Off-Label in New Zealand

I was pleased to be asked to contribute to the recent ABC documentary on the use of the antipsychotic medication quetiapine in Australia. I am a practicing forensic psychiatrist, with a research interest in the patterns and characteristics of off-label prescribing of antipsychotic medications. Off-label prescribing refers to the use of a medication outside the indications approved by the licensing authority; the approval process requires robust scientific evidence of efficacy and safety for specific clinical situations. Licensing for specific indications was in part designed to rationalize and limit the marketing claims made by the pharmaceutical industry in their thirst for profit and to prevent further disasters such as those that followed the excessive use of thalidomide in the 1960s, in which up to 10,000 infants across the US and Europe were born with malformation of the limbs and where only 50% of those affected survived.

Before the early 1990’s the use of antipsychotic medications was largely reserved for adults with severe psychotic disorders; unpleasant involuntary movement disorders (extrapyramidal side-effects) and cardiovascular risks appear to have largely limited their use outside these disorders. The introduction and intense marketing of what seemed to be better tolerated and safer (now proven not to be), second generation atypical antipsychotics (AAPs) such as risperidone, olanzapine, quetiapine, ziprasidone and aripiprazole from the mid 1990’s led to a rapid expansion of antipsychotic medication use for a wide variety of unlicensed conditions and in more diverse clinical populations. Part of the rapid diffusion of AAPs has been achieved by large increases in the rate of use in certain sub-populations, most notably children and youths for whom long term data on safety and efficacy are still lacking, and due to persisting use of AAPs over long periods of time (Crystal et al, 2009, Monasterio and McKean, 2013). This unlicensed use has predominantly not been supported by scientific evidence (McKean and Monasterio, 2012). At the same time the diagnosis of serious mental illness, particularly bipolar affective disorder and the use of antipsychotic medications in children and youth increased between 5-40 times in the US and parts of Europe (Moreno et al, 2007, Monasterio and McKean, 2013).

Antipsychotic global sales were US$25.4 billion and the seventh biggest therapeutic group in 2010; Seroquel™ (quetiapine), Zyprexa™ (olanzapine) and Abilify™ (aripiprazole) were the 5th, 10th and 13th biggest selling pharmaceuticals worldwide (IMS Health, 2011). Studies examining the use of AAPs across specialist inpatient and outpatient populations and general practice indicate that between 43% and 70% of atypical antipsychotic use is off-label.

In a recent study of prescribing patterns by psychiatrists in Christchurch, New Zealand in 2010we found that quetiapine was the preferred choice of 94% of prescribers, and that 58% of all respondents prescribed this medication off-label every week, generally in situations where there was little scientific evidence of safety and efficacy. The commonest indications were anxiety (89%), sedation (79%), and post-traumatic stress disorder (57%) (Monasterio and McKean, 2010).

There is a very real and concerning paradox in the current prescribing patterns of antipsychotic medications; noting that psychosis and psychotic spectrum disorders are relatively rare conditions in the general population (affecting less than 2% of the population), how is it that AAPs designed for the treatment of these conditions and licensed for few indications outside of psychosis, have become some of the most commonly prescribed medications in modern medicine? Off-label use of quetiapine has become particularly popular; the extent of its use in particular contrasts sharply with the limited evidence base for its safety and efficacy. The reason for this is not well understood and demands urgent investigation.

By now it is clear that pharmaceutical companies have influenced prescriber choices and have strongly encouraged off-label prescribing as it increases their total sales, despite this type of marketing not being permitted by the regulators. Recent landmark legal cases by the US Department of Justice, charging that the drug companies Eli Lilly and AstraZeneca illegally promoted the off-label use of the AAPs olanzapine and quetiapine have settled before trial for payments of US$1.4bn and US$520m respectively (Kmietowicz, 2009, Tanne, 2010). In commenting on the legal case against AstraZeneca, US Attorney General Eric Holder said that illegal acts by drug companies “can put the public health at risk, corrupt medical decisions by health care providers, and take billions of dollars directly out of taxpayers’ pockets” (Tanne, 2010). Pharmaceutical companies have extended sales into unapproved diseases, unapproved disease subtypes and unapproved drug doses; a series of recent publications based on the analysis of whistle-blower complaints, and civil and criminal charges have exposed the use of systematic, sophisticated and far-reaching promotional methods, some of which may be resistant to external regulatory approaches (Kesselheim et al, 2011).

Contrasting against the widespread use of quetiapine is the FDAs decision to decline approval for an extension of the licensing indications of quetiapine to include generalised anxiety disorder and major depressive disorder; in their decision they cited concerns about the public health ramifications of exposing a larger population of individuals to the drug, noting that it is associated with long term metabolic problems, tardive dyskinesia and increased risk of sudden cardiac death (Kuehn, 2009).

For any treatment intervention, proven benefits define the parameters of acceptable risks; although unfortunately it is often not the case, it is incumbent on the prescriber to ensure that the benefits of AAP treatment outweigh their risks. In most instances this has not been established with any degree of confidence. In this context I strongly encourage active involvement of consumers in the decision-making process around the use of this group of medications.

References

Crystal S, Olfson M, Huang C, et al. (2009) Broadened Use Of Atypical Antipsychotics: Safety, Effectiveness, And Policy Challenges. Health Affairs 28(5):w770-w781.

Kesselheim A, Mello M, Studdert D. (2011) Strategies and practices in off-label marketing of pharmaceuticals: A retrospective analysis of whistleblower complaints. PLoS Medicine 8(4):e1000431. doi:10.1371/journal.pmed.1000431

Kmietowicz Z. (2009) Eli Lilly pays record $1.4bn for promoting off-label use of olanzapine. British Medical Journal 338:b217

Kuehn BM. (2009) FDA Panel Issues Mixed Decision on Quetiapine in Depression and Anxiety. Journal of the American Medical Association 301(20): 2081-2.

Monasterio, E., & McKean, A. (2013). Use of quetiapine in child and adolescent populations–Response to letter from Dr Lambe. Australian and New Zealand Journal of Psychiatry, 47(11), 1084-1085.

McKean A, & Monasterio, E. (2012). Off-Label Use of Atypical Antipsychotics. CNS drugs, 26(5), 383-390.

Monasterio E, & McKean A (2010) Off-label use of atypical antipsychotic medications in Canterbury, New Zealand. The New Zealand Medical Journal 124 (1336) http://wwwnzma.org.nz/journal/124-1336/4700

Moreno, C., Laje, G., Blanco, C., Jiang, H., Schmidt, A. B., & Olfson, M. (2007). National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Archives of general psychiatry, 64(9), 1032.

Tanne JH. (2010) AstraZeneca pays $520m fine for off-label marketing. British Medical Journal; 340: c2380

Top 20 Global Therapeutic Products 2010, total audited markets (online). Available from URL: www.imshealth.com (Accessed 2011 August 16).