Committees

Published: 18 April 2018

MINUTES OF THE 173rd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING

MINUTES OF THE 173rd MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
8 March 2018

The one hundred and seventy third meeting of the Medicines Adverse Reactions Committee (MARC) was held on 8 March 2018 at the Ministry of Health. The meeting commenced at 9am and closed at 2pm.

MARC MEMBERS PRESENT

Associate Professor D Reith (Chair)
Dr S Hanna
Associate Professor D Menkes
Dr L Bryant
Dr S Jayathissa
Dr M Tatley
C Ryan
Dr K Eggleton
I Raiman

MARC SECRETARIAT PRESENT

J Solloway (Advisor, Pharmacovigilance)

MEDSAFE STAFF IN ATTENDANCE

S Kenyon (Manager, Clinical Risk Management)
L Chan (Senior Advisor, Pharmacovigilance)
M Bonne (Senior Medical Advisor)
M Storey (Senior Advisor, Pharmacovigilance)
G Hill (Senior Medical Advisor, Pharmacovigilance)
M Oldridge (Advisor, Pharmacovigilance)
J Lo (MCC and MAAC Secretariat)

1.0 MATTERS OF ADMINISTRATION

1.1 Welcome and Apologies

The Chair welcomed the attendees to the meeting. Apologies were received from Professor C Frampton, Dr C Cameron, Dr N Cole and J Tatler.

1.2 Minutes of the 172nd MARC Meeting

The minutes of the 172nd 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. 

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

The Committee noted that hospital doctors submitted the most reports and that nurses reported the most adverse reactions to vaccines. The Committee discussed whether different groups should be targeted to increase reporting of adverse drug reactions and what methods had been previously successful. Medsafe briefed the Committee on a new e-Learning tool being developed to provide education to health professionals on adverse drug reaction reporting.

2.1.1 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.

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

2.1.3 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.

2.1.4 Special Populations: Serious Non-Fatal Cases Associated with Critical Terms in Patients Over 80 Years (Causal Cases Only)

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

The Committee discussed case 126391 regarding the effects of stopping smoking on theophylline. The Committee noted that an article in Prescriber Update on medicines and smoking had been published in December 2013. The Committee also noted a patient leaflet on the same topic published in February 2016. It was discussed that not all nicotine replacement therapy providers were medically trained. The Committee considered that more information on this topic should be distributed to these providers.

The Committee discussed case 126323 which reported hypocalcaemia following a zoledronic acid infusion. The Committee noted that zoledronic acid is administered in both primary care and in hospitals and that rare, potentially fatal reactions may occur. Current protocols for administration of this medication are DHB or PHO specific and there is no current national standard on monitoring parameters/pre-medications.

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

Recommendation 1

The Committee recommended Medsafe communicates with the Tobacco Control Group at the Ministry of Health to request that they disseminate information on medicines and smoking cessation to nicotine replacement therapy providers.

Recommendation 2

The Committee recommended Medsafe publishes an article in a future edition of Prescriber Update on the risk of hypocalcaemia following zoledronic acid infusion.

Recommendation 3

The Committee recommended Medsafe communicates with the NZ Formulary to ensure that information on monitoring calcium levels is included in the zoledronic acid monograph.

2.1.5 Special Populations: Serious Cases in Patients 18 to 80 years (Causal Cases Only)

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

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 Levonorgestral emergency contraception and weight-based efficacy

Background

Levonorgestrel emergency contraception and weight-based efficacy was last reviewed by the Committee in June 2014. Data sheets were updated following this meeting. Since then, new information has become available from published studies. Medsafe has also become aware of New Zealand clinical guidelines that recommend doubling the dose of levonorgestrel to 3 mg when used in women over 70 kg or body mass index >26 kg/m2 – this is an unapproved dose.

The purpose of this paper was to review recent information that has become available since the last review in 2014. 

Discussion

The Committee discussed the guidelines promoting an unapproved dose of levonorgestrel despite the lack of supporting clinical trial data. The discussion included which professional organisations had endorsed the use of the higher dose. The Committee considered that use of the unapproved dose without clinical trial data was tantamount to an experimental use of the medication. In the absence of efficacy data, or extensive experience with this dose, the higher dose is unsupported by evidence and its use should be in the context of a clinical trial.

