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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.
Objectives: To compare treatment patterns, resource utilization, and healthcare costs for guanfacine immediate release (GIR) versus guanfacine extended release (GXR) in children and adolescents with attention-defi cit/hyperactivity disorder (ADHD).

Study Design: Retrospective claims analysis using the Truven Health MarketScan database.

Methods: Patients with ADHD aged 6 to17 years who initiated therapy with GIR or GXR between November 2009 and December 2010 were selected. Therapy adjustment rates (discontinuation, switching, augmentation), medication possession ratios (MPRs), resource utilization, and healthcare costs (2010 dollars) during the 6 months after therapy initiation were compared between GIR and GXR cohorts, using multivariate regressions controlling for baseline characteristics during the 6 months before therapy initiation.

Results: During the 6-month study period, GIR users (n = 743) had significantly higher rates of treatment discontinuation (adjusted hazard ratio [aHR] = 1.79; P <.001), switching (aHR = 2.32; P <.001), and augmentation (aHR = 1.55; P = .003) and signifi cantly lower MPRs (0.50 vs 0.64; P <.001) than GXR users (n = 2344). GIR users had signifi cantly more frequent all-cause inpatient admissions (P = .022) and emergency department visits (P = .016). GIR users incurred significantly lower all-cause pharmacy costs (P <.001) but significantly higher medical costs (P = .009), resulting in no significant difference in total all-cause healthcare costs (P = .068) between the 2 groups.

Conclusions: After adjustment, GIR users had significantly higher therapy adjustment rates, lower MPRs, and greater resource  utilization than GXR users. Total all-cause healthcare costs were comparable between the 2 groups.

Am J Pharm Benefits. 2013;5(4):e85-e94
Children and adolescents with attention-defi cit/hyperacti vity disorder (ADHD) treated with guanfacine immediate-release (GIR) had significantly higher resource use than those treated with guanfacine extended-release (GXR):
  •  Significantly higher therapy adjustment rates and signifi cantly higher resource utilization.

  • While drug costs were lower for GIR users, they were offset by higher medical costs; total healthcare costs were comparable between the 2 groups.

  • Further investigation is warranted on clinical outcomes associated with GIR’s off-label use in ADHD relative to GXR.
Attention-deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed pediatric psychiatric disorder in the United States, affecting about 7.2% of children and adolescents.1 The core symptoms of ADHD include hyperactivity, impulsivity, and inattention.2 If untreated, ADHD can delay social and academic development, with symptoms and dysfunction persisting into adulthood in approximately 70% of patients.3-5 In addition, children and adolescents with ADHD are likely to have mental health comorbidities.2 Attention-defi cit/hyperactivity disorder poses a substantial economic burden, with estimated annual societal costs of $143 to $266 billion (2010 dollars) in the United States.6 Furthermore, ADHD patients incur excess costs from treating mental health comorbidities that are commonly associated with ADHD.7

According to guidelines from the American Academy of Pediatrics, a school-aged child or adolescent diagnosed with ADHD should be treated with behavioral therapy and/or a stimulant as the fi rst-line medication.8 Although stimulants are the most frequently prescribed medications for ADHD up to 30% of patients using stimulants are intolerant to treatment or have an inadequate response.9 For these patients, a nonstimulant medication may be used.9 Nonstimulants approved by the US Food and Drug Administration (FDA) for ADHD treatment include atomoxetine, clonidine extended release, and guanfacine extended release (GXR).10

Guanfacine is a centrally acting slective alpha-2A adrenoceptor agonist that has been shown to improve prefrontal cortex neuronal firing and strengthen working memory in primates.11 This pharmacologic action is the basis for treating human prefrontal cortex–related cognitive disorders.11 Guanfacine extended release is used as monotherapy or adjunctive therapy to stimulants for ADHD treatment in children and adolescents.12 It appears to be more efficacious than atomoxetine, a commonly used nonstimulant, at the target dose in indirect comparison studies.13,14

Guanfacine is also marketed in an immediate-release formulation in the United States. Guanfacine immediate release (GIR) was approved by the FDA in 1986 for hypertension treatment only.15 However, its off-label use to treat psychiatric disorders, including ADHD, is common.11,16 Although GIR has the same active moiety as GXR, there is limited clinical evidence  supporting GIR use in the treatment of ADHD. Only 1 small (n = 34) placebo-controlled trial has been conducted to evaluate GIR’s efficacy and safety in children with concomitant tic disorders and ADHD.15,17

The 2 formulations of guanfacine have distinct pharmacokinetic profi les and dosing requirements.15 While GIR is metabolized quickly in children,11,16,18 GXR is synthesized with rate-controlling polymers and organic acids that lead to a prolonged half-life.19 Despite differences between GIR and GXR, payers and other decision makers (parents/caregivers) may treat the 2 drugs equally. Some payers who reimburse GXR may require a step-edit with GIR or a prior authorization prior to use of GXR.20,21 This policy assumes that GIR and GXR are reasonable substitutes in ADHD treatment, but this assumption needs to be tested in terms of efficacy, tolerability profiles, usage patterns, and economic outcomes.

To date, no study has directly compared the impact of GIR use versus GXR use among ADHD patients. To better understand the real-world differences between the 2 drugs with respect to their impact on patients, this retrospective cohort study compared the treatment patterns, resource utilization, and healthcare costs associated with GIR therapy versus GXR therapy in patients with ADHD.


Data Source

Data were extracted from the Truven Health MarketScan Commercial Claims & Encounters database for the period of 2009 to 2010. The database contains de-identified enrollment data and inpatient and outpatient medical and outpatient pharmacy claims from large employers and health plans across the United States.

