Names of individuals have also been deleted where that person's contribution is not in the public domain, or will not shortly be so. For example, the names of those to be approached to write an article are deleted, but the names of those who have contributed to a draft article are not usually deleted. In addition, names are not usually deleted when a contribution has been made in an official capacity.

The material listed as being considered on an issue is not intended to be exhaustive.

The recommendations of the Committee are in bold typeface.

Minutes:

The one hundred and fifty-first meeting of the Medicines Adverse Reactions Committee (MARC) was held on 13 September 2012 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9.00 am and closed at 4.15 pm.

marc members present

Associate Professor D Reith (Chair)
Dr L Bryant
Dr N Cole
Associate Professor P Jones
Dr S Jayathissa
Associate Professor D Menkes
C Ryan
Dr S Sime
Dr M Tatley
Dr K Wallis

marc secretariat present

J Carey (MARC Secretary, Medsafe)

MEDSAFE STAFF IN ATTENDANCE

C James (Manager, Clinical Risk Management)
S Kenyon (Senior Advisor, Pharmacovigilance)
R Pollock (Advisor, Pharmacovigilance)
E Yousuf (Principal Clinical Advisor)

Invited guests and experts IN ATTENDANCE

Dr R Savage
Thuy Nguyen Phoung (National Pharmacovigilance Centre, University of Pharmacy, Hanoi, Vietnam
Minh Chau Thi Anh (ChoRay Hospital, Ho Chi Minh City, Vietnam)

1. Matters of Administration

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Associate Professor Chris Frampton.

1.2 Minutes of the 150^th MARC Meeting

The minutes of the 150^th meeting of the Committee were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The date for the remaining 2012 MARC meeting was scheduled for 6 December.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflicts of Interest Declaration forms to the Secretary. The Chair reminded the MARC members that, in addition to conflicts disclosed in the declaration forms, members should declare conflicts of interest at the commencement of discussion of any relevant agenda item.

There were no potential conflicts of interest which were considered likely to influence the discussions or decisions of the MARC at this meeting.

1.5 Prescriber Update

1.5.1 Prescriber Update. Volume 33, Number 3. September 2012

Discussion

The Committee noted the latest edition of Prescriber Update.

2. STANDING AGENDA ITEMS

2.1 Report on Standing Agenda Items from Previous Meetings of the MARC

The Committee reviewed the list of outstanding recommendations made by the MARC at previous meetings. Background information on these issues can be found in the minutes of previous MARC meetings on the Medsafe website.

3. pharmacovigilance issues

3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981

No items.

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Antidepressants and the risk of QT prolongation

Background

In August 2011, the US Food and Drug Administration (FDA) issued a Drug Safety Communication that informed healthcare professionals that citalopram use is associated with a dose-dependent risk of QT prolongation and Torsades de Pointes (TdP). In November and December 2011, the European Medicines Agency (EMA) announced that both citalopram and escitalopram are associated with a dose-dependent increase in the QT interval. A number of risk management strategies were advised by both regulators including the addition of new warnings and contraindications. Subsequent to these announcements, the New Zealand citalopram and escitalopram data sheets were updated to include additional information on the risk of QT prolongation and TdP. In addition, articles were published in Prescriber Update and the BPAC journal.

Due to the possibility that the publication of warnings about the risk of QT prolongation associated with citalopram and escitalopram might lead to channelling of at risk patients to other antidepressants, a review of this risk with other antidepressants was undertaken by Medsafe. The sponsors of all antidepressants with ministerial consent for distribution in NZ were asked to provide Medsafe with the results of any clinical studies, including thorough QT studies, and any other relevant data (including spontaneous reports of QT prolongation/TdP or symptoms suggestive of arrhythmia) regarding the risk of QT prolongation/TdP or sudden cardiac death associated with their product.

The Medsafe report summarised the results of this review including data provided by the NZ sponsors, spontaneous reports received by the Centre for Adverse Reactions Monitoring (CARM) and a review of published literature. The Committee was asked to advise whether:

sufficient information has been provided to assess the QT prolonging potential of all the individual antidepressants and/or classes of antidepressants reviewed.
for each antidepressant the available data supports an association with therapeutic and/or supratherapeutic use and development of QT prolongation.
it is possible to rank the available antidepressants according to their risk of causing QT prolongation (individually or as a class)
updates to the data sheets for individual antidepressants or classes of antidepressants are required.
the results of this review should be communicated (eg, Prescriber Update article).

Discussion

The Committee noted the 2012 Medsafe report.

The Committee was provided with an overview of drug-induced QT prolongation and TdP. They noted that most medicines that are associated with drug-induced QT prolongation block the hERG potassium channel.

The Committee noted that following the FDA evaluation of the thorough QT study on citalopram, the following recommendations were made.

Citalopram should not be used in patients with congenital long QT syndrome (CLQTS).
Citalopram should no longer be prescribed at doses greater than 40 mg per day.
A maximum dose of 20 mg/day should be used in patients with hepatic impairment, who are greater than 60 years of age, who are CYP 2C19 poor metabolisers or who are taking concomitant cimetidine.
Patients should be informed of the signs and symptoms of arrhythmia and be advised to seek medical attention immediately if they occur.

They noted that in March 2012, the FDA announced they were replacing these contraindications with the following precautionary statements.

Citalopram is not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalaemia, or hypomagnesaemia, recent acute myocardial infarction, or uncompensated heart failure. Citalopram use is also not recommended in patients who are taking other drugs that prolong the QT interval. However, if citalopram is used in such patients then ECG monitoring and/or electrolyte monitoring should be performed.
Citalopram should be discontinued in patients who are found to have persistent QTc measurements greater than 500 ms.
Patients at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurement with periodic monitoring. Any abnormalities should be corrected prior to initiating treatment.
Advise patients on citalopram to contact a healthcare professional immediately if they experience signs and symptoms of an abnormal heart rate or rhythm (e.g, dizziness, palpitations, or syncope). If patients experience symptoms, the prescriber should initiate further evaluation, including cardiac monitoring.

The Committee noted that the NZ citalopram data sheets have been updated in line with the recommendations made by the FDA in August 2011. The Committee was advised that NZ experts are not generally supportive of contraindicating the use of QT prolonging medicines in patients with CLQTS. The MARC agreed that replacing the contraindications with detailed warning statements would be more helpful to NZ prescribers. The MARC recommended that the NZ citalopram data sheets be updated in line with the FDA's recommendations made in March 2012. The Committee noted that the thorough QT study for escitalopram (the S-enantiomer of citalopram), demonstrated that escitalopram is associated with a dose-dependent increase in the QT interval; however, the degree of QT prolongation only reached the level of regulatory concern with the supra-therapeutic 30 mg dose. The Committee noted that although the NZ escitalopram data sheet had been updated to include details of the thorough QT study, no additional precautionary statements were added to the data sheet. The Committee agreed that the thorough QT study results indicated that escitalopram is associated with a lower risk of QT prolongation than citalopram The Committee recommended that the NZ escitalopram data sheet be updated to include a warning that escitalopram is associated with a dose-related risk of QT interval prolongation and it should be used with caution in patients who have other risk factors for QT prolongation.

