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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5267_Библиотеки_им_академика_М_И_Перельмана
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reported. Seizures are a potential risk for atomoxetine (Eli Lilly and Company Ltd,
2008). Suicide-related behaviour (suicide attempts and suicidal ideation) has been
reported in patients treated with atomoxetine. In double-blind clinical trials, suicide-
related behaviours occurred at a frequency of 0.44% in atomoxetine-treated patients (6
out of 1,357 patients treated, one case of attempted suicide and five of suicidal ideation).
The age range of children experiencing these events was 7 to 12 years. There were no
events in the placebo group (n 851). It should be noted that the number of adolescent
patients included in the clinical trials was low (Eli Lilly and Company Ltd, 2008).
10.8.3 Clinical evidence for atomoxetine
Of the 49 included trials 14 included a comparison of atomoxetine with placebo. Of
these, 11 were of school-age children and three were of adults. In all trials, partici-
pants had been diagnosed with ADHD (common coexisting conditions included
oppositional defiant disorder and conduct disorder). One study (ALLEN2005)
recruited school-age children with ADHD and comorbid tic disorders. Two studies
(NEWCORN2008; WANG2007) involved a comparison of atomoxetine with
methylphenidate.
One trial (NEWCORN2006) included a comparison of atomoxetine low dose
(0.5 mg/kg/day) with atomoxetine high dose (1.8 mg/kg/day) in children with ADHD.
Another trial (ADLER2006), included a comparison of atomoxetine once daily with
atomoxetine twice daily in adults with ADHD.
For atomoxetine statistically significant adverse events and/or with an RR greater
than 5% are displayed in Table 27. For a full list of adverse events refer to Appendix
18 (forest plot).
Study information and evidence from the important outcomes and overall quality
of evidence are presented in Table 27. The full evidence profiles and associated forest
plots can be found in Appendix 19 and Appendix 18, respectively.
10.8.4 Long-term clinical evidence review
Evidence included
Long-term data of the use of atomoxetine was examined. The review team conducted
a search for long-term RCTs (more than 2 months’ duration) and observational stud-
ies (also more than 2 months) that assessed the safety of atomoxetine for children,
young people and adults with ADHD. There was only one study (a review of three 1-
year follow-up studies of children and young people with ADHD taking atomoxetine;
Wernicke et al., 2003) that met the criteria set by the GDG as well as one safety
review mentioned previously (Villalba et al., 2006).
Key findings
The evidence is inconclusive regarding the increase of heart rate and blood pressure
with the use of atomoxetine.
Pharmacological treatment
259
260
In school-age children In adults
Mixed comorbidity Specific comorbidity Mixed Mixed Mixed comorbidity
(tic disorder) comorbidity comorbidity
Atomoxetine versus Atomoxetine Atomoxetine Methylphenidate Atomoxetine Atomoxetine
placebo versus placebo (low dose) versus versus versus placebo (once daily) versus
atomoxetine atomoxetine atomoxetine
