also
prescribe behavior therapy, which when coupled with medication is preferred in this age group, too.
of short- versus long-acting products because the drug
formulations vary considerably. Coexisting conditions and
potential adverse effects may also steer drug selection. For
example, stimulants may exacerbate symptoms of comorbid anxiety and tic disorders; such patients may respond
better to guanfacine or clonidine. Finally, the patient’s
preference and the cost of the medication should also be
considered. Typically, generic medications and short-acting
agents are less expensive.
FIRST-LINE THERAPY: STIMULANTS
Although the precise role of catecholamines in ADHD is
not fully understood, stimulants combat the symptoms
of the disorder through their effects on these neurotransmitter levels. Both amphetamines and methylphenidate
prompt the release of dopamine and norepinephrine in the
central nervous system and also prevent their reuptake at
the synapses. The resulting rise in concentrations of these
catecholamines in the brain improves the function of vital
brain regions connected with classic ADHD symptoms.
Stimulants have a long-demonstrated history of effectiveness at reducing hyperactivity and impulsivity and
improving attention, social behaviors, and concentration.
Since their development more than 50 years ago, these
drugs and subsequent variations have been used to treat
the symptoms of what was ultimately classified as ADHD
in the 1980s. Decades of effectiveness, coupled with the
benefit of immediate symptomatic improvement upon drug
administration, have helped this class maintain its leadership status in ADHD treatment.
FDA-APPROVED DRUGS FOR ADHD
In most cases, the clinician’s first-line drug therapy is a
schedule II stimulant; options include methylphenidateand amphetamine-based products. As a class, stimulants
are an effective treatment for ADHD; more than 80 percent
of patients experience improved symptom control with one
of these agents. Three nonstimulants—atomoxetine, guanfacine, and clonidine—are also available in formulations
with an FDA-approved indication for ADHD. These second-line agents are generally reserved for use when stimulants are ineffective or cause unacceptable side effects,
or when special situations favor their selection first. For
example, a second-line agent is generally more appropriate in patients with cardiac arrhythmias, which precludes
the use of stimulants. Table 2 provides a summary of the
current FDA-approved drugs for treating ADHD.
All FDA-approved stimulants for the treatment of ADHD are
variations of methylphenidate or amphetamine. A multitude of immediate-release (IR) and extended-release (ER)
formulations are on the market. Although all but one are
orally administered, the products are distinguished by their
drug delivery systems and associated dosage schedules.
The risk evaluation and mitigation strategies (REMS) for
stimulant agents requires a medication guide to accompany all new and refill prescriptions. This medication guide
describes the risks for heart-related problems, mental
(psychiatric) problems, and circulation problems in fingers
and toes. Medication guides can be downloaded from
http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm if
one does not accompany the manufacturer’s bottle.
When choosing an initial medication among the many
available agents, clinicians must take into account several
factors on a case-by-case basis. The desired duration of
symptom coverage, the feasibility of multiple daily dosing,
and the ability of the patient to swallow the prescribed dosage form need to be evaluated. These practical considerations can influence decisions about the appropriateness
Methylphenidate: Today’s Drug of Choice
Methylphenidate IR products are available as tablets,
chewable tablets, and as an oral solution. IR brand names
Ritalin and Methylin are well known; generic products are
available for the tablets and oral solution. All of the methylphenidate IR formulations are FDA-approved for use in
patients 6 years of age and older. There is some evidence
www.americaspharmacist.net51
for its effectiveness in preschool age children, but use
of methylphenidate in this population remains off-label.
It is worth noting that when drug therapy is warranted in
preschool age children, the AAP practice guidelines prefer
the use of IR methylphenidate.
For children, usual daily doses of IR products range from 10
mg to 30 mg, depending on the patient’s age and weight.
Typically, 5 mg twice daily is the recommended starting
dosage, although 10 mg twice daily can be considered at
the time of initiation in children older than 8 years or heavier
than 25 kg. Adults can tolerate starting dosages of 5 mg to
10 mg two to three times per day. In all patients, the FDA
does not recommend exceeding daily doses greater than
60 mg of methylphenidate, although 100 mg per day has
be used in patients weighing more than 50 kg. All of the IR
products have a 3-5 hour duration of action, which necessitates multiple administrations during the day. Methylphenidate is preferably given 30-45 minutes before meals, usually
breakfast and lunch, and no later than 6 p.m. if a third daily
dose is necessary. This offsets the effect of food in delaying
the time to reach maximum blood concentrations and the
potential for insomnia with late evening administration.
However, clinicians do sometimes encourage patients to
take these products with meals to minimize the loss of
appetite, which often occurs secondary to stimulant use.
ER versions of methylphenidate expand the daily dosage
flexibility beyond IR capabilities. The variety of such methylphenidate ER products is considerable. Tablets, capsules,
oral solutions, and patches are marketed to meet the
various needs and preferences of patients.
Wax matrix tablets (Ritalin-SR and Metadate ER) are
designed to provide slow and continuous release of methylphenidate into the bloodstream. This results in a more
gradual onset, as well as a longer duration of action, up
to eight hours. These ER products can be administered
once or twice daily without regard to meals, depending on
the duration of coverage desired by the patient. Generally, children and adults who tolerate a regimen of the IR
methylphenidate product can be switched to the closest
eight-hour dosage equivalent available in the wax matrix
tablets, if this type of coverage is preferred. The smallest
strength of Ritalin-SR and its generic equivalents is 20 mg;
for Metadate ER, it is 10 mg. Unlike the IR counterparts,
these tablets cannot be crushed, chewed, or broken.