The Committee went on to review the available evidence for an association with QT prolongation/TdP for each of the following antidepressants.

Tricyclic antidepressants (TCAs): amitriptyline, nortriptyline, imipramine, clomipramine, trimipramine, doxepin and dosulepin
Tetra-cyclic antidepressants: maprotiline
Selective serotonin reuptake inhibitors (SSRIs): fluoxetine, paroxetine, sertraline, fluvoxamine
Serotonin/noradrenaline reuptake inhibitors (SNRIs) venlafaxine, duloxetine, reboxetine
Monoamine oxidase inhibitors (MAOIs): phenelzine, tranylcypromine, moclobemide
Other antidepressants: mianserin, mirtazapine.

The Committee reviewed each of the medicines separately. They noted that the available data are not consistent across the classes, making comparison between the different medicines difficult.

The Committee noted that the NZ amitriptyline data sheet includes a warning that TCAs have been associated with the development of arrhythmias. Neither QT prolongation nor TdP are specifically mentioned. The US and European data sheets list QT prolongation as occurring with overdose. The published literature indicates that amitriptyline has been shown to block hERG potassium currents. Cases of QT prolongation and TdP have been reported with therapeutic and supra-therapeutic doses of amitriptyline. QT prolongation was found to occur more commonly with amitriptyline than with placebo in two clinical trials. The Committee agreed that there is sufficient evidence to support an association between amitriptyline and the development of QT prolongation/TdP, and that this risk was increased in specific circumstances such as overdose, use in higher doses and the elderly. They recommended that the NZ data sheet should be updated to include information on the risk of QT prolongation including advice to use with caution in patients with other risk factors for QT prolongation. The data sheet should also include any additional information on the risk of cardiotoxicity in association with the TCAs that is included in international amitriptyline data sheets.

The Committee noted that the NZ nortriptyline data sheet includes a warning that TCAs have been associated with the development of arrhythmias. A specific mention is made that changes in QRS width or axis is an indicator of significant toxicity. Neither QT prolongation nor TdP are specifically mentioned. QT prolongation and TdP are listed in the European datasheet as occurring with overdose. The published literature indicates that nortriptyline has been shown to block hERG potassium currents. Cases of QT prolongation and TdP have been reported with nortriptyline primarily with overdoses and in association with other QT prolonging medicines. The MARC agreed that there is sufficient evidence to support an association between nortriptyline use and the development of QT prolongation/TdP, and that this risk is increased in specific circumstances such as overdose. They recommended that the NZ nortriptyline data sheet be updated in line with the amitriptyline data sheet.

The Committee noted that the NZ imipramine data sheet advises caution in patients with a history of arrhythmia and indicates that QTc prolongation and TdP have occurred with supratherapeutic doses (mostly overdoses but also in combination with other QT prolonging medicines). It also lists QT prolongation and TdP as occurring very rarely. Imipramine blocks hERG potassium currents and has been associated with the development of QT prolongation at therapeutic doses. The Committee agreed that there is sufficient evidence to support an association between imipramine use and the development of QT prolongation/TdP. They considered that this information was adequately covered in the imipramine datasheet and that no changes were required.

The NZ clomipramine data sheet advises use with caution in patients with pre-existing cardiovascular disorders including arrhythmias. Arrhythmias are listed as occurring rarely. Neither QT prolongation nor TdP are specifically mentioned. The European data sheet includes an extensive warning about the risk of QT prolongation/TdP particularly with supra-therapeutic concentrations or with concomitant administration of other QT prolonging medicines. QTc prolongation/TDP is also listed as occurring with overdose. Clomipramine has been shown to block hERG potassium currents and there have been reports that clomipramine is associated with moderate increases in the QTc interval and that rare cases of TdP have been reported with therapeutic use of clomipramine. The Committee agreed that there is sufficient evidence to support an association between clomipramine and the development of QT prolongation/TdP and that this risk is increased in specific circumstances such as in overdose and use in children. The Committee recommended that the NZ clomipramine data sheet be updated in line with the amitriptyline data sheet.

The Committee noted that the NZ trimipramine data sheet includes a warning about cardiac arrhythmias occurring with high doses. QT prolongation/TdP is not listed in the NZ, European or US data sheets. They noted that no specific literature was located regarding trimipramine and the risk of QT prolongation. No studies were identified which investigated the effects of trimipramine on hERG potassium channels. The Committee agreed that there is currently insufficient evidence to conclude that trimipramine is associated with a risk of QT prolongation/TdP. However, they agreed that QT prolongation in association with TCAs is likely to be a class effect and recommended that a warning to this effect be included in the NZ trimipramine data sheet. One member observed that the trimipramine data sheet includes a statement that a saline purge should be given in the event of adverse cardiac events following overdose. The Committee recommended that Medsafe request that the company clarify this statement.

The Committee noted that the NZ doxepin data sheet includes a warning to use with caution in patients with severe cardiac arrhythmias and states that ECG changes have been reported very rarely. QTc prolongation and TdP are listed as occurring with overdose. No information on QTc prolongation/TdP is included in the European or US data sheets. The Committee noted that a thorough QT study for doxepin has been undertaken which was negative at the 6 mg and 50 mg dose, although the QTc interval was higher at the 50 mg dose. However, as the recommended dose for depression is 75 mg-300 mg daily, the Committee considered this study did not provide any data on the effects of therapeutic or supra-therapeutic doses of doxepin on the QTc interval. The Committee agreed that there is sufficient evidence to support and association between doxepin use and the development of QT prolongation/TdP and that this risk is increased in specific circumstances. They recommended that the NZ doxepin data sheet be updated in line with the amitriptyline data sheet. The Committee noted that the NZ doxepin data sheet currently includes a statement that doxepin carries less risk of adverse cardiovascular events than other TCAs. They recommended that this statement should be removed from the data sheet unless the sponsor can provide evidence that doxepin is associated with less cardiovascular events than other TCAs.

The Committee noted that the NZ dosulepin (dothiepin) data sheet includes a warning that dosulepin may increase the risk of cardiovascular toxicity including cardiac arrhythmias. Cardiac arrhythmias are listed as symptoms of overdose. There was no specific mention of QT prolongation/TdP. No European or US data sheets were located. The Committee noted that case reports of QT prolongation and/or TdP have been reported in association with dosulepin use, particularly in the setting of overdose. The Committee agreed that there is sufficient evidence to support an association between dosulepin use and the development of QT prolongation/TdP and that this risk is increased in specific circumstances such as overdose. They recommended that the NZ dosulepin data sheet be updated in line with the amitriptyline data sheet.

The Committee noted that maprotiline is a tetracyclic antidepressant and the NZ maprotiline data sheet indicates that cardiac arrhythmias have been reported with TCA and tetracyclic antidepressant use. QT prolongation and TdP are listed as occurring very rarely. Fatal arrhythmias, including TdP, are listed as having occurred with overdose. The MARC noted that maprotiline has been found to block hERG potassium channels, and that there have been case reports of QT prolongation/TdP with both therapeutic use and overdose. The Committee agreed that there is sufficient evidence to support an association between maprotiline use and the development of QT prolongation/TdP, and that this risk is increased in specific circumstances. They recommended that NZ maprotiline data sheet be updated in line with the TCA data sheets.

