Report of the Psychiatric Drug Safety Expert Advisory Panel

REPORT OF THE PSYCHIATRIC DRUG SAFETY EXPERT ADVISORY PANEL

2009

Executive Summary

Recommended changes to Australian Product Information documents

Recommendations regarding prescriber education and the quality use of psychotropic medicines

Recommendations for enhanced pharmacosurveillance

Part A Context

Chapter 1Terms of Reference

Chapter 2Background

2.1 What is an adverse drug reaction?

References

2.2 Methods of assessing adverse effects of prescribed medicines

2.2.1 Research methods

2.2.2 Conclusions

Chapter 3Approach to the assessment of the reports

Part B Findings

Chapter 4Challenges in evaluating the reports

Chapter 5Assessment of the reported drug reactions

5.1 Findings in relation to antipsychotic medicines of interest

5.2 Findings in relation to antidepressant medicines of interest

5.2.1 Diagnosis

5.2.2 Medicines used

5.2.3 Adverse effects reported - their ratings and links with literature

5.2.4 Comments

Chapter 6SSRI Antidepressants and Suicide Mortality

6.1 Antidepressants and induction of mania/hypomania...... 23

6.1.1 SSRI Antidepressants and Suicide Mortality

6.1.3 Meta-analyses of Randomised Controlled Trials

6.1.2 Observational Studies of Suicide and SSRIs

6.1.3 Ecological Studies of Suicide and SSRI Use

6.1.4 High Risk Populations: Children and Adolescents

6.1.5 Summary

References

6.2 Antidepressants and induction of mania/hypomania

References

6.3 Serotonin syndrome arising from polypharmacy

6.3.1 Serotonin syndrome or a spectrum of serotonin toxicity?

6.3.2 Polypharmacy and serotonin toxicity

6.3.3 Clinical challenges

References

6.4 Akathisia and antipsychotic medicines

6.4.1 Pathophysiology

6.4.2 Diagnostic challenges with akathisia

References

6.5 Weight gain, obesity and diabetes

6.5.1 Summary of literature review

6.5.2 Possible confounding factors

References

6.6 Interactions between antipsychotic and antidepressant medications

6.6.1 Pharmacodynamic antidepressant-antipsychotic drug interactions

6.6.2 Pharmacokinetic antidepressant-antipsychotic drug interactions

References

6.7 SSRIs and Pregnancy

6.7.1 Review of the literature

6.7.2 Summary

References

Chapter 7Review of Australian Product Information (PI) documents

7.1 SSRI antidepressants and risk of clinical worsening and suicide

7.2 Antidepressants and the induction of mania/hypomania

7.3 Serotonin syndrome and polypharmacy

7.4 Akathisia and atypical antipsychotic medicines

7.5 Weight gain, obesity and diabetes

7.5.1 Atypical antipsychotics

7.5.2 SSRI and SNRI Antidepressants

7.6 Interactions between antipsychotic and antidepressant medications

7.7 Antidepressants and Pregnancy

Part C Conclusions and Recommendations

Chapter 8Are changes to Product Information documents warranted or are broader educational initiatives required?

8.1 What is the role of the Product Information document?

8.2 The broader prescribing environment and implications for quality use of psychotropic medicines

8.3 How to move forward with respect to the problem of polypharmacy – improving medicine usage

8.4 Recommended changes to the Australian PI documents

8.4.1 SSRIs and risk of clinical worsening and suicidality

8.4.3 Serotonin syndrome arising from polypharmacy

8.4.4 Akathisia and atypical antipsychotics

8.4.5 Psychotropic medication and obesity

8.4.6 Interactions between antipsychotic antidepressant medications

8.4.7 Other required changes

8.5 Recommendations regarding prescriber education and quality use of psychotropic medicines

References

Chapter 9Pharmacosurveillance

9.1 Background

9.2 Overseas initiatives

9.3 Advantages and disadvantages of using administrative data

9.4 Developments in Australia

9.5 Conclusions and recommendation

References

Executive Summary

In August 2008, the TGA established the Psychiatric Drug Safety Expert Advisory Panel (the Panel) to undertake a scientific review a series of case reports submitted to the TGA by a psychiatrist with a special interest in forensic and medico-legal psychiatry. Most of the reports described complicated medication and adverse event histories, in which numerous psychotropic medications had been administered over considerable time periods.

