Switching clonidine to guanfacine XR
The new switcheroo
I often am asked how to switch patients from clonidine IR to guanfacine XR. This may be needed when poor adherence to a clonidine IR regimen (typically requiring 3–4 doses daily) is identified, when clonidine dose-optimization is limited by sedation or hypotension, or when coverage situations change (e.g., a child enters ministry care or parental third-party prescription coverage is upgraded).
Guanfacine extended-release (XR), a selective α2A agonist, was first marketed in Canada in late 2013 for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. Guanfacine immediate release (IR) has been available in the US since 1985 for adult hypertension, but is not marketed in Canada.
Clonidine IR, a nonselective α2 agonist, is the only oral α2 agonist marketed in Canada for adult hypertension. A clonidine XR formulation is available in the US for ADHD, but not in Canada. Clonidine has been used off-label in children for many years for treatment of insomnia [1, 2, 3], ADHD [1, 4, 5], and disruptive behavior disorders . At the BC Children’s Hospital, an internal review noted a sharp uptick in clonidine IR use in children starting in 2010. This correlated with the publication of randomized controlled trial data showing the benefits of XR formulations of clonidine and guanfacine for treatment of children with ADHD and the introduction of these products in the US.
The guanfacine XR product monograph does not provide any guidance regarding how to switch from clonidine to guanfacine in children. The most obvious way is to taper fully off clonidine IR, and then start guanfacine XR according to the dosing instructions outlined in the guanfacine XR product monograph. Clonidine tapering is recommended to prevent rebound hypertension. The risk of rebound hypertension with clonidine discontinuation is assumed to likely be greater in adult hypertensives compared to children with normal pretreatment blood pressure. However, gradual tapering of the clonidine dose in children is considered good practice and is still recommended [6, 7]. A full clonidine taper before starting guanfacine XR titration, however, may take two weeks or longer. This can result in significant delays in achieving a therapeutic guanfacine XR dose. For parents, caregivers, and teachers working with children with ADHD, a few weeks of relative under-treatment can feel like a very long time!
A suggested switch method
At our hospital, we have successfully employed the following approach, which simultaneously reduces the risk for rebound hypertension and shortens the time the child receives a subtherapeutic α2 agonist dose. (Individual practitioners may have developed other methods to achieve the same outcome.) For patients who were hypertensive prior to starting clonidine, our switch method may not be appropriate.
Weight-based dosing guidelines exist for clonidine IR (0.003–0.08 mg/kg/day)  and guanfacine XR (0.05–0.08 mg/kg/day). From these guidelines and other literature [8, 9], guanfacine has an approximate 10-fold lower potency than clonidine. Most children who take clonidine IR for ADHD typically take a dosage in the range of 0.15–0.3 mg/day (in 3–4 divided doses).
When switching, we suggest tapering clonidine in 25% decrements twice weekly (based on the starting total daily dose, rounded to the closest available tablet strengths; the lowest tablet strength is 0.025 mg), until a total daily clonidine dose of 0.1 mg is reached. Then, guanfacine XR 1 mg/day is started and the remaining clonidine dose(s) are simultaneously discontinued. The guanfacine XR dose is then titrated up (by following the product monograph dosing guidelines) in 1 mg increments weekly as tolerated, to a target weight-based dosage range of 0.05–0.08 mg/kg/day (rounded to the nearest 1 mg tablet strength). If a guanfacine XR dosage of 0.08 mg/kg/day is well tolerated, it may be increased up to 0.12 mg/kg/day, to a maximum dose of 4 mg/day in children or 7 mg/day in adolescents.
Clonidine IR 0.1 mg and guanfacine XR 1 mg doses are roughly equipotent. Switching from clonidine to guanfacine at these dosage levels in children who were normotensive at baseline prior to starting α2 agonist treatment should be adequate to prevent rebound hypertension. For patients receiving clonidine doses at or below a total of 0.1 mg/day when a switch to guanfacine XR is contemplated, clonidine can be discontinued and guanfacine XR started at 1 mg/day. Box 1 provides an example of dosage titration for a clonidine IR to guanfacine XR switch in a 25 kg child. Please note that the dosing information below does not apply to clonidine XR and guanfacine IR, but to guanfacine XR and clonidine IR only.
