Abstract
OBJECTIVE:
In Canada, novo-methylphenidate extended-release capsules (Novo-MPH ER-C, Novopharm Limited, Canada) was approved as being bioequivalent to a current first-line treatment for attention deficit hyperactivity disorder (ADHD), CONCERTA (OROS-MPH, Janssen Inc, Canada). The present practice review was undertaken to determine whether bioequivalence of these products translates into therapeutic equivalence.
METHODS:
The present study was a retrospective, single-centre, observational review of consecutive paediatric ADHD patients prescribed OROS-MPH during a seven-month period.
RESULTS:
Of the 53 patients who had been switched to the bioequivalent product, 87% destabilized and 43% indicated a shorter duration of effect. In comparison, of those who never tried the second entry medication, only 26% destabilized. Qualitative data indicated differences with regard to side effects, efficacy and duration of effect.
CONCLUSIONS:
The present retrospective study indicated that Novo-MPH ER-C is not therapeutically equivalent to OROS-MPH. Once an individual with ADHD is effectively managed, disruption of their treatment should be avoided.
Keywords: Attention deficit hyperactivity disorder; Bioequivalence; Complex modified-release formulation; Methylphenidate; Pharmacokinetics, Therapeutic equivalence
Abstract
OBJECTIF :
Au Canada, on a approuvé la bioéquivalence des capsules de novo-méthylphénidate à libération prolongée (Novo-MPH ER-C, Novopharm Limitée, Canada) avec le CONCERTA (OROS-MPH, Janssen Inc., Canada), un traitement de première ligne du trouble de déficit de l’attention avec hyperactivité (TDAH). Les chercheurs ont entrepris la présente analyse de la pratique pour déterminer si la bioéquivalence de ces produits se traduit par une équivalence thérapeutique.
MÉTHODOLOGIE :
La présente étude était une analyse d’observation rétrospective monocentrique menée auprès de patients pédiatriques consécutifs ayant un TDAH à qui on avait prescrit de l’OROS-MPH pendant une période de sept mois.
RÉSULTATS :
Sur les 53 patients qu’on avait transférés au produit bioéquivalent, 87 % ont vu leur état se déstabiliser et 43 % ont indiqué que le produit faisait effet pendant une période plus courte. L’état de seulement 26 % de ceux qui n’avaient jamais essayé le deuxième médicament s’est déstabilisé. Des données qualitatives faisaient état de différences en matière d’effets secondaires, d’efficacité et de durée de l’effet.
CONCLUSIONS :
D’après la présente étude rétrospective, le Novo-MPH ER-C n’est pas un équivalent thérapeutique de l’OROS-MPH. Lorsque la prise en charge d’une personne ayant un TDAH est efficace, il faut éviter de perturber son traitement.
Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder in the paediatric population, affecting 5% of children and adolescents (1). Arising from the core symptoms of inattention, hyperactivity and impulsivity, this disorder has a broad functional impact on the lives of those it affects and their families. It impacts every aspect of their lives including impairment in academic achievement, social functioning and employment stability (2–6).
It has been well documented that stimulant medication not only treats the core symptoms of ADHD (7) but also results in improvement in cognitive performance, self-esteem, family functioning, academic focus, social adjustment and emotional dysregulation (7–11). Most clinicians treating ADHD find that such improvement can take time to achieve. The time from diagnosis to the point of implementation of an effective treatment regimen can take months to years. Once a person with ADHD is effectively managed, disruption of their treatment can have far-reaching implications; similar to the disorder itself. Therefore, for optimal management of this medical condition, it is important to minimize disruption of effective treatment.
