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ADALIMUMMAB (HUMIRATM)
NOVEL HUMAN MONOCLONAL
ANTIBODY FOR THE TREATMENT
OF RHEUMATOID ARTHRITIS

Anzeela Schentrup, Pharm.D. Candidate


Rheumatoid Arthritis (RA) is a debilitating
inflammatory disease that affects about 2.1 million
Americans, or 1% of the US adult population.
Women are affected 2-3 times more often than
men. Although the disease often begins in middle
age and occurs with increased frequency in the eld-
erly, children and young adults can also develop
RA.1 The total (direct and indirect) annual cost of
RA in the US is approximately $65 billion.2
Common symptoms of RA include tender
and swollen joints, fatigue, malaise and, occasion-
ally, fever. Over time, the disease leads to joint de-
struction and loss of function. Other uncommon
complications include cardiac, pulmonary and other
extra-articular inflammatory consequences. The eti-
ology of rheumatoid arthritis is unknown. Evidence
suggests that the disease is a result of an autoim-
mune process, with certain modulators of inflam-
mation such as tumor necrosis factor (TNF)-a and
interleukin 1 playing a significant role. According
to the 2002 practice guidelines for the management
of rheumatoid arthritis, the goals of treatment are to
control joint damage, prevent loss of function, and
to decrease pain.
Current treatment strategies for RA include
non-steroidal anti-inflammatory drugs (NSAIDs),
steroids, and disease-modifying anti-rheumatic
drugs (DMARDs). NSAIDs and steroids are useful
to treat pain and inflammation associated with RA,
but they do not alter the course of the disease nor


prevent joint destruction. On the other hand,
DMARDs have become the standard of care for RA
because they have the potential to reduce or prevent
joint damage, preserve joint function and integrity,
reduce health-care costs, and maintain patients'
economic productivity.
Adalimumab (HumiraTM) is manufactured by
Abbott Laboratories and was approved by the FDA
on December 31, 2002 to reduce signs and symp-
toms and inhibit the progression of structural dam-
age in adult patients with moderately to severely
active RA that have had an inadequate response to
one or more DMARDs.3 This article will focus on
the pharmacology, pharmacokinetics, toxicity,
safety, and clinical applications of adalimumab.

Pharmacology and Pharmacokinetics
Adalimumab is a recombinant human IgGI
monoclonal antibody specific for human TNF. It is
the first product consisting entirely of human pep-
tide sequences and joins etanercept and infliximab
in the arsenal of DMARDs available to RA pa-
tients. Etanercept is a recombinant TNF receptor:Fc
dimeric fusion protein, while infliximab is a chi-
meric human and murine monoclonal TNF-a anti-
body. Adalimumab binds specifically to TNF-a and
blocks its interaction with the p55 and p75 cell sur-
face receptors. In vitro, adalimumab causes lysis of
surface TNF-expressing cells when complement is
present. Elevated levels of TNF are found in the
synovial fluid of RA patients and are thought to
play an important and perhaps dominant role in the
development of rheumatoid synovitis and ulti-
mately joint destruction. After treatment with
adalimumab, there is a rapid decrease in acute
phase reactants such as C-reactive protein and
erythrocyte sedimentation rate. A decrease in serum
levels of matrix metalloproteinases, which are
thought to be responsible for tissue remodeling and


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Table 1. Percent of patients with ACR20, ACR50 and ACR70 responses at week 244
Response Placebo ADA 20mg qow ADA 40mg qow ADA 80mg qow
Criteria (N=62) (N=69) (N=67) (N=73)

ACR20* 9 (14.5) 33 (47.8);p<0.001 45 (67.2); p<0.001 48 (65.8); p<0.001

ACR50 5 (8.1) 22 (31.9); p=0.003 37 (55.2); p<0.001 31 (42.5); p<0.001

ACR70 3 (4.8) 7 (10.1); p-value NS 18 (26.9); p<0.001 14 (19.2); p<0.001
ADA adalimumab, N=number of patients, qow-every other week, NS=not significant.
Adalimumab vs. placebo by Dunnett's test (p=0.05). Adalimumab vs. placebo by unadjusted t-test (p=0.05).


