A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Strattera Side Effects, and Drug Interactions - Atomoxetine HCl
Strattera Side Effects, and Drug Interactions - Atomoxetine HCl
SIDE EFFECTS
STRATTERA was administered to 2067 children or adolescent
patients with ADHD and 270 adults with ADHD in clinical studies. During
the ADHD clinical trials, 169 patients were treated for longer than 1
year and 526 patients were treated for over 6 months.
The data in the following tables and text cannot be used
to predict the incidence of side effects in the course of usual medical
practice where patient characteristics and other factors differ from those
that prevailed in the clinical trials. Similarly, the cited frequencies
cannot be compared with data obtained from other clinical investigations
involving different treatments, uses, or investigators. The cited data
provide the prescribing physician with some basis for estimating the relative
contribution of drug and non-drug factors to the adverse event incidence
in the population studied.
Child and Adolescent Clinical Trials
Reasons for discontinuation of treatment due to adverse
events in child and adolescent clinical trials — In acute child and adolescent
placebo-controlled trials, 3.5% (15/427) of atomoxetine subjects and 1.4%
(4/294) placebo subjects discontinued for adverse events. For all studies,
(including open-label and long-term studies), 5% of extensive metabolizer
(EM) patients and 7% of poor metabolizer (PM) patients discontinued because
of an adverse event. Among STRATTERA-treated patients, aggression (0.5%,
n=2); irritability (0.5%, n=2); somnolence (0.5%, n=2); and vomiting (0.5%,
n=2) were the reasons for discontinuation reported by more than 1 patient.
Commonly observed adverse events in acute child and adolescent,
placebo-controlled trials — Commonly observed adverse events associated
with the use of STRATTERA (incidence of 2% or greater) and not observed
at an equivalent incidence among placebo-treated patients (STRATTERA incidence
greater than placebo) are listed in Table 1 for the BID trials. Results
were similar in the QD trial except as shown in Table 2, which shows both
BID and QD results for selected adverse events. The most commonly observed
adverse events in patients treated with STRATTERA (incidence of 5% or
greater and at least twice the incidence in placebo patients, for either
BID or QD dosing) were: dyspepsia, nausea, vomiting, fatigue, appetite
decreased, dizziness, and mood swings (see Tables 1 and 2).
|
Table 1: Common Treatment-Emergent Adverse Events
Associated with the Use of STRATTERA in Acute (up to 9 weeks) Child
and Adolescent Trials
|
|
Adverse Event1
|
Percentage of Patients Reporting Events from BID
Trials
|
|
|
STRATTERA (N=340)
|
Placebo (N=207)
|
|
Gastrointestinal Disorders
|
|
Abdominal pain upper
|
20
|
16
|
|
Constipation
|
3
|
1
|
|
Dyspepsia
|
4
|
2
|
|
Vomiting
|
11
|
9
|
|
Infections
|
|
Ear infection
|
3
|
1
|
|
Influenza
|
3
|
1
|
|
Investigations
|
|
Weight decreased
|
2
|
0
|
|
Metabolism and Nutritional Disorders
|
|
Appetite decreased
|
14
|
6
|
|
Nervous System Disorders
|
|
Dizziness (exc vertigo)
|
6
|
3
|
|
Headache
|
27
|
25
|
|
Somnolence
|
7
|
5
|
|
Psychiatric Disorders
|
|
Crying
|
2
|
1
|
|
Irritability
|
8
|
5
|
|
Mood swings
|
2
|
0
|
|
Respiratory, Thoracic, and Mediastinal Disorders
|
|
Cough
|
11
|
7
|
|
Rhinorrhea
|
4
|
3
|
|
Skin and Subcutaneous Tissue Disorders
|
|
Dermatitis
|
4
|
1
|
|
1 Events reported by at least 2% of
patients treated with atomoxetine, and greater than placebo. The
following events did not meet this criterion but were reported by
more atomoxetine-treated patients than placebo-treated patients
and are possibly related to atomoxetine treatment: anorexia, blood
pressure increased, early morning awakening, flushing, mydriasis,
sinus tachycardia, tearfulness. The following events were reported
by at least 2% of patients treated with atomoxetine, and equal to
or less than placebo: arthralgia, gastroenteritis viral, insomnia,
sore throat, nasal congestion, nasopharyngitis, pruritus, sinus
congestion, upper respiratory tract infection.
