By: Katharine Cimmino, Editor-in-Chief
Attention-deficit/hyperactivity disorder (ADHD) is the most common pediatric psychiatric disorder, and it affects the education, social interactions, and over-all wellbeing of both children and adolescents.1 Symptoms of ADHD can persist into adulthood, and those with this disorder are more likely to suffer from other mental health co-morbidities.2 According to guidelines from the American Academy of Pediatrics, a school-aged child or adolescent diagnosed with ADHD should be prescribed FDA approved medications and/or receive behavioral therapy. Evidence for stimulant medications is stronger than for other classes of drugs such as atomextine, extended-release guanfacine (GXR), and extended-release clonidine. However, up to 30% of children may not respond to stimulants or may not tolerate side effects of these medications.3 Furthermore, a significant number of patients are nonresponsive to treatment and require adjunct therapy to stimulants.4 Extended release guanfacine (Intuniv®) is one FDA approved non-stimulant for the treatment of ADHD. Currently, the immediate-release formulation of guanfacine (GIR) is not approved by the FDA for the treatment of ADHD, but it has been used off-label for over a decade.5
Comparing the pharmacokinetic profiles of GIR and GXR provides a better understanding of the differences between these formulations.
Pharmacokinetic properties of Guanfacine6-9
|Tmax||2.6 hours (range: 1 to 4 hours)||5 hours|
|T1/2||13-14 hours||17 hours (± 4 hours)|
|Metabolized||major substrate of CYP3A4|
|Excreted||Approximately 50% of the dose is eliminated unchanged in the urine. The metabolites are primarily excreted in the urine|
As evidenced from above, one limitation of the GIR formulation is its pharmacokinetic profile. Rapid absorption of the drug leads to high peak plasma concentrations that cause the unfavorable side effects of sedation, dry mouth, and hypotension. Despite the relative long half-life (~17hours), pharmacokinetic studies show a rapid decline after a dose. In hopes to avoid these high peaks, smaller doses are given at more frequent intervals. However, this can be problematic because it increases the pill burden on the patient and could decrease compliance.10
In a meta-analysis of monotherapy and multi-drug regimen trials for stimulant therapy, randomized controls trials studying guanfacine and clonidine were examined. In total, five guanfacine trials were analyzed- one GIR study and four GXR studies. The studies showed that for monotherapy, GXR was significantly superior to placebo for total ADHD symptoms. In addition, GIR was no different from placebo in any category. For hyperactive and inattentive symptoms, GXR (two trials) was found superior compared to placebo and GIR (one study) showed no statistical significance. However, it should be noted that there were more trials conducted on GXR.10
In another systematic review and meta-analysis, randomized control trials on the safety and efficacy of guanfacine in the pediatric ADHD population were examined. A total of seven studies were examined; six studies evaluating GXR and one study evaluating GIR. All studies were double blind, parallel group studies comparing guanfacine with placebo. The pooled analysis showed that 59% of children benefited from guanfacine compared to the 33.3% in the placebo group. When the study of GIR was excluded from the analysis, the efficacy results were unchanged. The pooled odds ratio was 3.18 (95% CI 2.44–4.13). The number needed to treat was 3.9 (95%CI 3.3–4.8). Between study heterogeneity was 26% (P=0.23). When examining safety, only 6 studies were included (the study with GIR was excluded because the authors did not report the number of participants who experienced at least one adverse effect). Pooling data from the 6 studies, the most common treatment-emergent adverse effects were somnolence (30.1%), headache (19.4%), fatigue (11.5%), and upper abdominal pain (8.6%). Overall, the 948 (82.4%) participants receiving guanfacine experienced at least one treatment-emergent adverse effect compared to the 376 (67.9%) receiving placebo. The pooled odds ratio was 2.62 (95% CI 1.57–4.38). Between study heterogeneity was 74% (P=0.002). Compared to placebo, the meta-analysis confirmed a favorable risk benefit profile for guanfacine for the treatment of ADHD.11 Again though, the limitation was that there was only one GIR study to pull data from.