The Panel was asked to assess which of the case reports submitted to the TGA described ‘new’ or ‘unrecognised’ adverse events caused by antidepressant and antipsychotic medications of interest. To avoid potential bias in the assessment of the case reports, each report was assessed and rated independently by two of the three Panel members. Once the rating process was completed the co-raters undertook a series of consensus meetings at which each item was discussed until agreement was reached on the rating for each case.

The Panel found the reports were most valuable for highlighting a number of issues associated with the use of psychotropic medicines, including:

the extent of and problems associated with polypharmacy - the presence of polypharmacy in the majority of the cases was of major concern given the lack of evidence for the use of many of the prescribed combinations and the increased potential for adverse effects when multiple medications are used concurrently;
the difficulties for clinicians in distinguishing some side effects, such as akathisia, from underlying psychiatric disorders; and
inconsistencies between current Australian Product Information documents and international monographs for some of these medicines.

Panel members were unable to draw any further conclusions on the information provided in this series of case reports. Polypharmacy and concurrent poly-substance use complicated the issue in the majority of these cases. As a result, a connection between the medication and the adverse report could be made only in a small proportion of case reports. In these cases there was usually clear evidence of a temporal relationship between the onset of symptoms (e.g. akathisia or suicidal ideation) and the use of medication and evidence that the symptom improved on discontinuation or reduction in dose of the drug. The other cases typically involved clear descriptions of serotonin syndrome occurring in a patient taking multiple serotonergic medications, including drugs like tramadol. None of these cases, however, was a new adverse report.

The Panel also undertook extensive literature reviews, with a view to examining the current state of knowledge of the following topics and reconciling this with the appropriateness of information in existing Australian prescribing information documents such the Product Information:

SSRI antidepressants and suicidal mortality, including in children;
Antidepressants and the induction hypomania/mania;
Serotonin syndrome arising from polypharmacy;
Akathisia and antipsychotic medicine;

Weight gain, obesity and diabetes;
Interactions between antipsychotic and antidepressant medications; and
SSRI antidepressants and pregnancy

Based on the collective findings of these all activities, the Panel has made recommendations in three main areas:

Changes to Australian Product Information documents;
Prescriber education activities; and
Enhancement of pharmacosurveillance activities

A consolidated list of recommendations follows this summary.