Capsules filled with a mixture of immediate- and long-acting beads (Ritalin LA and Metadate CD) provide rapid
and durable symptom control in one formulation. The
Ritalin LA mixture is evenly divided between IR beads and
enteric-coated, delayed-release beads. Formulations with
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this SODAS technology provide a drug release that mimics
twice daily dosing of conventional IR methylphenidate.
Alternatively, Metadate CD is composed of 30 percent IR
beads and 70 percent ER beads; in this design, a portion of
the dose is released immediately, and the rest then is released gradually into the bloodstream. Both products have
an approximate duration of action of 6-9 hours, so the capsules can be taken once daily every morning. Although the
whole capsule and the beads within cannot be crushed or
chewed, it is acceptable, especially when dosing for young
children, to sprinkle the contents of the capsule over applesauce for immediate ingestion. The typical starting dosage
of both products is 20 mg daily for children and adults.
Concerta provides a combination of IR and ER methylphenidate activity in tablet form by employing OROS technology. Concerta tablets have an IR overcoat but then rely
on osmotic pressure to release most of the drug from the
tablet over a 12-hour time period. Because of its extended
coverage, Concerta is administered once every morning;
its starting dose in all patients is 18 mg. The FDA notes
a maximum daily dose of 54 mg in children and 72 mg
in adults; higher doses have been prescribed off-label.
Although the tablet must be swallowed whole to maintain
its distinct coating and pressure drug releases, meals have
no significant effect on the drug’s absorption. Because
the tablet’s outer shell and elements of the inner core are
insoluble, patients may notice something that resembles
a tablet in their stools. Advise patients that the drug has
been delivered properly, and this elimination of the shell is
normal. The package insert also states that the tablet may
be visible on digitally enhanced abdominal x-rays.
The above, established methylphenidate formulations are
all available in generic equivalents. Be sure to note that
these generics are not necessarily bioequivalent with each
other but only with their corresponding brand formulation.
Two new ER methylphenidate products are available as
brand names only. Daytrana is a transdermal patch approved in 2006 for the treatment of ADHD in children ages
6-17 years, although it is prescribed off-label to adults. Transdermal administration of the drug slows its rate of absorption compared with oral IR products, so Daytrana should
be applied two hours before symptom control is needed.
Daytrana is worn for nine hours every day, which provides a
duration of action approaching 12 hours. However, the patch
can be left on the body for up to 16 hours if longer symptom
control is desired. The initial dose is 10 mg for patients who
are just starting methylphenidate or converting from an oral
formulation. Patches are available in 10-, 15-, 20-, and 30-mg
(maximum) strengths, and are supplied in sealed pouches;
patches should be used immediately after removal from the
America’s PHARMACIST | June 2014
individual pouches. Additionally, Daytrana should be applied
to clean, dry skin on the hip area, alternating sites each day.
Counsel caregivers or mature patients that the waistline
should be avoided because clothing may cause the patch to
rub off and to avoid application to oily, irritated or damaged
skin. Bathing and swimming may also reduce the patch’s
adherence to the skin; exposure to heat may increase drug
absorption from the patch.
Quillivant XR, the newest methylphenidate treatment
option, is the first ER oral suspension. It became available
in 2013 and is approved for patients 6 years of age and
older. The 5 mg/mL, banana-flavored suspension offers
long-awaited flexibility in dosing options for children who
cannot swallow whole tablets. Quillivant XR is administered
once daily in the morning without regard to meals, and
it has a duration of action of approximately 12 hours. The
starting dose is 20 mg for all patients, and like most other
oral methylphenidate products, 60 mg is the maximum
daily dose. The drug is manufactured as a powder for
suspension that the pharmacist must reconstitute before
dispensing. After reconstitution, it has a shelf life of up
to four months at controlled room temperature. Patients
should shake the product vigorously for 10 seconds before
each administration to ensure accurate dosing.
Methylphenidate can be provided in isomeric formulations,
also. Dexmethylphenidate is the more active isomer of
methylphenidate, and IR and ER formulations are marketed
for patients 6 years of age and older. Focalin, or its generic
equivalent, lasts approximately 4-5 hours and is given twice
daily. Focalin XR, which was made available as a generic
product in late 2013, has a duration of action of 8-12 hours.
Focalin XR uses the same delivery system (SODAS) as Ritalin LA, that mimics twice daily dosing in the convenience
of one capsule. The initial total daily dose for either product
is 5 mg in children and 10 mg in adults. Patients may take
the capsules whole or sprinkle the contents over applesauce for immediate use. Like other long-acting medications, Focalin XR should not be crushed or chewed.
Amphetamines: Another First-Line Option
Mixed and single amphetamine salt products contribute
additional treatment options for prescribers. Although all
of the IR formulations are FDA-approved in children 3-17
years of age, the AAP practice guidelines do not endorse
their use in preschool age children, citing insufficient
evidence for both its safety and efficacy. The AAP asserts
that approval in children younger than age 6 years was
more a result of lenient criteria than empirical research.
All of the amphetamine-based stimulants have been used
to treat ADHD in adults, although some currently lack FDA
indications in this population.