|
|
Table 2: Common Treatment-Emergent Adverse Events
Associated with the Use of STRATTERA in Acute (up to 9 weeks) Child
and Adolescent Trials
|
|
Adverse Event
|
Percentage of Patients Reporting Events from BID
Trials
|
Percentage of Patients Reporting Events from QD
Trials
|
|
|
STRATTERA (N=340)
|
Placebo (N=207)
|
STRATTERA (N=85)
|
Placebo (N=85)
|
|
Gastrointestinal Disorders
|
|
Abdominal pain upper
|
20
|
16
|
16
|
9
|
|
Constipation
|
3
|
1
|
0
|
0
|
|
Diarrhea
|
3
|
6
|
4
|
1
|
|
Dry mouth
|
1
|
2
|
4
|
1
|
|
Dyspepsia
|
4
|
2
|
8
|
0
|
|
Nausea
|
7
|
8
|
12
|
2
|
|
Vomiting
|
11
|
9
|
15
|
1
|
|
General Disorders
|
|
Fatigue
|
4
|
5
|
9
|
1
|
|
Psychiatric Disorders
|
|
Mood swings
|
2
|
0
|
5
|
2
|
The following adverse events occurred in at least 2%
of PM patients and were either twice as frequent or statistically significantly
more frequent in PM patients compared with EM patients: decreased appetite
(23% of PMs, 16% of EMs); insomnia (13% of PMs, 7% of EMs); sedation (4%
of PMs, 2% of EMs); depression (6% of PMs, 2% of EMs); tremor (4% of PMs,
1% of EMs); early morning awakening (3% of PMs, 1% of EMs); pruritus (2%
of PMs, 1% of EMs); mydriasis (2% of PMs, 1% of EMs).
Adult Clinical Trials
Reasons for discontinuation of treatment due to adverse
events in acute adult placebo-controlled trials — In the acute adult placebo-controlled
trials, 8.5% (23/270) atomoxetine subjects and 3.4% (9/266) placebo subjects
discontinued for adverse events. Among STRATTERA-treated patients, insomnia
(1.1%, n=3); chest pain (0.7%, n=2); palpitations (0.7%, n=2); and urinary
retention (0.7%, n=2) were the reasons for discontinuation reported by
more than 1 patient.
Commonly observed adverse events in acute adult placebo-controlled
trials — Commonly observed adverse events associated with the use of STRATTERA
(incidence of 2% or greater) and not observed at an equivalent incidence
among placebo-treated patients (STRATTERA incidence greater than placebo)
are listed in Table 3. The most commonly observed adverse events in patients
treated with STRATTERA (incidence of 5% or greater and at least twice
the incidence in placebo patients) were: constipation, dry mouth, nausea,
appetite decreased, dizziness, insomnia, decreased libido, ejaculatory
problems, impotence, urinary hesitation and/or urinary retention and/or
difficulty in micturition, and dysmenorrhea (see Table 3).