Consolidated list of recommendations

Recommended changes to Australian PI documents

Recommendation 1: Consideration should be given to requiring sponsors of all antidepressant medicines to include, as a minimum, standard text about the risks of inducing mania/hypomania in the Product Information documents, as follows:
“A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients at risk of bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder and depression.”
Recommendation 2: Consideration should be given to requiring PI documents of the SSRIs and SNRIs to have, as a minimum, standardised text in the Contraindications and Precautions sections, as follows:
Contraindications
Monoamine oxidase inhibitors (MAOI)
[Drug name] should not be used in combination with monoamine oxidase inhibitors (MAOI) or the reversible MAOI (RIMA), moclobemide, or within 14 days of discontinuing treatment with a MAOI. Similarly, at least [insert washout period] should be allowed after stopping [Drug name] before starting a MAOI. Cases of serious reactions, such as potentially life-threatening serotonin syndrome (characterised by neuromuscular excitation, altered mental status and autonomic dysfunction) have been reported in patients receiving an [SSRI/SNRI] in combination with MAOIs and RIMA, and in patients who have recently discontinued an [SSRI/SNRI] and have been started on a MAOI. (see also Precautions)”
Precautions
Serotonin syndrome
Development of serotonin syndrome may occur in association with treatment with SSRIs and SNRIs, particularly when given in combination with MAOIs or other serotonergic agents. Symptoms and signs of serotonin syndrome include rapid onset of neuromuscular excitation (hyperreflexia, incoordination, myoclonus, tremor), altered mental status (confusion, agitation, hypomania) and autonomic dysfunction (diaphoresis, diarrhoea, fever, shivering and rapidly fluctuating vital signs). Treatment with [Drug name] should be discontinued if such events occur and supportive symptomatic treatment initiated.”
Recommendation 3: Consideration should be given to requiring PI documents of the atypical antipsychotic medicines to have, as a minimum, standardised text about akathisia in the Precautions section, as follows:
“The presentation of akathisia may be variable and comprises subjective complaints of restlessness and an overwhelming urge to move and either distress or motor phenomena such as pacing, swinging of the legs while seated, rocking from foot to foot, or both. Particular attention should be paid to the monitoring for such symptoms and signs as, left untreated, akathisia is associated with poor compliance and an increased risk of relapse.”
Recommendation 4: The TGA should give consideration to including recommended glycaemic monitoring regimes in the PI documents of the atypical antipsychotic medicines.
Recommendation 5: The TGA should review the consistency and appropriateness of advice about monitoring of patients with diabetes mellitus contained within the PI documents of the SSRI class of antidepressants.
Recommendation 6: The TGA should give consideration to standardising the way in which important drug-drug interaction information is presented in the PI. A possible format is:
Pharmacodynamic interactions
-Interactions relevant to site of intended action (i.e. same system organ class SOC))
- Interactions at other sites (i.e. other SOCs)
Pharmacokinetic interactions
- Potential for other medicines to inhibit the metabolism of the medicine in question, with reference to metabolic pathway(s), and genetic polymorphism if relevant
- Potential for the medicine in question to inhibit the metabolism of other drugs, with reference to relevant metabolic pathway(s), and genetic polymorphism if relevant
- Interaction with highly protein bound medicines if relevant
- Other
Recommendation 7: The TGA should consider instituting a program in which Australian Product Information documents of medicines are routinely reviewed for consistency with international monographs throughout their life cycle.
Recommendation 8: The Use in Pregnancy section in the reboxetine PI should be amended to include advice about the potential for neonatal effects.
Recommendation 9: The Use in Pregnancy section in the PI documents of all the SSRIs should include advice about the risk of Persistent Pulmonary Hypertension in the Newborn.

Recommendations regarding prescriber education and quality use of psychotropic medicines

Recommendation 10: The TGA should consider instituting an outreach program (through its Principal Medical Adviser) to liaise with the National Prescribing Service and the various professional colleges on matters pertaining to medicines safety and quality use issues.
Recommendation 11: The TGA should include items on serotonin syndrome and akathisia in upcoming issues of its Adverse Drug Reactions Bulletin.

Recommendations for enhanced pharmacosurveillance

Recommendation 12: The TGA should be able to commission epidemiological studies using linked databases.
Recommendation 13: The TGA should consider implementing a post market surveillance system with the following elements:

Research networks, including strengthened relationships with researchers
Public oversight of independently conducted post-market research
Phased introduction of new drugs with potential for large scale use
A flexible and enforceable tool kit of regulatory options
Adequate funding
Active surveillance
Regional pharmacovigilance centres

Part A Context

Chapter 1Terms of Reference

Chapter 2Background

2.1What is an adverse drug reaction?

2.2Methods of assessing adverse drug reactions

Chapter 3Approach to the assessment of the reports

Chapter 1Terms of Reference

The reportscontained details of the experiences of several healthcare professionals involved in the management of patients who had received a variety of psychiatric medicines and experienced adverse events. In correspondence the psychiatrist had raised particular concerns over the safety of selective serotonin reuptake inhibitors (SSRIs) and atypical antipsychotic medicines, drawing attention to problems that may occur with polypharmacy.

The PDSEAP was asked to:

identify and document the reported adverse effects that may be reasonably attributed to the medicines specified therein;
review the relevant literature for those drugs and document their adverse effects with, wherever possible, quantitative information about incidence;
provide a commentary on the degree of congruence or dissonance between the recognised adverse effects of each of the identified medicines and those attributed to them in the case reports;
provide advice on the clinical importance of any adverse effects recorded in the case reports but not identified in the literature review; and
provide advice as to whether the adverse effects identified through the literature reviews are adequately described in the approved Australian product Information documents.

The members of the Panel were:

Professor Wayne Hall, a pharmacoepidemiologist who is an NHMRC Australia Fellow, Professor of Public Health Policy at the University of Queensland and Chair of the Drug Utilisation Subcommittee of the Pharmaceutical Benefits Advisory Committee (PBAC);
Professor Steve Kisely,a psychiatrist,epidemiologist and public health physician from the University of Queensland and Director of the Queensland Centre for Health Data Services; and
Dr Frances Wilson, a consultant psychiatrist at Westmead Hospital.