for cartilage destruction, was also observed.
Adalimumab is administered as a subcuta-
neous injection. The Cmax and Tmax are 4.71.6 ug/
mL and 131+56 h, respectively. Adalimumab's
bioavailability is 64% and it follows linear pharma-
cokinetics with a tl/2 of approximately 2 weeks.
Synovial fluid concentrations ranged from 31-96%
of serum levels in five patients. No gender related
differences were apparent and no data are available
in hepatic/renal impairment. Methotrexate (MTX)
reduced apparent clearance by 29% and 44% after
single dosing and multiple dosing, respectively.

Clinical Trials
Adalimumab's safety and efficacy was
evaluated in 4 randomized, double-blind, placebo-
controlled studies. Study I (ARMADA) evaluated
271 patients with active RA who had failed therapy
with at least one but no more than four DMARDs
and had an inadequate response with MTX. Doses
of 20, 40, or 80 mg were administered subcutane-
ously every other week for 24 weeks. The primary
efficacy endpoint was a 20% improvement in the
American College of Rheumatology (ACR20) rat-
ing criteria. ACR20 response criteria included
evaluation of the number of tender and swollen
joints, global assessment score by physician and pa-
tient, level of pain on a visual analog scale, disabil-
ity index based on the Health Assessment Question-
naire, and concentration of C-reactive protein. Sec-
ondary endpoints included ACR50 and ACR70 rat-
ings. Results are given in Table 1.4
Study II evaluated 544 patients who had
failed therapy with at least one DMARD. Subjects
received placebo, adalimumab 20 mg, or 40 mg
every other week or weekly for 26 weeks. Study III
evaluated 619 patients who had an inadequate re-
sponse to MTX. Patients were randomized to re-
ceive placebo, adalimumab 40 mg every other week


with placebo injections on alternate weeks, or
adalimumab 20 mg every week for up to 52 weeks.
Primary endpoints were ACR20, ACR50 and
ACR70 response rates. This study also evaluated
inhibition of disease progression at 52 weeks as de-
tected by radiography. Table 2 summarizes the re-
sults from studies II and III.5 Results from Study III
regarding radiographically detected changes be-
tween the MTX and adalimumab-MTX combina-
tion treatment groups are given in Table 3.5
Study IV assessed the safety of adalimumab
administration in 636 patients who were either
DMARD-naive or were permitted to remain on pre-
vious therapy that was stable for a minimum of 28
days. Patients received adalimumab 40 mg or pla-
cebo every other week for 24 weeks. Fifty-three pa-
tients treated with adalimumab 40 mg every other
week plus standard of care had an ACR20 response
at week 24, compared to only 35 that received pla-
cebo plus standard of care (p<0.001). No unique
adverse reactions related to the combination of
adalimumab with other DMARDS were observed.
All four clinical trials show that adalimu-
mab has the ability to ameliorate the symptoms of
RA in active patients. Preliminary findings also
show that it intervenes in the progression of the dis-
ease, which is similar to that found for both etaner-
cept and infliximab.5 There are no current head-to-
head trials comparing the various biologic
DMARDs.

Adverse Effects
Infection is a particular concern in patients
treated with monoclonal antibodies. In clinical tri-
als, the rate of infection was 1 per patient/year in
adalimumab-treated patients and 0.9 per patient/
year in placebo-treated patients. Infections con-
sisted primarily of upper respiratory tract infec-
tions, bronchitis and urinary tract infections. The


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Volume 18, Issue 10 July 2003








Table 2. Percent of adalimumab-treated patients achieving ACR20, ACR50, and ACR70 responses5