There are two oral formulations of mixed amphetamine
salts, composed of 75 percent dextroamphetamine and 25
percent l-amphetamine. Originally known as Adderall but
now only manufactured as a generic, the IR product lasts
5-8 hours, which offers somewhat longer symptom control
than the IR methylphenidate products. Once or twice daily
dosing is reasonable according to symptoms; however
twice daily administration should be imbalanced, with a
larger dose in the morning to minimize the potential for
sleep disturbances. Although the maximum recommended
daily dose of the IR product is 40 mg in all patients, clinicians should start at 2.5 mg to 5 mg per dose in children
and 10 mg in adults. Adderall XR, or its generic equivalent,
is an ER formulation approved for patients age 6 years and
older. Common starting doses are 10 mg in children and
20 mg in adults; the FDA has approved total daily doses up
to 30 mg. Adderall XR lasts 10-12 hours and is given once
daily without regard to meals. Like other capsules formulated for ADHD, its contents can be sprinkled on applesauce
for immediate use but cannot be crushed or chewed.
Dextroamphetamine is an isomer of amphetamine that
also comes in a variety of dosage forms: a short-acting
tablet, a solution, and a long-acting capsule. The IR tablet
Dextrostat, now only available as a generic product, lasts
4-6 hours; it is given two to three times a day. ProCentra, or
its generic equivalent, is a 5 mg/5 ml, bubble gum-flavored
oral solution of dextroamphetamine that has the same
duration of action and dosing as the IR tablet. Starting
doses for these IR dextroamphetamine formulations are
2.5 mg to 5 mg per dose in children, and 10 mg per dose in
adults. A long-acting product, Dexedrine Spansule, or its
generic equivalent, is a capsule composed of a mixture of
IR and ER beads that provide coverage for 6-8 hours. Similar to Metadate CD, this formulation is designed to release
some of the drug immediately and the rest of the dose
gradually. Although twice daily dosing is acceptable, once
daily dosing is more common. Doses are initiated at 5 mg
in children and 10 mg in adults. The same administration
guidelines for other long-acting capsules for ADHD apply
to this product, too.
A new amphetamine derivative approved in 2007, lisdexamfetamine (Vyvanse) offers another novel delivery
mechanism. This agent functions as a prodrug, requiring
conversion to dextroamphetamine in the gastrointestinal
tract for activation. Lisdexamfetamine has a duration of
10-12 hours in children, although it may last up to 14 hours
in adults. The gelatin capsules should be taken once
daily, either whole or with the powder contents dissolved
in a glass of water for immediate use. The initial dose for
patients of all ages is 30 mg; the maximum is 70 mg per
day according to the manufacturer. The need for activation
www.americaspharmacist.net53
in the gut also reduces its abuse potential, which may be
useful in some patients.
SECOND-LINE THERAPY: NONSTIMULANTS
Selective Norepinephrine Reuptake Inhibitors:
Atomoxetine
Atomoxetine, sold under the brand name Strattera, is a
non-stimulant FDA-approved for the treatment of ADHD
in children 6 years of age and older as well as adults. This
drug works as a selective norepinephrine reuptake inhibitor
and lasts at least 10-12 hours. The total prescribed dose
can be administered either once daily or divided into two
doses. If the patient weighs 70 kg or less, the starting dose
is approximately 0.5 mg/kg/day (maximum dose 1.4 mg/kg/
day); those weighing more than 70 kg can begin with 40 mg
(maximum daily dose 100 mg). Unlike stimulants, atomoxetine has a gradual onset of effect. It may take 1-2 weeks for
symptoms to start improving, and roughly 4-6 weeks are
necessary to see the full benefit at a given dose. The delay
results from the time required for synaptic changes in the
brain to occur, which atomoxetine mediates. Although the
response rate (approximately 60 percent) is lower than that
of methylphenidate, atomoxetine may be more appropriate
in those with significant anxiety or substance abuse. It
causes less nervousness, irritability, and insomnia than
stimulants and also lacks addictive properties. Atomoxetine
should not be taken with, or within two weeks of, a monoamine oxidase inhibitor (MAOI) and, like the stimulants,
must be dispensed with a medication guide that describes
risks for suicidal thoughts and actions in children and adolescents and the risk for severe liver damage (for online enrichment, the med guide can be downloaded at http://www.
fda.gov/downloads/Drugs/DrugSafety/ucm089138.pdf).
Alpha-2 Adrenergic Agonists: ER Clonidine
and ER Guanfacine
The alpha-2 adrenergic agonists guanfacine and clonidine
also play a role in the treatment of ADHD. Alpha-2 adrenergic agonists were originally marketed as antihypertensive
medications but were found to be useful in ADHD because
of their modulation of norepinephrine in the CNS. These
agents appear most useful in decreasing irritability, mood
swings, overarousal, and tics. ER formulations of both
drugs have FDA approval for use in children 6-17 years old
as a monotherapy and also as an adjunct to stimulants.
Kapvay, an ER clonidine tablet, has a duration of action of
at least 10-12 hours and is given twice daily. However, patients should begin at a dosage of 0.1 mg at bedtime; then
clinicians can titrate doses by 0.1 mg per week up to 0.4 mg
per day total in divided doses. Intuniv, an ER guanfacine
tablet, lasts at least 8-12 hours. It should be given once
daily at a typical starting dose of 1 mg; the FDA-approved
maximum dose is 4 mg per day. It should not be adminis54
tered with high-fat meals, as this increases drug exposure.
These alpha-2 adrenergic agonist tablets should not be
crushed, chewed, or broken because of their ER properties.
Because abrupt withdrawal of alpha-adrenergic activity can
precipitate transient elevations in blood pressure, the dose
of either agent must be tapered if therapy is to be discontinued. Pharmacists should help patients who are instructed
by the prescriber to discontinue treatment by planning a
slow taper. ER clonidine doses should be decreased by no
more than 0.1 mg every 3-7 days, and ER guanfacine doses
should be decreased by no more than 1 mg every 3-7 days.
