Published: 11 July 2017

Committees

MINUTES OF THE 170th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 170th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

8 June 2017

The one hundred and seventieth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 8 June 2017 at the Ministry of Health. The meeting commenced at 9am and closed at 3.10pm.

MARC MEMBERS PRESENT

Associate Professor D Reith (Chair)
Professor C Frampton
Dr N Cole
Dr S Jayathissa
Dr K Eggleton
I Raiman
C Ryan
J Tatler
Associate Professor D Menkes
Dr L Bryant
Dr R Savage

MARC SECRETARIAT PRESENT

J Prankerd (Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

R Pollock (Manager, Clinical Risk Management)
S Kenyon (Principal Technical Specialist, Pharmacovigilance)
A Taylor (Senior Advisor, Pharmacovigilance)
M Storey (Senior Advisor, Pharmacovigilance)
L Chan (Senior Advisor, Pharmacovigilance)
G Hill (Senior Medical Advisor, Pharmacovigilance)

INVITED GUESTS AND EXPERTS IN ATTENDANCE

Mr I Ross
Ms A Cossar

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Dr P Jones.

1.2 Minutes of the 169th MARC Meeting

The minutes of the 169th 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 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.

Associate Professor D Reith identified a potential conflict of interest from being a teacher of clinical pharmacology. The Committee discussed the potential conflict of interest and agreed Associate Professor D Reith should participate in the discussion of section 2.3 but be excluded from voting on all recommendations.

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

2.0 MEDSAFE PHARMACOVIGILANCE ACTIVITIES

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: www.medsafe.govt.nz/profs/MARC/Minutes.asp

2.1.1 Use of tramadol in children
June 2016 minute item 3.2.3

Recommendation 7

The MARC recommended the outcome of the FDA review investigating the use of tramadol in children aged 17 years and younger be reported back to the Committee at a future meeting.

Outcome

The outcome of the FDA review was published on 20 April 2017 (www.fda.gov/Drugs/DrugSafety/ucm549679.htm). The FDA are adding:

  • Contraindication to tramadol data sheets alerting that tramadol should not be used to treat pain in children younger than 12 years.
  • Contraindication to tramadol data sheets warning against its use in children younger than 18 years to treat pain after surgery to remove the tonsils and/or adenoids.
  • Warning to tramadol data sheets to recommend against use in adolescents between 12 and 18 years who are obese or have conditions such as obstructive sleep apnoea or severe lung disease, which may increase the risk of serious breathing problems.
  • Warning to mothers that breastfeeding is not recommended when taking tramadol due to the risk of serious adverse reactions in breastfed infants. These can include excess sleepiness, difficulty breastfeeding, or serious breathing problems that could result in death.
Discussion

The Committee discussed the statement published by the US FDA following their review on this issue. The Committee noted differences in the warnings and contraindications between recent New Zealand data sheet updates and United States statements. The Committee considered there are differences in the New Zealand and United States contexts. Tramadol is licensed and is being used in children 17 years and younger in New Zealand. The use of tramadol in the United States or Canada is not approved in children aged 17 years and younger.

The Committee noted that opioids together with an abnormal breathing pattern is a risk factor and deaths related to tramadol in the context of post tonsillectomy pain relief were included in the data presented to the US FDA. The Committee noted that whilst the data reviewed by the US FDA included fatal cases none of these cases occurred in the New Zealand context.

The Committee were reminded that there is a warning statement in the tramadol data sheet regarding the use of tramadol following recent tonsillectomy, adenoidectomy and throat surgery and that this is similar to that in codeine data sheets.

The Committee also discussed the use of tramadol by anaesthetists in a hospital context and considered tramadol is likely to be frequently used in hospitals. Appropriate post-operative monitoring was considered more important than substituting to another opioid.

There is value of having this medicine available for use post-operatively in New Zealand and therefore appropriate warnings regarding monitoring should be present in tramadol data sheets.

