PEDIATRIC PHARMACOTHERAPY A Monthly Newsletter for Health Care Professionals from the University of Virginia Children’s Hospital Volume 1 4 Number 4 April 20 08 New Treatment Options for Attention -Deficit/Hyperactivity Disorder (ADHD) : Part I I. Guanfacine Marcia L. Buck, Pharm.D., FCCP lonidine and g uanfacine, alpha -2A total of 34 children (mean age 10.4 years) with C adrenergic agonist s, ha ve been used off - ADHD and a tic disorder were randomized to label in the management of children with receive either guanfacine, beginning with 0.5 mg attention -de ficit/hyperactivity disorder (ADHD) and titrated as needed, or placebo for 8 weeks. for more than a decade . Guanfacine is preferred The effective dose of guanfacine ranged from 1.5 by many health care providers for its longer to 3 mg /day. Guanfacine produced a duration of action. 1,2 A new extended -release significantly greater improvement in ADHD formulation of guanfacine is currently under Rating Scale scores (37% versus 8% in the review by the Food and Drug Admin istration controls , p<0.001) . Clinical Global (FDA) specifically for the treatment of ADHD in Improvement (CGI) scale scores were rated as children between 6 and 1 7 years of age. 3 This much improved or very much improved in 9 of issue of Pediatric Pharmacotherapy will provide the 17 guanfacine patients, while none of the a basic review of guanfacine and highlight recent placebo patients achieved these scores studies of both the immediate -release and the (p<0.001). In addition, tic severity decreased by new ex tended -release product. 31% in the guanfacine group, with no improvement in the placebo group using the Yale Mechanism of Action Global Tic Severity Scale ( p=0.05). There w as Guanfacine, like clonidine, is a centrally acting no significant difference between the groups in selective alpha -2 adrenergic agonist. Stimulation mean p arent -rated hyperactivity index score s, of alpha -2 adrenergic receptors in the prefrontal with a 27% improvement in the guanfacine group cortex results in enhanced executive functioning, and a 21% improvement in the placebo group. increase d attentiveness, and improvements in working memory. In patients with ADHD, In 2001, Taylor and Russo conducted a improved neurotransmission in this region comparison study of guanfacine and increases the ability to control or inhibit dextroamphetamine in adults with ADHD. 8 inappropriate behaviors and increase focus. Seventeen adults were enrolled into this Guanfacine preferentially bind s alpha -2A randomized, double -blind, placebo -controlled receptor s, compared to the more general affinity crossover study. The subjects received each of clonidine for alpha -2A, B, and C and treatment (0.25 mg guanfacine, 2.5 mg imidazoline receptors. 1,2 dextroamphetamine, or placebo) for a 2 week period separated by 4 day wash -outs. Doses Clinical Studies in Children were titrated to achieve symptom control, up to a maximum of 2 mg guanfacine or 20 mg Immediate -release Guanfacine dextroamphetamine. The average final daily The first studies of guanfacine in children with dose s were 1.1 mg guanfacine and 10.2 mg ADHD were published in 1995. 4-6 These three dextroamphetamine . small open -label studies demonstrated the efficacy of immediate -release guanfacine in Both drugs signifi cantly reduced ADHD improving ADHD symptoms and served as a symptoms compared to baseline, using the foundation for further research . The first ADH D Behavior Checklist for Adults (p<0.05). placebo -controlled guanfacine trial was The only significant difference between the published by Scahill and colleagues in 2001. 7 A results achieved with the two drugs was in the Color -Word subscale of the Controlled Oral distribution throughout the body. Guanfacine is Word Associatio n Test, where guanfacine metabolized via hepatic conjugation. The parent produced a greater degree of improvement compound and metabolites are excreted in the (p<0.01). 8 urine. The elimination half -life of immediate - release guanfa cine is approximately 1 0 to 17 Two additional studies have evaluated the effects hours in adults .2 of guanfacine in children with pervasive developmental disorders (PDD) and ADH D or In 2007, Swearingen and colleagues conducted a hyperactivity. 