Study II Monotherapy (26 wks) Study III MTX Combination (24 and 52 wks)
Response PBO ADA 40mg qod ADA 40mg qwk PBO/MTX ADA/MTX 40mg qowk
(N=110) (N=113) (N=103) (N=200) (N=207)
ACR20
Month 6 19% 46%* 53%* 30%* 63%*
Month 12 NA NA NA 24%* 59%*
ACR 50
Month 6 8% 22%* 35%* 10%* 39%*
Month 12 NA NA NA 10%* 42%*
ACR70
Month 6 2% 12%* 18%* 3%* 21%*
Month 12 NA NA NA 5%* 23%*
MTX methotrexate, PBO placebo, ADA adalimumab, qod every other day, qwk every week, qowk every other week, N number patients, NA not applicable
*p 0.01. All treatment groups in studies II and III showed significant improvements in response criteria ACR20, ACR50, and ACR70.


incidence of serious infections, including pneumo-
nia, septic arthritis, prosthetic and post-surgical in-
fections, erysipelas, cellulitis, diverticulitis, and
pyelonephritis was 0.04 per patient/year in
adalimumab-treated patients and 0.02 per patient/
year in placebo-treated patients. Thirteen cases of
tuberculosis and 6 cases of invasive opportunistic
infections caused by histoplasma, aspergillus, and
nocardia were reported in trials. Therefore, con-
comitant immunosuppressive therapy increases the
risk of infections such as tuberculosis and invasive
fungal infections. Treatment with adalimumab
should not be initiated in patients with active infec-
tions including chronic or localized infections.
Careful monitoring is required in treating a patient
who develops infections while being treated with
TNF antagonists. Patients who reside in areas
where histoplasmosis or tuberculosis are endemic
are at particular risk. Prior vaccination is a consid-
eration before initiation of therapy.
Among the 2,468 RA patients treated in the
four clinical trials, 48 malignancies of various types
were observed. In particular, 10 patients developed
lymphoma. It is not clear whether this reflects a
higher incidence among RA patients or an effect of
treatment, however a increase of up to several fold
has been reported in the RA patient population. The
development of autoantibodies was monitored dur-
ing clinical trials with an incidence of 12% and 7%
in adalimumab- and placebo-treated patients re-
spectively. One patient of 2,334 in clinical trials de-
veloped a new-onset lupus-like syndrome that re-

mhrmhlinto


solved with discontinuation of therapy with no
complications. The impact of long-term treatment
with adalimumab on the development of autoim-
mune diseases is unknown. Based on enzyme-
linked immunoabsorbent assay (ELISA), approxi-
mately 5% (58 of 1,062) of adult rheumatoid arthri-
tis patients in studies I, II, and III developed low-
titer autoantibodies to adalimumab that were neu-
tralizing in vitro. Combined therapy with MTX
showed a 1% incidence of autoantibody develop-
ment compared to 12% in patients receiving mono-
therapy. The long-term immunogenicity of
adalimumab is unknown.
In clinical trials, the most common adverse
reaction from adalimumab was injection site reac-
tions, with an incidence of 20% compared to only
14% in placebo-treated patients. Injection site reac-
tions included erythema, itching, hemorrhage, pain
and swelling. Seven percent of adalimumab-treated
patients discontinued treatment due to adverse reac-
tions compared to only 4% of placebo-treated pa-
tients. The most common adverse reactions that
lead to discontinuation were clinical flare reaction
(0.7%), rash (0.3%), and pneumonia (0.3%).

Dosage and Administration
Adalimumab is supplied as a preservative-
free pre-filled syringe that must be stored under re-
frigeration. It is administered as a 40 mg subcutane-
ous injection every other week. Other pharmacol-
ogical therapies for RA, including NSAIDS, gluco-
corticoids, and other DMARDs may be continued


Volume 18, Issue 10 July 2003


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I I I I I I IP I W







Table 3. Mean radiographic changes over 12 months found in Study III5
PBO/MTX-ADA/MTX
Radiographic Changes PBO/MTX ADA/MTX 40mg qow (95% CI) p-value

Total Sharp score5 2.7 0.1 2.6 (1.4, 3.8) <0.001
Erosion score 1.6 0.0 1.6 (0.9, 2.2) <0.001
Joint Space Narrowing score 1.0 0.1 0.9 (0.3,1.4) 0.002
PBO placebo, MTX methotrexate, ADA adalimumab, qow-every other week, CI confidence interval,
*Based on rank analysis. Significant improvement in radiographically-detected changes at 1 year of treatment was detected in each criteria chosen.


