Since our original review of the methylphenidate SPC in 2008 , the CHMP has ensured a greater degree of consistency across the contraindications and other prescribing information listed in SPCs for the various formulations of methylphenidate. One formulation of methylphenidate, Equasym, has also been withdrawn and there have been three significant changes to the atomoxetine SPC. In terms of contraindications, there are numerically fewer in the atomoxetine SPC (five) than in any of the methylphenidate SPCs (maximum: 17), however, many of the specific contraindications in the methylphenidate SPCs can be found in the Special Warnings and Precautions for Use section of the atomoxetine SPC and recent changes to the contraindications for atomoxetine have made the prescribing information more similar. There remain some inconsistencies among the SPCs for methylphenidate although these are unlikely to be clinically significant. Given that atomoxetine and methylphenidate are different chemical compounds from different classes and have different pharmacokinetics and pharmacodynamics, it is unsurprising that the number and type of contraindications is also different. It is clearly important that clinicians are aware of the relative contraindications of all medications licensed to treat ADHD prior to prescribing for specific patients especially those with comorbidities which may be a contraindication for treatments.
There is disparity between the three sets of UK national guidance and the safety content and recommendations made in the SPCs for both atomoxetine and methylphenidate and to a lesser extent dexamfetamine. This lack of consistency and clarity within the information typically used to support prescribing decisions cannot help prescribers evaluate the suitability of specific medications for individual patients. It is of interest that the respective guidelines state that healthcare professionals are expected to take the SPC fully into account when exercising their clinical judgement and that the guidance does not override the individual responsibility of healthcare professionals to be informed by the SPC of any drugs .
There have been a number of initiatives in Europe and the United States over the last 10 years designed to increase the safety database in paediatric psychopharmacology. Specific requirements are detailed in the Food and Drug Administration Amendments Act of 2007 , while, in 2007, the EMA enacted a new "Paediatric Regulation" which mandates greater and more appropriate clinical trial activity and reporting of data during the development of medicines intended for use in children aged 0-17 years . Of relevance to ADHD is the announcement from EMA's European Network of Paediatric Research Group in December 2010 of the 7th European Commission's Framework Programme pharmacovigilance study into the long-term adverse effects of methylphenidate in ADHD (ADDUCE [Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects]) and a methodological study into the measurement of suicidality in paediatric clinical trials (STOP [Suicidality: Treatment Occurring in Paediatrics]) .
Suicidality is a key area of disparity between national guidance and SPCs. The SPC for atomoxetine specifically highlights the need for monitoring for the appearance or worsening of suicide-related behaviour and states that suicidal behaviours have occurred uncommonly in clinical trials. Suicide-related events are also listed as an uncommon Undesirable Effect on the SPC. The SPCs for methylphenidate list suicidal tendencies as a contraindication for usage, contain a warning relating to the emergence of suicidal behaviours and also list suicidal ideation as an uncommon Undesirable Effect. They also mandate monitoring for all psychiatric adverse events and this will include suicidal issues of all types. The dexamfetamine SPC states that any family history of suicide should be investigated prior to initiation of treatment as part of the screening for risk of bipolar disorder.
In contrast to the SPC content, the NICE guidelines warn clinicians of "...suicidal problems and self harming behaviour with atomoxetine" and make no mention of the risks associated with other treatments. The SIGN Guidelines repeat this disparity by stating the need to closely monitor patients on atomoxetine in particular for agitation, irritability, suicidal thinking and self-harming behaviour.
The atomoxetine suicidality data are derived from a retrospective analysis of atomoxetine usage in 14 paediatric trials which reported greater suicidal ideation with atomoxetine when compared with placebo (p = 0.016). In a cohort of 1,357 atomoxetine-treated subjects, there were five cases of suicidal ideation reported, no completed suicides and one suicidal attempt . The same database also reported a meta-analysis of the suicide-related events reported from comparator studies of atomoxetine and methylphenidate and reported no difference in rates between these agents (Maentzel-Haentzel incidence difference -0.12 (95% confidence interval -0.62 to 0.38; p = 0.649). Hence, there would seem to be no specific data that suggest any differential suicidality between the treatments which is clearly not reflected in the National Guidelines. Clinical studies now include rating scales as well as pragmatic outcome measurements to assess items such as suicidality .