Currently there are no head-to-head randomized controlled clinical trials that examine GIR versus GXR in the treatment of ADHD. A retrospective study comparing treatment patterns, resource utilization, and healthcare costs was conducted by Sikirica et al and compared GIR to GXR in children and adolescents with ADHD. During the 6-month study period, GIR users (n=743) had significantly higher rates of treatment discontinuation (adjusted hazard ratio [aHR]= 1.79; P<0.001), switching (aHR= 2.32; P <0.001), and augmentation (aHR=1.55; P=0.003) than GXR users (n=2344). GIR users had significantly more frequent all-cause inpatient admissions (P=0.022) and emergency department visits (P=0.016). While GIR users had lower all-cause pharmacy costs (P <0.001), they had significantly higher medical costs (P=0.009). This resulted in no significant difference in total all-cause healthcare costs between the two groups (P=0.68). Overall, after adjusting for baseline differences, the retrospective analysis found that GXR use was associated with lower rates of therapy adjustment and fewer ED visits compared to GIR use in children and adolescents with ADHD.2
When choosing an ADHD medication for children and adolescents, many factors need to be considered. Because GXR is FDA approved for ADHD, there is more evidence for its efficacy. However, the initial pharmacy cost of GIR (approximately $0.872 for one 1mg pill and $1.176 for one 2mg pill) may be cheaper than GXR (approximately $11.65 per pill).12 In addition, overall medical costs should be considered when evaluating cost effectiveness. Therefore, patients should be managed individually, with care tailored toward their specific needs.
- Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management, Wolraich M, Brown L, Brown RT, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-22.
- Sikirica V, Zie J, He L et al. Immediate-release versus extended-release guanfacine for treatment of attention-deficit/hyperactivity disorder. Am J Pharm Benefits. 2013;5(4):e85-e94.
- Banaschewski T, Roessner V, Dittmann RW, et al. Non-stimulant medications in the treatment of ADHD. Eur Child Adolesc Psychiatry. 2004;13(suppl 1):102-16.
- Sallee F, Connor DF, Newcorn JH. A review of the rationale and clinical utilization of α2-adrenoceptor agonists for the treatment of attention-deficit/hyperactivity and related disorders. J Child Adolesc Psychopharmacol. 2013;23(5):308-19.
- Buck M. New treatment options for attention-deficit/ hyperactivity disorder (ADHD): part II. Guafacine. Medscape. 2008. Available at http://www.medscape.com/viewarticle/578747. Accessed Sept 8, 2014
- Intuniv[package insert]. Wayne, PA: Shire Pharmaceuticals; February 2013.
- Pediatric & Neonatal Dosage Handbook [Lexicomp online database] http://online.lexi.com/lco/action/home (Date accessed: 2014 Sept 08) Hudson, OH. Copyright 1978-2014
- Tenex [package insert]. Bridgewater, NJ: Promius Pharma LLC; July 2013.
- Guanfacine. Drug Facts and Comparisons. Efacts [online]. 2008. Available from Wolters Kluwer Health, Inc. (accessed 9/4/14).
- Hirota T, Schwartz S, Correll CU. Alpha-2 agonists for attention-deficit/hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy. J Am Acad Child Adolesc Psychiatry. 2014;53(2):153-73.
- Ruggiero S, Clavenna A, Reale L, Capuano A, Rossi F, Bonati M. Guanfacine for attention deficit and hyperactivity disorder in pediatrics: A systematic review and meta-analysis. Eur Neuropsychopharmacol. 2014; http://dx.doi.org/10.1016/j.euroneuro.2014.08.001
- Lexicomp Online [online database] http://online.lexi.com/lco/action/home (Date accessed: 2014 Sept 05) Hudson, OH. Copyright 1978-2014.
[pubmed_related keyword1=”guanfacine” keyword2=”ADHD” keyword3=”FDA”]