(high dose) (twice daily)
Table 27: Study information and evidence summary table for trials of atomoxetine
Total no. of
trials (total
no. of
participants)
Study ID
Diagnosis
10 (1850)
BOHNSTEDT2005
BROWN2006
KELSEY2004
MICHELSON2001
MICHELSON2002
MICHELSON2004
SPENCER2002A
SPENCER2002B
WEISS2005
WERNICKE2004A
ADHD (coexisting
conditions:
oppositional defiant
disorder and/or
conduct disorder)
2 (189)
ALLEN2005
SPENCER2002C
ADHD and tic
disorders
2 (772)
NEWCORN2008
WANG2007
ADHD
3 (820)
MICHELSON
2003A
MICHELSON
2003B
WERNICKE
2004B
ADHD,
hyperkinetic
disorder
1 (218)
ADLER2006
ADHD
1 (229)
NEWCORN2006
ADHD
Baseline
severity
(mean range)
Dose
Treatment
length
(mean range)
ADHD-RS (total)
range:
Atomoxetine: 37.8
(7.9) to 42.1 (9.2)
Placebo: 37.6 (8.0) to
42.3 (7.1)
Low: 0.8 mg/kg/day
Medium: > 0.8 >
1.6 mg/kg/day
High: 1.6 mg/kg/day
49–238 days
ADHD-RS
(total):
Atomoxetine:
38.9 (9.1)
Placebo: 35.0
(9.5)
Medium:
1.33 mg/kg/day
102 days
CGI-ADHD-S:
Methylphenidate:
5.3 (0.9)
Atomoxetine:
5.3 (0.8)
Methylphenidate:
0.2 to
0.6 mg/kg/day
Osmotically
released
methylphenidate:
18 to 54 mg/day
Atomoxetine: 0.8
to 1.8 mg/kg/day
42–56 days
CAARS-Inv
(total) range:
Atomoxetine:
33.6 (7.2) to
34.9 (6.9)
Placebo:
33.2 (7.8) to
34.2 (7.5)
Medium:
60 mg/day
(max)
High:
90 mg/day
(max)
70 days
CAARS-Inv
(total):
Once daily: 38.4
Twice daily: 37.2
80 mg/day
42 days
ADHD-RS
(total):
Low dose:
15.1(7.7)
High dose:
14.0 (7.2)
Low:
0.5 mg/kg/day
High: max
1.8 mg/kg/day
240 days
Continued
261
262
In school-age children In adults
Mixed comorbidity Specific comorbidity Mixed Mixed Mixed comorbidity
(tic disorder) comorbidity comorbidity
Atomoxetine versus Atomoxetine Atomoxetine Methylphenidate Atomoxetine Atomoxetine
placebo versus placebo (low dose) versus versus versus placebo (once daily) versus
atomoxetine atomoxetine atomoxetine
(high dose) (twice daily)
Table 27: (Continued)
Benefits
ADHD core
symptoms
(mean
change)
(teacher-rated)
ADHD core
symptoms
(mean at
endpoint)
(parent-rated)
Medium dose:
SMD 0.43
(0.73 to 0.12)
Quality: High
K 1, N 171
High dose:
SMD 0.37
(0.54 to 0.21)
Quality: High
K 4, N 738
High dose: SMD
0.86
(1.16 to 0.57)
Quality: High
K 1, N 194
–
–
–
–
–
–
–
–
–
–
ADHD core
symptoms
(mean change)
(parent-rated)
ADHD core
symptoms
(mean change)
(investigator-
rated)
Low dose: SMD 0.33
(0.70 to 0.04)
Quality: Moderate
K 1, N 297
Medium dose:
SMD 0.65
(0.87 to 0.43)
Quality: High
K 2, N 468
High dose: SMD 0.59
(0.71 to 0.47)
Quality: High
K 7, N 916
–
ADHD-RS-P:
SMD 0.56
(0.89 to
0.23)
Quality: High
K 1,
N 148
–
ADHD-RS-IV-P:
SMD 0.05
(0.27 to 0.17)
Quality: Moderate
K 1, N 330
–
–
Medium dose:
CAARS:
SMD 0.44
(0.62 to 0.26)
Quality: High
K 2, N 572
High dose:
CAARS:
SMD: 0.37
(0.54 to 0.19)
Quality: High
K 2, N 515
–
–
–
ADHD-RS: SMD
0.19
(0.07 to 0.45)
Quality: Moderate
K 1, N 229
Continued
263
264
In school-age children In adults
Mixed comorbidity Specific comorbidity Mixed Mixed Mixed comorbidity
(tic disorder) comorbidity comorbidity
Atomoxetine versus Atomoxetine Atomoxetine Methylphenidate Atomoxetine Atomoxetine
placebo versus placebo (low dose) versus versus versus placebo (once daily) versus
atomoxetine atomoxetine atomoxetine
(high dose) (twice daily)
Table 27: (Continued)