Considering the new information, the Committee recommended that use in children should continue however warnings regarding appropriate use in this population should be included in data sheets. The Committee recommended that the current warning in tramadol data sheets be updated to include specific mention of the context of the fatal cases. The Committee noted further communication on this issue would also be desirable.

Recommendation 1

The Committee recommended Medsafe requests the sponsors of tramadol-containing products update the current warning in the data sheets to state the context of the fatal cases.

Recommendation 2

The Committee recommended Medsafe includes information on the Committee's discussion in the MARC's Remarks section of Prescriber Update for this meeting.

Recommendation 3

The Committee recommended Medsafe communicates with The New Zealand Society of Otolaryngology, Head and Neck Surgery Incorporated and the Australian and New Zealand College of Anaesthetists to highlight the importance of monitoring for signs of toxicity or overdose when tramadol is used following recent tonsillectomy, adenoidectomy and throat surgery.

[Associate Professor D Menkes joined the meeting at this time.]

2.1.2 Minutes of the 168th MARC Meeting
December 2016 minute item 1.2

Recommendation 1

The Committee recommended Medsafe explore the possibility of publishing papers presented by Medsafe so that these are more readily available to the public.

Outcome

Medsafe has considered this recommendation and intends to trial publishing MARC reports following the June 2017 MARC meeting. Medsafe would value a short discussion at the end of each agenda item in section 3 to highlight areas where redaction may be required in each paper.

Discussion

The Committee noted that following this meeting the papers presented by Medsafe will be published on the Medsafe website at the same time as the minutes. It is intended that there will be a link to the reports from the minutes. Confidential information in each report will be redacted.

The Committee also discussed other possible avenues that could be utilised to increase awareness and widen exposure to the papers presented by Medsafe. The Committee noted that it is current practice for Medsafe to include a link to the minutes in MARC's Remarks and this is still considered adequate as a way for interested parties to access the minutes and, in turn, the reports.

Recommendation 4

The Committee recommended Medsafe communicates MARC's Remarks articles to various publications and organisations such as the New Zealand Medical Journal, the Goodfellow Unit and the Best Practice Advocacy Centre to increase awareness of papers presented to the Committee by Medsafe.

[Professor C Frampton joined the meeting at this time.]

2.1.3 Special Reports: Annual Report ACC Cases (January 2016 - December 2016)
March 2017 minute item 4.1.5

Recommendation 19

The Committee recommended Medsafe approaches ACC to explore possibilities for widening the criteria for sharing cases of adverse events to medicines resulting in treatment injury with Medsafe.

Outcome

Medsafe is engaging with ACC to explore possibilities for widening the criteria for sharing cases of adverse events to medicines resulting in treatment injury.

Discussion

The Committee noted Medsafe is engaging with ACC to explore possibilities for widening the criteria for sharing adverse event cases. The Committee are interested in the outcome of this discussion.

Recommendation 5

The Committee recommended Medsafe provide an update on the progress of this discussion at a future meeting.

There were no other standing agenda items for which the MARC made further recommendations.

2.2 Medsafe Pharmacovigilance Activities

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

The Committee discussed the importance of blood count monitoring for patients taking methotrexate and the risk of methotrexate being inadvertently given more frequently than once weekly. The Committee also discussed the concomitant use of methotrexate and folic acid in the elderly. The Committee considered that communication to highlight monitoring requirements for methotrexate and use with folic acid would be beneficial to further mitigate any risk of methotrexate inadvertently being given too frequently.

Recommendation 6

The Committee recommended Medsafe explores the possibility of developing a consumer information leaflet to highlight the importance of monitoring when taking methotrexate.

Recommendation 7

The Committee recommended Medsafe contacts vendors of electronic prescribing software to explore the introduction of alerts regarding appropriate monitoring of methotrexate and of use with folic acid.

Recommendation 8

The Committee recommended Medsafe includes an article on the prescribing and monitoring of methotrexate in a future edition of Prescriber Update.

2.3 Prescriber Update Volume 38, Number 2, June 2017

The Committee noted the latest edition of Prescriber Update and mentioned they were impressed with the quality of the publication. The Committee discussed possible avenues to disseminate Prescriber Update more widely as well as the promotion of Prescriber Update in medical schools to enhance the safe use of medicines.