OROS-MPH (CONCERTA, Janssen Inc, Canada) is one such stimulant medication used to tread ADHD. It is a once-a-day, long-acting methylphenidate (MPH) capsule with an immediate-release (IR) coating. The initial maximum concentrations are comparable with IR formulations, followed by a gradual ascending plasma-concentration time profile (12,13). In April 2010, novo-methylphenidate ER-C extended-release tablets (Novo-MPH ER-C, Novopharm Limited, Canada) met Health Canada requirements for bioequivalence, and was listed as interchangeable in the Ontario Drug Benefit Formulary/Comparative Drug Index. Pharmacists in Ontario were then authorized to switch from OROS-MPH without consulting the prescriber. Since 2012, this product has been marketed under the name teva-methylphenidate ER-C (Teva, Canada). In Canada, current regulatory guidelines for determining bioequivalence rely on measurement of the rate and extent of drug absorption, which include the maximum concentration (Cmax) and area under the curve (AUC) (14,15). Bioequivalence is inferred if the 90% CI for the ratio of geometric means of the AUCs of the test drug and reference drug are completely in the range of 0.80 to 1.25, and for Cmax, if the point estimate of the ratio is within the same range (16).
It is generally assumed that the bioequivalence of two drug products infers therapeutic equivalence. Therapeutic equivalence, for the purpose of the present study, was defined as having the same therapeutic or clinical effect. There have been recent discussions regarding a number of mechanical release molecules that calls this assumption into question (16–19). This is due to the strong pharmacokinetic-pharmacodynamic relationship of such molecules. It has been shown in vitro and in vivo that dissolution and plasma concentration time profiles for Novo-MPH ER-C differ from those for OROS-MPH (Figure 1) (16). Subsequent to the bioequivalence ruling, Fallu and Dabouz (20) presented a randomized, double-blinded, cross-over single-centre study to evaluate the clinical difference between OROS-MPH and Novo-MPH ER-C. This prospective study also showed a statistically significant difference in the effectiveness and side effects between the use of OROS-MPH and Novo-MPH ER-C in an adult ADHD population. At the same time, the present review of a paediatric practice was undertaken to evaluate whether the bioequivalence of these two products would also translate into therapeutic equivalence in the paediatric population. The hypothesis was that, in the case of OROS-MPH and Novo-MPH ER-C, bioequivalence does not translate into therapeutic equivalence.
Figure 1).
In vivo mean plasma concentration-time dose-corrected curves of d-methylphenidate (MPH) following oral administration of 54 mg OROS-MPH (Janssen, Inc, Canada), 54 mg Novo-MPH-extended release capsule (Novopharm Limited, Canada) and 60 mg MPH-SR. The plasma concentration-time curve for 60 mg MPH-sustained release was dose-corrected by multiplying concentrations by a coefficient of 54/60. Reproduced with permission from reference 16
METHODS
The present study was a retrospective observational review of consecutive paediatric ADHD patients five to 18 years of age, who were prescribed OROS-MPH from May 1 to November 27, 2010. Patients were included if they met the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria for ADHD (any type) diagnosed by history, psychiatric examination, questionnaires completed by parents and school, the Swanson, Nolan and Pelham (SNAP) behavioural rating scale, and examination of report cards. Patients also had to be controlled on a stable dose of OROS-MPH for at least one month without significant adverse experiences. The final inclusion criterion was that patients were able to be monitored regularly in clinic or were available to be contacted by telephone. Patients were excluded if it was not possible, from the clinical chart, to determine whether the patient had been switched to a generic medication and the parent/legal guardian was unable to be contacted by telephone.
At follow-up visits or by telephone, patients and parents/guardians were, as per usual clinic protocol, interviewed with respect to their function and ADHD symptom control. Subsequently, they were asked whether they were taking generic or brand name Concerta. If the parent/patient did not know, and with their permission, clinic staff telephoned the pharmacy to determine what preparation of MPH they were actually dispensed.
Data extracted included demographics, medication information (dosage, if switch occurred), general treatment information (ie, change in medication or dosage, comorbid diagnoses, additional medications, and comments by patients, parents and legal guardians regarding the effects of medication before and after the medication switch). Quantitative and qualitative responses were categorized.
The primary outcome measure was the proportion of patients who destabilized. Destabilization was defined clinically as a change in symptoms and/or function resulting from a change in ADHD medication or dosage. The secondary outcome was a qualitative assessment of the effects of the switch. Ten months after the initial analysis, follow-up was subsequently conducted on two subpopulations. The first subpopulation examined the outcome of patients who destabilized and did not immediately restabilize when reinstated on OROS-MPH. The second subpopulation examined the outcome of patients who initially found Novo-MPH ER-C to be equivalent to OROS-MPH.
