Published: 20 July 2020
Revised:  17 August 2020

Committees

MINUTES OF THE 182nd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 182nd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
11 June 2020

Friday 7 August 2020

Secretary’s note regarding the minute below from the 182nd meeting of the Medicines Adverse Reactions Committee held on 11 June 2020. The minutes relating to item 3.1.1 Consideration of Cathejell (lignocaine) 2% gel under section 36 of the Medicines Act 1981 was delayed and were not included when the minutes were initially published.

The minutes have been updated below to include this section.   The one hundred and eighty second meeting of the Medicines Adverse Reactions Committee (MARC) was held on 11 June 2020 via videoconference. The meeting commenced at 9am and closed at 2.00pm.

MARC MEMBERS PRESENT

Associate Professor D Reith (Chair)
Dr C Cameron
Associate Professor D Menkes
L Te Karu
Associate Professor L Parkin
Research Associate Professor M Tatley
C Ryan
J Tatler
I Raiman
Professor L Stamp
Dr C Gresham
Dr S Hanna

MARC SECRETARIAT PRESENT

T Coventry (Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Manager, Clinical Risk Management)
G Hill (Senior Medical Advisor, Pharmacovigilance)
L Chan (Principal Technical Specialist, Pharmacovigilance)
M Storey (Senior Advisor, Pharmacovigilance)
V Cheer (Senior Advisor, Pharmacovigilance)
A Kerridge (Senior Advisor, Pharmacovigilance)
K Marsh (Advisor, Compliance)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting, acknowledging that the videoconference format represented a significant departure from the usual and was not the optimal platform for group discussion. Apologies were received from Dr K Eggleton.

1.2 Minutes of the 181st MARC Meeting

The minutes of the 181st meeting were accepted as a true and accurate record of the meeting.

1.3 Potential Conflicts of Interest

Committee members submitted their Conflicts of Interest Declaration forms electronically 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.

2.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

2.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

2.1.1 Overview of Reporting

As follow up to the March 2020 meeting, the Committee discussed the issue of the ethnicity of patients in the CARM Quarterly Report. The inclusion of separate tables in the CARM Quarterly Report for cases in Māori and Pacific populations was explained to the Committee, and the complex nature of ethnicity reporting was discussed.

The Committee noted that there is likely to be under-reporting of adverse drug reactions particularly in Māori and Pacific populations and raised the possibility of initiating research into the factors contributing to under-reporting in these groups. The Committee agreed that a proposal should be prepared by the CARM for presentation to the Health Research Council outside of the Committee process.

2.1.2 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 discussed case 135633, where a patient experienced hyperkalaemia and cardiac arrest after administration of amphotericin. This is the second fatal case report received by CARM which describes a possible association between amphotericin and hyperkalaemia. The Committee agreed this case should be highlighted in Prescriber Update.

Recommendation 1

The Committee recommended that this case of hyperkalaemia with amphotericin be highlighted in Prescriber Update.

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

Reports of serious cases associated with medicines in patients under 18 years were briefly outlined for the Committee.

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

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

Reports of events occurring in patients under 18 years were briefly outlined for the Committee.

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

2.1.5 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 discussed case 136060, where a patient experienced pancytopenia after concomitant prescribing of allopurinol and azathioprine. Medsafe confirmed that an article regarding this interaction will be published in a future edition of Prescriber Update.

2.1.6 Special Populations: Causal and Serious Cases in Patients Aged 18 to 80 Years

Reports of events occurring in patients 18 to 80 years were briefly outlined for the Committee.

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

2.1.7 Special Populations: Cases in patients aged 65 years and over – Ethnicity Māori

Reports of events occurring in patients aged 65 years and over (ethnicity Māori) were briefly outlined for the Committee.

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

2.1.8 Special Populations: Cases in patients aged 65 years and over – Ethnicity Pacific Peoples

Reports of events occurring in patients aged 65 years and over (ethnicity Pacific peoples) were briefly outlined for the Committee.

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

2.1.9 Special Reports: Lamotrigine Update

CARM gave an overview of reports received from 1 May 2019 to 21 May 2020 that describe a reaction to a lamotrigine-containing product following the decision by PHARMAC to move to one funded brand of lamotrigine.

The Committee considered there has been a reduction in the rate of reporting since the previous meeting.

