Effectiveness and safety of dexamphetamine sulfate (Attentin^®) in the routine treatment of children and adolescents with ADHD: results from a 12-month non-interventional study

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood, with an estimated worldwide prevalence of 7.2% in children ≤18 years (1). According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), ADHD is characterized by the core symptoms of inattention, hyperactivity and impulsivity that negatively impact social and academic/occupational functioning (2). The International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) refers to ADHD as Hyperkinetic Disorder and provides generally similar but stricter criteria for the diagnosis of the disorder (3).

Current practice guidelines recommend a comprehensive multimodal treatment approach for the management of ADHD (4-7). Stimulants, including methylphenidate (MPH) and amphetamines (AMP), are the most commonly used pharmacological treatment. Numerous randomized controlled trials (RCTs) and meta-analyses have demonstrated the efficacy and safety of stimulants for the treatment of ADHD in children and adolescents (8-12).

The exact mechanism of action of stimulants in humans with ADHD is not fully known, however, it is thought that both MPH and AMP increase levels of extracellular dopamine (DA) and norepinephrine (NE) in the synaptic cleft and thereby enhance noradrenergic and dopaminergic neurotransmission in the central nervous system (13). Both MPH and AMP inhibit the dopamine transporter (DAT) and norepinephrine transporter (NET) (14), resulting in increased extracellular DA and NE levels (13). In contrast to MPH, AMP also promotes the release of DA from the presynaptic neuron into the synaptic cleft (Supplementary Figure S1) (13, 15-17).

Various amphetamine products are currently marketed for the treatment of ADHD, including oral immediate-release and extended-release formulations containing different AMP salts and stereoisomers (18). Attentin/Amfexa/Tentin^® is an immediate-release tablet formulation of dexamphetamine sulfate that is available at doses of 5 mg, 10 mg and 20 mg (19). The product was first authorized in Germany in 2011 and has subsequently been approved in several further countries (Supplementary Table S1). For simplicity, the following sections refer to the product as Attentin^®.

Attentin^® is indicated as part of a comprehensive treatment program for ADHD in children and adolescents aged 6 to 17 years when response to previous methylphenidate treatment is considered clinically inadequate. A comprehensive treatment program typically includes psychological, educational and social measures. Diagnosis should be made according to DSM-5 criteria or the guidelines in ICD-10 and should be based on a comprehensive multidisciplinary evaluation of the patient. DEX is not indicated in all children with ADHD and the decision to use DEX must be based on a very thorough assessment of the severity and chronicity of the child’s symptoms in relation to the child’s age and potential for abuse, misuse or diversion. Treatment should be under the supervision of a specialist in childhood and/or adolescent behavioral disorders (19).

Careful dose titration is necessary at the start of treatment with DEX. Dose titration should be started at the lowest possible dose. The recommended starting daily dose is 5 mg once or twice daily (e.g. at breakfast and lunch), increasing if necessary by weekly increments of 5 mg in the daily dose according to tolerability and degree of efficacy observed. The regimen that achieves satisfactory symptom control with the lowest total daily dose should be employed. The maximum daily dose in children and adolescents usually is 20 mg, although doses of 40 mg may in rare cases be necessary for optimum titration (an overview of the dosing recommendations is given in Supplementary Figure S2) (19).

The pharmacokinetic properties of Attentin^® tablets were assessed in 18 healthy adults. Following the administration of one 5 mg tablet, average maximal plasma concentrations (C_max) of 11.5 ng/mL were achieved at a mean ± SD t_max of 1.5 ± 0.4 hours (Supplementary Figure S3) (19).

Several studies have demonstrated the superiority of DEX over placebo in improving core symptoms and functional outcomes in pediatric patients with ADHD. DEX was also shown to have equivalent efficacy compared to other stimulants (20-26). A network meta-analysis that assessed the comparative efficacy and tolerability of oral ADHD medications supports MPH in children and adolescents, and amphetamines in adults, as first-choice medications for short-term ADHD treatment (27). A review of response data from studies directly comparing MPH- and AMP-based stimulants found that 71% of patients responded to MPH, 68% responded to AMP, and 91% responded to either type of stimulant (28). These data indicate that, although the response rates to MPH and AMP are similar in the overall population, individual response to either class of stimulant may vary, i.e. some individuals respond better to MPH and some respond better to AMP. Thus, if an ADHD patient does not respond to or does not tolerate one type of stimulant, the other type of stimulant should be tried.

