Currently Viewing:
Currently Reading
Immediate-Release Versus Extended-Release Guanfacine for Treatment of Attention-Deficit/Hyperactivity Disorder
Vanja Sikirica, PharmD, MPH; Jipan Xie, MD, PhD; Tony Lizhang He, BS; M. Haim Erder, PhD; Paul Hodgkins, PhD, MSc; Hongbo Yang, PhD; Thomas Samuelson, BA; and Eric Q. Wu, PhD
Unused First-Fill Prescriptions: Cause for Concern?
Kimberly A. Burns, RPh, JD; Janene M. Madras, BS Pharm, PharmD, BCPS, BCACP; Mary E. Ray, BS Pharm, PharmD; Daniel P. O’Neil, PharmD; Andrew L. Bruinsma, PharmD; Emily Ferrare, PharmD, MS, RD, LDN;

Immediate-Release Versus Extended-Release Guanfacine for Treatment of Attention-Deficit/Hyperactivity Disorder

Vanja Sikirica, PharmD, MPH; Jipan Xie, MD, PhD; Tony Lizhang He, BS; M. Haim Erder, PhD; Paul Hodgkins, PhD, MSc; Hongbo Yang, PhD; Thomas Samuelson, BA; and Eric Q. Wu, PhD
Treatment patterns, resource utilization, and healthcare costs associated with guanfacine immediate release versus guanfacine extended release were compared in children and adolescents with attention-deficit/hyperactivity disorder.

Baseline Characteristics

The GIR and GXR cohorts included 743 and 2344 patients, respectively (Figure). At baseline, a higher proportion of GIR users were prescribed short-acting stimulants (23.96% vs 18.47%; P = .001), antidepressants (28.80% vs 24.74%; P = .027), and antipsychotics (24.76% vs 21.33%; P = .050), and a smaller proportion of GIR users were prescribed long-acting stimulants (66.89% vs 76.66%; P <.001). The GIR users had a higher prevalence of any MH comorbidity (47.11% vs 39.16%; P <.001). Inthe  baseline period, GIR users had significantly higher means of all-cause inpatient visits per patient (0.11 vs 0.06; P <.001), ED visits per patient (0.24 vs 0.19; P = .034), inpatient costs per patient ($926 vs $598; P <.001), and ED costs per patient ($142 vs $131; P = .020). The results were similar for MH-related baseline inpatient utilization and costs, but MH-related baseline ED utilization and costs were not significantly different (Table 1).

Study Outcomes

Results from the Kaplan-Meier analyses showed that GIR users had significantly higher 6-month rates of discontinuation (73.49% vs 53.67%; P <.001), switching (31.78% vs 15.59%; P <.001), and augmentation (16.13% vs 11.45%; P = .003) than GXR users. After adjusting for baseline characteristics, GIR users remained significantly more likely to discontinue (adjusted hazard ratio [aHR] = 1.79; P <.001), switch (aHR = 2.32; P <.001), and augment (aHR = 1.55; P = .003) treatment. Similar trends were observed when alternative definitions of switching (11.79% vs 5.70%, P <.001; aHR = 2.17, P <.001) and augmentation (16.27% vs 9.47%, P <.001; aHR = 1.58, P = .002) were used. In addition, GIR users had a significantly lower average MPR (0.50 vs 0.64; P <.001) than GXR users, indicating lower adherence to the index drug. The GIR users also had a significantly higher DACON (1.58 vs 1.07; P <.001) than GXR users (Table 2).

For resource utilizations, GIR users had significantly more frequent all-cause mean inpatient visits per patient (0.09 vs 0.05; P = .008), ED visits per patient (0.26 vs 0.16; P <.001), and outpatient visits per patient (9.76 vs 7.99; P <.001) than GXR users. After adjusting for baseline characteristics, GIR users had significantly more frequent allcause inpatient visits (adjusted incidence rate ratio [aIRR] = 1.61; P = .022) and ED visits (aIRR = 1.31; P = .016), but no statistically significant differences were observed in the number of outpatient visits (aIRR = 1.06; P = .080). Similar results were observed for MH-related utilizations. The GIR users had significantly more frequent MH-related visits than GXR users (inpatient visits per patient: 0.08 vs 0.04, P = .006; ED visits per patient: 0.09 vs 0.04, P <.001; outpatient visits per patient: 6.84 vs 5.30, P <.001). After adjusting for baseline characteristics, GIR users still had significantly more MH-related inpatient and ED visits than GXR users (inpatient visits: aIRR = 1.72, P = .013; ED visits: aIRR = 1.55, P = .030), but not more outpatient visits (aIRR = 1.07, P = . 104) (Table 3).