during treatment. According to study data, in pa-
tients not taking concomitant MTX, weekly dosing
may be indicated. Injection of adalimumab initially
should be supervised. However, self-administration
after proper training is appropriate making
adalimumab a more convenient alternative than in-
fliximab which is given as a continuous infusion.5

Cost
A one-month supply of Humira costs ap-
proximately $1,200, which is a box with 2 injec-
tions. In addition, there are initial administration
costs when injections are administered by a health
professional and these may vary. Initial tuberculin
skin test for latent tuberculosis infection must be
conducted prior to initiation and treated if such in-
fection is discovered. Monitoring parameters in-
clude antinuclear antibody development due to the
development of positive ANA titers in adalimumab
treated patients in clinical trials. Since information
about the long-term risk of developing lupus-like
syndrome is unknown, ANA titers should be moni-
tored at baseline, periodically throughout therapy
and with the development of symptoms of new-
onset lupus syndrome (manifested by abdominal
pain, fever, chills, arthralgia or arthritis, myalgia,
pericarditis, pleuritis, and/or skin rash).7

Summary
Adalimumab is a new fully human mono-
clonal antibody available for the treatment of RA,
either alone or in combination with other
DMARDs. It appears to be as effective as other
available biological agents, but head-to-head trials
are not available. It offers patients the convenience
of every other week administration, which is less
often than other currently available biological treat-
ments. In general, it represents a flexible treatment
for RA with the promise of true disease modifying
ability as evaluated by radiographic evidence.


References
1. Ruddy S, et al. Kelley's Textbook of Rheumatology, 6th
ed. Philadelphia (PA):W. B. Saunders Company; 2001. p.
921-1038.
2. Costs and predictors of costs in rheumatoid arthritis: a
prevalence-based study. Arthritis and Rheumatism. 2003;
49(1):64-70.
3. American College of Rheumatology Subcommittee on
Rheumatoid Arthritis Guidelines. Guidelines for the man-
agement of rheumatoid arthritis: 2002 Update. Arthritis
and Rheumatism 2002; 46(2): 328-46.
4. Weinblatt M, et. al. Adalimumab, a fully human anti-
tumor necrosis factor a monoclonal antibody for the treat-
ment of rheumatoid arthritis in patients taking concomi-
tant methotrexate (ARMADA). Arthritis and Rheuma-
tism 2003; 48(1): 35-45.
5. Humira" [Package Insert]. North Chicago, IL; Abbott
Laboratories; 2003.
6. Pincus T, et al. Evidence from clinical trials and long-
term observational studies that disease-modifying anti-
rheumatic drugs slow radiographic progression in rheu-
matoid arthritis: updating a 1983 review. Rheumatology
2002;41:1346-1356.
7. Reents S, et al. (accessed on [date]). Clinical Pharmacol-
ogy, Gold Standard Multimedia Inc [name of web page].
URL:http://cp.gsm.com.


The PharmaNote is Published by:
The Department of Pharmacy Services,
UF Family Practice Medical Group,
Departments of Community Health
and Family Medicine and Pharmacy
Practice
University of Florida


John G. Gums Editor
Pharm.D.

R. Whit Curry, M.D. Associate Editor

John M. Tovar Assistant Editor
Pharm.D.


