Table 4.
Reported Safety and Tolerability of Stimulant and Atomoxetine Combination Therapy
| |
AEs, n |
|
||
|---|---|---|---|---|
| Article n | AEs | Discontinuations | Serious | Other safety and tolerability findings |
| Patients with ADHD – prospective studies | ||||
| Carlson, 2007 9 |
6 (cardiac SE, GI discomfort, initial insomnia, rash, toothache, vomiting) | 1 (cardiac SE) | 0 |
Categoric increases BP: n=2 (diastolic; diastolic and systolic); HR: n=1 Change from start to end of treatment, ATMX+OROS MPH vs ATMX+PB, mean±SD Systolic BP: 2.1±11.2 vs 0.25±10.0 mm Hg; Diastolic BP: 3.0±8.5 vs 1.83±7.5 mm Hg; HR: 5.0±12.6 vs −2.0±12.3 bpm |
| Quintana, 2007 61 |
32 (≥2%: nausea, 5; fatigue, 3; headache, 3) | 1 (fatigue) | 0 |
Change from start to end of combination therapy, mean±SD Systolic BP: n.s.; Diastolic BP: +2.8±8.0 mm Hg*; HR: +6.2±10.4 bpm***; ECG RR interval: −58.3±114.1 ms***; no other clinically significant changes for ECG parameters reported |
| Wilens,2009 & Hammerness, 2009 50 |
NR (insomnia, 26; loss of appetite, 22; GI, 20; irritability, 16; headache,11; rhinitis, 11; fatigue, 5; othera, 15) | 8 (insomnia, GI upset, appetite loss, changes in mood after 1 week of treatment, 6) | 0 |
AE OR (95% CI) ATMX vs ATMX+OROS MPHb Fatigue: 0 (0–0.36)***; insomnia: 7.33 (2.20–38.27)***; irritability: 5.0 (1.10–46.93)*; loss of appetite: 6.0 (1.75–31.80)*** Start vs end of combination therapy, mean±SD Systolic BP: 104.5±9.4 vs 104.8±10.6 mm Hg; Diastolic BP: 64.5±9.2 vs 67.3±7.8 mm Hg*, HR: 93.3±12.7 vs 95.0±14.2 bpm; ECG PR: 132.7±19.7 vs 129.3±18.0 ms*; no significant changes for all other ECG parameters tested (QRS, QT, and QTc) or liver function & hematology parameters tested (SGOT, WBC, HCT, HGB) |
| Patients with ADHD – retrospective studies | ||||
| Adler, 2006 29 |
NR | NR | NR | n=22 reported acceptable tolerability |
| Brown, 2004 4 |
2 (initial somnolence, 2; minor GI complaint, 1; difficulty falling asleep, 1) | NA | NR | NR |
| Agarwal, 2008 1 |
NR | NA | NR | Improvement in decreased appetite and delayed onset of sleep associated with MPH use with ATMX+MPH combination therapy; no additional side effects were reported |
| Healthy volunteers | ||||
| Kelly, 2005 12 |
NR (most common: tachycardia, dry mouth, thirst) Frequency was no greater for MPH+ATMX than MPH monotherapy |
1 (ATMX+MPH: palpitations, postural drop in BP, and postural tachycardia) | NR |
Change from baseline Mean systolic BP 1 to 4 hours after dosing, MPH+ATMX:+13 mm Hg vs PB: NR*; max. mean HR, MPH+ATMX: 26 bpm vs PB: 10* at 1.5 to 6 hours; no significant effects for SVR were reported Baseline vs 4 hours after dosing, MPH+ATMX Epinephrine: 147 vs 344 pmol/L; no significant effects for norepinephrine were reported |
| Sofuoglu, 2009 10 |
NR | 0 | NR |
Change from max. post to pre dextroamphetamine dose score, PB or ATMX, treatment effect Systolic BP (F [1, 18]): 8.8**; diastolic BP (F [1, 18]): 610.6**; cortisol (F [1, 62]): 4.4*; POMS: n.s.; DEQ “stimulated” (F [1, 9]): 5.9*; DEQ “high” (F [1, 9]): 5.4*; DEQ “good drug effects” (F [1, 9]): 5.3* |
p<0.05, **p<0.01, ***p<0.001.
Includes enuresis (n=3), talking fast /on edge (n=2), nosebleed (n=1), itchy eyes/dilated pupils (n=2), anxiety (n=1), mouth pain (n=1), irregular mood/decreased personality (n=2), dry mouth (n=2), arm pain (n=1), and urinary (n=1).
Only those ORs that were statistically significant are reported in this table.
ADHD, attention-deficit/hyperactivity disorder; AE, adverse event; ATMX, atomoxetine; BP, blood pressure; bpm, beats per minute; CI, confidence interval; DEQ, Drug Effects Questionnaire; ECG, electrocardiogram; GI, gastrointestinal; HCT, hematocrit; HGB, hemoglobulin; HR, heart rate; max., maximum; MPH, methylphenidate; ms, millisecond; NA, not applicable; NR, not reported; n.s. not significant; OR, odds ratio; OROS, Osmotic-controlled Release Oral delivery System; PB, placebo; POMS, Profile of Mood States; SD, standard deviation; SE, supraventricular extrasystoles; SGOT, serum glutamic oxaloacetic transaminase; SVR, systemic vascular resistance; WBC, white blood cells; vs, versus.