Off-Label Drugs for ADHD
A few medications have been used off-label to treat ADHD,
most often in adult populations. Research to substantiate
the use of these drugs is slim. Practice guidelines for the
pediatric population do not endorse the use of any off-label
agents. Modafinil (Provigil), a drug primarily used for the
treatment of narcolepsy, has shown some effectiveness in
ADHD at doses of 200 mg to 300 mg per day. The precise
mechanism in this setting is unclear, but it does increase
mental alertness and vigilance through several CNS
pathways. Small-scale studies with adults and children
have shown that modafinil improves symptoms of ADHD,
although it is not superior to methylphenidate.
Several antidepressants have also been used off-label for
ADHD. Bupropion, an atypical antidepressant, may be especially helpful for those adults with comorbid substance
abuse and mood disorders. Bupropion is presumed to
work by preventing the reuptake of dopamine and norepinephrine. Like atomoxetine, the onset of clinical effect
is gradual; improvements may be evident as early as two
weeks after initiation. Total daily doses of 200 mg to 450 mg
have been used. It should not be used in patients with a
history of seizures, as it lowers the seizure threshold. Secondary to its metabolism by cytochrome P450 enzymes,
relevant drug interactions should also be considered.
Similarly, tricyclic antidepressants (TCAs), which block the
reuptake of norepinephrine, have been used off-label in
adults. Secondary-amine TCAs like desipramine and nortriptyline may be the best choices because they have a greater
effect on norepinephrine than serotonin. The initial dosage
of desipramine, which has been studied the most, is usually
25 mg daily; the drug is titrated to a target of 150 mg to 200
mg daily. Despite the modest reductions in hyperactivity and
improvements in mood, TCAs are still inferior to stimulants.
Moreover, they have little or no effect on concentration and
cognition, and use is limited because of the high rate of
drug interactions and adverse effects. Patients commonly
experience dry mouth, drowsiness, and constipation with
these older antidepressants; there is also a risk of QT interAmerica’s PHARMACIST | June 2014
val prolongation. TCAs must also be tapered for discontinuation because of the likelihood of precipitating withdrawal,
secondary to their effects on serotonin.
ADJUSTING THE REGIMEN
Dose Titration
The AAP practice guidelines emphasize that clinicians
should titrate doses according to symptoms to optimize
pharmacotherapy. Like any condition, the goal is to achieve
the greatest treatment benefit with the fewest adverse
effects. It may take 1-3 months to determine the best
medication and dose, and monitoring at regular intervals
is critical in these initial stages. Patients should follow up
with the clinician on a weekly basis at first, although not
all of the follow-up has to be done in person. Less frequent
checks can be arranged as the regimen is stabilized. Adherence to the drug regimen is crucial to accurately assess
and maintain its effectiveness.
Dosage adjustments are warranted when patients are not
well controlled with initial therapy or if patient adherence
issues make success with a particular product unlikely.
Adjustments are also warranted if patients experience “rebound,” in which ADHD symptoms or adverse effects occur
as the prescribed medication wears off during the day.
Medications should be started at the lowest dose that may
have a clinical effect and increased from that point. Clinicians should also recognize that patients may have variable
metabolisms and also respond differently to a given medication. One special consideration in starting drugs for ADHD
in preschool age children pertains to pharmacokinetics. As
a result of naturally slower metabolism of stimulants in 4-5
year olds, lower doses should be initiated in this population,
and doses should also be titrated in smaller increments.
Polymorphisms in the dopamine transporter gene DAT1 are
also linked to variable responses to stimulants. More pharmacogenetics research will likely find other relationships
between ADHD drugs and clinical responses in the future.
Titration recommendations are specific to each drug, but
some general statements can be made for each class. With
stimulants, immediate symptomatic improvements occur
within 30 minutes to an hour of drug administration, but
these effects will still increase gradually over the course of
a few days. To see the maximal improvement, doses should
be increased no faster than every 3-7 days and titrated until
symptoms improve by approximately 50 percent, or until adverse effects become unacceptable. Atomoxetine dosages
can be increased in both adults and children after the first
3-4 days of therapy and then usually at 2-4 week increments
because of the gradual onset of its clinical effect with each
new dose. Titration of the alpha-2 adrenergic agonists can
be done on a weekly basis up to the maximum dose.
In most cases, monotherapy is sufficient, but combination drug therapy is an option if optimal disease control
cannot be achieved with tolerable doses of a single agent.
A stimulant coupled with an alpha-2 adrenergic agonist or
off-label drug is most common. Using two medications of
the same therapeutic class is not clinically appropriate. For
example, there is no benefit to combining methylphenidate
with dextroamphetamine.
Changing Medications
If core diagnostic ADHD symptoms do not improve at all
after appropriate titration to the maximum dose of the initial
agent, it may be prudent to switch to another drug. In these
cases of treatment failure, clinicians can switch within or
between stimulant subclasses or change to a different,
non-stimulant, drug class altogether. At least half of patients
who do not respond to one type of stimulant will have favorable outcomes with another. Patients may also opt to try new
drugs or different formulations to better suit their schedules,
address cost concerns, or meet other personal needs.
Maintaining symptom control during a medication change
depends on the appropriate dosing of the new agent.
Dosing guidelines for transitions among the different
formulations of a given stimulant are readily available in
the prescribing information. When switching from methylphenidate to dexmethylphenidate, clinicians should initially
prescribe half of the patient’s total daily dose of methylphenidate to achieve a similar effect. Unfortunately, reliable
data are limited for dose conversions between products
with methylphenidate and those with amphetamines,
especially the ER agents. For these conversions, it may be
safest to simply start with the initial recommended dose of
the new agent and titrate to the desired effect.