The Committee discussed the newly available data and noted the lack of a proven pharmacokinetic/pharmacodynamic relationship. Although there is pharmacokinetic evidence that there is a lower exposure of levonorgestrel in women of higher weight or BMI, there is no pharmacodynamic evidence to show a double-dose would be effective at preventing pregnancy. So although the new pharmacokinetic studies show that some parameters are improved by using a double dose in women with higher weight or BMI this does not provide any evidence on efficacy.

The Committee discussed the access to intrauterine devices as emergency contraception when levonorgestrel cannot be used. The Committee noted the difficult access outside of Family Planning Clinics, especially in rural and low socioeconomic areas.

The Committee discussed the ethics of using an unapproved dose. It was noted that it is important for patients to give informed consent and be given full information when health professionals use an unapproved dose. The Committee agreed that the patient should be aware that a double dose may, or may not, work and the final decision should be made by the patient.

The Committee determined that there is not enough evidence to provide a recommendation on the-benefit of using a double-dose of levonorgestrel and risks of harm. The Committee were therefore unable to recommend the use of a higher dose. The current evidence is insufficient to update data sheets. The Committee agreed that the current dose of 1.5 mg may be less efficacious in women of either heavy weight or high BMI and that the current data sheet wording adequately described this effect.

The Committee discussed the legality of standing orders using unapproved doses. The Committee considered further advice is required to determine if an unapproved dose of levonorgestrel can be legally provided under a standing order.

Recommendation 4

The Committee recommended that Medsafe obtains further information and advice on whether an unapproved dose of levonorgestrel can be legally provided under a standing order.

3.2.2 Codeine - safety concerns when used in children

Background

Regulatory action on the use of codeine in children has been taken in a number of countries. For example the Food and Drug Administration (FDA) has contraindicated use of codeine-containing medicines for any indication in children under 12 years of age (April 2016), and for post-tonsillectomy pain in children and adolescents under 18 years of age (May 2013). Most recently the FDA has further limited the use of cough and cold medicines containing codeine to adults 18 years and older.

Similarly the European Medicines Agency (EMA) has restricted the use of codeine-containing medicines to children 12 years of age and older for pain management and coughs and colds, and contraindicated codeine-containing medicines in all children and adolescents aged under 18 years who undergo surgery for the removal of the tonsils or adenoids. .

The Australian Therapeutic Goods Administration (TGA) has also contraindicated codeine for any indication in children under the age of 12 years, and in children aged 12-18 years for pain after surgery to remove the tonsils or adenoids.

The age recommendations for codeine-containing pain and cough medicines in New Zealand are inconsistent and out of step with other countries. Therefore the Committee were asked to review the use of codeine in children.

Discussion

The Committee discussed the variations in the metabolism of codeine prodrug to morphine by CYP 2D6. It was noted that there is a certain population of ultra-rapid metabolisers who are more susceptible to adverse reactions of the morphine metabolite, including respiratory depression. There are also slow-metabolisers, who experience little to no benefit from codeine.

The Committee discussed the use of codeine in both the primary and secondary care setting. The Committee determined that paediatric palliative care was outside the scope of this item. It was noted that the use of codeine varies between clinicians and that other opioids would be more suitable for use.

The Committee discussed the various paediatric populations that may be more vulnerable to the adverse effects of codeine. The Committee considered that these vulnerable populations may need additional protections against the adverse effects of codeine. These populations included any children or adolescents who may have respiratory issues, including post-tonsillectomy and cough.

One member expressed a preference to keeping children in hospital where morphine can be used under monitoring, rather than sending children home with codeine. It was noted that the analgesic effectiveness and safety of the child would be better assured by doing this.

The Committee noted the importance of New Zealand being up to date with international guidelines, especially Australia. Major regulatory agencies such as the EMA and FDA have restricted the use of codeine products in children and the Committee agreed, by majority, that New Zealand should do the same. In addition the WHO has removed codeine from pain relief guidelines for children.

The Committee discussed the recent reclassification of codeine-only products from prescription medicines to restricted medicines, as per the recommendations of the 59th meeting of the Medicines Classification Committee. The Committee expressed a concern that the members had not considered the safety of codeine when making their recommendation. The Committee agreed that it was important for the Minister’s Delegate to be aware of their concerns over this recommendation.

The Committee considered the means in which safety information and the changes to the contraindication status of codeine can be disseminated to health professionals. The Committee determined that an article in a future edition of Prescriber Update and an alert communication is the best way of doing so.

Recommendation 5

The Committee recommended that codeine should be contraindicated in children aged under 12 years old for all indications.