The Committee noted a recent fatal case is before the Coroner and they await the coronial findings. The Committee expressed sympathy to the family of the patient who died.

The Committee noted that from 1 May 2019 to 21 May 2020 there have been a total of 204 case reports that describe a reaction to a lamotrigine-containing product of which 185 report a brand switch. This number includes six cases reporting death as an outcome.

CARM and the Committee will continue to monitor reports of reactions to lamotrigine-containing products.

3.0 PHARMACOVIGILANCE ISSUES

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

3.1.1 Consideration of Cathejell (lignocaine) 2% gel under section 36 of the Medicines Act 1981

Background

The purpose of this report was to review the information provided by KSJ Pharmatech Limited (the sponsor) that had been supplied by Montavit (the manufacturer) in response to the section 36 notice.

In June 2019 it was announced that PHARMAC were to award sole subsidy to Cathejell (lignocaine) 2% gel from November 2019. Following this decision Medsafe received notification from two DHBs expressing their concerns with Cathejell (lignocaine) 2% gel. The DHB’s outlined issues associated with the use of Cathejell (lignocaine) 2% gel, including:

  • A rough edge at the top of the applicator that is uncomfortable for patients and could cause harm.
  • Pain on insertion as the user found it difficult to create sufficient pressure to release the gel on insertion.
  • The gel was painful causing a ‘stinging’ sensation.
  • During insertion air bubbles can be introduced and there is potential to create a vacuum immediately following insertion.
  • It is easy to spill the product, potentially resulting in an incomplete dose.
  • The product requires training to ensure safe use, which is not currently available.

The New Zealand sponsor for Cathejell (lignocaine) 2% gel at the time, Healthcare Logistics NZ Limited, were issued with a notice under section 36 of the Medicines Act 1981 regarding Cathejell (lignocaine) 2% gel on 19 November 2019 outlining the reported safety concerns.

As at 1 April 2020 Cathejell (lignocaine) 2% gel has been removed from the PHARMAC schedule, and Instillagel Lido (lignocaine) 2% gel has sole subsidised supply. Instillagel Lido (lignocaine) 2% gel is an approved medicine New Zealand and the sponsor is Pharmacy Retailing (NZ) Limited trading as Healthcare Logistics.

The company have disagreed with the safety concerns outlined in the section 36 notice, but have proposed that a third-party company could provide training to users as a possible corrective action to reduce the risk of injury.

The Committee was asked to provide a recommendation on the acceptability of the risk-benefit profile of the medicine and whether any further regulatory action is needed.

Discussion

The Committee discussed the safety concerns associated with the product and considered the possible regulatory actions available to mitigate these concerns.

The Committee noted the current funding situation and noted that even if the product is not funded it would still be available for purchase in New Zealand. The Committee agreed that the safety of the product is the key issue, regardless of the funding status.

The Committee agreed that the product poses a risk of injury to patients, particularly through the sharp edge of the applicator tip, as evidenced by New Zealand reports. The Committee agreed that use of this type of product should not require extensive training, and that the risk associated with sharp edge of the applicator tip and force required to compress the accordion syringe would not be remedied by additional user training or product information.

The Committee agreed that the consent to distribute the medicine should be revoked. The appropriate timeframe for withdrawal of this medicine is to be determined by Medsafe.

Recommendation 2

The Committee recommended to the Minister's delegate that the sale and provision of Cathejell Lignocaine 2% gel be prohibited (ie, that the consent to distribute should be revoked), as it could no longer be regarded as a medicine that could be administered or used safely for the purposes indicated in the application for consent.

3.2 Matters Referred to the MARC by Medsafe

3.2.1 Antiepileptic medicines and neurodevelopmental disorders

Background

The purpose of this report was to review the literature and other information on neurodevelopmental adverse effects in children exposed to approved first-line antiepileptic drugs (AEDs) in utero. The review compared the risk of neurodevelopmental adverse effects between different AEDs, and examined whether the current data sheets contain adequate information on these risks.

Maintaining seizure control throughout pregnancy is important for both maternal and fetal health. It is therefore usually necessary for women with epilepsy to continue treatment with an AED throughout her pregnancy. Information on the potential risks associated with AEDs is necessary to enable women to make informed decisions about treatment options during pregnancy.