While a patient transitions from any drug to atomoxetine,
an overlap is warranted for a few weeks, at doses with
tolerable adverse effect profiles. The agent being replaced
provides coverage for a patient’s symptoms while atomoxetine reaches its therapeutic concentrations. Conversely,
if a patient is being switched from atomoxetine to another
drug, no overlap is necessary; atomoxetine can be stopped
immediately. No withdrawal symptoms have been noted
with abrupt discontinuation. When switching from an
alpha-2 adrenergic agonist to another medication, it must
still be tapered on a weekly basis and not abruptly discontinued to avoid short-term elevations in blood pressure.
Clinicians should also recognize that dosages of the ER
clonidine and ER guanfacine products do not convert
on a mg per mg basis to those of their corresponding IR
formulations. Instead, patients using IR clonidine or IR
guanfacine off-label for ADHD who are switching to the
FDA-approved ER agents should be started on the recom-
www.americaspharmacist.net55
mended initial dose and have the dose titrated to achieve
the desired effect.
Interruption and Discontinuation of Drug Therapy
The issue of whether a medication can or should be held for
certain periods of time arises frequently. Parents of children
with ADHD are especially curious to know if these agents
are necessary on weekends or during the summer, when
school-level focus is less relevant, and they need guidance
about using ADHD medications noncontinuously.
Drug holidays are only feasible for patients taking stimulants. Stimulants as prescribed for ADHD lack many of the
characteristics that facilitate physical dependence, such
as developing tolerance, inducing cravings, and prompting the desire for compulsive or uncontrolled use. Thus,
these agents can be stopped abruptly without the risk of
severe withdrawal or drug-seeking behavior. When used in
clinically appropriate ways, this class of drugs poses little
risk of physical dependence in adults or children, even
with long-term use. On the contrary, the long half-lives of
atomoxetine and alpha-2 adrenergic agonists make any
interruption in therapy impractical and can undercut their
effectiveness. Implementing a drug holiday with ER clonidine or guanfacine would also precipitate adverse effects.
Every patient’s situation is different, and appropriate patient selection for a drug holiday is crucial to disease control. Adherence relies on daily therapy routines, and dosing
consistency is essential for adequate symptom management. If symptoms are fairly mild or primarily associated
with inattention, then breaks from stimulants on weekends
or other less demanding times could be considered.
However, clinicians usually do not recommend drug
holidays unless the patient is experiencing considerable
adverse effects. Without stimulants, any ADHD symptoms
will return, so patients with moderate to severe symptoms
may not benefit as much from drug holidays. The lack of
noradrenergic stimulation can also make patients initially
feel fatigued and moody, among other effects. Moreover,
adolescents and adults with ADHD are typically involved
in tasks that require attention and concentration outside
of academic and occupational settings, so drugs holidays
become less feasible. For example, safe driving and participation in extracurricular activities often necessitate the
therapeutic effects obtained from stimulants consistently.
The decision to terminate drug therapy altogether for
ADHD is also individualized. For many patients, the symptoms of ADHD improve naturally over time. This may evolve
by several mechanisms: the development of coping skills,
cultivation of compensatory strategies, or even natural
56
biological repair of the affected CNS pathways. The AAP
practice guidelines acknowledge that, if a patient has been
stable on an effective regimen for several years, a trial
without medication can be attempted to see if treatment is
still necessary. For those whose ADHD symptoms return
or worsen, the medication regimen should be resumed. If
appropriate, this process can be undertaken periodically to
reassess whether the patient can successfully discontinue
therapy. Although these trials are warranted to avoid unnecessarily medicating patients, the AAP does not specify
any maximum duration of drug therapy for ADHD.
Alternative Therapies
Although not endorsed by the AAP practice guidelines,
certain supplements and dietary modifications are believed by the public and some researchers to mitigate the
symptoms of ADHD. One of the most studied supplements
is omega-3 fatty acid. A recent meta-analysis of 10 trials
showed that nonprescription options with high doses of
eicosapentaenoic acid (EPA) cause modest improvements
in ADHD symptoms. Such benefits are presumed to result
from the effects of omega-3 fatty acids on cell membranes,
which indirectly increase transmission of catecholamines
in the CNS. However, these studies show that omega-3
fatty acids with EPA are still inferior to the current pharmacologic agents available for ADHD and should not replace
standard treatment. Proponents suggest that omega-3 fatty acid supplementation could be considered as an adjunct
to traditional prescription medications. Other supplements
and herbal products, such as zinc, St. John’s wort, and
melatonin, have not shown any substantial benefit.
Parents of children with ADHD sometimes try increasing dietary protein intake to mitigate symptoms of the
disease. High-protein diets are believed to boost levels of
neurotransmitters associated with alertness. The Feingold
diet, which involves eliminating artificial flavorings, food
colorings, sweeteners, and preservatives, is similarly popular with parents who believe that these additives worsen
the symptoms of ADHD in their children through various
biochemical mechanisms. With the Feingold diet, salicylates found in aspirin and in certain fruits and vegetables,
are eliminated, because some studies have suggested that
these compounds increase hyperactivity and irritability.
Similar arguments have been made for sugar, so many parents try to minimize its intake in their children with ADHD.
However, most research strongly suggests that symptoms
of ADHD are not influenced by diet. General information on
the more popular alternative treatments and dietary modifications is provided on public websites of national organizations such as Children and Adults with Attention-Deficit/
Hyperactivity Disorder (CHADD) (www.chadd.org) and
ADDitude. (www.additudemag.com).