-
Pha rma Note Volume 18, Issue 10 July 2003


PharmaNote


Volume 18, Issue 10 July 2003







ATOMOXETINE (STRATTERATM)
THE FIRST NON-STIMULANT
FOR THE TREATMENT OF ADHD


Eric Peters, Pharm.D. Candidate


Introduction
Attention-deficit/hyperactivity disorder
(ADHD) is a psychiatric disorder that is character-
ized by difficulties maintaining attention and prob-
lems with impulse control. ADHD has been linked
to poor academic performance and impaired social
functioning.1 The American Psychiatric Associa-
tion estimates that ADHD affects an estimated 3-
7% of school aged children,2 although other
sources suggest that the prevalence of ADHD in
children may be as high as 10%.3 Often, the symp-
toms of ADHD gradually become less problematic
as children grow older. In some individuals, the
disorder may persist into adulthood resulting in sig-
nificant morbidity, decreased productivity, and
other psychosocial problems.4
Until recently, the only pharmacological
agents with an FDA approved indication to treat
ADHD in children and adults were the stimulant
salts methylphenidate and amphetamine. These
psychostimulants have demonstrated efficacy, and
are considered standard treatment in ADHD. How-
ever, adverse effects such as insomnia, anorexia,
and irritability have left many patients, parents, and
clinicians dissatisfied with these agents. In addi-
tion, the psychostimulants are controlled sub-
stances, which have a high potential for abuse and
diversion. Other non-stimulants including desip-
ramine and bupropion have demonstrated a reduc-
tion in ADHD symptoms,5 but to date have not
been approved for children and adults with ADHD.
Atomoxetine (StratteraTM) is the first non-
stimulant agent approved for ADHD. The FDA
granted atomoxetine approval for the treatment of
ADHD on December 3, 2002. Eli Lilly and Com-
pany subsequently released atomoxetine into the
market during the first quarter of 2003. Atomoxet-
ine was originally known as tomoxetine, however
the name was changed to avoid confusion with the
drug tamoxifen. Atomoxetine has been shown to
be safe and efficacious in children > 6 yrs, adoles-
cents, and adults with diagnosed ADHD. This arti-


cle will focus on the pharmacology, pharmacoki-
netics, clinical trials, dosage, administration, toxic-
ity, safety, and clinical applications of atomoxetine.

Pharmacology and Pharmacokinetics
The mechanism by which atomoxetine re-
duces the symptoms of ADHD is unknown. Unlike
the stimulants methylphenidate and amphetamine
which work primarily on dopaminergic neurons,
atomoxetine affects noradrenergic neurons. Phar-
macodynamic studies in rats have demonstrated
that atomoxetine increases norepinephrine in the
prefrontal cortex, a region of the brain involved in
attention and memory.6 The R(-) isomer of ato-
moxetine inhibits the reuptake of norepinephrine by
selectively inhibiting the presynaptic norepineph-
rine transporter.
Oral administration of atomoxetine results
in rapid absorption from the GI tract. Food does
not affect the area under the curve (AUC) of ato-
moxetine, but reduces the peak plasma concentra-
tion (Cmax) by 37% and prolongs the time to maxi-
mum concentration (Tmax) by 3 hours. Normal Tmax
of atomoxetine occurs in 1-2 hours. Atomoxetine
is highly protein-bound (98%) to albumin. The vol-
ume of distribution is approximately 0.85 L/kg.
First pass metabolism of atomoxetine oc-
curs via the CYP450 2D6 isoenzyme. Genetic
polymorphisms of this enzyme exist, with individu-
als described as extensive metabolizers (EM) or
poor metabolizers (PM). Poor metabolizers of
CYP2D6 (7% of Caucasians and 2% of African
Americans) have impaired activity of this pathway,
resulting in increased serum levels of atomoxetine.
Coadministration of atomoxetine with inhibitors of
CYP2D6 (SSRIs, TCAs, amiodarone, cimetidine,
anti-psychotics) may result in increases in the se-
rum concentration of atomoxetine. Dosage adjust-
ment may be warranted. Eighty percent of ato-
moxetine is excreted in the urine as the inactive
metabolite, 4-hydroxyatomoxetine-O-glucuronide.
Approximately 17% of atomoxetine is eliminated
in the feces as this metabolite.