Sample Selection

The study sample consisted of ADHD patients who initiated therapy with GIR or GXR from November 2009 to December 2010 (GXR was launched in November 2009). The first fill of either drug during this period was defi ned as the index drug, and the date of the fill was defi ned as the index date. The 6 months before and the 6 months after the index date were defi ned as thepreindex period and the study period, respectively. Patients were further required to meet the following criteria: (1) to have at least 1 primary diagnosis of ADHD, identified by International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 314.00 and 314.01, during the preindex period; (2) to be aged 6 to 17 years as of the index date; and (3) to have continuous eligibility during the preindex and study periods. Patients were excluded if they used GIR or GXR during the preindex period or were diagnosed with hypertension (ICD-9-CM codes 401.xx, 459.3x, 642.3x, 643.3x, and 997.91) during the preindex or study periods. Patients were allowed to take other ADHD medications during the preindex period.

Study Outcomes

Outcomes categories measured during the 6-month study period included treatment patterns, resource utilization, and healthcare costs.

Treatment Patterns. Treatment patterns included medication possession ratio (MPR), daily average consumption (DACON), discontinuation, switching, and augmentation. Defi nitions of treatment patterns used in this study are in concordance with International Society for Pharmacoeconomics and Outcomes Research guidelines22 and have been used previously.23,24 Medication possession ratio, defi ned as the total number of days of drug supply divided by the total number of days in the study period (ie, 6 months), was used to measure adherence to the index drug. Daily average consumption was defi ned as the quantity of pills supplied during the study period divided by total number of days supplied within the study period.

Discontinuation of the index drug was defined as a gap of more than 30 days since the last day of supply of the previous index drug fill. Switching was defined as the initiation of a new ADHD medication not used during the preindex period within 30 days before or after the discontinuation of the index drug. The switched-to ADHD medication had to be taken for 30 days or longer. Augmentation was defined as the initiation of a new ADHD medication not used during the preindex period before the discontinuation of the index drug. The augmenting drug must have at least 30 days of supply overlap with the index drug. The ADHD medications considered for switching and augmentation included the 2 comparators, GIR and GXR, and other FDA-approved ADHD medications (stimulants, atomoxetine, clonidine extended release).

Sensitivity analyses for switching and augmentation were conducted by expanding the list to include other medications that are not FDA approved for treatment of ADHD, but are sometimes used for ADHD treatment: clonidine immediate release, bupropion, typical and atypical antipsychotics, selective serotonin reuptake inhibitors, and tricyclic antidepressants. In addition,switching required the new ADHD medication be taken for 60 days or longer, and augmentation required thaugmenting drug to have 60 days or more of supply overlap with the index drug.

Resource Utilization. Types of resource utilization measured during the study period included inpatient, emergency department (ED), and outpatient visits. The mean numbers of inpatient, ED, and outpatient visits per patient were calculated for each cohort. Both all-cause utilization and utilization related to mental health (MH) were measured. Utilization related to MH was identified based on claims associated with a primary diagnosis of an MH condition (ICD-9-CM codes 290-319).

Healthcare Costs. Healthcare costs measured during the study period included medical service and prescription drug costs. Both all-cause and MH-related costs were estimated. Mental health–related medical costs were defined as costs associated with an MH-related utilization, and MH-related drug costs were identified using therapeutic class codes. Cost analyses were conducted from a third-party payer’s perspective (ie, the amount paid by third-party payers). Costs were inflated to December 2010 US dollars using the medical component of the Consumer Price Index.25

Statistical Analyses

Baseline characteristics were compared between the GIR and GXR cohorts using c2 tests for categorical variables and Wilcoxon rank sum tests for continuous variables. Baseline characteristics include demographics, baseline medications and psychotherapies, comorbidities, resource utilizations, healthcare costs, and use of the index therapy as combination therapy or monotherapy. Combination therapy with the index drug was defined as fills of the same nonindex ADHD drug during the preindex period and within 30 days after GIR or GXR initiation; the nonindex drug must have 30 days or more of overlapping use with the index drug.

Rates of therapy discontinuation, switching, and augmentation during the study period were estimated using Kaplan-Meier survival analysis and compared descriptively between the 2 cohorts using log-rank tests. The hazard ratios of discontinuation, switching, and augmentation between GIR and GXR users were calculated using multivariate Cox proportional hazards models. Medication possession ratio and DACON were compared between GIR and GXR users by using generalized linear models.

The all-cause and MH-related incidence rate ratios for each resource utilization category, which measured the relative frequency of resource use for GIR users compared with GXR users, were calculated using univariate and multivariate negative binomial models.

Healthcare costs corresponding to each resource utilization category were compared descriptively between GIR and GXR users using Wilcoxon rank sum tests. In the multivariate models, cost outcomes for which 95% or more of patients had nonzero values were compared using generalized linear models with gamma distribution and log link. The cost outcomes for which less than 95% of patients had a nonzero value were estimated using 2-part models. Adjusted cost differences between the 2 groups were calculated. P values for the 2-part models were estimated via bootstrapping (500 iterations of sampling with replacement).

Multivariate models adjusted for baseline variables that were statistically different between the 2 cohorts. Specifically, baseline characteristics that were adjusted for included age, sex, region, healthcare provider type, use of index drug in combination therapy, use of baseline treatments, MH comorbidities, and the corresponding baseline utilization or cost.

Sensitivity analyses were performed for all multivariate regression analyses, where use of the index drug in combination therapy was redefined as at least 1 nonindex ADHD drug fill during the preindex period, coupled with any nonindex ADHD drug fill within 30 days of the index date. The nonindex ADHD drug used in the study period must have 30 days or more of supply overlap with the index drug.

All analyses were performed using SAS 9.2 (SAS Institute, Cary, North Carolina). The significance for all statistical tests was assessed based on a type I error of .05.

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