Clonidine to guanfacine XR switch: titration example
25 kg patient, taking clonidine 0.05 mg at 0800h and 1400h and 0.1 mg qhs (total of 0.2 mg/day)
- Reduce clonidine to 0.025 mg at 0800h and 1400h and keep clonidine 0.1 mg qhs (total of 0.15 mg/day).
- After three days, reduce clonidine to 0.025 mg at 0800h and 1400h, and 0.05 mg hs (total of 0.1 mg/day).
- After three days (on the day of switch to guanfacine XR), give the clonidine 0.025 mg 0800h and 1400h doses, then discontinue clonidine, and start guanfacine XR 1 mg qhs.
- After one week, increase guanfacine XR to 2 mg qhs (0.08 mg/kg/day [target dose]).
Time saved (compared to a regimen employing a full clonidine taper): 6 days
Regular blood pressure monitoring should occur during the clonidine tapering and guanfacine up-titration processes. Titration rates should be slowed if significant blood pressure changes are detected.
Guanfacine XR can be taken once daily, either in the morning or evening without significant differences in efficacy . Many prescribers prefer evening or bedtime administration to allow the peak serum level (which occurs approximately 5 hours after the dose) to occur overnight, in order to reduce daytime sedation. Guanfacine XR tablets should never be split or crushed, as this can lead to earlier than expected peak serum levels and increased adverse effects.
- Hunt, R. D., Capper, L., & O'Connell, P. (1990). Clonidine in child and adolescent psychiatry. Journal of Child Adolescent Psychopharmacology, 1, 87–102.
- Rubinstein, S., Silver, L. B., & Licamele, W. L. (1994). Clonidine for stimulant-related sleep problems. Journal of the American Academy of Child and Adolescent Psychiatry, 33, 281–282.
- Efron, D., Lycett, K., & Sciberras, E. (2014). Use of sleep medication in children with ADHD. Sleep Medicine, 15, 472–475.
- Palumbo, D. R., Sallee, F. R., Pelham, W. E. Jr, Bkstein, O. G., Daviss, W. B., McDermott, M. P., & Burrows-MacLean, L. (2008). Clonidine for attention-deficit/hyperactivity disorder: I. Efficacy and tolerability outcomes. Journal of the American Academy of Child and Adolescent Psychiatry, 47, 180–188.
- Jaselskis, C. A., Cook, E. H., Fletcher, K. E., & Leventhal, B. L. (1992). Clonidine treatment of hyperactive and impulsive children with autistic disorder. Journal of Clinical Psychopharmacology, 12, 322–327.
- Green, W. H. (2007). Child and adolescent clinical psychopharmacology (4th ed.). Philadelphia, PA: Lippincott, Williams & Wilkins.
- Elbe, D., Bezchlibnyk-Butler, K., Virani, A. S., & Procyshyn, R. M. (2015). Clinical handbook of psychotropic drugs for children and adolescents (3rd ed.). Boston, MA: Hogrefe Publishing.
- Elbe, D., & Reddy, D. (2014). Focus on guanfacine extended-release: A review of its use in child and adolescent psychiatry. Journal of the American Academy of Child and Adolescent Psychiatry, 23, 48–60.
- Stahl, S. M. (2008). Stahl's essential psychopharmacology (3rd ed.). Cambridge, MA: Cambridge University Press.
- Newcorn, J. H., Stein, M. A., Childress, A. C., Youcha, S., White, C., Enright, G., & Rubin, J. (2013). Randomized, double-blind trial of guanfacine extended release in children with attention-deficit/hyperactivity disorder: Morning or evening administration. Journal of the American Academy of Child and Adolescent Psychiatry, 52, 921–930.