Clinical Trials
Numerous clinical trials have examined the
efficacy of atomoxetine in reducing the symptoms
of ADHD. Michelson and colleagues conducted a
dose range finding study,8 as well as, compared
once daily dosing of atomoxetine vs. placebo in pa-


Pha rma Note Volume 18, Issue 10 July 2003


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Table 1. Summary of StratteraTM clinical trials

Authors Study Design N Age Dose Primary Outcome Significance
Michelson et al. 8-wk R, PC 297 8-18 0.5, 1.2, and 1.8 Mean change in the Atomoxetine 1.2 and 1.8
20018 mg/kg/d bid ADHD RS vs. placebo mg/kg/day superior to pla-
cebo
Michelson et al. 6-wk R, PC 171 6-16 1.0-1.5 mg/kg/d Mean change in the Superior outcomes in ato-
20029 qd ADHD RS vs. placebo moxetine treated group vs.
placebo
Biederman et al. 9-wk R, PC 52 7-13 Max. 2.0 mg/kg/d Mean change in the Superior outcomes in ato-
200210 divided bid ADHD RS vs. placebo moxetine treated group vs.
placebo
Michelson et al. 10-wk R, PC 536 41 Max. 120 mg/d Sum of the investiga- Superior outcomes in ato-
20031 (average) divided bid tor-rated CAARS val- moxetine treated group vs.
ues placebo
N=number of patients, R=randomized, PC placebo-controlled, bid twice daily, ADHD attention-deficit/hyperactivity disorder, RS rating scale-parent version,
qd once daily, CAARS Conners' adult attention-deficit/hyperactivity disorder rating scale.


tients with ADHD.9 Other studies have also demon-
strated atomoxetine's efficacy in reducing symp-
toms of ADHD in school-aged girls1 and adults.1
Available clinical trials are presented in Table 1.
Michelson and colleagues8 conducted a ran-
domized, placebo-controlled, dose-response study
that examined the relative efficacy of 3 different
doses of atomoxetine vs. placebo in 297 children
and adolescents between the ages of 8-18 who had
ADHD. Patients were randomized to receive either
placebo or atomoxetine dosed by weight at 0.5 mg/
kg/day, 1.2 mg/kg/day, or 1.8 mg/kg/day for 8
weeks. The study medication was administered in
equally divided doses in the morning and late after-
noon. The primary outcome was the change in total
score in the ADHD rating scale-parent version
(RS), an 18-item scale based on a semi-structured
interview with the patient's parent or caregiver.
Atomoxetine doses of 1.2 mg/kg/day and 1.8 mg/
kg/day resulted in nearly identical improvements in
ADHD symptoms that were superior to placebo.
The atomoxetine dose of 0.5 mg/kg/day did not
provide significant reduction in the symptoms of
ADHD compared with placebo. This study suggests
that an atomoxetine dose of 1.2 mg/kg/day is
equally effective to a dose of 1.8 mg/kg/day, and is
likely to be the target dose for most patients.
Michelson and colleagues9 also conducted a
randomized, multi-center, placebo-controlled study
that assessed the efficacy of once-daily atomoxetine
dosing in 171 children and adolescents aged 6-16
with ADHD. Patients were randomized to receive a
single dose of placebo or atomoxetine every morn-
ing for 6 weeks. Patients in the atomoxetine treat-


ment arm were started at a dose of 0.5 mg/kg/day
and were titrated to a target dose of 1.0 mg/kg/day
by the end of the first week of treatment. The pri-
mary outcome measured in this study was improve-
ment in the ADHD RS. This study also utilized
teachers' observations of patients to determine the
efficacy of once daily dosing of atomoxetine. Mean
reductions in the ADHD RS were significant for
the atomoxetine group beginning in week one and
lasted for the remainder of the study.
Biederman and colleagues10 conducted two
identical, double-blind, placebo-controlled, multi-
center trials were a total of 52 girls with ADHD be-
tween the ages of 7-13 were followed for a period
of 9 weeks. Patients were divided into two groups
based on their previous psychostimulant treatment.
The stimulant naive subgroup was randomized to
receive atomoxetine, placebo, or methylphenidate.
Patients who had previous psychostimulant expo-
sure were randomized to receive either atomoxetine
or placebo. The atomoxetine dose was titrated
based on clinical response to a maximum daily
dose of 2.0 mg/kg/day or 90 mg/day. Patients ran-
domized to the atomoxetine treatment group were
given atomoxetine in two daily doses (morning and
late afternoon). The primary outcome was improve-
ment in the ADHD RS. Significant improvement in
the symptoms of ADHD was demonstrated in the
atomoxetine treatment groups beginning one week
after randomization, and continuing for the remain-
der of the trial. Due to a relatively small sample
size in the methylphenidate treatment arm, efficacy
comparisons were not made between methylpheni-
date and atomoxetine.