The Committee noted that the NZ mianserin data sheet lists arrhythmias as occurring with overdose, and there is no specific mention of QT prolongation or TdP. No US or European data sheets were located. They noted that mianserin is associated with low affinity block of hERG currents, and that case reports of QT prolongation and TdP have been reported with therapeutic use and overdose of mianserin. The Committee agreed that there is some evidence to support an association between the use of mianserin and the development of QT prolongation/TdP, including a plausible biological mechanism. They recommended that the NZ mianserin data sheet should be updated to indicate that cases of QT prolongation and ventricular arrhythmias (including TdP) have been reported with the post-marketing use of mianserin.

The Committee noted that the NZ fluoxetine data sheet indicates that cardiovascular dysfunction including cardiac arrhythmia and cardiac arrest have occurred with overdose. QT prolongation/TdP is not specifically mentioned. In the US data sheet, QT prolongation is listed as occurring with post-marketing use and both QT prolongation and TdP are listed as occurring with overdose. The sponsor provided clinical studies which provided evidence for an effect of fluoxetine on the QT interval. The Committee noted that the sponsor proposes to update the Warnings and Precautions and Overdose sections of the Prozac data sheet to include information on the risk of QT prolongation/TdP occurring. The MARC agreed that the pre-clinical, clinical and post-marketing data support a causal association between fluoxetine use and the development of QT prolongation and/or TdP, and that this risk is likely to be increased in the presence of other risk factors. They recommended that the NZ fluoxetine data sheets be updated to include a warning about the risk of QT prolongation/TdP with fluoxetine and should advise caution in patients with others risk factors.

The Committee noted that the NZ paroxetine data sheet lists sinus tachycardia as occurring uncommonly. There is no specific mention of QT prolongation or TdP. In the US data sheet, TdP is listed as being reported with post-marketing use and with paroxetine overdoses. The MARC noted that a substantial number of cases of QT prolongation and/or TdP have been reported in association with paroxetine use. It was noted that the majority of the reports occurred with overdose or in patients with other risk factors for QT prolongation. It was noted that a paroxetine thorough QT study has not been performed, although the sponsor indicates that there was no evidence of QT prolongation in paroxetine clinical trials. The Committee agreed that there is sufficient evidence to support an association between paroxetine use and the development of QT prolongation/TdP, and that this risk is increased in the presence of other risk factors for QT prolongation/TdP. The MARC recommended that the NZ paroxetine data sheet be updated in line with the fluoxetine data sheet. They considered a thorough QT study would be useful to add to the level of evidence to that of similar medicines in the same class, and recommended that Medsafe determine if a thorough QT study is to be performed for paroxetine, and if so, Medsafe should seek assurance that the results will be communicated to Medsafe as soon as possible.

The Committee noted that palpitations and tachycardia are listed in the NZ sertraline data sheet. There is no mention of QT prolongation/TdP. In the US data sheet, QT prolongation and TdP are listed as occurring with post-marketing use and QT prolongation is listed as occurring with overdose. The Committee noted that cases of QT prolongation and TdP have been reported with therapeutic doses and overdoses of sertraline. The Committee agreed that there is sufficient evidence to support an association between sertraline use and the development of QT prolongation/TdP, and that this risk is increased in specific circumstances. They recommended that the NZ sertraline data sheet be updated in line with the fluoxetine data sheet changes.

The Committee noted that the NZ fluvoxamine data sheet lists palpitations/tachycardia as occurring commonly. There is no mention of QT prolongation/TdP. The US data sheet indicates that TdP has occurred with post-marketing use, and QT prolongation is listed as occurring with overdose. The MARC noted that cases of QT prolongation and/or TdP have been reported in association with fluvoxamine use, and although the majority of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, cases have also been reported with therapeutic use. The Committee agreed that there is sufficient evidence to support an associations between fluvoxamine use and the development of QT prolongation/TdP, and that this risk is increased in specific circumstances. They recommended that the NZ fluvoxamine data sheet be updated in line with the fluoxetine data sheet changes.

The Committee noted that the NZ phenelzine data sheet does not mention cardiac arrhythmias, QT prolongation or TdP. The European data sheet indicates that arrhythmias are uncommon. The Committee noted that there is very limited data available investigating the effects of phenelzine on the risk of QT prolongation/TdP, and that there is insufficient evidence to conclude that phenelzine is associated with a risk of QT prolongation/TdP. They considered that no data sheet changes were warranted at this time. The Committee noted that the NZ tranylcypromine data sheet lists tachycardia as occurring in overdose. They noted that there is very limited data available on the effects of tranylcypromine on the QT interval, and that there is insufficient evidence to conclude that phenelzine is associated with a risk of QT prolongation/TdP. They considered that no data sheet changes were warranted at this time.

The Committee noted that the NZ moclobemide data sheet lists tachycardia and palpitations as occurring in less than 1 % of patients. The MARC noted that data from observational studies suggests that moclobemide is associated with clinically significant QT prolongation in overdose. They considered that there is sufficient evidence to support an association between excessive doses of moclobemide and the development of QT prolongation/TdP. The Committee recommended that the NZ moclobemide data sheet be updated to include information on the risk of QT prolongation/TdP in association with overdose.

The Committee noted that the NZ mirtazapine data sheet indicates that careful monitoring is required in patients with cardiovascular disease. There is no specific mention of QT prolongation or TdP. The US data sheet indicates that 4 cases of TdP have been reported since market introduction. The Committee noted that mirtazapine consists of two isomers, both of which are thought to contribute to its antidepressant activity. It was noted that no thorough QT studies have been performed for mirtazapine; however, a thorough QT study has been performed for esmirtazapine (the S enantiomer). This study found that supratherapeutic doses of esmirtazapine (4-12 times therapeutic dose) reached the threshold of regulatory concern, which may indicate that esmirtazapine overdoses (and potentially mirtazapine overdoses) may be associated with the development of clinically significant QT prolongation. The MARC noted that there have been cases of QT prolongation reported with both therapeutic doses and overdoses of mirtazapine - the majority of which had other risk factors for QT prolongation/TdP. The Committee considered that there is sufficient evidence to support an association between mirtazapine use and the development of QT prolongation/TdP. The MARC recommended that the NZ mirtazapine data sheet be updated to include QT prolongation/TdP as a rare ADR and/or an effect of overdose. The Committee recommended that Medsafe determine if a thorough QT study is to be performed for mirtazapine, and if so, Medsafe should seek assurance that the results will be communicated to Medsafe as soon as possible.

