Off-label prescribing by psychiatrists

AIMS AND METHOD

To report on the use of atypical antipsychotics in one healthdistrict by examining secondary care prescribing patterns forthese medicines in North Staffordshire between 1994 and 2001.With one exception, these drugs were licensed solely for usein schizophrenia during the study period.

RESULTS

A total of 502 patients were initiated on atypical antipsychoticsin the study period. Of these, 297 (59.2%) had a diagnosisof schizophrenia (ICD-10 codes F20-29). Off-label prescribingwas common, but psychiatrists were least likely to prescribeclozapine off-label (2.2%). Affective (18.4%) and organic disorders(12.4%) were the main disorders treated off-label. Olanzapinehad the highest off-label use (44.5%).

CLINICAL IMPLICATIONS

The high off-label use of atypical antipsychotics has clinicaland economic implications. Although off-label prescribing maybe in the patient’s best interests, they should be informedand give their consent. Commissioning bodies, such as primarycare organisations, are basing their budgets on guidance fromthe National Institute for Clinical Excellence, which can have implications for funding this off-label use.

Introduction

TOP

Introduction

The use of atypical antipsychotics has increased dramaticallysince their introduction in the 1990s. Expenditure on atypicalantipsychotics in the West Midlands rose by 105% between July1999 and September 2002 and the number of prescriptions increasedfivefold between 1996 and 2001 (Ashcroft et al, 2002). Withinthe study period reported here (1994-2001), these drugs weresolely licensed for the treatment of schizophrenia, with the exception of risperidone, which was licensed for ‘acuteand chronic psychosis’. This diagnostic specificity isin contrast to the broader licensed indications for many conventionalantipsychotics when initially licensed. In the UK, clozapinewas licensed in 1989, risperidone in 1993 and olanzapine in1996.

In June 2002, The National Institute for Clinical Excellence (NICE, 2002) recommended the first-line use of atypical antipsychoticsfor the treatment of schizophrenia along with further researchin their use. Health organisations are expected to implementNICE technology assessments within 3 months. Funding is made available centrally for implementing NICE guidance, althoughincorporation in local budgets may not be transparent. Morerecently, funding is via generic uplifts, which further cloudthe allocation of NICE budgets. In reality the National HealthService has struggled to keep up with the pace of output from NICE (Shannon, 2003).

In the UK, the Medicines Act 1968 was introduced to controllicensing of medications, following difficulties with drugssuch as thalidomide. The licensing process is administeredby the Medicines Control Agency on behalf of health ministerswho are advised by the Committee on Safety of Medicines. This was the sole licensing route for medicines in the UK priorto the establishment of the European Medicines Evaluation Agency(EMEA) in 1995. The EMEA was established to coordinate theprocessing of European Union licence applications in orderto minimise duplication and ensure regulatory homogeneity throughoutthe Union. Currently, this process is under review, but sinceits establishment drug companies have usually chosen this routeif they wish to market their product in more than one countryof the European Union.

Once a medicine is licensed a marketing authorisation is grantedand the clinical indications, dosage, precautions and otherinformation derived from the marketing authorisation are presentedas the summary of product characteristics. Pharmaceutical companiesmay only promote their product for the indications and usesgiven in this summary. For example, Pfizer, the world’slargest drug manufacturer, was fined $392 m in 2004 for promotinggabapentin off-label (Lenzer, 2004). Patient information leafletsmust reflect the information in the summary of product characteristicsand are legally required to be issued with dispensed medication.

Using unlicensed medicines or using licensed medicines outsidethe parameters of the marketing authorisation (off-label) isnot illegal or inappropriate and is accommodated in the MedicinesAct 1968. However, if a doctor prescribes off-label then heor his employers have increased liability, as the pharmaceuticalcompany would now be only liable for defects in the manufacturingprocess (Consumers’Association, 1992). However, refusingto prescribe off-label may also have legal implications, especiallyas off-label prescribing indications are often described instandard medical textbooks as the treatment of choice (Henry, 1999, Henry, 1999).

Method

TOP

Method

We identified patients in secondary care that were prescribedatypical antipsychotics in North Staffordshire (population460 000) between 1994 and 2001. Prescriptions were identifiedfrom hospital pharmacy records and confirmed by analysis ofcase notes. The ICD-10 diagnosis (World Health Organization, 1993)at time of prescription was obtained from case notes. Previous research in North Staffordshire has shown satisfactorydiagnostic accuracy using this method (Boardman et al, 1997).Only the index atypical antipsychotic prescribed was consideredfor patients treated with more than one atypical in the study period.