Consistent with the findings regarding utilization, GIR users had higher all-cause mean medical care costs compared with GXR users (unadjusted costs: $2775 vs $2104; P <.001), which were observed across different types of services, with unadjusted cost differences between the 2 groups of $278, $49, and $344 for inpatient, ED, and outpatient visits, respectively. Although GIR users had lower unadjusted all-cause drug costs ($1439 vs $1830; P <.001), unadjusted all-cause total healthcare costs were significantly higher ($4214 vs $3934; P = .009). After adjusting for baseline characteristics, all-cause medical care costs were still significantly higher among GIR users (adjusted cost difference [aCD] = $331; P = .009), and total drug costs remained significantly lower (aCD = –$438; P <.001). The adjusted difference in all-cause total healthcare costs was not significant (aCD = –$239; P = .068). Similar patterns were observed for MH-related costs. Without adjustment, GIR users had significantly higher mean MH-related total healthcare costs ($3062 vs $2784; P <.001), higher medical care costs ($1891 vs $1220; P <.001), and lower drug costs ($1171 vs $1564; P <.001). After adjusting for baseline characteristics, GIR users still had significantly higher MH-related medical costs and significantly lower MH-related drug costs (medical care: aCD = $401, P <.022; drugs: aCD = –$440, P <.001). Mental health–related total healthcare costs were not significantly different between the 2 cohorts (aCD = –$159; P = .085) (Table 3).

Using the alternative definition to define combination therapy with the index drug, sensitivity analyses were conducted for all adjusted models. Results for all study outcomes remained robust except for the hazard ratio for augmentation (sensitivity: aHR = 1.32; P <.059), which became insignificant between the 2 cohorts.


This study examined the real-world differences between GIR and GXR in the treatment of ADHD in children and adolescents using a nationwide claims database. Results showed that GIR users were more likely than GXR users to adjust therapy (discontinue, switch, or augment). In addition, patients treated with GIR had significantly lower adherence to their medication than GXR users. GIR users were also found to have significantly more inpatient and ED visits than GXR users. Even though GIR users incurred significantly lower drug costs compared with GXR  users, the difference was offset by significantly higher medical care costs. Thus, the total healthcare costs were comparable between the 2 groups.

The findings from this study were consistent with previous research examining the differences between immediate-release and extended-release neuropsychological medications, in which extended-release formulations were associated with greater adherence, efficacy, and effectiveness than their immediate-release counterparts.26,27 The higher rates of discontinuation, switching, and augmentation and greater utilization of ED and inpatient visits among GIR users are consistent with the possibility that patients may not have optimal treatment response compared with GXR users.23,28 Prior research has indicated that immediate-release nonstimulants such as clonidine immediate release and GIR are limited by quick absorption and clearance.29 Due to the high peak-to-trough fluctuations of GIR relative to the flatter, sustained plasma concentration profile of GXR, patients using GIR may experience lower efficacy (eg, ADHD symptom control), which could potentially lead to more follow-up medical visits in order to better control ADHD symptoms. This might explain the higher medical resource utilization among GIR patients. In addition, this study found better drug adherence among GXR-treated patients, which may be related to GXR’s less complicated dosing schedule (GXR once per day vs GIR 2 or 3 times per day, as was shown by the difference inDACON).15 As better adherence is associated with better clinical responses and less medical care utilization,30,31 the lower adherence rate with GIR could be another contributor to the observed higher urgent care utilization among its users.

Given that GIR and GXR have the same active moiety, decision makers may assume that GIR and GXR are interchangeable and consider the use of GIR instead of GXR to reduce drug costs. However, clinical evidence supporting GIR use in ADHD has been limited. The current study showed that the lower pharmacy costs associated with GIR use were offset by higher medical costs, resulting in comparable total healthcare costs. Results of this study, combined with prior evidence,12,15,29 indicate the need for further investigation of health outcomes associated with GIR’s off-label use in ADHD relative to GXR to assess thistreatment strategy’s relative value.