Recommendation 6

The Committee recommended that codeine should be contraindicated in adolescents aged under 18 years old for pain following surgery to remove tonsils or adenoids.

Recommendation 7

The Committee recommended that codeine should be contraindicated in adolescents aged under 18 in whom respiratory function might be compromised.

Recommendation 8

The Committee recommended that codeine should be contraindicated in children under 18 for use in coughs.

Recommendation 9

The Committee recommended that the warning to avoid using codeine in breast-feeding mothers should be strengthened to a contraindication.

Recommendation 10

The Committee recommended that an alert communication is sent out by Medsafe stating the above changes to contraindications of codeine.

Recommendation 11

The Committee recommends that an article on the safety of codeine is published in a future edition of Prescriber Update.

Recommendation 12

The Committee recommended the Chair of this committee sends a letter to the Minister’s Delegate regarding the Committee’s clinical concern of reclassifying codeine-only products from prescription medicines to restricted medicines.

3.2.3 Medroxyprogesterone and withdrawal syndrome

Background

Depo-Provera is a progestin (a synthetic form of progesterone) indicated for contraception, treatment of endometriosis, adjunctive and/or palliative treatment of recurrent and/or metastatic endometrial or renal carcinoma and treatment of hormonally-dependent recurrent breast cancer in post-menopausal women.

The Centre for Adverse Reactions Monitoring (CARM) recently received a case report describing withdrawal symptoms after stopping medroxyprogesterone acetate, (brand name Depo-Provera).

The reported withdrawal symptoms included: feeling of having a viral infection with fatigue, eye pain, visual disturbance, itching, restlessness, agitation, shaking, nausea and shortness of breath. The reporter refers to internet forums where other women report the same symptoms on stopping Depo-Provera.

There is very limited information on this issue in the medical literature. . However, there are many reports in blogs and on discussion forums from women who discuss problems of weight gain, hot flashes, painful breasts, sleeping problems, headaches, flu symptoms and nausea when discontinuing Depo-Provera.

Discussion

The Committee discussed the nuances between the definitions of ‘withdrawal syndrome’ and ‘discontinuation symptoms’. The Committee determined that although the reporter of the case presented described the symptoms as a withdrawal syndrome the correct terminology is a discontinuation effect.

The Committee discussed whether the data sheet required updating. The Committee determined that the evidence was very weak and no updates were needed. The Committee agreed that it was important for healthcare professionals to discuss potential side effects and discontinuation effects with women using this medicine. The Committee determined that no further communication or regulatory action was required.

The Committee discussed the use of social media as a means of safety signal detection. It was noted that personal opinions of people on social media are too complicated to detect signals from, but can be useful as a general indicator. Potential safety signals from social media should not be ignored, but adequate methodology would be needed to address any concerns arising from these platforms.

3.2.4 NSAIDs and cardiovascular risk

Background

Medsafe has received a Changed Medicine Notification (CMN) from Pfizer regarding the datasheet of Celecoxib Pfizer (celecoxib), 100 mg and 200 mg capsules. The CMN seeks to relocate the contraindication for patients with significant established ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease to the precaution section.

The CMN is supported by the results from the Prospective Randomized Evaluation of Celecoxib Integrated Safety vs. Ibuprofen Or Naproxen (Precision) Study.

Medsafe sought MARC advice about the CMN proposal and whether this change would impact the contraindications for similar medicines.

Discussion

The Committee discussed the definition of contraindication in the context of this item. The Committee determined that the regulatory definition of a contraindication should be used: there is positive evidence that an unfavourable risk-benefit is present in a defined population where the risk cannot be avoided. It was further stated that prescribers should not use the medication in the contraindicated population.

The Committee discussed if it is reasonable to group all non-aspirin NSAIDs collectively when considering the regulatory changes proposed. It was noted that there may be variance between the individual medicines and risks may differ between medicines in this class. Without a thorough review of all the available information for all NSAIDs, the Committee was not in a position to make recommendations for all medications in the NSAID class.

The Committee noted that the patients most likely to use celecoxib long term were older and therefore were likely to have a higher cardiovascular disease risk at baseline. With the recent change to the funding of celecoxib, it is expected that the number of prescriptions is likely to increase. This medication is likely to fill a gap in pain management for elderly patients with osteoarthritis, who would also be most at risk of cardiovascular side effects.