The Committee noted that the NZ venlafaxine data sheet lists QT prolongation and TdP as very rare adverse effects. QT prolongation is also listed as occurring with overdose. Similar information is included in the European and US data sheets. The MARC noted that cases of QT prolongation and TdP have been reported with both therapeutic doses and overdoses of venlafaxine. Clinical studies have identified small, statistically significant increases in the QT prolongation in patients receiving treatment with venlafaxine. The Committee agreed that there is sufficient evidence to conclude that venlafaxine is associated with a risk of QT prolongation/TdP, and that this risk is increased in specific circumstances. The MARC recommended that the venlafaxine data sheet be updated in line with the fluoxetine data sheet.

The Committee noted that the NZ reboxetine data sheet includes a warning about the risk of tachycardia occurring. No specific mention is made of QT prolongation or TdP. The European data sheet indicates that there have been no reports of ECG abnormalities associated with overdoses of reboxetine alone. The Committee noted that there have been a limited number of cases of QT prolongation reported in association with reboxetine use; however there is a lack of supporting data from clinical studies. The MARC noted that a thorough QT study carried out by Fleishaler et al. found a negative association between reboxetine and QT prolongation. The MARC considered that the available data did not support an association between reboxetine and the development of QT prolongation/TdP. However, the MARC recommended that further information on the reboxetine thorough QT study as well as any data on hERG channel effects be sought from the sponsor. This data should be brought back to the Committee for review.

The Committee noted that the NZ duloxetine data sheet states that duloxetine is not associated with clinically significant ECG abnormalities. Palpitations are listed as occurring commonly and tachycardia uncommonly. The European and US data sheets contain similar information. The Committee noted that there have been cases of QT prolongation/TdP reported with duloxetine use, and experimental studies have found that duloxetine causes blockade of hERG potassium channels at supratherapeutic plasma concentrations. However, data from clinical studies including a thorough QT study found that duloxetine is not associated with QT prolongation and may actually cause QT interval shortening. The MARC concluded that the available data does not support an association between duloxetine use and the development of QT prolongation/TdP. Therefore, no data sheet changes are required at this time.

Recommendation 1

The MARC recommended that further changes be made to the NZ citalopram data sheet in line with the FDA's recommendations made in March 2012 of replacing the previous contra-indications with precautionary statements.

Recommendation 2

The MARC recommended that the NZ escitalopram data sheet be updated to include a warning that escitalopram is associated with a dose-related risk of QT interval prolongation and it be used with caution in patients who have other risk factors for QT prolongation.

Recommendation 3

The MARC recommended that the NZ amitriptyline data sheet be updated to include information on the risk of QT prolongation in line with the US and EU data sheets, along with including a more general warning on the risk of cardiotoxicity in association with the TCAs.

Recommendation 4

The MARC recommended that that the NZ nortriptyline data sheet be updated in line with the amitriptyline data sheet.

Recommendation 5

The MARC recommended that the NZ clomipramine data sheet be updated in line with the amitriptyline data sheet.

Recommendation 6

The MARC recommended that the NZ trimipramine data sheet be updated to include a warning that QT prolongation has been reported in association with other TCAs and it is unclear if trimipramine is associated with this adverse effect.

Recommendation 7

The MARC recommended that Medsafe request the product sponsor to clarify the statement regarding a saline purge contained in the NZ trimipramine data sheet.

Recommendation 8

The MARC recommended that the NZ doxepin data sheet be updated in line with the amitriptyline data sheet.

Recommendation 9

The MARC recommended that Medsafe request the sponsor of doxepin to remove the statement from the data sheet stating that doxepin carries less risk of adverse cardiovascular events than other TCAs.

Recommendation 10

The MARC recommended that the NZ dosulepin data sheet be updated in line with the amitriptyline data sheet.

Recommendation 11

The MARC recommended that NZ maprotiline data sheet be updated with the warnings on the risk of QT prolongation, along with including a more general warning on the risk of cardiotoxicity in line in line with the TCA data sheets.

Recommendation 12

The MARC recommended that NZ mianserin data sheet be updated to include a statement that there have been case reports of QT prolongation/TdP in association with mianserin; however, causality has not been shown. They also recommended that Medsafe contact the product sponsor, requesting further details on the cases reported to them.

Recommendation 13

The MARC recommended that the NZ fluoxetine data sheets be updated in line with the citalopram data sheet changes.

Recommendation 14

The MARC recommended that the NZ paroxetine data sheets be updated in line with the citalopram data sheet changes.

Recommendation 15

The MARC recommended that Medsafe determine if a thorough QT study is to be performed for paroxetine, and if so, Medsafe should seek assurance that the results will be communicated to Medsafe as soon as possible.

Recommendation 16

The MARC recommended that the NZ sertraline data sheets be updated in line with the citalopram data sheet changes.

Recommendation 17

The MARC recommended that the NZ fluvoxamine data sheet be updated in line with the citalopram data sheet changes.

Recommendation 18

The MARC recommended that the NZ moclobemide data sheet be updated to include information on the risk of QT prolongation/TdP in association with overdose.

Recommendation 19

The MARC recommended that the NZ mirtazapine data sheet be updated to include QT prolongation/TdP as a rare ADR and/or an effect of overdose.

Recommendation 20

The MARC recommended that Medsafe determine if a thorough QT study is to be performed for mirtazapine, and if so, Medsafe should seek assurance that the results will be communicated to Medsafe as soon as possible.

Recommendation 21

The MARC recommended that the sponsor for venlafaxine be requested to clarify the information regarding the risk of QT prolongation and TdP contained in the Warnings and Precautions section.

Recommendation 22

The MARC recommended that the sponsor of reboxetine be requested to provide further details on the thorough QT study carried out by Fleishaker et al published in 2001, and that this information be brought back to the Committee.

Recommendation 23

The Committee recommended that a Prescriber Update article be published advising healthcare professionals of the data sheet update to antidepressants regarding QT prolongation and TdP.

3.2.2 Serotonin syndrome with the use of fentanyl, ondansetron, or donepezil in combination with a serotonergic agent

Background

The purpose of this review was to consider whether there is an increased risk of serotonin syndrome (SS) when taking fentanyl, ondansetron or donepezil in combination with a serotonergic agent.

The signals for these possible associations have come from a range of sources. In April 2012, an article was published in the Canadian Adverse Reaction Newsletter to remind healthcare professionals and patients to report cases of SS suspected of being associated with the use of fentanyl. The possible associations of ondansetron or donepezil and SS were considered in separate publications in the WHO Pharmaceuticals Newsletter in April and June 2012.

Serotonin toxicity is characterised by the presence of a triad of clinical features: neuromuscular excitation, autonomic stimulation and changes in mental state. Serotonin toxicity may be mild (serotonergic features that may or may not concern the patient), moderate (toxicity which causes significant distress and deserves treatment, but is not life-threatening) or severe (a medical emergency characterised by rapid onset of severe hyperthermia, muscle rigidity and multiple organ failure).

Serotonergic medicines most commonly associated with SS include selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and serotonin noradrenaline reuptake inhibitors (SNRIs).

Any serotonergic agent has the potential to cause SS; however, the effect is generally thought to be dose-dependent and predictable, rather than an idiosyncratic reaction. Medicines with effects on catecholamines, tryptamine and dopamine may have secondary effects on serotonin release or reuptake and also be implicated.