|
Table 3: Common Treatment-Emergent Adverse Events
Associated with the Use of STRATTERA in Acute (up to 10 weeks) Adult
Trials
|
|
Adverse Event1
|
Percentage of Patients Reporting Event
|
|
System Organ Class/Adverse Event
|
STRATTERA (n=269)
|
Placebo (n=263)
|
|
Cardiac Disorders
|
|
Palpitations
|
4
|
1
|
|
Gastrointestinal Disorders
|
|
Constipation
|
10
|
4
|
|
Dry mouth
|
21
|
6
|
|
Dyspepsia
|
6
|
4
|
|
Flatulence
|
2
|
1
|
|
Nausea
|
12
|
5
|
|
General Disorders and Administration Site Conditions
|
|
Fatigue and/or lethargy
|
7
|
4
|
|
Pyrexia
|
3
|
2
|
|
Rigors
|
3
|
1
|
|
Infections
|
|
Sinusitis
|
6
|
4
|
|
Investigations
|
|
|
|
Weight decreased
|
2
|
1
|
|
Metabolism and Nutritional Disorders
|
|
Appetite decreased
|
10
|
3
|
|
Musculoskeletal, Connective Tissue, and Bone
Disorders
|
|
Myalgia
|
3
|
2
|
|
Nervous System Disorders
|
|
Dizziness
|
6
|
2
|
|
Headache
|
17
|
17
|
|
Insomnia and/or middle insomnia
|
16
|
8
|
|
Paraesthesia
|
4
|
2
|
|
Sinus headache
|
3
|
1
|
|
Psychiatric Disorders
|
|
Abnormal dreams
|
4
|
3
|
|
Libido decreased
|
6
|
2
|
|
Sleep disorder
|
4
|
2
|
|
Renal and Urinary Disorders
|
|
Urinary hesitation and/or urinary retention and/or
difficulty in micturition
|
8
|
0
|
|
Reproductive System and Breast Disorders
|
|
Dysmenorrhoea3
|
7
|
3
|
|
Ejaculation failure2 and/or ejaculation
disorder2
|
5
|
2
|
|
Erectile disturbance2
|
7
|
1
|
|
Impotence2
|
3
|
0
|
|
Menses delayed3
|
2
|
1
|
|
Menstrual disorder3
|
3
|
2
|
|
Menstruation irregular3
|
2
|
0
|
|
Orgasm abnormal
|
2
|
1
|
|
Prostatitis2
|
3
|
0
|
|
Skin and Subcutaneous Tissue Disorders
|
|
Dermatitis
|
2
|
1
|
|
Sweating increased
|
4
|
1
|
|
Vascular Disorders
|
|
Hot flushes
|
3
|
1
|
|
1 Events reported by at least 2% of
patients treated with atomoxetine, and greater than placebo. The
following events did not meet this criterion but were reported by
more atomoxetine-treated patients than placebo-treated patients
and are possibly related to atomoxetine treatment: early morning
awakening, peripheral coldness, tachycardia. The following events
were reported by at least 2% of patients treated with atomoxetine,
and equal to or less than placebo: abdominal pain upper, arthralgia,
back pain, cough, diarrhea, influenza, irritability, nasopharyngitis,
sore throat, upper respiratory tract infection, vomiting.
|
|
2 Based on total number of males (STRATTERA,
n=174; placebo, n=172).
|
|
3 Based on total number of females (STRATTERA,
n=95; placebo, n=91).
|
Male and female sexual dysfunction — Atomoxetine appears
to impair sexual function in some patients. Changes in sexual desire,
sexual performance, and sexual satisfaction are not well assessed in most
clinical trials because they need special attention and because patients
and physicians may be reluctant to discuss them. Accordingly, estimates
of the incidence of untoward sexual experience and performance cited in
product labeling are likely to underestimate the actual incidence. The
table below displays the incidence of sexual side effects reported by
at least 2% of adult patients taking STRATTERA in placebo-controlled trials.
|
Table 4.
|
| |
STRATTERA
|
Placebo
|
|
Erectile disturbance1
|
7%
|
1%
|
|
Impotence1
|
3%
|
0%
|
|
Orgasm abnormal
|
2%
|
1%
|
|
1Males only.
|
There are no adequate and well-controlled studies examining
sexual dysfunction with STRATTERA treatment. While it is difficult to
know the precise risk of sexual dysfunction associated with the use of
STRATTERA, physicians should routinely inquire about such possible side
effects.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class
STRATTERA is not a controlled substance.