Associate Professor D Reith identified a potential conflict of interest from being a teacher of clinical pharmacology. The Committee discussed the potential conflict of interest and agreed Associate Professor D Reith should participate in the discussion of section 2.3 but be excluded from voting on all recommendations.

Recommendation 9

The Committee recommended Medsafe communicates with relevant health professional schools and organisations to promote Prescriber Update and enhance the safe use of medicines in New Zealand.

2.4 Quarterly Summary of Medsafe Early Warning System

The Committee noted the quarterly summary of Medsafe early warning system communications.

[Dr S Jayathissa left the meeting at this time.]

3.0 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 Safety of antibiotic ear drops in children with grommets

Background

The Centre for Adverse Reactions Monitoring (CARM) received a report of Locorten-Vioform use in a child with grommets. The Locorten-Vioform data sheet contraindicates use in patients with a perforated ear drum. The Netherlands Pharmacovigilance Centre, Lareb, has also received reports which indicate ear drops had been used in patients with non-intact tympanic membranes. An assessment of the safety of using ear drops in children with grommets was considered necessary. The purpose of this report was to review the safety of using antibiotic containing ear drops in children with grommets.

Discussion

The Committee discussed the information presented to them.

The Committee discussed the differences in the risk of ototoxicity between the antibiotic containing ear drops when used in children with grommets or in patients with a perforated tympanic membrane and considered that there are differences in the risk of ototoxicity. The Committee considered that ciprofloxacin has less risk of ototoxicity than other antibiotic-containing eardrops.

The Committee noted current data sheet wording and made recommendations for data sheet updates.

Based on the available evidence, the Committee recommended that the sponsor for Ciproxin HC (quinolone) should be given the opportunity to remove the contraindication for use in patients with a perforated tympanic membrane and to replace it with a warning statement. The sponsor of Locorten-Vioform/Locacorten-Viaform (hydroxyquinolone) should include information in the data sheet on the risk of ototoxicity. The sponsors for Sofradex, Soframycin and Kenacomb (aminoglycosides) should add a warning statement indicating that the risk of ototoxicity is increased with increasing duration of use and continuation of treatment of symptoms.

The Committee additionally discussed the need for communicating this safety concern. The Committee considered this safety issue may also be an equity of access to medicines issue and the Committee's discussion should be communicated with PHARMAC.

Recommendation 10

The Committee recommended Medsafe gives the sponsor for Ciproxin HC ear drops the opportunity to remove the contraindication for use in patients with a perforated tympanic membrane and replace it with a warning statement.

Recommendation 11

The Committee recommended Medsafe requests the sponsor for Locorten-Vioform/Locacorten-Viaform to update the data sheet to include information on the risk of ototoxicity.

Recommendation 12

The Committee recommended Medsafe requests the sponsors for Sofradex, Soframycin and Kenacomb to add a warning statement indicating that the risk of ototoxicity is increased with increasing duration of use and continuation of treatment after resolution of symptoms.

Recommendation 13

The Committee recommended Medsafe considers including an article in a future edition of Prescriber Update on this topic.

Recommendation 14

The Committee recommended Medsafe communicates with PHARMAC to highlight the Committee's discussion on this topic.

The paper provided to the MARC on this topic can be found at www.medsafe.govt.nz/committees/MARC/Reports.asp

3.2.2 NSAIDs and spontaneous abortion

Background

On 11 October 2016, the Therapeutic Goods Administration (TGA) of Australia released their safety review on non-steroidal anti-inflammatory drugs (NSAIDs) and spontaneous abortion. The TGA reviewed data sheets and package warnings for information on the potential increased risk of miscarriage due to exposure in early pregnancy.

The purpose of this paper was to review the information on the risk of spontaneous abortion with the use of NSAIDs. Aspirin and indometacin are excluded from this review due to the conditions they are used to prevent or treat. Topical preparations such as gels and skin sprays are also excluded as systemic absorption from these formulations is expected to be low.