This study is subject to several limitations. First, although the study uses multiple regressions to control for the observed baseline characteristics, unobserved confounding, which is a common limitation in observational studies, might still impact the analysis. At baseline, it appeared that patients in the GIR cohort might have been more severely ill because they generally had a higher prevalence of comorbidities and utilized more resources than the GXR cohort. Adjusting for differences in observed baseline characteristics, including comorbidities, and the corresponding resource utilization and costs, might control for the difference in disease severity to a certain extent. However, the difference in clinical severity was unobserved. If this difference remained after controlling for the baseline variables in the model, the results could be biased. More information on clinical severity or symptoms might help improve the study, but only randomized, controlled studies can validly address the unobserved confounding issue. Second, because this study only examined data collected from commercial health plans, caution should be exercised in generalizing this study’s results to other populations. Lastly, only the first 6 months following treatment initiation were analyzed due to the recent entry of GXR. Further research with a longer time horizon in which treatment outcomes can be assessed is warranted to better compare the longterm impacts of GIR and GXR use.


After adjustment for observed baseline differences, this retrospective claims analysis found that GXR use by children and adolescents was associated with lower rates of therapy adjustment and fewer inpatient and ED visits compared with GIR use. Medical costs were higher among GIR users than GXR users, which offset the lower drug costs associated with GIR use and led to comparable total healthcare costs between the 2 groups. These findings could inform decision and policy makers by highlighting the tradeoffs associated with the use of GIR and GXR.

Author Affiliations: From Analysis Group, Inc (JX, TLH, HY, TS, EQW), Boston, MA; Shire Development LLC (VS, MHE, PH), Wayne, PA.

Funding Source: This research was funded by Shire Developmet LLC.

Author Disclosures: Drs Sikirica, Erder, and Hodgkins report employment with Shire Development LLC, as well as stock ownership in the company. Drs Xie, Yang, and Wu, Mr He, and Mr Samuelson report employment with the Analysis Group, Inc, which received funding from Shire Development Inc for the preparation of this manuscript.

Authorship Information: Concept and design (VS, JX, TL, MHE, TS, EQW); acquisition of data (VS, JX, TL, TS); analysis and interpretation of data (VS, JX, TL, PH, HY, TS, EQW); drafting of the manuscript (VS, TL, PH, TS); critical revision of the manuscript for important intellectual content (VS, JX, TL, MHE, PH, HY, TS, EQW); statistical analysis (TL, HY, TS); obtaining funding (VS, JX, EQW); administrative, technical, or logistic support (VS, JX, TL, MHE, PH, HY, TS, EQW); and supervision (VS, JX, MHE, PH, HY, EQW).

Address correspondence to: Vanja Sikirica, PharmD, MPH, Shire, 725 Chesterbrook Blvd, Wayne, PA 19087. E-mail:
1. Centers for Disease Control and Prevention. Increasing prevalence of parentreported attention-deficit/hyperactivity disorder among children—United States, 2003 and 2007. MMWR. 2010;59(44):1439-1443.

2. Spencer TJ, Biederman J, Mick E. Attention-deficit/hyperactivity disorder: diagnosis, lifespan, comorbidities, and neurobiology. J Pediatr Psychol. 2007;32(6):631-642.

3. Goksøyr PK, Nøttestad JA. The burden of untreated ADHD among adults: the role of stimulant medication. Addict Behav. 2008;33(2):342-346.

4. Adler LA. Epidemiology, impairments, and differential diagnosis in adult ADHD: introduction. CNS Spectr. 2008;13(8)(suppl 12):4-5.

5. Biederman J, Petty CR, Evans M, Small J, Faraone SV. How persistent is ADHD? a controlled 10-year follow-up study of boys with ADHD. Psychiatry Res. 2010; 177(3):299-304.

6. Doshi JA, Hodgkins P, Kale J, et al. Economic impact of childhood and adult attention-deficit/hyperactivity disorder in the United States. J Am Acad Child Adolesc Psychiatry. 2012;51(10):990-1002.

7. Birnbaum HG, Kessler RC, Lowe SW, et al. Costs of attention deficit-hyperactivity disorder (ADHD) in the US: excess costs of persons with ADHD and their family members in 2000. Curr Med Res Opin. 2005;21(2):195-206.

8. 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):1007-1022.

9. Banaschewski T, Roessner V, Dittmann RW, et al. Non-stimulant medications in the treatment of ADHD. Eur Child Adolesc Psychiatry. 2004;13(suppl 1):102-116.

10. Duong S, Chung K, Wigal SB. Metabolic, toxicological, and safety considerations for drugs used to treat ADHD. Expert Opin Drug Metab Toxicol. 2012;8(5): 543-552.

