This paper will review the use of quetiapine in New Zealand. Quetiapine, a dibenzothiazepine derivative, is a second-generation antipsychotic, licensed in the US by the FDA for the treatment of schizophrenia and bipolar disorder and as adjunctive treatment for major depressive disorder.1 In New Zealand, quetiapine is approved for the treatment of schizophrenia, acute mania associated with bipolar I disorder and maintenance treatment of bipolar I disorder.2 However, in New Zealand and in a number of other countries,3 there is growing evidence that quetiapine is largely prescribed ‘off-label’, ie, not for the licensed indication.

At low doses (25mg), quetiapine is a histamine-1 receptor and alpha-1 adrenergic antagonist. At doses between 50–200mg, it increasingly antagonises serotonin receptors, and at higher doses (above 300mg) it antagonises dopamine-2 receptors.4,5 Low-dose ‘off label’ use exploits the histamine-1 receptor blockade causing sedation and the antagonism of the alpha-1 adrenergic receptors for its anxiolytic effect. The higher doses acting on the serotonergic and dopaminergic receptors provide the antidepressant and antipsychotic effects respectively.

In an article in the Australian Prescriber, Jonathan Brett reported that in Australia between 2000 and 2011, quetiapine’s use had increased from 0.01 to 2.3 defined daily doses/1,000 population/day and noted that these changes cannot be accounted for by patients being switched from older to newer antipsychotic drugs or changes in the diagnosis of long-term mental illness.6,7

McKean and Monasterio reported that off-label use of quetiapine accounted for about 17% of the budget for atypical antipsychotics in New Zealand,8 while Huthwaite and colleagues reported that in an audit of the hypnosedative prescribing patterns of New Zealand community psychiatrists, quetiapine was the most commonly hypnosedative, with 38.4% of the patients being prescribed it for this purpose.9 Ilyas and Moncrieff reported that in 2010, quetiapine accounted for 23% of antipsychotic prescription items in England with 54% of these prescriptions, for the 25mg tablets.10 The Drug Utilisation Sub-Committee of the Pharmaceutical Benefits Advisory Committee in Australia reported that off-label use was most evident for the 25mg strength of quetiapine.11 The prescribing of quetiapine for the treatment of insomnia has become common practice despite the paucity of evidence to support its efficacy as a hypnotic.12

A concerning trend are the reports of quetiapine having street value, being used to recover from or enhance the effects of drugs of misuse.13 In Australia and the US, quetiapine misuse is now increasingly documented in case reports, case series and emergency department presentations with increasing reports of overdosing, poison information center data and coronial data and quetiapine overdoses have been reported as causing hypotension, respiratory depression, sinus tachycardia, delirium, coma or death and that these complications were more likely to occur with quetiapine than with overdoses by all the other antipsychotic drugs put together.14,15

To aid the understanding of quetiapine prescribing in general practice, a retrospective audit of the prescribing of quetiapine in 57 practices in the Compass Health Primary Health Organisation (PHO) was undertaken. This was in response to a concern by the Clinical Quality Board of Compass Health that quetiapine was being prescribed off label.

Method

The audit was conducted from January 2015 to January 2016 in 57 general practices in the Compass Health Network. The network is located in the lower North Island and at the time included 59 practices. The auditors were PHO employed pharmacists. Data regarding the quetiapine prescriptions were extracted from the clinical records in the shared Practice Management Systems (PMS) and therefore represented prescribing data not dispensing data. Using the list of indications in quetiapine’s data sheet, the auditors made an a priori decision about what indications would be considered licensed and which would be considered ‘off-label’. The clinical notes and relevant correspondence (eg; psychiatrist letters, discharge summaries) were scrutinised to determine the indication for its use. Approval for this audit of Medical Practice Activity was gained from the Royal New Zealand College of General Practitioners. Data were entered in a Microsoft Excel (2010) spreadsheet and statistical analyses were conducted using Microsoft Excel.

Results

Two hundred and seventy prescribing general practitioners in 57 practices were audited. A total of 2,161 patients were prescribed quetiapine in the one year of the audit. Only 460 (21.3%) were prescribed quetiapine for a licensed indication, with 1,556 (72%) receiving quetiapine for an ‘off-label’ indication. For the remaining 6.7%, the prescribing indication was unclear. In over half the sample (56.2%), the quetiapine prescribing was initiated in primary care, 39% in secondary care, while for 4.8% of the sample it was unclear who had initiated the prescribing. In the primary care initiated group, full consent for the ‘off-label’ prescribing was documented in 11% of the patient’s records. (The “Prescribing Unapproved Medicines” section of the New Zealand Medical Council statement “Good Prescribing Practice” was used as a guide to determine consent). Table 1 shows the gender and age demographics of those persons prescribed quetiapine.