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Table 2. Common adverse events associated with the use of StratteraTM in acute (<10 wks) adult trials


Adverse Event
System Organ Class/Adverse Event


Percentage of Patients Reporting Event
Strattera (n=269) Placebo (n=263)


Cardiac Disorders
Palpitations
Gastrointestinal Disorders
Constipation
Xerostomia
Dyspepsia
Flatulence
Nausea
General Disorders
Fatigue/lethargy
Pyrexia
Rigors
Weight decreased
Metabolism/Nutritional Disorders
Appetite decreased
Musculoskeletal/Connective Tissue/Bone Disorders
Myalgia
Nervous System Disorders
Dizziness
Headache
Insomnia
Paresthesia
Sinus headache
Psychiatric Disorders
Abnormal dreams
Libido decreased
Sleep disorder
Renal/Urinary Disorders
Urinary hesitation and/or urinary retention


Atomoxetine's efficacy was also evaluated
in two identical, placebo-controlled studies that
randomized 536 adults with ADHD to a 10-week
treatment with either placebo or atomoxetine given
twice daily." Patients in the atomoxetine group
were started on a dose of 60 mg/day, with dosage
increases to 90 mg/day after 2 weeks, and 120 mg/
day after 4 weeks based on clinical response. Ato-
moxetine was administered in the morning and late
afternoon in two equally divided doses. The pri-
mary outcome was a repeated measures, mixed
model analysis of post-baseline values of the Con-
ners' adult attention-deficit/hyperactivity disorder
rating scale (CAARS). In both studies, atomoxetine
was superior to placebo in reducing the symptoms
of ADHD in adults.


Toxicity and Safety
Initial atomoxetine safety trials spanned a
period of over one year and included over 2067
children and 270 adults. The most common adverse
events reported by patients were nausea/vomiting
(10-30%), anorexia (2-14%), and dizziness (6%).
The most common reasons for therapy discontinua-
tion were increased heart rate and elevated blood
pressure, which occurred in 4% of patients. A com-
plete comparison of adverse events reported in >
1% of adults are listed in Table 2.
Long-term studies are not available to char-
acterize the effect of atomoxetine on physical
growth in pediatric patients. However, short-term
studies (up to 9 weeks) of atomoxetine have shown
that up to 3.5% of body weight can be lost. Height


Ph ra ot Vlue 8,Isue10Juy 00


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Volume 18, Issue 10 July 2003







and weight should be monitored in all children and
adolescents who are taking atomoxetine or any
other drug indicated for attention-deficit/
hyperactivity disorder. An interruption in therapy
should be considered in any child who exhibits
growth inhibition.

Dosage and Administration
Treatment of ADHD in children, adoles-
cents, and adults with oral atomoxetine should be
individualized based on a patient's clinical re-
sponse. The lowest effective dose of atomoxetine is
recommended and periodic assessment of patient
response should be charted. In patients weighing >
70 kg (including children > 6 years of age, adoles-
cents, and adults) atomoxetine should be initiated at
40 mg/day in 1-2 divided doses. After 3 days, ato-
moxetine may be titrated up to 80 mg/day. If neces-
sary, the dose may be increased to 100 mg/day and
given in 1-2 divided doses.12 In children and adoles-
cents weighing < 70 kg, atomoxetine should be ini-
tiated at 0.5 mg/kg/day in 1-2 divided doses. If well
tolerated, dose may be increased after 3 days up to
a maximum dose of 1.2 mg/kg/day in 1-2 divided
doses. Doses > 1.2 mg/kg/day are not associated
with increased clinical response. 12

Cost
In a survey of three retail pharmacies in the
Gainesville area, the cost of a month supply or
sixty 40 mg capsules of StratteraTM ranged from
$187.99-$207.89 with an average cost of approxi-
mately $196.72.