Discussion

The Committee discussed the evidence presented to them on the risk of spontaneous abortion from the use of NSAIDs. The Committee noted the potential for systemic exposure to occur from the use of eye drops however the Committee considered this to be low. The Committee also discussed the use of these medicines in different trimesters.

The Committee noted an association was seen in some studies and not in others, the choice of confounders differed and confounding between potential indications for using NSAIDs and spontaneous abortion is unlikely to be accounted for. Issues with the data may have also arisen from many of the studies being retrospective in design. The Committee considered the strength of the evidence to be equivocal. At this time, the Committee does not consider there is conclusive evidence to suggest an association between NSAIDs and spontaneous abortion.

Although the evidence to date is relatively weak, the Committee considered that a woman who is trying to get pregnant would want to know that spontaneous abortion from the use of NSAIDs is a potential concern. The Committee considered the focus should be on the perspective of the consumer and discussed possible wording options for a warning.

Recommendation 15

The Committee recommended Medsafe request sponsors update the data sheets with information on the risk of spontaneous abortion with the use of NSAIDs.

Recommendation 16

The Committee recommended Medsafe updates the Label Statements Database to include a warning for over-the-counter NSAID products.

The paper provided to the MARC on this topic can be found at www.medsafe.govt.nz/committees/MARC/Reports.asp

3.2.3 The risk of haemorrhage from concomitant use of statins and dabigatran

[Dr S Jayathissa re-joined the meeting at this time.]

Background

Medsafe became aware of an article published in the Canadian Medical Association Journal (CMAJ) examining the association between statin use and subsequent hospital admissions or emergency department visits for ischaemic stroke or major haemorrhage in patients with atrial fibrillation treated with dabigatran etexilate.

The authors consider that it is possible that co-administration of dabigatran and other inhibitors of carboxylesterase or p-glycoprotein could increase the absorption of dabigatran etexilate and/or prevent its bioactivation to dabigatran.

Considering the use of statins and dabigatran in New Zealand, Medsafe considered that these safety concerns should be reviewed by the Medicines Adverse Reactions Committee. The purpose of this paper was to review the information on the use of statins in patients taking dabigatran and the risk of stroke or haemorrhage.

Discussion

The Committee discussed the available evidence presented to them. The recent study published in the CMAJ looked specifically at the risk of haemorrhage and stroke from the use of simvastatin and lovastatin. Lovastatin is not available in New Zealand at this time.

The Committee considered the strength of the evidence to be relatively low. Limitations of the CMAJ article were noted as small participant numbers, the extent of statin use was uncertain, a large number of confounding variables were adjusted for which could produce inaccurate results when associated with small numbers of outcomes and the adjusted odds ratio was relatively small.

The Committee also noted that age is a confounder and those aged over 75 years are at a higher risk of both haemorrhage and thrombosis. Consequently confounders may be present between those who may be prescribed a statin and those who may not.

The Committee discussed pharmacokinetic and pharmacodynamic data, statin doses and the clinical significance of the possible interaction.

The Committee considers that the evidence for a class effect is very poor and the available evidence does not suggest a clinically relevant interaction between dabigatran and statins.

Recommendation 17

The Committee recommended Medsafe includes information on this discussion in the MARC's Remarks section of Prescriber Update for this meeting.

The paper provided to the MARC on this topic can be found at www.medsafe.govt.nz/committees/MARC/Reports.asp

3.2.4 Gadolinium based contrast agents and accumulation in brain tissue

Background

Gadolinium based contrast agents (GBCA) are diagnostic agents that may be given to patients before or during MRI scans to help obtain better images of organs and tissues. After administration, gadolinium agents are mostly eliminated via the kidneys but studies indicate that deposits can build up in some body tissues, including in brain, skin and bone.

Recently concerns have been expressed regarding deposits of gadolinium in the brain. Whether these deposits are toxic remains to be fully elucidated.

The purpose of this paper was to review the available information on the extent to which gadolinium is deposited in the brain, possible mechanisms, the potential toxicity which may be expected to result from these brain deposits and if there are any risk factors which predispose patients to brain deposits.