Physical and Psychological Dependence
In a randomized, double-blind, placebo-controlled, abuse-potential
study in adults comparing effects of STRATTERA and placebo, STRATTERA
was not associated with a pattern of response that suggested stimulant
or euphoriant properties.
Clinical study data in over 2000 children, adolescents,
and adults with ADHD and over 1200 adults with depression showed only
isolated incidents of drug diversion or inappropriate self-administration
associated with STRATTERA. There was no evidence of symptom rebound or
adverse events suggesting a drug-discontinuation or withdrawal syndrome.
Animal Experience
Drug discrimination studies in rats and monkeys showed
inconsistent stimulus generalization between atomoxetine and cocaine.
Laboratory Tests
Routine laboratory tests are not required.
CYP2D6 metabolism — Poor metabolizers (PMs) of
CYP2D6 have a 10-fold higher AUC and a 5-fold higher peak concentration
to a given dose of STRATTERA compared with extensive metabolizers (EMs).
Approximately 7% of a Caucasian population are PMs. Laboratory tests are
available to identify CYP2D6 PMs. The blood levels in PMs are similar
to those attained by taking strong inhibitors of CYP2D6. The higher blood
levels in PMs lead to a higher rate of some adverse effects of STRATTERA
(see SIDE EFFECTS
).
Drug-Drug Interactions
Albuterol — STRATTERA should be administered with
caution to patients being treated with albuterol (or other beta2
agonists) because the action of albuterol on the cardiovascular system
can be potentiated.
CYP2D6 inhibitors — Atomoxetine is primarily metabolized
by the CYP2D6 pathway to 4-hydroxyatomoxetine. In EMs, selective inhibitors
of CYP2D6 increase atomoxetine steady-state plasma concentrations to exposures
similar to those observed in PMs. Dosage adjustment of STRATTERA may be
necessary when coadministered with CYP2D6 inhibitors, eg, paroxetine,
fluoxetine, and quinidine (see DOSAGE
AND ADMINISTRATION). In EM individuals treated with paroxetine
or fluoxetine, the AUC of atomoxetine is approximately 6- to 8-fold and
Css,max is about 3- to 4-fold greater than atomoxetine alone.
In vitro studies suggest that coadministration of cytochrome
P450 inhibitors to PMs will not increase the plasma concentrations of
atomoxetine.
Monoamine oxidase inhibitors — See CONTRAINDICATIONS.
Pressor agents — Because of possible effects on blood
pressure, STRATTERA should be used cautiously with pressor agents.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis — Atomoxetine HCl was not carcinogenic
in rats and mice when given in the diet for 2 years at time-weighted average
doses up to 47 and 458 mg/kg/day, respectively. The highest dose used
in rats is approximately 8 and 5 times the maximum human dose in children
and adults, respectively, on a mg/m2 basis. Plasma levels (AUC)
of atomoxetine at this dose in rats are estimated to be 1.8 times (extensive
metabolizers) or 0.2 times (poor metabolizers) those in humans receiving
the maximum human dose. The highest dose used in mice is approximately
39 and 26 times the maximum human dose in children and adults, respectively,
on a mg/m2 basis.
Mutagenesis — Atomoxetine HCl was negative in
a battery of genotoxicity studies that included a reverse point mutation
assay (Ames Test), an in vitro mouse lymphoma assay, a chromosomal aberration
test in Chinese hamster ovary cells, an unscheduled DNA synthesis test
in rat hepatocytes, and an in vivo micronucleus test in mice. However,
there was a slight increase in the percentage of Chinese hamster ovary
cells with diplochromosomes, suggesting endoreduplication (numerical aberration).
The metabolite N-desmethylatomoxetine HCl was negative
in the Ames Test, mouse lymphoma assay, and unscheduled DNA synthesis
test.