Similar inconsistencies arise with other sections of the SPCs. The NICE guidelines suggest using either atomoxetine or methylphenidate with co-morbid anxiety, but specifically recommend the need for observation for agitation or irritability only with atomoxetine despite a strong warning on the methylphenidate SPC relating to the need to clinically evaluate patients for agitation and irritability prior to the use of methylphenidate. The SPC also advises that patients should be regularly monitored for the emergence or worsening of these symptoms during treatment, at every adjustment of dose and then at least every 6 month or every visit. The atomoxetine SPC states that whilst treatment emergent agitation can be caused by atomoxetine at usual doses there are no specific monitoring recommendations around agitation and irritability. Methylphenidate is associated with the worsening of pre-existing anxiety, agitation or tension. Clinical evaluation for anxiety, agitation or tension should precede use of methylphenidate and patients should be regularly monitored for the emergence or worsening of these symptoms during treatment, at every adjustment of dose and then at least every 6 months or every visit. Recent changes to the atomoxetine SPC highlight that anxiety was not worsened in clinical trials but that patients being treated with atomoxetine should be monitored for the appearance or worsening of anxiety. The wording around the recommendations in the guidelines does not fully reflect the SPC content of either product.
A similar disparity exists for usage of either agent when tics or Tourette's syndrome are present. Both NICE and SIGN recommend use of either methylphenidate or atomoxetine although the SPCs have differences. The atomoxetine SPC reports that there was no worsening of tics or Tourette's in a placebo-controlled trial, very rare post-marketing reports of tics have been received and that patients should be monitored for the appearance or worsening of tics. The methylphenidate SPC states that methylphenidate is associated with the onset of tics, that both tics and Tourette's may worsen with methylphenidate treatment and that clinical evaluation and examination should precede methylphenidate treatment.
Other areas of debate include adverse events attributed to a drug. For example, in both National Guidelines, it is recommended that sexual dysfunction is monitored in atomoxetine patients (children and adults) but this requirement is not reflected in the SPC. The SPC contains no clinical trial data on sexual dysfunction specifically in children, only post-marketing surveillance data which includes children, adolescents and adults.
The disparity between these independent data sources may be complex for clinicians to interpret particularly when the NICE guidelines recommend use of methylphenidate in adults which has only been an approved indication for one form of methylphenidate (Concerta®) since June 2011 [13, 14].
Stimulant misuse or diversion is another potential area of concern due to the nature of ADHD. No clear guidance is given in NICE despite clinical evidence that atomoxetine is not a drug of abuse. The methylphenidate SPC advises clinicians to prescribe atomoxetine in high risk cases and contains warnings and caveats about the potential for misuse or diversion. These distinctions in the SPCs are not translated into the guidelines.
It is frequently reported that co-morbidities are common in ADHD patients. A recent study on a cohort of 1,068 subjects with ADHD symptoms reported high rates of Generalised Anxiety Disorder (16.8%), dysthymic disorder (13.5%) and Major Depressive Disorder (3%)  when using the Diagnostic and Statistical Manual of Mental Disorders, volume 4 (DSM IV). Clinicians may thus be regularly evaluating drug choices in the presence of significant co-morbidities and any disparity between guidelines and SPC content may add to this complexity.
An important consideration is the balance of regulatory statements as contained in the SPC and the expertise of those routinely prescribing medications. Clinicians have had significant experience of using methylphenidate for many years in many children and as such have considerable expertise in weighing up potential tolerability and safety risks with the benefits of medication to individual patients. Relevant clinical publications, clinical expertise in using the medications and achieving positive results in cases that are contraindicated according to the SPC are highly influential in determining future drug use. There is experience of contraindicated medications being prescribed to patients with positive outcomes despite the potential risk of rare adverse events. The advantage of the regulatory statements is that they are based on cumulative case reports and as such reveal the rarer adverse events that would not otherwise be picked up in routine practice. As a consequence, appropriate levels of monitoring and precaution can be recommended for different products. These types of issue are evidenced by the level of debate in the scientific literature regarding the potential for methylphenidate to cause or worsen tics [1, 10, 20].
Clearly data are emerging rapidly in ADHD with the advent of new treatments and epidemiological research but national guidelines and SPCs cannot be updated as frequently as data emerge. For the period from January 2009 to April 2011, the search term "atomoxetine" in Pub Med generates 245 citations with at least 94 citations likely to contain clinical data, meta-analyses or reviews. The future safety of paediatric treatments are paramount and are likely to be advanced by the FDA and EMA regulations and the ability of large databases to address outcome measures of a more pragmatic kind. Some safety aspects may even be improved by drug treatment. Recent data on atomoxetine usage in a cohort of 13-16 year old children improving unhealthy dietary behaviours and physical activity as well as reducing behaviours contributing to unintentional injuries .
To be able to make prescribing decisions based on sound evidence, clinicians need to be aware of, and be familiar with, the different sources of information available to them. The SPC, as an independent document reflecting current knowledge, may be the best way of achieving this.