Statistical analysis
Data analysis was performed using SPSS version 16.0 (IBM Corporation, USA). Categorical data were compared using Fisher’s exact tests and continuous variables were compared using the two-tailed Student’s t test or the Mann-Whitney U test. Statistical significance was set a priori at alpha = 0.05.
RESULTS
The study population consisted of 162 patients who were prescribed and adequately controlled on OROS-MPH. Nine patients were excluded because it was not known whether they had received Novo-MPH ER-C. Of the remaining 153 patients, 53 were switched to Novo-MPH ER-C and 100 remained on OROS-MPH. A comparison of the demographics between the two groups is shown in Table 1. The only significant difference between the two groups was the duration patients were prescribed OROS-MPH before being switched to Novo-MPH ER-C. The duration of OROS-MPH use before switch (months) for those who remained on OROS-MPH was 15.3±21.5 versus 22.5±17.0 (P=0.024). One possible explanation for this is that patients who are stable on their current treatment protocol are seen less frequently in clinic. As a result, there would have been more opportunity (more months) for the medication that is renewed monthly to be switched by the pharmacist from OROS-MPH to Novo-MPH ER-C.
TABLE 1.
| OROS-MPH (Concerta) (n=100) | Novo-MPH ER-C (n=53) | P | |
|---|---|---|---|
| Age, years | 0.329 | ||
| Mean ± SD | 10.9±3.1 | 11.3±2.6 | |
| Median | 11 | 11 | |
| Range | 5–17 | 5–16 | |
| Sex, n (%) | 0.661 | ||
| Male | 83 (83) | 42 (79) | |
| Female | 17 (17) | 11 (21) | |
| Dose, mg | 0.168 | ||
| Mean ± SD | 48.8±17.3 | 53.0±18.1 | |
| Median | 54.0 | 54.0 | |
| Range | 18.0–90.0 | 27.0–108.0 | |
| Other behavioural diagnoses, n (%) | 41 (41) | 29 (55) | 0.126 |
| Concomitant behaviour-related medications, patients, n (%) | 29 (29) | 16 (30) | >0.999 |
| Duration of most recent dose, months, mean ± SD | 10.1±15.7 | 10.0±10.7 | 0.923 |
| Duration of OROS-MPH before switch, months, mean ± SD | 15.3±21.5 | 22.5±17.0 | 0.024 |
Janssen Inc, Canada;
Novopharm Limited, Canada. MPH Methylphenidate; ER-C Extended release capsule
Primary outcome
Forty-six (87%) patients destabilized with the switch from OROS-MPH to Novo-MPH ER-C, whereas only 26 (26%) patients who remained on OROS-MPH experienced destabilization (P<0.001). Of the 46 patients who destabilized when switched to Novo-MPH ER-C, 21 (43%) reported a shorter duration of action and 36 (78%) eventually restabilized on OROS-MPH. Ten patients who were switched to Novo-MPH ER-C did not restabilize immediately on restarting OROS-MPH. In this group, seven required a change in medication to restabilize, two required an increase in dosage and one required intensive nonpharmacological intervention in the form of placement in a classroom for children with behavioural difficulties. Of the 26 patients who destabilized despite remaining on OROS-MPH, 14 (54%) required an increase in dosage and 12 (46%) required a change in medication.
Secondary outcome
A review of the qualitative comments made by patients and parents organized the comments into three main groups: efficacy, side effects and duration of action. With respect to efficacy, it was reported that Novo-MPH ER-C did not appear to be as effective as OROS-MPH. Comments included “it feels like not taking the medication at all”, the patient was “completely destabilized” and “bouncing off the walls”. When reporting side effects, patients and parents/guardians reported different side effects on Novo-MPH ER-C including dizziness, eating more, not sleeping well and anger. These differed compared with the side effects previously experienced by the same patients while on OROS-MPH. Finally, the effects of Novo-MPH ER-C were reported to diminish faster than OROS-MPH, with patients/parents consistently reporting 7 h to 8 h of effect; in some cases, patients required an additional dose of IR MPH in the late afternoon to ensure adequate control of ADHD symptoms in the evening hours. There were no spontaneously submitted positive comments about Novo-MPH ER-C.