The safety profiles of different stimulant classes and formulations are generally comparable (18). A recent Cochrane review found that the most common adverse events (AEs) reported in RCTs of pediatric ADHD patients treated with AMP products included decreased appetite, insomnia/trouble sleeping, abdominal pain, nausea/vomiting, headaches, and anxiety (9). Most AEs are mild and/or temporary and can be managed by the clinician through dose and timing adjustments (29). In most cases, medication discontinuation is not necessary (30). Serious side effects are rare and disappear when the dose is reduced or treatment is discontinued (29).

RCTs are considered the gold standard of evidence-based medicine, providing the highest level of evidence on clinical efficacy and safety of therapeutic interventions. However, most RCTs have strict inclusion criteria, meaning that the trial populations are highly homogeneous and often not representative of the prevailing patient population in a real-world community-based setting. Real-world studies can complement the results from RCTs by providing data on the treatment effectiveness in heterogeneous patient populations encountered in routine clinical practice (31).

The non-interventional study (NIS) ATTENTION (Attentin^® in children and adolescents with ADHD – a non-interventional study) investigated the real-world effectiveness and safety of Attentin^® in children and adolescents with ADHD.

RCTs are considered the gold standard of evidence-based medicine; however, RCTs usually have strict enrolment criteria and treatment protocols, meaning that the patient samples and treatment conditions are often not representative of real-world clinical practice. In contrast, observational, non-interventional studies provide data on the effectiveness and tolerability of medications in routine clinical practice. The ATTENTION study was a prospective, observational, non-interventional study that investigated the effectiveness and safety of DEX treatment under routine conditions in pediatric ADHD patients with a clinically inadequate response to previous MPH treatment. DEX treatment significantly improved ADHD symptoms over the whole study period. The mean ADHD-RS-IV total score change from baseline to the first follow-up visit after approx. 6 months (primary endpoint) was -11.9 (27.1 vs. 13.4, p < .001). Significant reductions in ADHD-RS-IV total scores were observed in the titration phase and were maintained up to the second follow-up visit after approx. 12 months of DEX treatment, indicating that the therapeutic effectiveness of DEX is maintained during long-term treatment in routine clinical practice. These findings are in line with results from a long-term, placebo-controlled study conducted by Gillberg and colleagues that showed sustained efficacy of amphetamines in children with ADHD over a treatment period of 15 months (25). Furthermore, beneficial effects of DEX were observed on both ADHD-RS-IV subscales (‘hyperactivity/impulsivity’ and ‘inattention’) and in both children and adolescents. Patients with more severe ADHD symptoms at baseline appear to benefit the most from DEX treatment.

The study population consisted of patients with a clinically inadequate response to MPH. A high response rate was observed in the study, with 78.1% of patients responding to DEX. These data confirm findings from other studies that have shown that some individuals respond preferentially to MPH whereas others respond preferentially to DEX (20, 21, 26, 28), indicating that a trial of both MPH and DEX may increase the probability for a favorable response and optimal response strength for an individual patient. Therefore, in children with an unsatisfactory response to MPH, a trial of DEX should be considered. The response to DEX was not dose-dependent, which confirms findings from clinical trials and clinical experience that indicate that the dose needs to be individually titrated for each patient.

Patients in this study reported an average onset of action of 36.2 minutes and an average duration of action of 6.5 hours after intake of the first dose of DEX in the morning. These findings are in line with results from earlier studies that reported a rapid onset of action of DEX in the 30 to 60 min range (35) and a duration of action in the 4 to 6 hour range (35-38).

DEX was administered as a single dose in the morning by 58.9% of patients, suggesting that the reported duration of the therapeutic effect is sufficient for most patients, while 38.8% of patients administered two doses per day, presumably to extend the duration of action to the late afternoon and evening. Administering DEX twice or more daily is in line with the Attentin^® label, which recommends that the times at which the doses are administered should be selected to provide the best effect when it is most needed to combat school and social behavioral difficulties (19). Current practice guidelines also note that immediate-release formulations of stimulants may be more suitable than extended-release formulations if flexible dosing regimens are needed (7).