The data sheets for valproate, carbamazepine, phenytoin and phenobarbital include information on the risk of neurodevelopmental adverse effects. There is no mention of neurodevelopmental adverse effects in the lamotrigine, levetiracetam or topiramate data sheets.

Ministry of Health National Collections data indicates that over the past 10 years, the numbers of women using valproate, carbamazepine and phenytoin have decreased, while the numbers using lamotrigine and levetiracetam in pregnancy have increased.

Discussion

The Committee reviewed the available literature on risk of neurodevelopmental disorders in children exposed to antiepileptic drugs in utero. The pregnancy prescribing trends for each antiepileptic drug were noted. It was noted that many women need to continue taking antiepileptic drugs during pregnancy.

The Committee noted that the burden of neurodevelopmental disorders in children particularly for parents with long-term conditions such as epilepsy is significant.

The Committee reviewed the evidence presented and noted that an association between lamotrigine and Autism Spectrum Disorder had been identified in one network meta-analysis. The Committee debated whether the evidence from this one study was sufficient to be added to the lamotrigine data sheets.

The Committee noted that the data sheets for lamotrigine do not include any information regarding risk of Autism Spectrum Disorder. The limitations of the studies pertaining to this association were acknowledged. The Committee considered that any recommendation should take into account the uncertainty of the evidence, but that patients have a right to informed consent.

The Committee considered that the data sheets for lamotrigine should be updated with wording that reflects the level of evidence for an association with Autism Spectrum Disorder. It was acknowledged that the data sheets belong to the Sponsors, and any changes to the data sheets are at the discretion of the Sponsor.

Recommendation 3

The Committee recommended Medsafe writes to the sponsor about the possible association between lamotrigine and the development of autism spectrum disorder in children exposed in utero and whether this information should be included in the data sheet.

3.2.2 Fluconazole and use in pregnancy

Background

In February 2019, Bérard et al published a paper in the Canadian Medical Association Journal which concluded that any maternal exposure to fluconazole during pregnancy may increase the risk of spontaneous abortion and that doses higher than 150 mg during the first trimester may increase the risk of cardiac septal closure anomalies.

The Committee previously considered fluconazole and use in pregnancy at the September 2016 meeting. At this meeting, the Committee’s recommendations focussed on spontaneous abortions.

The purpose of this report was to review the data on fluconazole and its use in pregnancy. This report considered major congenital malformations and still births, as well as spontaneous abortions, as reported by Bérard et al.

Discussion

The Committee discussed the available evidence on use of fluconazole in pregnancy, including single dose treatment for vulvovaginal candidiasis.

The Committee had overall confidence in the study published by Bérard et al and noted that there were some limitations, but these were well managed. The Committee considered that information available to health care professionals should be updated to reflect the results of recent studies suggesting a possible association between low dose fluconazole treatment and adverse pregnancy outcomes. The plausible physiological basis for the association reinforced this opinion.

It was noted that the fluconazole usage data for New Zealand provided in the report relates only to pharmacy dispensing as there is no data available for over-the-counter sales. The number of units provided to women could be significantly higher. The Committee discussed the fact that there does not appear to be specific published guidance for New Zealand pharmacists around ruling out pregnancy before providing fluconazole.

The Committee considered that they should communicate with pharmacists and other health care professionals stating that topical treatment remains an effective first-line therapy for most pregnant women, and that questions around the possibility of pregnancy should be included in routine patient counselling.

Recommendation 4

The Committee recommended Medsafe writes to sponsors requesting fluconazole data sheet updates. The data sheet should include information on the effects of low dose fluconazole treatment during pregnancy, results from the Bérard et al study and pregnancy information harmonised across all fluconazole data sheets.

Recommendation 5

The Committee recommended that this topic be addressed in a Prescriber Update article and communicated to pharmacists, general practitioners, sexual health clinics and midwives through the relevant professional bodies.

3.2.3 Use of oral sedating antihistamines in children for sedation

Background

Oral sedating antihistamines are used for a range of conditions in both adults and children. Although the use of oral sedating antihistamines for insomnia is contraindicated for children under 12 years old, there are products available for use in children from the age of 2 years for sedation. Therefore, this paper focuses on the use of these medicines in children aged 2 to <12 years for sedation.