Impairment of fertility — Atomoxetine HCl did
not impair fertility in rats when given in the diet at doses of up to
57 mg/kg/day, which is approximately 6 times the maximum human dose on
a mg/m2 basis.
Pregnancy — Pregnancy Category C
Pregnant rabbits were treated with up to 100 mg/kg/day
of atomoxetine by gavage throughout the period of organogenesis. At this
dose, in 1 of 3 studies, a decrease in live fetuses and an increase in
early resorptions was observed. Slight increases in the incidences of
atypical origin of carotid artery and absent subclavian artery were observed.
These findings were observed at doses that caused slight maternal toxicity.
The no-effect dose for these findings was 30 mg/kg/day. The 100-mg/kg
dose is approximately 23 times the maximum human dose on a mg/m2
basis; plasma levels (AUC) of atomoxetine at this dose in rabbits are
estimated to be 3.3 times (extensive metabolizers) or 0.4 times (poor
metabolizers) those in humans receiving the maximum human dose.
Rats were treated with up to approximately 50 mg/kg/day
of atomoxetine (approximately 6 times the maximum human dose on a mg/m2
basis) in the diet from 2 (females) or 10 (males) weeks prior to mating
through the periods of organogenesis and lactation. In 1 of 2 studies,
decreases in pup weight and pup survival were observed. The decreased
pup survival was also seen at 25 mg/kg (but not at 13 mg/kg). In a study
in which rats were treated with atomoxetine in the diet from 2 (females)
or 10 (males) weeks prior to mating throughout the period of organogenesis,
a decrease in fetal (female only) weight and an increase in the incidence
of incomplete ossification of the vertebral arch in fetuses were observed
at 40 mg/kg/day (approximately 5 times the maximum human dose on a mg/m2
basis) but not at 20 mg/kg/day.
No adverse fetal effects were seen when pregnant rats
were treated with up to 150 mg/kg/day (approximately 17 times the maximum
human dose on a mg/m2 basis) by gavage throughout the period
of organogenesis.
No adequate and well-controlled studies have been conducted
in pregnant women. STRATTERA should not be used during pregnancy unless
the potential benefit justifies the potential risk to the fetus.
Labor and Delivery
Parturition in rats was not affected by atomoxetine.
The effect of STRATTERA on labor and delivery in humans is unknown.
Nursing Mothers
Atomoxetine and/or its metabolites were excreted in the
milk of rats. It is not known if atomoxetine is excreted in human milk.
Caution should be exercised if STRATTERA is administered to a nursing
woman.
Pediatric Use
The safety and efficacy of STRATTERA in pediatric patients
less than 6 years of age have not been established. The efficacy of STRATTERA
beyond 9 weeks and safety of STRATTERA beyond 1 year of treatment have
not been systematically evaluated.
A study was conducted in young rats to evaluate the effects
of atomoxetine on growth and neurobehavioral and sexual development. Rats
were treated with 1, 10, or 50 mg/kg/day (approximately 0.2, 2, and 8
times, respectively, the maximum human dose on a mg/m2 basis)
of atomoxetine given by gavage from the early postnatal period (Day 10
of age) through adulthood. Slight delays in onset of vaginal patency (all
doses) and preputial separation (10 and 50 mg/kg), slight decreases in
epididymal weight and sperm number (10 and 50 mg/kg), and a slight decrease
in corpora lutea (50 mg/kg) were seen, but there were no effects on fertility
or reproductive performance. A slight delay in onset of incisor eruption
was seen at 50 mg/kg. A slight increase in motor activity was seen on
Day 15 (males at 10 and 50 and females at 50 mg/kg) and on Day 30 (females
at 50 mg/kg) but not on Day 60 of age. There were no effects on learning
and memory tests. The significance of these findings to humans is unknown.
Geriatric Use
The safety and efficacy of STRATTERA in geriatric patients
have not been established.
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