Overall, “insufficient efficacy” was reported as a reason for switching to DEX for 79.1% of patients, while “insufficient tolerability” was reported for 18.0% of patients. The mean total daily MPH dose was 27.5 mg (ranging from 5.0 to 80.0 mg). One possible explanation for these findings is that the recommended up-titration to the maximum tolerable dose of MPH, as recommended by current practice guidelines (4), was not performed in all patients. Current ADHD treatment guidelines recommend optimizing MPH dosage to the patients’ individual needs (39). Clinicians should initiate treatment at a low dose and slowly increase the dose until maximum benefit with minimum adverse effects is achieved. These recommendations are based on studies that have shown a substantial interindividual variability in clinical response to MPH. It is also possible that patients who reported “insufficient tolerability” as reason for switching to DEX experienced intolerable ADRs, such as insomnia or weight loss, that precluded any further up-titration of MPH.

DEX was generally well tolerated during the course of the study, and no new safety findings were identified. The most commonly reported ADRs to DEX were decreased appetite and depressed mood. Mean BMI z-scores significantly decreased during the study, however, the changes in BMI z-scores were not large enough to be clinically meaningful. A review of longitudinal studies investigating growth effects of stimulant treatment in children with ADHD found that stimulants led to modest reductions in expected height and weight, although these effects attenuated over time (40). More clinical studies are needed to elucidate the impact of stimulant treatment on final height and weight. Current practice guidelines recommend regular monitoring of weight and height in children and adolescents receiving stimulant treatment (4, 6-7).

A statistically significant increase in mean systolic and diastolic blood pressure was observed during the study, whereas no significant changes in heart rate were observed. Small but significant increases in blood pressure and heart rate are well documented adverse effects of stimulant treatment in children and adults (27, 41-43). In a meta-analysis of cardiovascular effects of stimulants in adults, the mean increase in heart rate was 5.7 beats/min and the mean increase in systolic blood pressure was 2.0 mmHg (43). Generally small increases in blood pressure (≤ 5 mmHg) and heart rate (≤ 10 beats/min) have also been observed in children and adolescents treated with stimulants (44). However, a recent meta-analysis found no association between ADHD medications and risk of sudden death/arrhythmia, stroke, myocardial infarction and all-cause death, although some of the confidence intervals for the pooled risk ratios did not exclude modest elevated risks (45). Cardiovascular status, including blood pressure and heart rate, should be carefully and regularly monitored during stimulant treatment (4-6).

The findings of this study should be interpreted in light of several limitations. The main limitation is the uncontrolled, open-label design, which may have introduced bias in the estimation of treatment effects. Furthermore, the small sample size may limit the validity and generalizability of study results. Another limitation is the potential for recall bias, as the data regarding previous ADHD/MPH treatment (including data on effectiveness and safety) were reported retrospectively by the patient at the baseline visit. Since the study only included patients with a clinically inadequate response to previous MPH treatment, the study results may not be generalized to a broader population of ADHD patients that includes e.g. treatment-naïve patients. Conversely, the patient population in this study is consistent with the population for which Attentin^® is indicated according to the approved label, thus, the study population is likely similar to the patient population that is prescribed Attentin^® in routine clinical practice. ADRs were not assessed in a structured fashion in this study, for example by using an adverse event checklist or questionnaire. This was an observational study that aimed to gain insights into the use of DEX in routine clinical practice; thus, additional diagnosis or monitoring procedures for the patient beyond the usual medical practice were not included in the observational study plan. Therefore, a specific adverse event questionnaire, that may not be a part of routine practice, was not employed in this study. Unsystematic documentation of ADRs through general inquiry prompts has several drawbacks, including reliance on patient/parent recall and potential misclassification of adverse events by the investigator, especially behavioral changes. Since no structured method was used for the collection of ADRs in this study, the incidence of ADRs may have been underestimated. Nevertheless, the ADRs observed in this study are in line with the known safety profile of stimulant medications.

Future research on the treatment of ADHD should focus on providing insights into the long-term effects of stimulants, using randomized withdrawal trials, population-based studies with self-controlled methodologies and longitudinal follow-up studies (46).

The study shows that Attentin^® is an effective and well-tolerated long-term treatment option for pediatric ADHD patients with a clinically inadequate response to MPH treatment. The results of this real-world study conducted in a heterogeneous patient population under naturalistic treatment conditions complement the findings from randomized controlled trials of DEX in children and adolescents with ADHD. Furthermore, the high response rate achieved in this study confirms the findings from other studies that have shown that some individuals respond preferentially to MPH whereas others respond preferentially to DEX. Thus, in ADHD patients who do not respond to or do not tolerate MPH, treatment with DEX should be tried.