Guidelines suggest sedation in children can be considered for diagnostic, interventional, medical or surgical procedures, including dental procedures. There could be anecdotal evidence suggesting oral sedating antihistamines may be used during travel, such as for sedation on long-haul flights, but this doesn’t appear to be supported by clinical guidelines or information in lay media.

Discussion

Promethazine is currently the only oral sedating antihistamine that can be used in children from the age of 2 years. The Committee was advised Phenergan (the promethazine innovator product) was first approved for use in New Zealand in December 1969. Due to its date of approval, it is likely an assessment was never conducted as part of the approval process.

The Committee reviewed the available information about use of promethazine in children for sedation. It was noted that there is no efficacy data for use of promethazine as a sedative in children, and it does not appear in clinical or professional body guidelines in New Zealand or internationally. Products containing promethazine are restricted (pharmacist only) medicines, which can be purchased over-the-counter provided there is a consultation with a pharmacist at the time of purchase.

The Committee considered that there are more appropriate medicines to use for this indication and that sedation of children should occur under the guidance of a medical practitioner. The sale of promethazine for sedation of children in a pharmacy setting was considered inappropriate for children of any age.

The Committee was reminded this review does not cover the use of oral sedating antihistamines for other indications in children, and these indications will therefore remain unchanged at this time.

Recommendation 6

The Committee recommended that the indication for sedation of children be removed from all over-the-counter medicines containing sedating antihistamines.

Recommendation 7

The Committee recommended that this topic is communicated to healthcare professionals through a Prescriber Update article and with relevant professional bodies.

3.2.4 Protease inhibitors for Hepatitis C and risk of serious liver injury

Background

In August 2019 the US Food and Drug Administration (FDA) issued a warning concerning the rare occurrence of serious liver injury affecting some patients with advanced liver disease who were treated with the hepatitis C medicines Maviret, Zepatier, and Vosevi. The warning was based on 63 reported cases of worsening liver function in relation to treatment with these medicines, sometimes leading to liver failure and death.

Maviret, Zepatier and Vosevi all contain a hepatitis C virus (HCV) protease inhibitor. Maviret is the only product that is currently marketed and funded for use in New Zealand; Zepatier and Vosevi are approved but not available. Maviret is used for treating patients with chronic hepatitis C with none to mild liver impairment; it is not recommended in patients with moderate liver impairment and is contraindicated in patients with severe liver impairment.

Many of the patients in the cases reported to the FDA had moderate to severe liver impairment. In some cases, patients were incorrectly reported to have no or mild liver impairment when they had more severe liver disease. Other significant pre-existing risk factors were sometimes present.

Overall, data on potential hepatic adverse reactions in association with Maviret is limited and consists of case reports. No cases have been reported in NZ.

Discussion

The Committee reviewed the case reports of hepatic injury relating to protease inhibitors.

The Committee noted that Maviret is prescribed mostly by general practitioners in New Zealand and that there is significant complexity in prescribing. As the medicine is widely regarded as not requiring monitoring via blood tests, it was considered important to communicate the importance of prescribing the medicine to the right patient group. The Committee considered the data sheet should be updated to strengthen the warning not to use Maviret in patients with moderate to severe liver disease.

Recommendation 8

The Committee recommended that the risk of liver injury in patients with hepatitis C induced advanced liver disease treated with Maviret be addressed in a Prescriber Update article.

Recommendation 9

The Committee recommended that Medsafe write to the sponsor requesting updates to the data sheet to strengthen the warning to not use Maviret in patients with advanced liver disease.

4.0 MEDSAFE PHARMACOVIGILANCE ACTIVITIES

4.1 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.

4.2 Medsafe Pharmacovigilance Activities

The Committee noted the report detailing Medsafe’s recent pharmacovigilance activities.

4.3 Prescriber Update Volume 41, Number 2, June 2020

The Committee noted the latest edition of Prescriber Update.

4.4 Quarterly Summary of Medsafe Early Warning System

The Committee noted the quarterly summary of Medsafe safety communications.

5.0 OTHER BUSINESS

The Chair noted that while the videoconference format was adequate, the Committee meetings were more productive when held face-to-face. The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2.00pm.

Associate Professor D Reith
Chair, Medicines Adverse Reactions Committee
Date: 13 July 2020

Hide menus
Show menus
0 1 2 4 5 6 7 9 [ /