Follow-up
Of the 22% (n=10) of patients who did not immediately restabilize when switched back from Novo-MPH ER-C to OROS-MPH, 10 months later, 10% were stable on the same dose of OROS-MPH, 20% were stable on a different dose of OROS-MPH, 10% were stable on the same dose of OROS-MPH with adjunct clonidine therapy, 10% were stable on a different medication, 30% were still trying to re-stabilize and 20% were lost to follow-up. Also, 30% of these patients tried a different medication but returned to using OROS-MPH. Of the seven patients who did not initially notice a difference on Novo-MPH ER-C, five returned to OROS-MPH within 10 months. Three pateints switched back to OROS-MPH because Novo-MPH ER-C was not working as well, one remained on Novo-MPH ER-C and one was no longer taking medication. Hence, over the course of the review, 92% of patients believed that Novo-MPH ER-C was not equivalent to OROS-MPH.
DISCUSSION
Based on in vivo and in vitro pharmacokinetic studies, there is evidence that various once-daily MPH formulations have differing concentration patterns (16,21–23). Current regulatory requirements rely on Cmax and AUC to deem two products bioequivalent. It has been suggested, however, that this may not translate into therapeutic equivalence. Shram et al (16) showed that the in vivo pharmacokinetic profiles of OROS-MPH and Novo-MPH ER-C were quite different and proposed that if partial AUC was included as a criterion for bioequivalence, these two products would not be considered bioequivalent. The present study examined whether OROS-MPH and Novo-MPH ER-C yielded different clinical responses (despite having been deemed bioequivalent by Health Canada) in a paediatric clinical setting, with the aim of addressing the question of therapeutic equivalence.
The present study found that 87% of patients who were switched from OROS-MPH to Novo-MPH ER-C clinically destabilized, corresponding to a 66% increase in destablization compared with those who were left on OROS-MPH. It is also concerning that 10 months later, 30% of patients who destabilized when switched from OROS-MPH to Novo-MPH ER-C remained unstable on a new treatment regimen. Finally, qualitative data found worse side effects, lower efficacy and consistently shorter duration of action with Novo-MPH ER-C. This has significant implications for the functioning of the individuals affected. As previously mentioned, ADHD has a broad functional impact affecting academic, employment, social and emotional well-being. Destabilizing patients who are on an effective treatment regimen negatively impacts not only the individuals with ADHD but also their families.
Historically, measures comparing various products, including brand name with generic products, involve examining prospective, classroom studies in which measures of behaviour and standardized testing are completed. However, as a first measure to examine what was being seen in practice, a retrospective review was undertaken. When moving forward to a prospective study, it would be important to use standardized scales, such as the ADHD-Rating Scale, to quantify the differences. The retrospective design of the present study did pose some limitations; however, it involved a relatively large sample size and the differences with respect to destabilization in the two groups were substantial. Another strength of the study was that it examined true clinical patients rather than ‘pure’ patients, which are often used in randomized controlled trials.
The current practice review reported that 66% more paediatric ADHD patients destabilized when they were switched to Novo-MPH ER-C compared with those who continued using OROS-MPH. When combining these data with the data from Fallu and Dabouz (20), which showed worse clinical outcomes with Novo-MPH ER-C compared with OROS-MPH in an adult ADHD population, it suggests that these products are not, in fact, therapeutically equivalent, despite the fact that Health Canada has deemed them to be bioequivalent. Additional research in the form of a prospective clinical comparative study with defined end points in children could help to further clarify this clinical issue.
Given the current information, it is important that both patients and prescribers are aware what their patients are actually taking to ensure optimal management and, hence, the optimal functioning of individuals with ADHD. Furthermore, Canadian requirements for bioequivalence may not be sufficient for complex release medications such as OROS-MPH. A recent United States Food and Drug Administration panel recommended partial AUC criteria for some modified-release products, including modified-release MPH (15,24). Inclusion of such criteria for bioequivalence may better translate into therapeutic equivalence.
Footnotes
DISCLOSURES: The present study was funded by a grant from Jannsen Inc. The funding company did not have any input into the design and execution of the study, collection, analysis and interpretation of the data, or drafting or approval of the manuscript.
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