The Expert Committee, after evaluation, declines to list the medicine proposed in the application.
The Model List of Essential Medicines reports reasons that Committee Members have identified for denying listing.
The Committee did not recommend the addition of methylphenidate to the
complementary list of the EML and EMLc for the treatment of attention-deficit
hyperactivity disorder (ADHD) due to concerns regarding the quality and
interpretation of the evidence for benefits and harms.
The application requested the inclusion of methylphenidate on the complementary
list of the EML and EMLc for the treatment of attention-deficit hyperactivity
Methylphenidate had not previously been considered for inclusion on the Model
Public health relevance
The mental disorders that methylphenidate is approved to treat have a high
global disease burden. In 2010, mental neurological and substance use disorders
accounted for 10.4% of global disability-adjusted life years (DALYs) and 28.5%
of years of life lost due to disability, illness, or premature death (YLDs), making
them the leading cause of YLDs (1). The Global Burden of Disease Study 2010
(GBD 2010) is the first to include conduct disorder (CD) and attention-deficit
hyperactivity disorder (ADHD) for burden quantification (2). Globally, CD was
responsible for 5.75 million YLDs/DALYs with ADHD responsible for a further
491 500 (3). Collectively, CD and ADHD accounted for 0.80% of total global
YLDs and 0.25% of total global DALYs (3).
The prevalence of ADHD is a controversial issue with varying estimates
across populations, using different diagnostic criteria and reporting. A 2015
systematic review and meta-analysis of 175 studies reporting point prevalence
estimates of ADHD estimated the pooled prevalence to be 7.2% (95%CI 6.7%
to 7.8%) (4).
A 2007 systematic review and meta-regression analysis of 102 studies
(171 756 subjects) investigating the prevalence rates of ADHD/HD worldwide
found large variability of ADHD/HD prevalence rates worldwide resulting
mainly from methodological differences across studies. When adjusted for
methodological differences, prevalence rate variability was only detected
between studies conducted in North America and those conducted in Africa and
the Middle East (5).
A literature review undertaken by the applicants included 28 studies and review
articles as evidence for the comparative effectiveness of methylphenidate for the
treatment of ADHD versus placebo or other stimulants (6–15), versus secondline non-stimulant therapies (16–25), and in patients with ADHD comorbid with
other conditions (26–31) in children, adolescents and adults. The large majority
of the trials and reviews were conducted in children and adolescents and were of
short duration (three months). Summaries of the findings of the included trials
Based on this review, the applicants concluded that in the treatment of
ADHD, methylphenidate has shown similar efficacy to amphetamine-based
drugs with varying results on different psychometric scales. Some individual
studies have demonstrated superiority of methylphenidate over amphetaminebased medicines, some have found superiority of amphetamine-based medicines
over methylphenidate, and others have shown no difference between the two
treatments. Given the currently available evidence, it has not been demonstrated
that one stimulant is more efficacious than any other at a population level. In the
comparison of methylphenidate with non-stimulant medications for treatment
of ADHD, non-stimulant medications appear to have a lower efficacy though
some studies show equivalent efficacy with atomoxetine. The application stated
that methylphenidate is effective in reducing fatigue in palliative care patients
when compared to placebo and that there is also evidence of methylphenidate
being effective in reducing symptoms in patients with ADHD comorbid with
oppositional defiant disorder and aggression. No assessment was made in the
application regarding the quality of the evidence or confidence in the estimates
A literature review undertaken by the applicants included 29 studies and review
articles as evidence for the comparative safety of methylphenidate for the
treatment of ADHD versus placebo (6, 32–34), versus other stimulants and nonstimulants (9, 11, 12, 14, 16–19, 21, 35–38), and in patients with ADHD comorbid
with other conditions (26, 27, 30, 39–43). The large majority of the trials and
reviews were conducted in children and adolescents and were of short duration.
Summaries of the findings of the included trials were presented.
Based on this review, the applicants concluded that there is considerable
overlap in the adverse event profiles of methylphenidate- and amphetaminebased ADHD medications. Both have been associated with insomnia and
appetite suppression as the most common adverse events. Overall, studies suggest
that the frequency and severity of adverse events may be somewhat greater
with amphetamine-based products. In comparison to other non-stimulant
medications, methylphenidate was associated with less sleeping problems and
higher tolerability. No assessment was made in the application regarding the
quality of the evidence or confidence in the estimates of harm.
As methylphenidate is a controlled Schedule II substance under the
1971 Convention on Psychotropic Substances, the application addressed the
issue of potential misuse. Methylphenidate-specific misuse data generally mimic
results of studies looking at stimulant medication misuse in general. While
there are limited data on malingering specifically for methylphenidate, studies
of malingering for stimulants in general are likely generally applicable (44).
Overall, the misuse of methylphenidate raises legitimate safety concerns for
overdose and drug interactions with other medications or nonmedical use drugs,
particularly since illicit users are generally unaware of these issues and often use
methylphenidate with other recreational drugs. However, studies suggest that
amphetamine-based drugs are being used more often than methylphenidate for
non-medical use, particularly in immediate-release formulations (45–48).
A 2014 Cochrane systematic review of immediate-release methylphenidate for
treatment of adults with ADHD was withdrawn in 2016 following failure by
the authors to satisfactorily address a number of criticisms of the methodology
used and conclusions drawn (49, 50). A commentary on the withdrawn review
summarized the criticisms, which primarily focussed on the methodological flaws
and “misleading conclusions that gave a false sense of certainty of the benefits
and the absence of harms, when this in fact could not be concluded” (51).
Cost / cost effectiveness
The median buyer price of immediate release methylphenidate 10 mg, according
to the International Medical Products Price Guide is US$ 0.067 per tablet/
A literature review undertaken by the applicants included 11 articles as
evidence for the comparative cost-effectiveness of methylphenidate (54–65).
Summaries of economic evaluations of methylphenidate for ADHD were
presented, and the application concluded that the identified literature favoured
methylphenidate as cost-effective or cost-neutral relative to stimulant and non-stimulant treatments.
The Committee considered that while methylphenidate appeared to
be low cost and affordable, no conclusions could be drawn regarding the cost-effectiveness of the medicine given the considerable uncertainty in the estimates
of benefit and harms.
The 2016 WHO mhGAP intervention guide for mental, neurological and
substance use disorders in non-specialized health settings (version 2.0) includes
a recommendation to refer children (aged 6 years and above with a diagnosis
of ADHD in whom other treatment approaches have failed) to a specialist for
methylphenidate treatment (52).
Methylphenidate immediate release tablets are available internationally in
innovator and generic brands.
Public comments on the application were received from Professor Ole Jakob
Storebø and Dr Christian Gluud, authors of a 2015 Cochrane systematic review of
methylphenidate use in children and adolescents (6) included in the application.
They expressed concern in relation to limitations in the reporting and summary
of the evidence in the application, with particular regard to the quality of
the evidence, duration of trials, misplacement of evidence, and suspected
selective biases. They stated that their assessment of the evidence supporting
methylphenidate for ADHD (and other disorders) was more critical than that
of the applicants, noting that the high risk of bias in the randomized trials likely
overestimates positive intervention effects and underestimates risk of harms.
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