Comparison of the real-world safety of two different long-acting methylphenidate formulations (Medikinet^® MR and Concerta^®) – a Danish nationwide register-based cohort study

Attention-deficit/hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder, affecting 8% of children and adolescents and 3.1% of adults (1, 2). The disorder is characterized by symptoms of inattention, hyperactivity, and impulsivity that cause significant impairment in academic, social, and occupational functioning (3).

Stimulant medications, including methylphenidate (MPH) and amphetamines, are first-line pharmacotherapies for the treatment of ADHD in children, adolescents and adults (4,5,6). MPH is the most commonly prescribed ADHD medication in most countries, and its use has considerably increased in recent years (7,8,9).

The short-term safety profile of MPH is well established. Adverse events (AEs) commonly associated with MPH use include insomnia, anorexia, decreased weight, headache, and abdominal pain. MPH use is also associated with increases in blood pressure and pulse (10,11,12). AEs are usually mild and transient or can be managed by dose adjustments (5, 10). As ADHD is a chronic condition, patients require long-term treatment. However, the long-term safety of MPH is less well documented. Additionally, few head-to-head studies have directly compared the safety profiles of two or more MPH formulations (13). Furthermore, population-based register studies are needed to compare the real-world safety of different MPH formulations.

Several long-acting MPH formulations are available that provide efficacy throughout the day with once-daily dosing. These formulations use different drug delivery technologies, incorporating varying proportions of immediate-release (IR) and extended-release (ER) MPH, resulting in different pharmacokinetic and pharmacodynamic profiles (13). One long-acting MPH formulation is currently marketed in several countries, most commonly under the brand names Medikinet^® MR or Medikinet^® XL, for the treatment of ADHD in children aged 6 years and over and adults (14). The formulation consists of hard gelatin capsules containing 50% of the total MPH dose as IR pellets and the other 50% as enteric-coated ER pellets (15). The duration of action is 8 hours. Another long-acting MPH formulation (Concerta^®) is available in several countries for the treatment of pediatric and adult ADHD. Concerta^® uses the ‘Osmotic-Release Oral System’ (OROS) technology to provide an immediate release of 22% of the total MPH dose followed by a gradual release of the remaining 78% of the MPH dose throughout the day, resulting in a duration of action of 12 hours (16).

Two head-to-head randomized controlled trials (RCTs) compared the short-term efficacy and safety of Medikinet^® MR and Concerta^® in children and adolescents with ADHD. The two formulations showed generally comparable AE profiles (17, 18). Real-world evidence on the comparative safety profiles of the two formulations is not available.

The objective of this study was to compare the real-world safety profiles of Medikinet^® MR and Concerta^® using Danish register data. We conducted a comparative population-based cohort study to assess the risk of selected adverse outcomes in individuals with long-term exposure (i.e., ≥12 months) to either Medikinet^® MR or Concerta^®. These outcomes included, among others, AEs commonly associated with MPH use, such as insomnia, anorexia, and hypertension, as well as rare but significant AEs, such as sudden death and cerebral arteritis.

This is the first nationwide register-based cohort study that evaluated the risk of selected adverse outcomes in patients with long-term exposure to Medikinet^® MR or Concerta^®. The study found low and comparable numbers of adverse outcomes in both cohorts. The results were consistent in the sensitivity analysis excluding patients exposed to Concerta^® generics.

This is the first study to provide real-word evidence on the comparative safety profiles of Medikinet^® MR and Concerta^® during long-term use. Two short-term RCTs compared the efficacy and safety of the two formulations in children and adolescents with ADHD. The formulations showed generally comparable AE profiles, although one of the studies reported an increased frequency of insomnia and euphoria with Concerta^® compared to Medikinet^® MR (17, 18). No head-to-head RCTs have been performed on the long-term (i.e., ≥12 months) safety of Medikinet^® MR and Concerta^®.