The true incidence of SS is difficult to estimate as many cases go unrecognised due to lack of awareness of the syndrome and the difficulty in diagnosis. The awareness is increasing; however, and along with the growing number of serotonergic agents available and the increased use of these in clinical practice, the incidence of SS is rising. SS is most likely to occur when the serotonergic agent is first started or dosage is increased, or with the addition of a second serotonergic agent.

Neuroleptic Malignant Syndrome (NMS) is a rare, life-threatening idiosyncratic reaction which is difficult to predict. Differentiating between NMS and SS can be challenging because of shared clinical features, in particular pyrexia, hypertonia, and mental state changes. NMS is associated with the use of antipsychotic medications and is further characterised by hyporeflexia, haemodynamic dysregulation, elevated serum creatine kinase and rigors. SS in general occurs with use of multiple serotonergic medications and is, distinct from NMS, associated with hyperreflexia or clonus. The agents which precipitate each syndrome are somewhat indicative; however, this becomes difficult to assess when concomitant medications are used. Moreover, serotonergic agents, most commonly SSRIs, are often implicated in SS but can also contribute to NMS as they are indirect dopamine antagonists.

The Committee was asked to advise whether:

an increased risk of serotonin syndrome when using a serotonergic agent in combination with ondansetron, fentanyl, or donepezil has been established
any regulatory action needs to be taken (and if so what this action should be) • the results of this review should be communicated (and if so how).

Discussion

The Committee noted the 2012 Medsafe report.

The Committee considered the three medicines separately.

The Committee noted that the signal for the association with fentanyl came from an article in the Canadian Adverse Reaction Newsletter. The authors considered that there was a potential association of fentanyl with SS, when used concomitantly with a serotonergic agent. The Committee noted that Health Canada is reviewing the available evidence on the association and will communicate any new safety information or action resulting from the review.

The Committee reviewed the published literature describing SS precipitated by fentanyl in patients receiving other serotonergic agents. They agreed that the literature supports the association. The Committee noted that CARM has received four reports of SS in association with fentanyl.

The MARC reviewed the NZ fentanyl data sheet and noted that it currently contains some adverse reactions which could also be symptoms of SS. They recommended that the data sheet warnings be strengthened with respect to interactions with other serotonergic agents, particularly monoamine oxidase inhibitors (MAOIs).

The Committee noted that the possible signal for ondanestron came from VigiBase, the World Health Organisation's database. Seven of the nine cases (as at January 2012) reported other medicines that, alone or in combination with other drugs, are known to have the ability to cause SS. The Committee reviewed the published literature describing ondansetron in association with SS. They agreed that there was insufficient evidence at present to confirm an association. They noted that the use of ondansetron is increasing, and recommended that more information be sought by placing ondansetron and the risk of SS on .

The possible signal for donepezil also came from VigiBase. All 13 reports (as at October 2011) showed that SSRIs, SNRIs or the Serotonin Antagonist and Reuptake Inhibitor (SARI) were also co-reported. The Committee noted that clinical trials of donepezil included six million patient days of exposure with no reports of SS. Post market and literature reports indicate a very rare incidence of SS in association with donepezil, and the Committee agreed that there was insufficient evidence to suggest an association at this time.

The Committee noted the review by the European Medicines Agency Pharmacovigilance Working Party, which concluded that there is not currently enough evidence for a causal relationship between donepezil and SS. They considered that there was however, enough evidence of an increased risk of NMS in patients treated with donepezil. The Working Party recommended that if a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, donepezil should be discontinued. They also required changes to the summary of product characteristics (SPC) of all donepezil-containing products authorised in the European Union to include information about NMS as an adverse reaction. The Committee agreed that as the evidence supported an association between donepezil and NMS, it was recommended that the data sheet be updated to include information on the risk of NMS.

The MARC agreed that SS was difficult to diagnose and that awareness should be raised amongst prescribers, in particular differentiating between SS and NMS. The MARC recommended that a Prescriber Update article be published to raise awareness amongst healthcare professionals, and should include the symptoms of SS and NMS, how to differentiate between the two syndromes, and what to do if a patient presents with symptoms.

Recommendation 24

The MARC recommended that the warnings section in the NZ data sheet for fentanyl be strengthened with respect to interactions with other serotonergic agents.

Recommendation 25

The MARC recommended that more information about a possible association between ondansetron and the risk of serotonin syndrome be sought by including the combination on.

Recommendation 26

The MARC recommended that the NZ data sheet for donepezil be updated to include information in the warnings and precautions section about the risk of NMS. NMS also to be listed as an adverse reaction.

Recommendation 27

The MARC recommended that a Prescriber Update article be published to raise awareness amongst healthcare professionals, and include the symptoms of serotonin syndrome and neuroleptic malignant syndrome and how to differentiate between the two syndromes, what to do if a patient presents with symptoms.

3.2.3 Pantoprazole/lansoprazole and hypomagnaeseamia

Background

The potential safety signal of pantoprazole/lansoprazole and hypomagnesaemia was placed on on 1 September 2011. The purpose of this report was to review the evidence of an association between pantoprazole/lansoprazole and hypomagnesaemia.

An association has already been detected between omeprazole and hypomagnesaemia and the NZ data sheets updated accordingly. The purpose of placing this issue on was to investigate whether hypomagnesaemia is a class effect with the proton-pump inhibitors (PPIs).

The Committee was asked to advise whether there is enough evidence to request sponsors to update their data sheets to include information on hypomagnesaemia in the warnings and adverse effects sections of pantoprazole and lansoprazole.

Discussion

The Committee noted the 2012 Medsafe report.

The Food and Drug Administration (FDA) published a safety announcement in March 2011 stating that low magnesium levels can be associated with long-term use of PPIs. The UK Medicines and Healthcare Products Regulatory Agency (MHRA) published information about this issue in Drug Safety Update in April 2012.

The Committee reviewed the published literature and agreed that whilst overall the number of case reports is low, under-reporting is likely as serum magnesium concentration is not always routinely measured. They agreed that the data reviewed here are suggestive of a class effect for PPIs causing hypomagnesaemia. Supporting factors included that patients only recovered when PPI treatment was discontinued, cases of positive rechallenge with the same PPI and upon switching to an alternative PPI. It was noted that in the event of a rechallenge the hypomagnesaemia occurred within a much shorter time scale.

The Committee noted that hypocalcaemia may also be linked with hypomagnaesemia.

The Committee noted thatprior to this issue being included on CARM had received one report of hypomagnesaemia with pantoprazole and no reports with lansoprazole. Following the listing one additional report was received for pantoprazole. This likely reflects the lower use of lansoprazole.

The MARC considered that there is enough evidence to include a warning about the risk of hypomagnesaemia in the data sheets for pantoprazole and lansoprazole and recommended that the NZ data sheets be updated to include this warning, along with the possible association of hypocalcaemia. The Committee recommended that this be communicated to healthcare professionals via a Prescriber Update article.

Recommendation 28

The Committee recommended that the NZ data sheets for pantoprazole and lansoprazole be updated to include a warning about the risk of hypomagnesaemia as an adverse effect, along with the possible association of hypocalcaemia.