11. Arnsten AF, Jin LE. Guanfacine for the treatment of cognitive disorders: a century of discoveries at Yale. Yale J Biol Med. 2012;85(1):45-58.

12. Childress AC. Guanfacine extended release as adjunctive therapy to psychostimulants in children and adolescents with attention-deficit/hyperactivity disorder. Adv Ther. 2012;29(5):385-400.

13. Signorovitch J, Sikirica V, Erder MH, et al. Matching-adjusted indirect comparisons: a new tool for timely comparative effectiveness research. Value Health. 2012;15(6):940-947.

14. Signorovitch J, Erder MH, Xie J, et al. Comparative effectiveness research using matching-adjusted indirect comparison: an application to treatment with guanfacine extended release or atomoxetine in children with attention-deficit/ hyperactivity disorder and comorbid oppositional defiant disorder. Pharmacoepidemiol Drug Saf. 2012;21(suppl 2):130-137.

15. Strange BC. Once-daily treatment of ADHD with guanfacine: patient implications. Neuropsychiatr Dis Treat. 2008;4(3):499-506.

16. Posey DJ, McDougle CJ. Guanfacine and guanfacine extended release: treatment for ADHD and related disorders. CNS Drug Rev. 2007;13(4):465-474.

17. Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry. 2001;158(7):1067-1074.

18. Boellner SW, Pennick M, Fiske K, Lyne A, Shojaei A. Pharmacokinetics of a guanfacine extended-release formulation in children and adolescents with attention-deficit-hyperactivity disorder. Pharmacotherapy. 2007;27(9):1253-1262.

19. Vivek K, Fanda AK, Varshney S, et al. Extended release pharmaceutical compositions of guanfacine hydrochloride. US Patent Application 20110217373. September 8, 2011.

20. Humana Inc. Provider drug search results. Accessed September 25, 2012.

21. Aetna, Inc. Pharmacy clinical policy bulletins—Aetna non-Medicare prescription drug plan—attention deficit hyperactivity disorder (ADHD) agents. Accessed September 25, 2012.

22. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health. 2008;11(1):44-47.

23. Erder MH, Signorovitch JE, Setyawan J, et al. Identifying patient subgroups who benefit most from a treatment: using administrative claims data to uncover treatment heterogeneity. J Med Econ. 2012;15(6):1078-1087.

24. Rubino M, Summers KH, Puenpatom A, Fu C, Ohsfeldt RL, Ben-Joseph RH. A comparison of daily average consumption (DACON) of oxycodone and oxymorphone long-acting oral tablets. J Manag Care Pharm. 2011;17(5):367-376.

25. Bureau of Labor Statistics, US Department of Labor. Measuring the price change for medical care in the CPI. Accessed September 10, 2012.

26. Döpfner M, Gerber WD, Banaschewski T, et al. Comparative efficacy of oncea- day extended-release methylphenidate, two-times-daily immediate-release methylphenidate, and placebo in a laboratory school setting. Eur Child Adolesc Psychiatry. 2004;13(suppl 1):I93-I101.

27. Wilens TE, Gignac M, Swezey A, Monuteaux MC, Biederman J. Characteristics of adolescents and young adults with ADHD who divert or misuse their prescribed medications. J Am Acad Child Adolesc Psychiatry. 2006;45(4):408-414.

28. Christensen L, Sasané R, Hodgkins P, Harley C, Tetali S. Pharmacological treatment patterns among patients with attention-deficit/hyperactivity disorder: retrospective claims-based analysis of a managed care population. Curr Med Res Opin. 2010;26(4):977-989.

29. Sallee FR. The role of alpha2-adrenergic agonists in attention-deficit/hyperactivity disorder. Postgrad Med. 2010;122(5):78-87.

30. Al-Zakwani IS, Barron JJ, Bullano MF, Arcona S, Drury CJ, Cockerham TR. Analysis of healthcare utilization patterns and adherence in patients receiving typical and atypical antipsychotic medications. Curr Med Res Opin. 2003;19(7): 619-626.

31. Cantrell CR, Eaddy MT, Shah MB, Regan TS, Sokol MC. Methods for evaluating patient adherence to antidepressant therapy: a real-world comparison of adherence and economic outcomes. Med Care. 2006;44(4):300-303.
Copyright AJMC 2006-2018 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
Welcome the the new and improved, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up

Sign In

Not a member? Sign up now!