OROS methylphenidate (Concerta) for the treatment of children and adults with ADHD

23 Apr 2010 OROS methylphenidate (Concerta) for the treatment of children and adults with ADHD

Introduction

Pharmaceutical Services Division (PSD) requested an update to the 2006 Therapeutics Initiative review of Concerta (OROS MPH) for the treatment of children and adults with ADHD. The 2006 report included a systematic review in children and adolescents with ADHD. The recent submission includes additional new information in children and adolescents and also an additional new indication, for the treatment of adult patients with ADHD.

Drug

OROS methylphenidate is a central nervous system stimulant and a controlled substance under Schedule II. The OROS delivery technology provides a mixture of immediate and delayed release. Within 1 hour, plasma MPH concentrations reach an initial plateau, followed by a gradual increase over the next 5 to 9 hours. The recommended dose is 18 – 54 mgs once daily in the morning. Maximum recommended dose for children and adolescents is 54 mg/day, and adults, 72 mg/day.

ADHD

ADHD typically starts in early childhood and may persist into adulthood although there is an age-dependent decline in symptoms. Diagnosis is more common in boys than girls. A number of genes are implicated in the pathogenesis as well as psychosocial adversity. Co-morbid conditions include oppositional defiant disorder/conduct disorder, anxiety disorders, affective disorders and learning disorders, which can influence both diagnosis and response to treatment.

Current standards of treatment

Pharmacological therapy should be integrated into a program that includes environmental and behavioural modification. Target symptoms are individualized as well as optimal dose and dose interval. Medications include methylphenidate, amphetamine and atomoxetine.

Research questions

1. In double blind randomized controlled trials, does OROS-MPH provide a significant therapeutic advantage in terms of mortality or morbidity, long-term developmental and short-term behavioural (i.e. academic or work performance) outcomes compared to other approved drugs in the treatment of ADHD in patients 6 years or older including adults (19 to 65 years of age)?
2. Is there any new evidence evaluating long-term effectiveness and safety of Concerta?
3. Is there any data evaluating the abuse potential and/or diversion of Concerta compared to other formulations of methylphenidate?

Assessment principles: Included trials are double-blind randomized controlled trials (RCTs) in patients 6 years or older diagnosed with ADHD and comparing OROS formulation of methylphenidate to other long or short acting formulations of MPH or other standard therapy (amphetamine or atomoxetine) available in Canada.

Methylphenidate formulations available in Canada are short-acting or “immediate-release” tablets: Ritalin and the generics: PMS-methylphenidate and Apo-methylphenidate; sustained-release tablets: Ritalin SR; controlled-release capsules: Biphentin. Amphetamine preparations available in Canada are short-acting or “immediate-release” tablets: Dexedrine; sustained-release spansules: Dexedrine Spansule; and extended-release dextroamphetamine capsules: Adderall XR. Strattera (atomoxetine) is a long acting, non-stimulant.

Therapeutic advantage will be assessed according to the following hierarchy of health outcomes – all-cause mortality; serious adverse events (SAEs); long-term developmental outcomes (e.g. academic achievement); withdrawals due to adverse events (WDAEs); short-term behavioural and academic or work performance outcomes using published and validated criteria; quality of life (QoL) measured by validated indices; adverse events (including appetite suppression, weight loss, insomnia, neuropsychiatric symptoms).

Search strategy and findings: Medline (1966-October 24, 2008), EMBASE (1988-October 24, 2008), The Cochrane Database of Systematic Reviews and the Cochrane Central Registry of Clinical Studies (up to October 24, 2008) were searched to identify relevant trials.

Results

11 double blind RCTs met the inclusion criteria of which 8 RCTs were in children and adolescents and 3 in adults.

Overview of RCTs in children (6-12 years)

Overview of RCTs in children and adolescents (6-16 years)

Overview of RCT in adolescents (13-18 years)

Overview of RCTs in adults (18 to 65 years)

Children (6-12 years)

Five DB RCTs were identified. Three trials compared OROS MPH to an IR MPH an active comparator available in Canada. Two RCTs compared OROS MPH to Metadate CD and MPH patch that are not available in Canada.

All three RCTs included for critical appraisal enrolled known responders to MPH (N = 446) and compared OROS MPH 18 to 54 mg once daily to IR MPH tid or placebo for duration of 1 to 4 weeks (Wolraich 2001, Pelham 2001 and Swanson 2003). In summary, OROS MPH provided no significant therapeutic advantage or disadvantage versus IR MPH.