Summary
Atomoxetine is currently the only non-
stimulant agent approved by the Food and Drug
Administration that is available for the treatment of
attention-deficit/hyperactivity disorder. Atomoxet-
ine is a non-scheduled, non-habit forming drug
with a low potential for abuse. Clinical trials have
demonstrated atomoxetine's superiority over pla-
cebo in reducing the symptoms of ADHD in chil-
dren, adolescents, and adults. Whether long-term
treatment with atomoxetine inhibits growth in chil-
dren and adolescents remains unknown. Until ex-
tended safety trials are published, patients requiring
long-term therapy with atomoxetine should be rou-
tinely monitored and consideration should be given


to interrupting therapy in patients who exhibit be-
low average growth. Clinical trials have yet to be
performed comparing the efficacy and safety of
atomoxetine to the FDA-approved stimulants meth-
ylphenidate and amphetamine. Atomoxetine ap-
pears to be a safe and efficacious ADHD treatment
option for patients and clinicians.

References
1. Hechtman L. Assessment and diagnosis of attention-
deficit/hyperactivity disorder. Child Adolesc Psychiatr
Clin North Am 2000;9:481-498.
2. American Psychiatric Association. Diagnostic and Statis-
tical Manual of Mental Disorders: DSM-IV-TR. Wash-
ington DC: American Psychiatric Association.
3. American Academy of Pediatrics, Committee on Quality
Improvement and Subcommittee on Attention-Deficit/
Hyperactivity Disorder. Clinical practice guideline: diag-
nosis and evaluation of the child with attention-deficit/
hyperactivity disorder. Pediatrics 2000;105:1158-1170.
4. Klein RG, Mannuzza S. (1989): The long-term outcome
of the attention-deficit disorder/hyperkinetic syndrome.
In: Sagvolden T, Archer T, editors. Attention Deficit Dis-
order: Clinical and Basic Research. Hillsdale, NJ: Law-
rence Earlbaum Associates, pp. 71-91.
5. Wender PH, Reimherr FW. Buproprion treatment of at-
tention-deficit hyperactivity disorder in adults. Am J
Psychiatry 1990;147:1018-1020.
6. Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine
increases extracellular levels of norepinephrine and dopa-
mine in prefrontal cortex of rat: A potential mechanism
for efficacy in attention deficit/hyperactivity disorder.
Neuropsychopharmacology 2002;27:699-711.
7. Sauer JM, Ponsler GD, Mattiuz EL et al. Disposition and
Metabolic Fate of Atomoxetine Hydrochloride: The Role
of CYP2D6 in Human Disposition and Metabolism. Drug
Metabolism and Disposition 2003. 31:98-107.
8. Michelson D, Faries DE, Wernicke J et al. Atomoxetine
in the Treatment of Children and Adolescents With At-
tention-Deficit/Hyperactivity Disorder: A Randomized,
Placebo-Controlled, Dose-Response Study. Pediatrics
2001; 108(5):83-91.
9. Michelson D, Allen AJ, Busner J et al. Once-Daily Ato-
moxetine Treatment for Children and Adolescents With
Attention Deficit Hyperactivity Disorder: A Randomized,
Placebo-Controlled Study. Am J Psychiatry 2002; 159
(11):1896-1901.
10. Biederman J, Heiligenstein JH, Faries DE et al. Efficacy
of Atomoxetine Versus Placebo in School-Age Girls
With Attention-Deficit/Hyperactivity Disorder. Pediatrics
2002. 110(6):75-81.
11. Michelson D, Adler L, Spencer T et al. Atomoxetine in
Adults with ADHD: Two Randomized, Placebo-
Controlled Studies. Biol. Psychiatry 2003. 53:112-120.
12. Reents S, et al. (accessed on [date]). Clinical Pharmacol-
ogy, Gold Standard Multimedia Inc [name of web page].
URL:http://cp.gsm.com.


Pha rma Note Volume 18, Issue 10 July 2003


PharmaNote


Volume 18, Issue 10 July 2003




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