Recommendation 29

The Committee recommended that the association between hypomagnesaemia/hypocalcaemia and proton-pump inhibitors be communicated to healthcare professionals via a Prescriber Update article.

3.2.4 Varenicline tartrate IMMP study report

[..]

Background

Varenicline tartrate (Champix) was approved for use in New Zealand in March 2007 and placed on the Intensive Medicines Monitoring Programme (IMMP) in that same year. The IMMP study report was submitted to Medsafe in June 2012 and forms the basis for this latest review by the MARC.

The MARC has previously reviewed varenicline on several occasions. In March 2008, the MARC was notified that psychiatric reactions were emerging as a possible safety issue with varenicline. At that time, the NZ data sheet had recently been updated to include information about psychiatric adverse events and update the precautions section.

In March 2009, the MARC was presented with an overview of the interim IMMP results from the first year of the varenicline study. At that time, the most common adverse effects reported were psychiatric events, including depression, suicidal ideation, sleep disorders, anxiety disorders and withdrawal symptoms. The MARC recommended that an article be published in Prescriber Update describing the psychiatric adverse events that have been reported in association with varenicline use and reminding prescribers to continue reporting adverse drug reactions. This Prescriber Update article was published in May 2009.

In December 2009, the MARC reviewed the IMMP report following completion of the first year of follow up of the IMMP cohort. Medsafe also provided an update on the varenicline safety profile, including a summary of the latest Periodic Safety Update Report (PSUR) and interim results from a UK based Prescription Event Monitoring (PEM) study. Psychiatric events were the most common adverse effects reported particularly depression and sleep disturbance. The MARC noted that the majority of these psychiatric adverse effects were now listed in the NZ varenicline data sheet. The MARC agreed that no regulatory action was required at this time and noted that Medsafe will continue to monitor and evaluate international regulatory activity and safety-related data as it arises and would report back to the MARC as necessary.

In December 2010, an article was published in Prescriber Update reminding prescribers about the recommended course of treatment. This followed an IMMP finding that patients were regularly not receiving the full recommended 12 week course.

In September 2011, the MARC reviewed varenicline and cardiovascular events and were asked to to advise whether a causal association between varenicline treatment and cardiovascular events had been demonstrated and if any regulatory action was recommended. The MARC considered that although cardiovascular related safety concerns have been raised in association with varenicline, a causal relationship had yet to be demonstrated. The MARC agreed that this information did not alter the benefit-risk balance for varenicline, which remained positive. The MARC recommended that the NZ varenicline data sheet be updated to include information about reports of cardiovascular related adverse events associated with the use of varenicline. The data sheet was updated as recommended by the MARC.

A Prescriber Update article was published in March 2012 with an update on the interim findings from the IMMP study to date.

The data for the IMMP study were obtained from dispensing data collected from community and hospital pharmacies for four years (from 1 April 2007 to 31 March 2011). Follow-up questionnaires were sent to all identifiable patients with identifiable prescribers. The IMMP questionnaire asked doctors to document:

smoking history
previous attempts at smoking cessation
any past medical history of psychiatric illness, convulsions/seizures, ischaemic heart disease or any other significant history • new clinical events (since starting varenicline treatment)
details of first treatment course of varenicline, including reason for stopping treatment
details of further courses of varenicline
current smoking status
concomitant medicines.

Patient follow-up and adverse event analysis was presented in the IMMP report for the first three years of the study. The report did not include patient questionnaire responses and adverse event information for patients who were dispensed the medicine in the fourth year of the study. In the IMMP analysis, the event period included the month after the patient stopped taking varenicline. Events that occurred between one month and six months after stopping varenicline were also assessed and defined as 'post-medicine' events. The IMMP report assessed each drug-event relationship as 'definite', 'probable', 'possible', 'unlikely' or 'unclassified' as defined by the WHO. The IMMP report assessed the specific safety issues of psychiatric adverse events, suicide and suicidal ideation, memory impairment, cardiovascular adverse events, glycaemic control, adverse events in the eye, haematological events, adverse events in the skin and pregnancy.

PHARMAC began funding varenicline during the final year of the study, in October 2010. Prior to this, varenicline was not funded and patients were required to meet the full cost of the medicine.

The purpose of this 2012 Medsafe report was to review the IMMP study report for varenicline and determine whether further information is required, or if any actions are necessary as a result of this report.

The Committee was asked to advise whether:

any regulatory action is recommended
changes to the medicine data sheet are warranted
any communication is required.

Discussion

The Committee noted the 2012 Medsafe report.

The Committee noted that during the four year period of the IMMP study, 23,721 patients were dispensed varenicline and of these less than 40 % of valid questionnaires were returned from the first three years. The Committee considered that this low response rate limited the conclusions that could be drawn from the study. The data show a large increase in dispensings in the fourth year, which the Committee considered was likely to be a direct result of PHARMAC funding, which began six months into the final year. The Committee noted that the follow-up data did not include any of the 10,882 patients who were dispensed varenicline in the fourth year of the study, and that no patient follow-up was analysed for those patients who were dispensed the medicines after it was funded. The Committee noted that as the cost of treatment was one of the main reasons for stopping varenicline prematurely, it would have been interesting to know if the treatment duration altered after varenicline was funded. The MARC recommended that this data and an analysis of this data be provided.

The IMMP questionnaire specifically enquired whether the patient had a medical history of psychiatric illness, convulsions/seizures, ischaemic heart disease or any other significant history. Of the responses, 1032 were stated to have some other significant history, of which no further details were provided. The Committee agreed that the lack of this information was a limiting factor.

The Committee noted that in the IMMP analysis, the event period included the month after the patient stopped taking varenicline. Events that occurred between one month and six months after stopping varenicline were also assessed and defined as 'post-medicine' events. The Committee was unclear why these events were included in the analysis and considered that these data should be included as a separate data set. The MARC recommended that a re-analysis of the data be undertaken, removing 'post-medicine' events.

Adverse events that occurred in the first three years of the IMMP study were examined. The occurrence of the top ten events reported during varenicline treatment (including the month after the patient stopped varenicline) was reported. The Committee considered that further information regarding these events is necessary in order to draw robust conclusions. The Committee considered that adverse event data is confounded by the symptoms of nicotine withdrawal. The Committee agreed that the symptoms of nicotine withdrawal are well documented, and these are many of those attributed to Champix in the IMMP analysis.

The Committee reviewed the psychiatric adverse events reported in the study. They noted that in the MARC review of 2009, the MARC was presented with a report following completion of the first year of follow up of the IMMP cohort. Psychiatric events accounted for one third of all events identified in the IMMP study at this time. The MARC noted that the majority of these events were now listed in the Champix data sheet. The MARC agreed that no regulatory action was required at that time. The 2012 IMMP report stated that the most commonly reported psychiatric events were depression, insomnia, dreams, paranoia, fatigue, sleep disturbance, depression worse, anxiety, irritability, depersonalisation, stress reaction, mood swings, somnolence, concentration impaired, malaise and suicide ideation. The Committee noted that the IMMP report goes on to conclude that there is a causal relationship for the majority of these events and that psychiatric reactions including sleep disturbances and symptoms of depression are common adverse reactions to varenicline. They agreed that no data was provided to support this conclusion and recommended that full case details be provided in order for a full analysis to be undertaken. They considered that this was particularly relevant due to the finding that 18 % of patients who returned a valid questionnaire had a history of psychiatric illness. The Committee agreed that the data in the complete IMMP report does not provide sufficient evidence to require any further updates to the data sheet with respect to psychiatric adverse events. The MARC recommended that this supporting evidence be provided.