America’s PHARMACIST | June 2014
DRUG TREATMENT CAUTIONS
Adverse Effects
For stimulants, the most common adverse effects include
decreased appetite, weight loss, headache, insomnia, mood
lability, and gastrointestinal upset. This is secondary to their
stimulation of the sympathetic nervous system. Tics occur in
some patients, especially those taking methylphenidate-based
products; it may be necessary to switch to a nonstimulant
in these cases. Rarely, psychosis and hallucinations may
occur; the drug should be discontinued, and the patient
should also be evaluated for other psychiatric disorders.
Long-term use of higher doses of stimulants in children can
slightly slow growth rates, ultimately reducing height by 1
cm to 2 cm. Although this effect appears to diminish by the
third year of therapy, no rebound growth occurs with drug
discontinuation. Growth reductions presumably result from
changes in dopamine activity in the hypothalamus, which
mediates such endocrine functions.
Cardiovascular adverse effects can also be serious and
life threatening. Strokes and heart attacks have been
reported in adults taking stimulants. Sudden death has
occurred in patients who have a history of heart defects
or other heart problems, although this is extremely rare
in children. Less severe cardiovascular effects include
slight elevations in blood pressure and heart rate. In any
case, a complete medical history is critical, but at this
time an electrocardiogram is not necessary. Another rare
but serious adverse reaction caused by methylphenidate
products is priapism. The FDA released a warning in December 2013 and encouraged health care professionals
to educate caregivers and patients on signs, symptoms,
and the need for immediate medical care. The risks of
priapism, sudden cardiac events, and serious psychiatric
effects are detailed in the medication guide that must
be provided to patients when stimulants are dispensed.
Stimulants are listed as Pregnancy Category C drugs, in
which risk cannot be ruled out; however, data clarifying
actual fetal risks are limited.
Common adverse reactions of atomoxetine are similar to
those of stimulants because it also activates the sympathetic nervous system. Patients may experience decreased
appetite, headache, insomnia, gastrointestinal upset, and
also dry mouth. Gastrointestinal upset, specifically nausea, vomiting, and abdominal pain, as well as initial somnolence, are especially common if the dose is increased
too quickly. Although rare, priapism may also occur in
patients taking this medication. Atomoxetine also carries
an FDA black box warning regarding use in pediatric
patients because of a potential increased risk of suicidal
ideation. Patients should be monitored closely for clinical
worsening, unusual behavior, or suicidal thoughts when
therapy is initiated. The FDA requires that a medication
guide be dispensed with atomoxetine. It carries a Pregnancy Category C rating, as well.
Adverse effects associated with ER clonidine and guanfacine include dry mouth, somnolence, dizziness, headache,
constipation, and hypotension. Most of these effects are
dose-related. Withdrawal symptoms include nervousness
and anxiety, and rebound hypertension, and these can
occur when alpha-2 adrenergic agonists are stopped
abruptly. Although clonidine is a Pregnancy Category C
agent, guanfacine is defined as Pregnancy Category B, in
which there is no risk to the fetus.
Relevant Drug Interactions
Certainly pharmacists should screen for any drug interactions, but this may be more important for adults with
ADHD as they are more likely to be taking other medications. Administration of stimulants during or within 14 days
of any MAOIs is contraindicated, as this can precipitate a
hypertensive crisis. To a lesser severity, methylphenidate
can reduce the effect of antihypertensive drugs because of
their sympathetic activation in the vasculature. Stimulants
can also increase the effects of some anticonvulsants
such as phenobarbital and phenytoin through inhibition of
their metabolism; concomitant use with tricyclic antidepressants may increase the risk for cardiovascular effects.
Monitoring therapy is usually sufficient with these interactions, although dose adjustments may be necessary in
some cases. Additionally, vitamin C and acidic foods and
drinks reduce absorption of amphetamines and consequently, its clinical effects; the drug should not be administered with such supplements, foods or beverages.
Like stimulants, atomoxetine is also contraindicated with
MAOIs, but due to the risk of serotonin syndrome, which
can be fatal. Patients should be cautioned that atomoxetine can also enhance tachycardia associated with beta-2
agonists, such as albuterol. Although not substantial
enough to warrant a change in therapy, monitoring therapy
is adequate. Because atomoxetine is partly metabolized
by CYP2D6, inhibitors and inducers of this isoenzyme may
alter atomoxetine concentrations.
ER clonidine and ER guanfacine tend to increase the
hypotensive effect of any drug designed to lower blood
pressure or that has this adverse effect. Patients’ blood
pressure should be monitored in these cases. Patients taking beta-blockers concomitantly carry the risk of worsening
rebound hypertension upon discontinuation of the alpha-2
adrenergic agonist because alpha stimulation in the
vasculature is unopposed. Patients should be monitored
especially closely when treatment is terminated. There
www.americaspharmacist.net57
are two other interactions with guanfacine worth noting.
Strong CYP3A4 inhibitors or inducers alter guanfacine’s
concentrations significantly; alternative therapy may need
to be considered, or the dose of guanfacine may need to
be adjusted, with close patient monitoring. St. John’s Wort
has also been shown to reduce concentrations of guanfacine, and if the patient chooses to take both, the guanfacine dose may need to be as much as doubled to achieve
therapeutic effects.
For all of these drugs, alcohol should be avoided. CNS depression from both substances is augmented when used
in combination. Alcohol can even enhance the effect of
stimulants by increasing their concentrations in the blood.
