Safety
In general, clonidine and clonidine extended-release were reported to be safe and well tolerated in children and adolescents. Jain et al15 reported an overall general tolerance to clonidine extended-release. Somnolence and fatigue were the predominant side effects reported. There was no difference of prevalence of side effects in the two dosage groups. However, the number of subjects who discontinued clonidine extended-release was greatest in the higher-dose group (0.4 mg daily), and the most common reasons for discontinuation were somnolence and fatigue. There were electrocardiographic changes in QT and PR intervals, but these were clinically insignificant. Heart rate and blood pressure were lower in the clonidine extended-release groups treated with the extended-release formulation. No significant laboratory changes were reported.
Kollins et al16 reported that a maximal daily clonidine extended-release dose of 0.4 mg was well tolerated in their cohort, although somnolence, headache, fatigue, and slight changes in QT intervals were higher in prevalence in the clonidine extended-release plus stimulant group. However, it is not possible to attribute the reported side effects to clonidine extended-release alone, because stimulants were also used. Palumbo et al17 reported transient sedation that was tolerated by a majority of subjects. No electrocardiographic changes were found. In this study, clonidine was given in 3–4 divided doses. This fact may be a potential explanation for the lower prevalence of side effects. Daviss et al18 analyzed all 122 subjects from the same cohort as Palumbo et al17 and reported that bradycardia was significantly more common in patients treated with clonidine. A greater increase in orthostatic systolic blood pressure was reported as significant in the subjects taking clonidine. Somnolence, nervousness, and fatigue were more prevalent in the clonidine-treated groups. Eight subjects withdrew from the study due, at least in part, to the side effects. Although there were electrocardiographic changes, the only significant finding among the groups was bradycardia in the clonidine-treated groups. The remaining clinical trials20–24 reported similar side effects, such as sedation, somnolence, bradycardia, and electrocardiographic changes. Most of the clinical trials reported transience or tolerability of these side effects. It is not clear whether clonidine extended-release is better tolerated than clonidine, because clonidine extended-release was not compared with clonidine alone in any of the studies reviewed.
A case study51 of an eleven-year-old with a tic disorder reported a transient ischemic attack while taking risperidone and clonidine. It is not clear whether the medications, or which of the two medications, caused the transient ischemic attack. Another case study52 reported new onset of seizure in a nine-year-old girl with ADHD who was taking clonidine. However, this patient had other potential etiologies for seizures. Long-term side effects were not assessed by any of the studies reviewed.
None of the clinical trials included in this review reported any serious or fatal side effects of treatment with clonidine or clonidine extended-release. However, there have been some concerns regarding cardiac toxicity and the use of these medications.53–57 Maloney and Schwam described three unpublished cases of death associated with clonidine and methylphenidate use. These children had other comorbidities which confounded their deaths. They also discussed five other cases of cardiac complications while taking clonidine.53 The electrocardiographic changes returned to normal when the dosage of clonidine was lowered or discontinued. Fenichel57 described three of the four children with cardiac side effects who died while taking clonidine with methylphenidate. All of the three cases had other etiological confounders that could explain the deaths. Cantwell et al54 described one death in a child with a congenital cardiac malformation when taking clonidine. While the exact contribution of clonidine to the serious side effects described in these cases cannot be ascertained, serious cardiac side effects can occur, especially in individuals with coexisting cardiac or noncardiac risk factors. Periodic monitoring for cardiac side effects with clonidine is advised.