9,10 In 2004, Posey and coll eagues Phase I open -label single -dose pharmacokinetic conducted a retrospective study in 80 children study of extended -release guanfacine in 52 9 12 (3 -18 years of age) who received guanfacine. adults . The maximum serum concentrations The authors found a response rate of 23.8% (C max ) ranged from 0.98 +0.26 ng/mL with a 1 mg (19/80), using an average dose of 2.6 +1.7 dose to 3.58 +1.39 ng/mL with the 4 mg dose. mg/day. The children most likely to respond to Area under the concentration -time curve (AUC 0- -1 guanfacine were those with PDD alone or in ) ranged from 32.4 +8.78 ng/mL ·h for the 1 mg combination with Asperger’s. Patients with co - dose to 124.1 +45.1 ng/mL ·h-1 for the 4 mg dose. morbid autism or mental retardation were less The average elimination half -life ranged fro m likely to benefit from treatment. 16.6 +3.8 to 17.5 +3.8 hours . Scahill and colleagues conducted a prospective The pharmacokinetic profile of extended -release open -label study of guanfacine in 25 children guanfacine was also recently studied in a group with PDD -ass ociated hyperactivity. 10 After 8 of 14 children (6 -12 years of age) and 14 weeks of treatment, there was significant adolescents (12 -17 years of age). 13 All subjects improvement in parent -rated hyperactivity using received a single 2 mg dose on the first day of the Aberrant Behavior Checklist , a decline from the study, followed by a wash -out period, then 31.1 +8.89 at baseline to 18.9 +10.37 at study sequential doses of 2 mg, 3 mg, and 4 mg each completion ( p<0.001). The teacher -rate d scores for a week. After the 2 mg dose, the younger also declined, from 29.9 +9.12 at baseline to children achieved a higher AUC 0-, with an 22.3 +9.44 (p<0.01). Forty -eight percent of the average of 62.5 +23.9 ng ·hr/mL compared to children achieved a rating of much improved or 47.3 +13.7 ng ·hr/mL in the adolescents. Time to very much improved on their CGI scores. The maximum plasma concentration was average final dose in this study ranged from 1 to approximately 5 hours for both age groups. The 3 mg/day. Cmax increased proportionally to the dose, with the 2 mg dose producing C max values of Ex tended -release Guanfacine 4.39 +1.66 ng/mL and 2.86 +0.77 ng/mL in the In the January 2008 issue of Pediatrics , younger and older groups, respectively. For Biederman and colleagues published the results comparison, a week of treatment with the 4 mg of a randomized, double -blind, placebo - dose produced C max values of 10.1 +7.09 ng/L controlled trial of extended -release guanfacine in and 7.01 +1.53 ng/mL. The average elimination children with ADHD. 11 A total of 345 children half -life was 14.4 +2.39 hours in younger children betwe en 6 and 17 years of age were enrolled in and 17.9 +5.77 hours in adolescents. this multicenter study. Patients were randomized to receive extended -release guanfacine (at a dose Drug Interactions of 2 mg, 3 mg, or 4 mg) or placebo once daily. Administration of guanfacine with other central There was significant improvement in ADHD nervous system depressants may result in Rating Scale total score s in each of the three excessive sedation. 1,2 treatment groups, with a mean reduction at endpoint of -16.7 compared to -8.9 for the Contraindications /Precautions placebo group (p < 0.0001) . Significant Abrupt discontinuation of guanfacine may result improvement in CGI scores was demonstrated in in increased levels of serum catecholamines. In 55.95% of the 2 mg group, 50% of the 3 mg comparison to clonidine, guanfacine produces group, and 55.56% of the 4 mg group, compared less of an effect on blood pressure because of its to only 25.64% of the placebo group. weaker binding affinity for imidazoline receptors. In patients taking guanfacine for Pharmacokinetics hypertension, abrupt discontinuation has result ed Immediate -release guanfacine is well absorbed, in mild rebound hypertension, anxiety, and with an oral bioavailability of approximately irritability. I t is recommended that guanfacine 80%. Peak concentrations occur 1 -4 hours after doses be slowly tapered over a period of several an oral dose. It has a large vo lume of weeks to avoid these effects. 1,2 distribution, 6.3 L/kg, reflecting extensive The incidence of rebound hyper tension with In 1999, Horrigan and Barnhill published a case guanfacine discontinuation in patients wi th series of five children who develop ed symptoms ADHD appears to be low . Kisicki and of mania after being treated with guanfacine. 15 colleagues compared abrupt discontinuation of Symptoms began 1 to 3 days after starting extended -release guanfacine to a taper in 45 therapy and resolved with discontinuation of healthy young adults (ages 19 -24 years). 14 All therapy. All of the children had developmental subjects received a sta ndardized dose -escalation, disorders in addition to ADHD and several had starting with 1 mg extended -release guanfacine risk factors for bipolar disorder, which may have followed by a 1 mg increase every 4 days. placed them at higher risk for this adverse effect.