Children and adolescents (6-16 years)

Two DB RCTs were identified of which one trial Stein 2003 did not include an active treatment arm.

Newcorn 2008 randomized 516 participants who were stimulant naïve or stimulant responsive and compared OROS MPH to atomoxetine for a 6 week period. The study was powered (90%) to declare non-inferiority margin of up to 15% in response rates on the ADHD RS between OROS MPH and ATX treatment groups. The primary outcome “Response” was defined as a decrease from baseline of 40% or more in the total ADHD Rating Scale score at week 6. OROS-MPH showed a significant improvement in response rate as compared to Atomoxetine (56% vs. 45%, p = 0.02, ARR =11%, NNT = 9). There is a bias in favor of MPH because this trial excluded subjects with increased risk for poor response or tolerability with methylphenidate. Statistically significant improvements were reported in the mean ADHD-RS-IV score by 2.5 points [four-point scale (0 to 3) and total score range is between 0 and 54], CPRS-R score by 2.4 points [48 items using a 4-point scale (0 to 3) total range is 0-144], CGI-S score by 0.3 points [7-point scale with a range of 0 to 6 for each item scored and total range from 0 to 42] and QOL score using the Child Health Questionnaire by 2.4 (CHQ score range is 0 to 100 on 11 health domains) points as compared to atomoxetine. The clinical significance of these statistically significant changes is not known. Incidence of any report of insomnia was significantly increased in the OROS MPH group compared to atomoxetine (ARI=6%, NNH=17), and somnolence was significantly reduced (ARR=4%, NNT=25).

Adolescents (13-18 years)

No active comparator RCT was identified. One DB parallel group RCT (Wilens 2006) randomized 220 MPH responders to 2 weeks of DB treatment with OROS MPH vs. placebo following a 4-week open-label dose titration phase.

Adults (18 to 65 years)

No DB RCT was identified comparing OROS MPH vs. other formulations of MPH or other active comparators in adult patients with ADHD. 3 DB RCTs in 593 adult patients with ADHD diagnosed with DSM-IV criteria compared OROS MPH to placebo for a period of 4 to 6 weeks. All three trials reported statistically significant improvements in ADHD scores as compared to placebo, the clinical significance of which is not known. There was a significant increase in several adverse events versus placebo. Withdrawals due to adverse events were reported in 2 of the 3 trials and were significantly increased in OROS MPH 18 to 72mg versus placebo [p = 0.0006, RR with 95% CI 3.5(1.2, 10.5); ARI = 5%, NNH = 20]

Critical appraisal issues of active comparator trials

In children aged 6-16 years trials comparing OROS MPH vs. IR MPH had a small sample size, were of short duration (1 to 4 weeks) and included MPH responders. In addition the high attrition in the trial of 4 weeks duration limits interpretation of efficacy and adverse effects. In the only other active comparator trial in children and adolescents comparing OROS MPH to Atomoxetine, the significant increase in response rate in ADHD-RS total score may be due to bias in favor of MPH introduced by excluding subjects with increased risk for poor response or tolerability to methylphenidate. The clinical significance of the statistically significant mean change in ADHD-RS-IV by 2.5 points, in CPRS-R score by 2.4 points and in the CGI-S score by 0.3 points is not known. 16% to 23% of patients withdrew from the first phase of the study.

In all RCTs meeting the inclusion criteria since the outer shell of Concerta does not dissolve as it moves through the GI tract and is excreted in the stool, this could affect the validity of the blinding for the patient and possibly the clinician.

“Is there any new evidence evaluating long-term effectiveness and safety of Concerta?”

Two long-term open-label studies in children and adolescents 6-16 years of age showed an increased incidence of some adverse events with OROS MPH. Only 53% of patients (n=56) completed the 12-month study (Hoare 2005). In the 24-month study (Wilens 2005), 69% (n=282) of patients reported adverse events possibly or probably related to OROS MPH, the most frequent of which was headache in 30% of patients (n=123). Tics were the leading cause of early discontinuation from the study and were reported in 10% of patients. (n=40).

An observational study (Stein 2003) reported headache (11%), insomnia (6.6%) and nervousness (5.1%) as emergent adverse events in adults with ADHD treated with methylphenidate. Only 60% of adults were followed to 9 months.

A small retrospective review of 11 adults with narcolepsy who had been taking high doses of methylphenidate (> 100 mg daily) for 5 years or more reported psychotic symptoms (1 subject), hallucinations and persecutory delusion (1 subject) and hypnogogic hallucinations (1 subject). Six of the subjects met DSM-III-R criteria for dysthymia or major depression. The contribution of co-morbidities to the reported events was unclear from Godfrey’s review.