ADHD core
symptoms
(mean
change)
(self-report)
Conduct
problems
(mean
change)
(teacher-rated)
Conduct
problems
(mean
change)
(parent-rated)
–
Medium dose:
SMD 0.0
(0.24 to 0.24)
Quality: Moderate
K 1, N 416
Low dose: SMD
0.46
(0.83 to 0.08)
Quality: High
K 1, N 297
Medium dose: SMD
–
–
–
–
–
–
High dose:
CAARS:
SMD 0.39
(0.57 to 0.22)
Quality: High
K 2,
N 536
–
–
–
–
–
–
–
–
Clinical
improvement
(clinician-
rated)
Harms
Nausea
0.31
(0.49 to 0.14)
Quality: High
K 2, N 713
High dose: SMD 0.23
(0.54 to 0.07)
Quality: Moderate
K 1, N 297
Various measures:
High dose: RR 1.46
(0.92 to 2.31)
Quality: High
K 3, N 669
Medium dose: NNTH 20
(9 to ∞)
Quality: High
K 2, N 468
10% population:
NNTH 10 (5 to 33)
Quality: Moderate
K 2, N 275
–
NNTH 10
(5 to 33)
Quality: High
K 1,
N 148
ADHD-RS:
RR 0.80
(0.66 to 0.97)
Quality: High
K 1, N 442
CGI-ADHD-S:
SMD 0.15
(0.37 to 0.07)
Quality: Moderate
K 1, N 330
–
–
High dose:
NNTH 14
(8 to 33)
Quality: High
K 1,
N 280
–
NNTB 6
(3 to 20)
Quality:
Moderate
K 1, N 218
–
–
Continued
265
266
In school-age children In adults
Mixed comorbidity Specific comorbidity Mixed Mixed Mixed comorbidity
(tic disorder) comorbidity comorbidity
Atomoxetine versus Atomoxetine Atomoxetine Methylphenidate Atomoxetine Atomoxetine
placebo versus placebo (low dose) versus versus versus placebo (once daily) versus
atomoxetine atomoxetine atomoxetine
(high dose) (twice daily)
Table 27: (Continued)
Cough
Decreased
appetite
Low dose: NNTH 11
(NNTH 5 to ∞ to
NNTB 50)
Quality: Moderate
K 1, N 297
Medium dose:
NNTH 9
(5 to 25)
Quality: High
K 2, N 468
High dose: NNTH 11
(6 to 33)
Quality: High
K 2, N 494
10% population:
NNTH 7
(4 to 14)
Quality: High
K 2, N 275
–
NNTH 7
(4 to 14)
Quality: High
K 1, N 148
–
–
–
High dose:
NNTH 12
(7 to 25)
Quality: High
K 1,
N 280
–
–
–
–
Dyspepsia
Vomiting
Asthenia
Dizziness
Medium dose: NNTH 11
(6 to 33)
Quality: High
K 1, N 171
High dose: NNTH 20
(NNTH 10 to ∞ to
NNTB 100)
Quality: Moderate
K 1, N 197
Medium dose: NNTH 12
(7 to 50)
Quality: High
K 2, N 468
High dose: NNTH 20
(10 to ∞)
Quality: High
K 2, N 494
Medium dose: NNTH 25
(NNTH 12 to ∞ to 100)
Quality: Moderate
K 2, N 468
Medium dose: NNTH 25
(14 to ∞)
Quality: High
K 2, N 468
High dose: NNTH 25
(NNTH 11 to ∞ to
NNTB 50)
–
–
–
–
–
–
–
–
Medium dose:
NNTH 50
(NNTH 25 to
∞ to NNTB
100)
Quality:
Moderate
K 1,
N 284
–
–
High dose:
NNTH 25
(12 to 100)
Quality:
Moderate
K 1,
N 280
–
–
–
–
–
–
–
–
Continued
267
268
In school-age children In adults
Mixed comorbidity Specific comorbidity Mixed Mixed Mixed comorbidity
(tic disorder) comorbidity comorbidity
Atomoxetine versus Atomoxetine Atomoxetine Methylphenidate Atomoxetine Atomoxetine
placebo versus placebo (low dose) versus versus versus placebo (once daily) versus
atomoxetine atomoxetine atomoxetine
(high dose) (twice daily)
Table 27: (Continued)
Pruritus
Somnolence
Fatigue
Quality: Moderate
K 1, N 297
Medium dose:
NNTH 100
(NNTH 25 to ∞ to
NNTB 50)
Quality: Moderate
K 1, N 297
High dose: NNTH 16
(8 to ∞)
Quality: Moderate
K 1, N 297
High dose: NNTH 10
(6 to 20)
Quality: High
K 2, N 494
High dose: NNTH 12
(7 to 50)
Quality: Moderate
K 1, N 197
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
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