Discussion

The Committee discussed the evidence presented to them. The Committee discussed the use of GBCAs in New Zealand and noted there are different GBCA types (linear and macrocyclic).

The evidence presented to the Committee included a review of the extent to which gadolinium is deposited in the brain and any resulting harm. The Committee considered the evidence indicates that gadolinium can be found in the brain after administration of all of the available GBCAs. Deposits have been shown to occur with the less stable linear GBCAs, there is little evidence of deposits with the use of macrocyclic GBCAs. However it was noted that the use of MRI in humans is an indirect measure of gadolinium, therefore it is not certain that there is gadolinium deposited after use of macrocyclic agents. The Committee agreed that the available evidence does not show any harm from brain deposition.

The Committee considered that the GBCAs used in MRI had already been changing due to the recommendations to reduce the risk of patients developing nephrogenic systemic fibrosis.

Whilst the available information does not show evidence of harm from deposition of gadolinium in the brain, the Committee considered that this does not mean evidence of no harm. The possible responses to the information presented were discussed. The Committee agreed that in the absence of evidence of harm a statutory risk benefit review for these medicines was inappropriate. However, updates to data sheets for gadolinium-containing products to describe the risk of gadolinium deposits were recommended.

Based on this review and noting the evidence does suggest gadolinium can remain in a person's brain after use of GBCAs, the Committee considered that this information should be communicated to consumers and healthcare professionals.

Recommendation 18

The Committee recommended Medsafe requests sponsors update the data sheets to include information about the risk of gadolinium deposits.

Recommendation 19

The Committee recommended Medsafe communicates the Committee's discussion on this topic with consumers and healthcare professionals.

The paper provided to the MARC on this topic can be found at www.medsafe.govt.nz/committees/MARC/Reports.asp

4.0 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.1 Centre for Adverse Reactions Monitoring (CARM) Quarterly Reports

4.1.1 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 did not consider any of the reports required further action.

4.1.2 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 noted that there was a report of hyperthermia resulting from the use of topiramate in a patient under 18 years. The Committee considered the use of topiramate is increasing and a reminder on the use of topiramate is desirable.

Recommendation 20

The Committee recommended that Medsafe includes a general article on topiramate in a future edition of Prescriber Update.

The Committee did not consider any other reports required further action.

4.1.3 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 did not consider any of the reports required further action.

4.1.4 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 did not consider any of the reports required further action.

[Dr K Eggleton left the meeting at this time.]

4.1.5 Special Reports: Annual Review of Fatalities (January 2016 - December 2016)

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

5.0 OTHER BUSINESS

5.1 Therapeutic Products Regulation Project - Update

The Committee were given an update on the therapeutic products regulation project.

6.0 ANNEXES

3.2.1 Safety of antibiotic ear drops in children with grommets
  1. Locorten-vioform data sheet
  2. Ciproxin HC data sheet
  3. Sofradex data sheet
  4. Soframycin data sheet
  5. Kenacomb data sheet
  6. Venekamp et al. 2016
  7. Harris et al. 2016
  8. Chee et al. 2016
  9. Matz et al. 2004
  10. Mahadevan et al. 2008
  11. CARM Data 12. Usage Data
3.2.2 NSAIDs and spontaneous abortion
  1. TGA Safety Review October 2016
3.2.3 Risk of haemorrhage from concomitant use of statins and dabigatran
  1. Boehringer Ingelheim Signal Assessment Report 2. Merck Sharpe & Dohme Signal Evaluation 3. Antoniou et al, 2016 4. CARM Data
3.2.4 Gadolinium based contrast agents and accumulation in brain tissue
  1. ANZ Radiologists Guide and Newsletter
  2. Presentation
  3. Case Reports from IDIS Insight
  4. Information from GE Healthcare
  5. Information from Bayer
  6. Overview ofCARM cases

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 3.10pm.

Associate Professor D Reith
Chair, Medicines Adverse Reactions Committee
Date 8 June 2017

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