The Committee reviewed the data provided on suicide and suicidal ideation. Suicide and suicidal ideation adverse events were identified in patients for the first three years of the study. There were five cases of completed suicide and one case of fatal overdose reported. The Committee noted that the IMMP report states of these six cases, three occurred whilst the patient was on varenicline treatment or within a month of stopping. A summary of these cases is provided below:

Age Group	Gender	Time from last dose to death	Past medical history
20-30	M	On medicine	Depression
31-40	F	65 days	Depression
41-50	M	14 days	Nil reported
51-60	F	164 days	Unknown
	M	143 days	Possible depression
>60	M	19 days	Unknown

The Committee considered that the inclusion of the remaining cases of suicide occurring more than one month after treatment ceased, needs to be justified. In addition, of the six cases, three patients appeared to have a history of depression, and in another case, it was unclear if the patient had been taking varenicline. They agreed that the report does not provide sufficient evidence to assess causality for either suicide or suicidal ideation. The Committee recommended that this section of the report be reanalysed, taking into account the limitations of the data, confounding factors, and the nature of the population included in the study. They reviewed the information contained in the current Champix data sheet regarding suicide and suicidal ideation, and agreed that given the evidence provided, the data sheet contain adequate information about suicide and suicidal ideation at this time.

There were six reports of memory impairment identified in the first three years of the IMMP study. Further analysis identified seven more reports in the total four year cohort. Memory impairment is not listed in the NZ data sheet for varenicline. The Committee noted that the varenicline data sheet states that difficulty in concentration has been associated with smoking cessation with or without treatment, and that this was a confounding factor, amongst others such as concurrent medical problems or medications, which had not been adequately addressed in the IMMP report.

The Committee noted that the IMMP report contains very limited additional information about cardiovascular adverse events than that presented to the MARC in September 2011. They noted that the FDA has requested a further study (called 'CAT') of approximately 8000 patients (comparing varenicline, bupropion and nicotine replacement therapy) with the study designed to have major cardiovascular events as a primary outcome. The results of this study are not likely to be published until 2017. The Committee recommended that the results of the CAT study be reviewed when they are published.

Following a report of a possible link between varenicline and hyperglycaemia published by Health Canada in Type 1 and Type 2 diabetics, the IMMP reviewed all reports of new-onset hyperglycaemia, impaired glucose tolerance, diabetes mellitus, non-insulin-dependent diabetes mellitus and worsening diabetes mellitus in the cohort. The Committee noted that of the reports of altered glycaemic control, none were assessed as having a 'probable' relationship with varenicline and only 10 of the 29 reports were assessed as having a 'possible' relationship with varenicline. The current NZ Champix data sheet contains a warning that dose adjustments of insulin may be required during smoking cessation, and the Committee agreed that no further action was required at this time.

The IMMP study identified 39 events in the eye group that occurred whilst taking varenicline and within one month of stopping. The NZ data sheet includes a range of eye disorders in the adverse events section, and the Committee agreed that no further action was required at this time.

In the first three years of the IMMP study, there were 44 adverse events in the haematological group, of which 19 occurred whilst the patient was taking the medicine or within one month of stopping. No other information about the events was included in the report. The Committee noted the information contained in the current NZ data sheet regarding haemorrhagic events and agreed that no action was required at this time.

The IMMP study identified 89 events in the skin group that occurred whilst taking varenicline and within one month of stopping. The Committee considered that there was inadequate information in the report to undertake a full analysis and agreed that no further action was required at this time.

The utilisation and safety of varenicline in pregnancy has been investigated by the IMMP during the monitoring of varenicline because of the scarcity of information on this issue. The study identified 15 reports of exposure to varenicline during pregnancy. Of these cases there were no reports of major abnormalities and one report of a minor abnormality (ankyloglossia). The varenicline data sheet states that the safety of varenicline in human pregnancy has not been established and that the use of Champix in pregnant women is not recommended. The Committee noted that the product sponsor routinely analyses pregnancy reports in the Periodic Safety Update Review (PSUR) and agreed that no further action is required at this time.

The Committee agreed that there is a lack of discussion throughout the report of the limitations of the data, and recommended that this be addressed. They considered that there is inadequate discussion of possible confounding factors or a comparison with other data sources to place any possible safety signals in context. The MARC recommended that these deficiencies be addressed.

The MARC considered that in order in to understand the profile of varenicline use in NZ, it was necessary that an overall summary of all event reported be provided, along with line listings of all cases. The MARC recommended that these be requested from the IMMP.

The MARC recommended that the IMMP report on varenicline be brought back to the Committee when sufficient information and clarification had been provided to enable a robust review of the conclusions stated by the IMMP and whether any regulatory action is required,

Recommendation 30

The MARC considered that the varenicline IMMP study report has a number of deficiencies and does not represent a "final" report, and recommended that the IMMP be requested to provide further information.

Recommendation 31

The MARC recommended that data from the fourth year of the study and an analysis of these data be provided. Recommendation 32 The MARC recommended that a re-analysis of the IMMP data be undertaken, removing events that occurred between one month and six months after stopping varenicline ('post-medicine' events).

Recommendation 33

The Committee recommended that full case details be provided relating to the section of the report regarding psychiatric events be provided.

Recommendation 34

The Committee recommended that the section of the report regarding suicide and suicidal ideation be reanalysed, taking into account the limitations of the data, confounding factors, and the nature of the population included in the study.

Recommendation 35

The Committee recommended that the results of the CAT study requested by the FDA be reviewed when they are published.

Recommendation 36

The Committee recommended that the lack of discussion in the IMMP report regarding the limitations of the data be addressed. Recommendation 37 The Committee recommended that the lack of discussion in the IMMP report regarding possible confounding factors and comparison with other sources be addressed.

Recommendation 38

The Committee recommended that an overall summary of all events reported in the IMMP study, along with line listings of all cases be provided.

Recommendation 39

4. Matters arising from the New Zealand Pharmacovigilance Centre

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1 Potential Safety Signals from Single Case Reports

No potential safety signals were identified by CARM this quarter.

4.1.2 Fatal Cases (Causal Cases Only)

Members were given a brief description of the fatal reports for which CARM had assessed the causality to be at least possible. The Committee were given the option of requesting that any particular reports be discussed at the current or a subsequent meeting if they considered that there may be a safety issue that prescribers should be informed about or for which regulatory action was required.

The Committee did not consider any of the reports required further action.