Stimulant Abuse
Schedule II stimulants, as a class, are controlled substances with a high potential for abuse because of their effects
on dopamine pathways. Besides recreational pleasure,
anyone can abuse stimulants in attempts to lose weight
or temporarily enhance mental performance at school or
work. Individuals may take large doses or consume the
drugs around the clock to precipitate the desired effects.
For example, college students may take several tablets of
methylphenidate to stay awake all night and study “better”
for an exam scheduled the next day.
Substantially larger doses than those typically prescribed
for ADHD are required to elicit the euphoric effects that encourage abuse. The effects of stimulants are also generally
more pronounced in individuals without ADHD, so patients
taking their prescribed dose are even less likely to experience a “high” with usual treatment. Whereas other commonly abused stimulants are frequently snorted or injected
for rapid absorption, these routes of administration are
more difficult to achieve with the newer, complex delivery
systems of prescription stimulants for ADHD. This further
reduces the likelihood of abuse of prescription stimulants
among patients.
Among all adolescents, abuse of stimulants has been
declining since 2011, according to the National Institutes
of Health. Nevertheless, the issue remains a concern in
the general public as more stimulants are prescribed for
patients of all ages. Interestingly, research continues on
whether stimulants actually have an effect on the likelihood of developing substance abuse disorders in ADHD
patients. In 2013 alone, numerous studies conducted in
pediatric ADHD patients came to opposing conclusions.
Some studies found that stimulants actually reduce the
risk of substance abuse among ADHD patients. These
researchers believe that stimulants mitigate the behaviors
and associated consequences that can lead to drug abuse.
58
However, others concluded that the use of stimulants in
ADHD patients had no effect on substance abuse disorders. In either case, it appears that treatment with stimulants does not encourage drug abuse, which may alleviate
the concerns of parents and even adult patients.
In general, some populations may be at higher risk of
stimulant abuse. For example, children or adults with concomitant psychiatric or sociobehavioral issues are more
likely to misuse prescription medications or obtain drugs
illegally. Problems in school, work, or home settings can
instigate these changes as well. When abuse of stimulants by the patient or someone else in the household is
a genuine concern, a number of signs may help identify
a potential problem. Behavioral changes, problems at
school or work, legal trouble, secrecy, isolation, and long
periods of not sleeping or eating could be manifestations
of stimulant abuse. Additionally, some notable effects
observed by colleagues, family, and clinicians can include
memory lapses, confusion, aggression, euphoria, weight
loss, dilated pupils, and even seizures. Comments that the
patient makes and newly developed habits may also serve
as indicators of stimulant reliance or abuse. The Substance
Abuse and Mental Health Services Administration (SAMHSA) has information about preventing prescription drug
abuse, helping patients and caregivers screen for abuse
and locating treatment services at www.findtreatment.
samhsa.gov, or 1-800-662-4357.
SUMMARY
ADHD prevalence in the community necessitates ongoing
awareness of the disorder and regular evaluation of our
diagnostic methods and treatment for optimal patient care.
The updated DSM-5 offers revised criteria for diagnosing
this chronic condition in both children and adults. The AAP
continues to review its own practice guidelines for ADHD
and gives a creditable foundation to steer clinicians. As
the disorder receives more attention, newer formulations
of stimulants with advanced delivery systems, and second-line agents, have entered the market to offer greater
flexibility to the patients.
Research is now suggesting that there is no association
between the use of stimulants for ADHD and substance
abuse disorders, although some patients may be at risk for
other reasons. Pharmacists can be an excellent source of
information for patients and their families and work with
providers to optimize drug therapy. ■
Ashley Khan, PharmD, is a clinical pharmacist at Carilion Roanoke Memorial Hospital in Roanoke, Va., focusing on pediatrics,
psychiatry, and neurology. She also works as a freelance medical
writer/editor and as a public speaking consultant.
America’s PHARMACIST | June 2014
CE QUIZ
Continuing Education Quiz
Select the correct answer.
Answer questions 1-5 using the following case.
Mrs. Barton comes to the pharmacy and wants to speak
with a pharmacist about her 15-year-old son. Since Alex
was diagnosed with ADHD in first grade, he has been prescribed stimulants to manage his symptoms. He has been
taking Metadate CD 60 mg (ER methylphenidate) daily for
the past year. Unfortunately, during the past few months,
he’s been doing poorly in school: not paying attention
in class, failing to do his homework, interrupting his
teachers, and “bouncing off the walls.” His two younger
brothers also have ADHD, but both of them are doing well
on their medications.
1. Which of the following could be risk factors for the development of ADHD in Alex’s case?
a. Genetics
b. History of cardiac arrhythmias
c. C
hronically low magnesium levels
d. All of the above
2. Which neurotransmitters play a critical role in the pathophysiology of ADHD, causing symptoms like the ones Alex
experiences?
a. D
opamine and serotonin
b. Dopamine and glutamate
c. N
orepinephrine and dopamine
d. Norepinephrine and serotonin
3. According to the new DSM-5, if Alex had presented with
symptoms at age 10 instead of in first grade, he would still
meet the age requirement for ADHD diagnosis.
a. True
b. False
4. On the basis of his recent behavior, Alex most likely has
which type of ADHD?
a. P
redominantly inattentive type
b. Predominantly hyperactive-impulsive type
c. C
ombined type
d. Alex was misdiagnosed and actually has bipolar disorder.
5. When it was first prescribed for Alex, Metadate CD was
a reasonable choice because
a. It can be given once daily.
b. It is a stimulant, which is a first-line treatment option
for ADHD.
c. It is affordable because it is available as a generic product.
d. All of the above
Answer questions 6-8 using the additional
case information.