The Committee reviewed the PRECISION trial and noted that the results show celecoxib does not have an increased risk of cardiovascular events over naproxen and ibuprofen. One member noted that the doses of ibuprofen, naproxen and celecoxib used in the PRECISION study were not equivalent. There is also difficulty in stratifying the risk of developing adverse cardiovascular events/reactions from NSAID use between people of varying cardiovascular risk status. These issues need to be addressed in further studies.

The Committee discussed the specific use of NSAIDs in heart failure. There was unanimous concern from members that there is a high risk of worsening heart failure if NSAIDs are taken. The Committee concluded that NSAIDs should not be used in this patient population and the contraindication listed in the data sheet should not be changed. 

The Committee determined they were not provided with enough evidence to relocate the cardiovascular contraindications for celecoxib to the precaution section.

Recommendation 13

The Committee recommended that further information on celecoxib and cardiovascular risk should be provided by Pfizer before any changes to the contraindications are made.

Recommendation 14

The Committee recommended that Medsafe reviews the risk of adverse cardiovascular events with NSAIDs following the recent publication of a number of studies on this topic.

3.2.5 Risk Management Plan for nusinersen

Background

Nusinersen is an antisense oligonucleotide (ASO) specifically designed to treat spinal muscular atrophy (SMA), an autosomal recessive progressive neuromuscular disease, due to mutations in the chromosome 5q. SMA is a clinical spectrum of disease, with age of onset and disease severity linked to the number of SMN2 gene copies present; fewer SMN2 gene copies are associated with earlier age of onset and increased severity of symptoms. Nusinersen increases the amount of functional SMN2 protein.

An application for consent to distribute nusinersen has been made to Medsafe by Biogen. This is a new category of medicine and therefore Medsafe is seeking the Committee’s opinion on whether any additional post-market activities will be required, should this medicine be approved. The RMP provided to Medsafe is version 5.0, dated 24 April 2017.

Discussion

The Committee considered each area of the RMP for completeness and appropriateness. The Committee considered the potential risks, missing information and risk minimization activities. Members did not express any concerns with the RMP. The Committee unanimously endorsed this RMP. No changes to the RMP were recommended.

3.2.6 Ulipristal acetate and drug induced liver injury

Background

In December 2017, the European Medicines Agency (EMA) started a review of Esmya (ulipristal acetate). This followed reports of serious liver injury associated with ulipristal use, three of which resulted in liver transplantation.

In January 2018, the EMA announced temporary measures while the review is ongoing. The Pharmacovigilance Risk Assessment Committee (PRAC) recommended that regular liver function monitoring for woman taking Esmya should be done, no new patients should be started on Esmya and no patients who have completed a course of treatment should start another one.

Discussion

The Committee discussed the potential association between ulipristal and hepatotoxicity. It was noted that the typical time to onset is one week to two months which is in line with clinical expectations for drug induced liver injury.

The Committee reviewed the three cases where a liver transplant was required in more detail. For the first case, it was determined that either cefuroxime or ulipristal may have been contributory and there were no other obvious contributing factors. For the second case, it was considered plausible that ulipristal had caused non-cirrhotic hepatotoxicity as other diseases were extensively excluded. The third case was also considered a plausible association.

The Committee considered the frequency of reports of elevated liver enzymes from clinical trials and post-marketing provided evidence of association. The Committee considered this a relatively high frequency for a serious adverse drug reaction.

The Committee stated this risk would only apply to ulipristal acetate used in its currently approved indication. The Committee considered that information on the efficacy of this medicine was needed for the decision making process, since the risk of hepatotoxicity impacts the benefits and risks of harm for this medicine

Recommendation 15

The Committee recommended that Medsafe conducts a risk benefit review of Esmya (ulipristal acetate) under Section 36 of the Medicines Act 1981.

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:

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

4.1.1 Modified release paracetamol


December 2017 minute item 3.2.2

The Committee was provided an update to the outcome of this agenda item as changes had occurred since item 4.1 was finalised.

Recommendation 7

The Committee recommended Medsafe requests sponsor(s) of modified-release paracetamol products update the overdose section of their data sheets.

Recommendation 8

The Committee recommended the Medicines Classification Committee considers reclassifying modified-release paracetamol from pharmacy-only medicines to pharmacist-only medicines.

Recommendation 9

The Committee recommended Medsafe communicates with the National Poisons Information Centre to inform them of the Committee’s discussion on this topic.