Results

TOP

Results

A total of 502 patients were identified. Of these, 52.8% weremale and the mean age was 41.8 years. Mean daily doses were:clozapine 332.3 mg (s.d.=150.3); olanzapine 12.1mg (s.d.=4.6);and risperidone 4.7 mg (s.d.=2.4). Two patients with schizophreniawere prescribed doses above those recommended in the BritishNational Formulary (British Medical Association & Royal Pharmaceutical Society, 2002).Both were prescribed 30 mg of olanzapine.

Only one patient was prescribed clozapine off-licence (Table 1).Olanzapine was the most commonly prescribed atypical antipsychoticin North Staffordshire and was prescribed for schizophreniain 176 of 310 prescriptions (56.8%). Risperidone was used on-labelin 72 of 131 prescriptions (55%) and 63.4% of prescriptions were within licence, if the licence was interpreted as includingaffective psychosis.

View this table:
[in this window]
[in a new window]
Table 1. Prescription of atypical antipsychotic according to ICD-10 diagnosis

Discussion

TOP

Discussion

Our results show high levels of off-label prescribing. Ratesof off-label prescribing would have been even higher if wehad restricted our coding to F20 of the ICD-10 by not includingschizoaffective disorder, delusional disorder and transientpsychotic disorders. Also, we did not assess contraindications or prescribing outside the licensed age range. Our resultsindicate that it cannot be assumed that the growth in atypicalantipsychotic prescribing noted by Ashcroft et al (2002) isfor patients with schizophrenia. This would also suggest thatatypical prescribing rates cannot be assumed to be an accuratereflection of adherence to NICE guidance for schizophrenia(NICE, 2002).

This prescribing may be clinically appropriate but it has alarge impact on prescribing budgets. For example, prescribingcosts for 1 year at the mean prescribed North Staffordshiredose are £1493 and £1094 for olanzapine and risperidone,respectively. Potentially, much of this funding may not bedirectly financed by NICE and this may cause dilemmas for clinicians,users and trusts. Clinicians may be discouraged from using diagnosesother than schizophrenia for patients with psychotic disorders,so that the most appropriate drug for clinical use can be funded.

Douglas-Hall et al (2001) reported similar off-label prescribingrates for atypical antipsychotics and, as in our study, thatolanzapine was the only atypical antipsychotic prescribed aboveits licensed dose. Lowe-Ponsford & Baldwin (2000) reportedthat 65% of psychiatrists acknowledged that they had prescribedoff-label in the preceding month, although Douglas-Hall etal (2001) reported that only 10% of off-label prescribingwas recorded in the patient’s notes. Off-label prescribingis common in paediatrics, oncology and infectious diseases (Conroy et al, 2000;McIntyre et al, 2000).

Licensed indications for antidepressants have become more specificand the reasons for this have been debated (Healey, 2002).This trend to more indication-specific licensing is likelyto continue owing to regulatory requirements. Pharmaceuticalcompanies are unlikely to pursue licences for indications thatare uneconomical. Also further studies to extend licensed indicationsmay be counterproductive. This is exemplified in psychiatryby an apparent increase in the rate of cerebrovascular adverseevents noted in trials of olanzapine and risperidone for behaviouralproblems in patients with dementia. The subsequent warningfrom the Committee on Safety of Medicines (2004) has implicationsfor psychiatrists prescribing off-label in this patient groupand necessitated a change in the summary of product characteristicsfor both these drugs. However, the growth in atypical antipsychoticprescribing for patients with dementia was partly related toconcerns about the safety of typical antipsychotics, such asthioridazine.

Given delays in the licensing process, clinicians may anticipatechanges in dosing strategies or use in other indications. Forexample, after our study was completed, olanzapine receiveda licence for ‘the treatment of moderate to severe manicepisode’, and more recently, ‘in patients whosemanic episode has responded to olanzapine treatment, olanzapineis indicated for the prevention of recurrence in patients withbipolar disorder’. These further indications would havereduced olanzapine off-label prescribing to 22%.

Acknowledgments

We thank Professor Gilbert MacKenzie and Dr Yasin Al-tawarahfor statistical advice.

References

TOP