One systematic review (Godfrey 2008) documented the dearth of published information on the long-term safety of methyphenidate use in adults with ADHD was reviewed, critiqued and summarized. It included reports on 881 adults in 26 placebo-controlled trials. Although no serious (life threatening or irreversible) adverse effects were reported the included trials have obvious limitations and were not appraised for risk of bias. The largest limitation for evaluating safety was the duration of included studies. Seventeen of the trials were between 3 and 6 weeks with the longest being 12 weeks. Godfrey concluded that little information on long-term safety has been identified but that the number of serious adverse events reported to regulatory authorities has been low.

“Is there any data evaluating the abuse potential and/or diversion of Concerta compared to other formulations of methylphenidate?”

Pharmacologic dependence on a drug develops as a result of relatively continuous exposure. Hence, while a long-acting formulation may potentially be less likely to induce concentration-dependent or concentration velocity-dependent euphoria, it should not be expected to produce less dependence than its shorter acting counterpart.

OROS formulation of methylphenidate cannot be expected to eliminate the ability of prescription recipients to abuse the drug for non-medical purposes. The true prevalence of abuse and/or dependence in comparison with IR methylphenidate cannot be ascertained from controlled clinical trials nor from the pharmacokinetic properties of the two formulations when used as intended under prescription.

There is possibly less drug diversion and abuse when compared to short acting MPH or dextroamphetamine (dosed twice or thrice daily) since the outer shell of Concerta is impenetrable to chewing and even if one were to break open the formulation, the inner contents is a paste-like substance so less suitable for intra-nasal administration.

Conclusions

Children and adolescents

1. There are no DB, RCTs longer than 6 weeks that assess OROS MPH in ADHD in children or adolescents.
2. There are no DB RCTs that compare OROS MPH to other long-acting psychostimulants available in Canada (e.g. Ritalin SR, Adderall XR).
3. Three DB RCTs of 7 to 28 days, in children 6 -12 years who are known MPH responders found OROS MPH had similar efficacy and harm compared to IR MPH. However neither the benefit or harm conclusions are considered valid due to incomplete reporting of trial participants from all treatment groups, particularly placebo.
4. There are no active comparator double blind randomized controlled trials in adolescents.
5. One DBRCT included 516 children and adolescents who were stimulant naïve or stimulant responsive and compared OROS MPH (18 to 54 mg) to atomoxetine (0.8 to 1.8 mg/kg/day) or placebo. The primary outcome “Response” was defined as a decrease from baseline of 40% or more in the total ADHD Rating Scale score at week 6. OROS-MPH showed a significant improvement in response rate as compared to Atomoxetine (56% vs. 45%, p = 0.02, ARR =11%, NNT = 9). There is a bias in favor of MPH because this trial excluded subjects with increased risk for poor response or tolerability with methylphenidate. This trial also reported statistically significant improvement in mean scores of several ADHD rating scores as compared to atomoxetine the clinical significance of these changes are not known. Incidence of any report of insomnia was significantly increased in the OROS MPH group compared to atomoxetine (ARI=6%, NNH=17), and somnolence was significantly reduced (ARR=4%, NNT=25).

Adults

Double blind randomized controlled trials do not compare OROS MPH to IR MPH or to other long acting psychostimulants available in Canada (e.g. Ritalin SR, Adderall XR).

Overall

1. These studies are inadequate to assess the impact of therapy on childhood development, functional capacity of adults, or serious adverse events.
2. One systematic review (Godfrey 2008) documented the dearth of published information on the long-term safety on the safety of methylphenidate use in adults and concluded that little information on long-term safety has been identified but that the number of serious adverse events reported to regulatory authorities has been low.
3. OROS formulation of methylphenidate cannot be expected to eliminate the ability of prescription recipients to abuse the drug for non-medical purposes. The true prevalence of abuse and/or dependence in comparison with IR methylphenidate cannot be ascertained from controlled clinical trials or from the pharmacokinetic properties of the two formulations when used as intended under prescription. There is possibly less drug diversion and abuse when compared to short acting MPH or dextroamphetamine since the outer shell of Concerta is impenetrable to chewing and even if one were to break open the formulation, the inner contents is a paste-like substance so less suitable for intra-nasal administration.
4. Studies of longer duration are required to gain a better appreciation for both efficacy and safety and to evaluate the impact of convenience advantage of a single daily administration schedule.

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