Psychiatric disorders were the most common AEs in both cohorts. Psychiatric AEs commonly associated with MPH use include depression, anxiety, irritability, and aggression (14). The 2-year naturalistic, prospective ADDUCE study found that long-term use of MPH was not associated with a significantly increased risk of psychiatric symptoms in children and adolescents with ADHD (24). Overall, the available evidence suggests that long-term MPH use is associated with favorable outcomes regarding depression (25,26,27). Findings from a population-based cohort study from South Korea suggest that long-term MPH use may be associated with a decreased risk of depression, conduct disorders and oppositional defiant disorder (28). The existing evidence is not sufficient to conclude whether or not MPH increases the risk of psychotic symptoms. However, the available data indicate that psychotic symptoms may occur in 1.1% to 2.5% of children and adolescents with ADHD (25, 29). Two population-based cohort studies found that long-term treatment with MPH was associated with a significantly decreased risk of suicide attempt in pediatric and adult ADHD patients (30, 31). Fewer than five cases of essential hypertension were identified in each cohort. MPH treatment is associated with small increases in blood pressure and heart rate, although some patients may experience higher increases (24, 32, 33). Therefore, blood pressure and heart rate should be regularly monitored during MPH treatment (5).

No cases of sudden death were identified in the Medikinet^® MR cohort and fewer than five cases were identified in the Concerta^® cohort. Sudden cardiac death is rare in children and young adults without structural heart disease.

Studies investigating the association between MPH use and sudden death have provided mixed findings. Schellemann et al. found an increased risk of sudden death or ventricular arrhythmia (adjusted hazard ratio 1.84; 95% CI 1.33–2.55) in adult MPH users compared to non-users, while several cohort studies found no evidence of an increased risk of sudden cardiac death associated with the use of ADHD medications in children and adults (34, 35). A recent meta-analysis of 10 cohort studies found no association between ADHD medications and sudden death/arrhythmia, stroke, myocardial infarction and all-cause death, although some of these outcomes are associated with uncertainty due to wide confidence intervals (36).

Few cases of tics were identified in either cohort. Some studies have suggested an increased risk of tics with long-term MPH use (25). MPH should be used with caution in patients with tics or tic disorders (5, 14).

The number of mental and behavioral disorders due to psychoactive substance use was comparable between the cohorts. Substance use disorder (SUD) is a common comorbidity of ADHD (37). According to a recent meta-analysis, treatment with stimulant medication for ADHD neither increases nor decreases the risk of developing SUD (38). The presence of risk factors and a history of SUD should be considered before initiation of MPH treatment.

Overall, the study found low and comparable numbers of adverse outcomes in both cohorts, indicating a similar safety profile for the two medications. These findings may have positive implications for prescribing practices. The favorable safety profiles of the two medications may enhance physicians’ confidence in prescribing the studied treatments. Physicians may be more willing to switch a patient from one formulation to another if the initial treatment proves ineffective or the drug does not align with the patient’s preferences (e.g., onset of action, duration of action, sleep problems). This flexibility may lead to more individualized treatment plans.

The present study has several strengths. The main strength is the use of Danish nationwide registry data covering the entire Danish population, which reduces the risk of selection bias (20). In addition, recall bias is eliminated, since the data are collected prospectively rather than by interview or questionnaire. A limitation from this study is that we used retrieved prescriptions as a proxy for drug exposure. On the one hand, this may not accurately reflect actual drug intake, as patients may be non-adherent to treatment, which is not uncommon among those on long-term medications. Studies have shown that the average rates of non-adherence to medication in pediatric and adult patients with ADHD range from 15% to 87% (39). As our approach does not account for patient adherence, it may lead to an overestimation of exposure, which in turn may result in an underestimation of AEs. On the other hand, patients experiencing AEs are likely not only to be non-adherent but also to be receiving no further prescriptions, which in turn does not lead to an underestimation. Another limitation of this study is that the Danish National Patient Registry only contains information from hospitals, meaning our analysis is restricted to AEs recorded during a hospital contact (i.e., severe/serious AEs). Thus, our analysis does not include less severe AEs recorded and managed in primary care by general practitioners and specialists in private practice. Furthermore, while register studies are highly valuable for “hard” outcomes, such as cerebral arteritis and seizures, they are less reliable for AEs that do not typically receive a diagnostic code, such as priapism or non-organic sleep disorders. This limitation may impact the validity of the analysis for these types of AEs. Additionally, children are more likely to receive diagnostic codes for such AEs since they are usually followed in a hospital setting, where these AEs are more likely to be coded diagnostically. Given that the Concerta^® group includes a higher proportion of adult patients, this could lead to an underestimation of the actual risk in this group.

This is the first study to provide real-world evidence on the comparative safety profiles of Medikinet^® MR and Concerta^® during long-term use. The number of adverse outcomes was low and comparable in both cohorts, indicating a similar safety profile for the two formulations.