4.1.3 Special Populations: Serious Cases Associated with Medicines in Children under 18 years (Causal Cases Only)

Reports of serious cases associated with medicines in children under 18 years were briefly outlined for the Committee. The Committee were given the opportunity to request further information on particular reports which may be discussed at a future meeting.

The Committee did not consider any of the reports required further action.

4.1.4 Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Children under 18 years

Reports of events occurring in children under 18 years were briefly outlined for the Committee. The Committee was given the opportunity to request further information on particular reports which may be discussed at a future meeting.

The Committee did not consider any of the reports required further action.

4.1.5 Special Populations: Serious Non-Fatal Cases Causally Associated with Critical Terms in Patients Over 80 Years

Reports of events occurring in patients over 80 years were briefly outlined for the Committee. The Committee had the opportunity to request further information on particular reports which may be discussed at a future meeting.

The Committee did not consider any of the reports required further action.

5. ANNEXES

3.2.1 Antidepressants and the risk of QT prolongation

Medsafe. 2012. Drug induced QT prolongation and Torsades de Pointes.
CARM. 2012. Reports of increased QT interval and Torsades de Pointes with antidepressants and reports suggestive of these conditions.
Medsafe 2012. Summary and comparison of New Zealand, US and European antidepressant data sheet information.
Arizona CERT Centre for Education and Research on Therapeutics.
Drugs with risk of Torsades de Pointes.
Drugs to be avoided by congenital long QT patients.
www.azcert.org Accessed 3 September 2012.
Medsafe. 2012. Summary of published literature - Antidepressant use and the risk of QT prolongation/TdP.
Sala M et al 2006. Antidepressants: Their effects on cardiac channels, QT prolongation and TdP. Current Opinion in Investigational Drugs 7(3): 256-263.
Van Noord C et al. 2009. Psychotropic Drugs Associated with Corrected QT Interval Prolongation. Journal of Clinical Psychopharmacology 29(1): 9-15.
Wenzel-Seifert K et al. 2011. QTc Prolongation by Psychotropic Drugs and the Risk of Torsade de Pointes. Deutsches Arzteblatt International 108(41): 687-693.

3.2.2 Serotonin syndrome with the use of fentanyl, ondansetron, or donepezil in combination with a serotonergic agent

Signals
- Canadian Adverse Reactions Newsletter. 2012. Volume 22, Issue 2.
- WHO Pharmaceuticals Newsletter. No. 2, 2012
- WHO Pharmaceuticals Newsletter. No. 3, 2012
Dunkley, EJC, Isbister, GK, Sibbritt, D, Dawson, AH and Whyte. IM 2003. The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity. Quarterly Journal of Medicine, Sep; 96: 635-642.
Gurrera, RJ, Caroff, SN and Cohen A et al. 2011. An International Consensus Study of Neuroleptic Malignant Syndrome Diagnostic Criteria Using the Delphi Method. Journal of Clinical Psychiatry, Sep; 72: 9, 1222-1228 4.
CARM. 2012. Serotonin syndrome with fentanyl, ondansetron, or donepezil as an involved medicine.

3.2.3 Pantoprazole/lansoprazole and hypomagnaeseamia

CARM. 2012. Review and Analysis of issue - Pantoprazole/Lansoprazole and hypomagnaesaemia.

3.2.4 Varenicline tartrate IMMP final report

IMMP.2012. Varenicline tartrate Final report for Medsafe.
Medsafe. 2009. Psychiatric reactions with varenicline: interim results from intensive monitoring in New Zealand. Prescriber Update 30: 9
Medsafe. 2010. The use of varenicline (Champix) in NZ: key finding from IMMP study Prescriber Update 31: 22
Medsafe. 2012. IMMP update: varenicline (Champix) monitoring. Prescriber Update 33: 9
Pfizer New Zealand Ltd. 2012. Champix (varenicline) data sheet.
Health Canada. 2011. Varenicline and hyperglycemia in patients with diabetes. Canadian Adverse Reaction Newsletter 21(2): 3-4
Harrison-Woolrych M, Harmark L, Tan M, et al. 2012. Epistaxis and other haemorrhagic events associated with the smoking cessation medicine varenicline: a case series from two national pharmacovigilance centres. European Journal of Clinical Pharmacology

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 4.15 pm.

Associate Professor D Reith
Chair
Medicines Adverse Reactions Committee

Committees

Minutes of the 151st Medicine Adverse Reactions Committee Meeting 13 September 2012

Preface:

Minutes:

marc members present

marc secretariat present

MEDSAFE STAFF IN ATTENDANCE

Invited guests and experts IN ATTENDANCE

1. Matters of Administration

1.1 Welcome and Apologies

1.2 Minutes of the 150th MARC Meeting

1.3 Dates of Future MARC Meetings

1.4 Potential Conflicts of Interest

1.5 Prescriber Update

1.5.1 Prescriber Update. Volume 33, Number 3. September 2012

Discussion

2. STANDING AGENDA ITEMS

2.1 Report on Standing Agenda Items from Previous Meetings of the MARC

3. pharmacovigilance issues

3.1 Matters Referred to the MARC under Section 36 of the Medicines Act 1981

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Antidepressants and the risk of QT prolongation

Background

Discussion

Recommendation 1

Recommendation 2

Recommendation 3

Recommendation 4

Recommendation 5

Recommendation 6

Recommendation 7

Recommendation 8

Recommendation 9

Recommendation 10

Recommendation 11

Recommendation 12

Recommendation 13

Recommendation 14

Recommendation 15

Recommendation 16

Recommendation 17

Recommendation 18

Recommendation 19

Recommendation 20

Recommendation 21

Recommendation 22

Recommendation 23

3.2.2 Serotonin syndrome with the use of fentanyl, ondansetron, or donepezil in combination with a serotonergic agent

Background

Discussion

Recommendation 24

Recommendation 25

Recommendation 26

Recommendation 27

3.2.3 Pantoprazole/lansoprazole and hypomagnaeseamia

Background

Discussion

Recommendation 28

Recommendation 29

3.2.4 Varenicline tartrate IMMP study report

Background

Discussion

Recommendation 30

Recommendation 31

Recommendation 33

Recommendation 34

Recommendation 35

Recommendation 36

Recommendation 38

Recommendation 39

4. Matters arising from the New Zealand Pharmacovigilance Centre

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1 Potential Safety Signals from Single Case Reports

4.1.2 Fatal Cases (Causal Cases Only)

4.1.3 Special Populations: Serious Cases Associated with Medicines in Children under 18 years (Causal Cases Only)

4.1.4 Special Populations: Serious Cases Reporting Adverse Events Following Immunisation Terms with Vaccines in Children under 18 years

4.1.5 Special Populations: Serious Non-Fatal Cases Causally Associated with Critical Terms in Patients Over 80 Years

5. ANNEXES

3.2.1 Antidepressants and the risk of QT prolongation

3.2.2 Serotonin syndrome with the use of fentanyl, ondansetron, or donepezil in combination with a serotonergic agent

Minutes of the 151^st Medicine Adverse Reactions Committee Meeting 13 September 2012

1.2 Minutes of the 150^th MARC Meeting