Table 1: Demographics.

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Table 2 shows the duration of use and Table 3 lists the non-approved indications for which quetiapine was prescribed.

Table 2: Duration of the prescribing of quetiapine (off label).

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Table 3: ‘Off-label’ prescribing of quetiapine: non-approved conditions for which quetiapine was prescribed.

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Figure 1 shows the percentage for the groups of non-approved conditions for which quetiapine was prescribed.

Figure 1: Non-approved conditions for which quetiapine was prescribed.

Full metabolic monitoring was recorded as being done in only 2.3%, while partial monitoring occurred in 68% and no monitoring in 29.7%. Full monitoring comprised all the tests listed in the Capital and Coast District Health Board’s antipsychotic metabolic monitoring guidelines. Partial monitoring included those with three or more of the recommended tests.

The dose range for ‘off-label’ prescribing was between 6.25mg–800mg, with 91% (1,416) being prescribed less than 100mg daily (see Figure 2). Only 2.3% (36) of those prescribed quetiapine for an ‘off–label’ indication were prescribed more than 300mg daily. A relatively wide dose range was noted in many cases, for example: 25 to 100mg at night (or daily) as required, with the largest of these being 6.25 to 300mg daily as required.

Figure 2: Dose range for ‘off-label’ prescribing.

It was noted during this study that several patients asked for quetiapine, claiming that a “neighbour, relative or friend” had given them some.

Discussion

This audit confirms previous New Zealand studies that quetiapine is largely being used ‘off-label’ and that there is a growing trend for it to be prescribed to exploit the sedating effects and mild anxiolytic effects in the lower dose range. The results of this audit indicate that there is little monitoring of the metabolic side effects. At the recommended doses for the licensed indications (ie, the treatment of mania and schizophrenia), quetiapine is associated with metabolic adverse events (ie, diabetes, hyperlipidemia and obesity) and other serious adverse events, including QT interval prolongation, orthostatic hypotension, hyperprolactinemia, extrapyramidal symptoms, tardive dyskinesia and neuroleptic malignant syndrome. There is some evidence (one review and two data papers) that these adverse effects can occur at low doses;16,17 more studies are needed. Prescribers, using low doses may erroneously presume that because the drug is not being prescribed as an atypical antipsychotic, and in the lower dose range, that metabolic monitoring is not desirable. When prescribing in the real world, ‘off-label’ prescribing may be warranted and even advantageous, limiting the inappropriate use of benzodiazepines and zopiclone and their associated problems of dependence and abuse. Prescribers making decisions to prescribe quetiapine in this manner may resent the implication that they are doing something wrong.18

However, prescribers should be aware of the currently available risk-benefit profile for the relevant non-approved indication in each patient, noting the rationale behind their decision to use this drug at this dose. Even when ‘off-label low doses’ are being prescribed, the prescriber should be aware that the dose equivalent for the elderly patient (especially the female elderly patient) is about half that used for the younger patient19 and that the elderly are at increased risk of the adverse effects described above.8

The ‘off-label’ use should be discussed with the patient. The prescriber should ensure that the patient is making an informed decision about using the quetiapine in this manner and this should all be clearly documented in the clinical record.20 This places all the onus of the prescriber, while the pharmaceutical companies passively enjoy the profits of ‘off-label’ on trend prescribing. It is interesting to note that in April 2010, Astra-Zeneca signed a civil settlement to pay $US 520 million to “resolve allegations” that it had illegally marketed Seroquel (original brand of quetiapine) for uses not approved as safe and effective by the FDA.21 Then in March 2011, it agreed to pay a further $US 68.5 million in a multi-state agreement over off-license marketing of the same drug. Other substantial settlements within the US over the marketing of unapproved uses have also been reached.

Conclusion

Most quetiapine prescriptions reviewed in an audit of a large PHO were for ‘off -label’ use. While it is commonly accepted that prescribing off-label is at the prescriber’s discretion, and not necessarily a “bad thing to do”, the authors suggest that when prescribing quetiapine for a non-approved condition, or to a specific clinical population (the elderly and the young), the thoughtful prescriber will carefully document not only the clinical rationale for this prescribing but also that they have discussed this with their patient (and in some instances their families or caregivers).22 It is unlikely that the pharmaceutical suppliers of quetiapine will apply for new approved indications for its use. The respective Colleges and other representative bodies (like BPAC or Medsafe) may wish to develop guidelines for the non-approved prescribing of quetiapine to allow prescribers to act in accordance with accepted practice and current best practice guidelines.

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