Mrs. Barton also tells you that a few weeks ago, Alex
transferred to a different school. Because he liked the new
school and wasn’t getting into trouble, he quit taking his
medication. Alex had been complaining that Metadate
CD made him feel jittery and agitated; he’d also been
having trouble falling asleep and never felt hungry. Since
he stopped taking Metadate CD, these side effects have
resolved, but his ADHD symptoms are worsening again.
6. If he were to resume Metadate CD, what would you
tell Mrs. Barton to help reduce the risk of some of these
adverse reactions?
a. A
lex should divide his total dose to allow twice daily
administration and mix the capsule contents in pudding
to reduce his nervousness.
b. A
lex should take the medication early in the morning to
minimize sleep problems.
c. A
lex should take the medication with acidic foods and
drinks to limit its effects on his appetite.
d. T hese adverse effects cannot be mitigated.
7. If Alex were switched to an amphetamine-based stimulant to see if he tolerates it better than Metadate CD, what
would be the best initial regimen?
a. V
yvanse (lisdexamfetamine) 30 mg daily
b. V
yvanse (lisdexamfetamine) 60 mg daily
c. IR mixed amphetamine salts 30 mg twice daily
d. E
R dexmethylphenidate 40 mg twice daily
8. If Mrs. Barton asks about treatment alternatives to prescription medications, what could you suggest?
a. Z
inc supplements
b. B
ehavior therapy
c. S
ugar-free diet
d. Acupuncture
Answer questions 9-12 using the case information
below.
Two weeks later, Mrs. Barton returns to the pharmacy with
a new prescription for Intuniv (ER guanfacine).
9. The prescription is written for Intuniv 0.1 mg by mouth
twice daily. Based on the FDA’s initial dosing recommendations, what concerns do you have?
a. T his product cannot be administered orally.
b. The strength is incorrect, but the frequency is acceptable.
c. The strength and frequency are both incorrect.
d. T he dosage is correct.
www.americaspharmacist.net59
CE QUIZ
10. Which of the following statements about Intuniv is true?
a. The dose can be increased every 2-4 weeks.
b. T he drug is a beta-2 adrenergic agonist.
c. T he drug can be discontinued abruptly.
d. T he duration of action is approximately 8-12 hours.
11. Alex has also recently started taking propranolol for
migraine prophylaxis. What should be monitored when this
is taken with Intuniv?
a. Liver function
b. R
enal function
c. B
lood glucose
d. B
lood pressure
12. If Mrs. Barton asks if Alex can take a drug holiday
during the summer, what would you suggest?
a. Drug holidays are only feasible with stimulants.
b. D
rug holidays are never appropriate for any patient.
c. Drug holidays are very effective for patients taking Intuniv.
d. D
rug holidays are usually more effective during the
school year.
13. What information would you tell a patient with a new
prescription for Daytrana (transdermal ER methylphenidate)?
a. The patch should be applied four hours before the patient needs symptom control.
b. Bathing or swimming may reduce the patch’s adherence
to the skin.
c. Exposure to heat may decrease absorption from the patch.
d. A
ll of the above
14. The American Academy of Pediatrics recommends that
pharmacologic treatment for ADHD be limited to three
years, and only behavior therapy should be used thereafter.
a. True
b. False
15. Bupropion is similar to Strattera (atomoxetine) in its
gradual onset of clinical effect and utility in ADHD patients
with comorbid substance abuse disorders.
a. True
b. False
Answer questions 16-20 using the case below.
Tammy is a 32-year-old female who comes to the pharmacy with questions about her Strattera (atomoxetine)
prescription. She tells you that she was recently diagnosed
with ADHD and wants to know more about the disorder
and its treatment.
60
16. On the basis of current research on adults and females
with ADHD, which of the following statements might be
true in Tammy’s case?
a. Females are more frequently diagnosed with the predominantly inattentive type of ADHD.
b. A
s patients with ADHD age, symptoms of hyperactivity
decline, whereas inattention and impulsivity increase.
c. Most adults with ADHD have at least one other psychiatric condition.
d. A
ll of the above are true.
17. What should Tammy know about how Strattera works?
a. H
er ADHD symptoms should improve immediately.
b. S
trattera is a selective serotonin reuptake inhibitor.
c. It may take 4-6 weeks to achieve maximal benefit at a
given dose.
d. S
trattera tends to cause more nervousness and insomnia than stimulants.
18. Tammy is concerned that Strattera might interact with
her other medications. She takes an oral contraceptive and
occasionally uses an albuterol inhaler. How do you advise
Tammy?
a. S
trattera may decrease the effectiveness of the oral contraceptive, so she should use a back-up method.
b. T aking Strattera with albuterol might increase her heart
rate, but she and her doctor can monitor this effect.
c. Both A and B are correct.
d. T here are no drug interactions.
19. A common adverse effect that Tammy may experience
with Strattera is
a. W
eight gain
b. Aphasia
c. Dry mouth
d. B
lurred vision
20. Tammy mentions that she’s worried about things she’s
read on the Internet regarding drug abuse with ADHD
medications. She’s afraid she’ll become addicted to the
Strattera or any other drug she’s later prescribed. What
can you tell her?
a. S
trattera lacks addictive properties and has little to no
abuse potential.
b. R
esearch now suggests that the use of stimulants
has no effect on the risk of substance abuse disorders
among ADHD patients.
c. Doses of stimulants typically prescribed for ADHD do
not produce euphoria.
d. A
ll of the above are true.
America’s PHARMACIST | June 2014