Chapter 2Background

2.1What is an adverse drug reaction?

The Panel noted the TGA has well established guidelines setting out requirements for the reporting of adverse drug reactions1. Although these guidelines outline the regulatory responsibilities of sponsors, they nevertheless provide insight into the TGA’s approach to the assessment of adverse drug reactionsand identification of possible safety signals as well as its expectation of the key information required in order to adequately assess the causality of events observed.

An adverse event is any untoward medical occurrence in a patient administered a medicinal product, which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (for example, an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not the outcome is considered to be related to that medicinal product.

A reaction, in contrast to an event, is characterised by the fact that a causal relationship between the drug and the occurrence is suspected. It follows that the minimum information required of a report of a suspected adverse drug reaction is an identifiable patient,an identifiable reporter, a suspected reaction and a suspect medicine. The key data elements required to enable evaluation of reports and attribution of causality include:

Patient Details – initials, gender, age or date of birth, concomitant conditions, medical history and relevant family history;
Suspected Medicinal Product(s) - brand or generic name, batch/lot number, indication(s) for which suspect medicinal product was prescribed, dosage form and strength, daily dose and regimen, route of administration, starting date and stopping date or duration of treatment;
Other Treatment(s)–for medicines, the same information as for the suspected medicine, as well as details of any medical devices used; and
Details of the suspected adverse drug reaction(s) - full description of reaction(s), including body site and severity and a description of the reported signs and symptoms, specific diagnosis for the reaction, onset and stop date of the reactionor duration of reaction, de-challenge and rechallenge information, relevant diagnostic test results and laboratory data, outcome (recovery and any sequelae), including for a fatal outcome, stated cause of death or relevant autopsy or post-mortem findings.

The submission of an individual report does not in itself constitute evidence of a safety issue. Although most reports are implicitly attributed to one or more medicines, any individual report may have several possible explanations that include confusion with complications due to the underlying illness (so-called confounding by indication), confounding by other co-morbidities, prescription errors and the chance occurrence of a new illness unrelated to either the original condition being treated or the medicine (especially if it has been used long term).

Thus, it is important to assess not only the individual reports but all similar reports collectively and robustly for evidence of a safety signal. Sir Bradford Hill established the following nine criteria for causation (does factor A cause disorder B) which are relevant to the detection of safety signals from adverse drug reaction reports 2:

Strength of the association: How large is the effect?
The consistency of the association: Has the same association been observed by others, in different populations, using a different method?
Specificity: Does altering only the cause alter the effect?
Temporal relationship: Does the cause precede the effect?
Biological gradient: Is there a dose response?
Biological plausibility: Does it make sense?
Coherence: Does the evidence fit with what is known regarding the natural history and biology of the outcome?
Experimental evidence: Are there any clinical studies supporting the association?
Reasoning by analogy: Is the observed association supported by similar associations?

References

Australian Guideline for Pharmacovigilance Responsibilities of Sponsors of Registered Medicines Regulated by Drug Safety and Evaluation Branch (July 2003 – Amended 31 May 2005).
Bradford-Hill A. The environment and disease: Association or causation?Proc R Soc Med 1965;58:295-300.

2.2Methods of assessing adverse effects of prescribed medicines[1]

Generally, drugs are only approved for medical use if they have been shown to be safe and effective in randomised controlled trials (RCTs). Although data from RCTs provide good reasons for expecting that widely prescribed medicines may improve health outcomes, outcomes observed in such trials may not occur in routine clinical use. Controlled clinical trials may therefore provide optimistic estimates of effectiveness under routine clinical care because the medicines are used to treat more seriously ill patients in the community than were studied in clinical trials1, 2. Drugs may also be prescribed inappropriately, or patients not comply with recommended use of the drugs. Clinical trials will also only detect common adverse drug reactions (ADRs); uncommon ADRs will often only be detected after a drug has been approved and widely used. This section evaluates the research methods that can be used to assess the adverse effects of prescribed medicines on health outcomes in the community. It reviews methods used to make causal inferences about the relationships between medicine use and adverse health outcomes (e.g.3, 4).

Report of the Psychiatric Drug Safety Expert Advisory Panel