Recommendation 10

The Committee recommended communication with authors of the guidelines on the management of paracetamol poisoning in Australia and New Zealand to inform them of the Committee’s discussion on this topic.

Recommendation 11

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

Recommendation 12

The Committee recommended Medsafe requests Periodic Benefit Risk Evaluation Reports from the sponsor(s) of modified-release paracetamol products. This report should include worldwide usage data and New Zealand usage data.

Outcome

Medsafe has reviewed the Periodic Risk Benefit Evaluation Reports from the sponsor(s). The sponsor(s) have updated their respective data sheets on modified release paracetamol products in response to the Medsafe request. This item is on the agenda for the next Medicines Classification Committee meeting. A communication has been made with the National Poisons Centre and the authors of the Australia New Zealand guidelines on paracetamol poisoning. A future Prescriber Update article is planned when the outcome of these activities are known.

Discussion

The Committee noted the guidelines on management of paracetamol poisoning were currently being updated. The Committee did not consider further recommendations were required.

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

4.2 Medsafe Pharmacovigilance Activities

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

The Committee noted that Medsafe has released an alert communication on Arthrem and liver toxicity. The Committee did not make recommendations on this topic.

4.3 Prescriber Update Volume 39, Number 1, March 2018

The Committee noted the latest edition of Prescriber Update. The Committee noted they were very impressed with the quality of the publication.

4.4 Quarterly Summary of Medsafe Early Warning System

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

5.0 OTHER BUSINESS

5.1 Therapeutics products regulation project - Update

The Committee were unable to be provided an update on the Therapeutic products regulation project due to unforeseen circumstances.

6.0 ANNEXES

3.2.1 Levonorgestrel emergency contraception and weight-based efficacy

  1. Levonorgestrel emergency contraception and weight-based efficacy. MARC Paper June 2014
  2. PSNZ ECP practice guidelines
  3. Edelman A, Cherala G, Blue S, et al. 2016. Impact of obesity on the pharmacokinetics of leonorgestrel0based emergency contraception: single and double dosing. Contraception 94: 52-7
  4. Praditpam P, Hamouie A, Basaraba C, et al. 2017. Pharmacokinetics of levonorgestral and ulipristal acetate emergency contraception in women with normal and obese body mass index. Contraception 95: 464-9
  5. CARM report

3.2.2 Codeine – Safety concerns when used in children

  1. FDA drug safety communication
  2. Crews K, Gaedigk A, Dunnenberger H, et al. 2014. Clinical pharmacogenetics implementation consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Nature 95(4): 376-82

3.2.3 Medroxyprogesterone and withdrawal syndrome

  1. Pfizer review [confidential]
  2. CARM report

3.2.4 NSAIDs and cardiovascular risk

  1. FDA drug safety communication
  2. Medsafe clinical evaluation report
  3. Oral NSAIDs. NHS medicines update (Aug 2017)
  4. Nissen S, Yeomans N, Solomon D, et al. 2016. Cardiovascular safety of celecoxib, naproxen or ibuprofen for arthritis. The New England Journal of Medicine 375(26):2519-29
  5. Pepine C & Gurbel P. 2017. Cardiovascular safety of NSAIDs: Additional insights after PRECISION and point of view. Clinical Cardiology 40: 1352-6
  6. Sondergaard K, Weeke P, Wissenberg M, et al. 2017. Non-steroidal anti-inflammatory drug use is associated with increased risk of out-of-hospital cardiac arrest: a nationwide case-time-control study. European Heart Journal – Cardiovascular Pharmacotherapy 3(2): 100-7
  7. Bally M, Dendukuri N, Rich B, et al. 2017. Risk of acute myocardial infarction with NSAIDs in real world use” ayesian meta-analysis of individual patient data. British Medical Journal 357: 1-13.

3.2.5 Risk Management Plan for nusinersen

  1. Spinraza risk management plan ver. 5. Biogen Idec Ltd

3.2.6 Ulipristal acetate and drug induced liver injury

  1. Responses to PRAC request. Gedeon Richter. EMEA/H/C/2041/LEG 019 (Nov 2017)
  2. Esmya Risk management plan ver 15.1. Gedeon Richter
  3. Esmya Periodic Safety Update Report #8

The Chair thanked members, the Secretariat and Medsafe staff for their attendance and closed the meeting at 2pm.

Associate Professor David Reith
Chair, Medicines Adverse Reactions Committee
Date 8 March 2018