Committees

Updated 20 May 2013

Minutes of the 139th Medicines Adverse Reactions Committee Meeting - 10 September 2009

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

MEDSAFE STAFF PRESENT

1 MATTERS OF ADMINISTRATION

2 STANDING AGENDA ITEMS

2.1 REPORT ON STANDING AGENDA ITEMS FROM PREVIOUS MEETINGS OF THE MARC MEETING

2.1.1 Paracetamol associated with childhood asthma
2.1.2 Clozapine and neutropenia, lymphopenia,anaemia [death] (76419)
2.1.3 Methylphenidate SR (Rubifen SR) brand switch-aggressive and defiant behavioural reactions- Scheduled Review
2.1.4 Diclofenac and intestinal perforation, sepsis, multiple organ failure [death] (82166)
2.1.5 Infanrix-hexa, Prevenar and sudden death [death] (82290)
2.1.6 Trastuzumab, tamoxifen and renal disorder not-otherwise-specified (NOS), respiratory infection, oligohydramnios (mother), pregnancy exposure (mother) [death] (81237)
2.1.7 Sodium valproate, topiramate, levetiracetam and hyponatraemia, cerebral infarction, peripheral oedema (81286)
2.1.8 Vitamin D and renal failure, hypervitaminosis D, medication error (81804)
2.1.9 Etanercept and uveitis (76978, 76980)
2.1.10 Oral bisphosphonates and the risk of atrial fibrillation
2.1.11 Ropivacaine and convulsion grand mal, cardiac arrest, drug overdose [death] (80093)
2.1.12 SSRI antidepressants
2.1.13 Removal of specialist prescribing restriction from retinoids
2.1.14 Reporting of patient allergies to the Centre for Adverse Reactions Monitoring (CARM)
2.1.15 All adverse reactions to complementary and alternative medicines
2.1.16 Dextropropoxyphene/ paracetamol combination products and the risk of overdose.
2.1.17 The safety and efficacy of cough and cold medicines for use in children
2.1.18 Ornidazole and vertigo, somnolence, vision disorder (83131)
2.1.19 Entanercept and meningoencephalitis (82750)
2.1.20 Sodium valproate and foetal valproate syndrome, drug exposure during pregnancy (82615)
2.1.21 Infanrix-hexa (DTaP-IPV & HepB-Hib) (83019)
2.1.22 Influenza virus vaccine and cardiac arrest, bradycardia, diarrhoea, abdominal pain, gastrointestinal disorder NOS (83046
2.1.23 Atorvastatin and rhabdomyolysis [death] (77591), Simvastatin and abdominal pain, rhabdomyolysis, acute renal failure, respiratory failure [death] (76185) Simvastatin and rhabdomyolysis [death] (77669) Simvastatin and rhabdomyolysis, creatine kinase increased, hepatic function abnormal, hyperkalaemia, cardiac arrest [death] (78076)
2.1.24 Lamotrigine and convulsion [death] (74826)
2.1.25 Clozapine and haematological malignancies

3 PHARMACOVIGILANCE ISSUES

3.1 RISK OF CANCER IN ASSOCIATION WITH INSULIN GLARGINE (LANTUS) TREATMENT
3.2 STIMULANT USE AND SUDDEN DEATH IN CHILDREN WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER
3.3 CONVENTIONAL ANTIPSYCHOTICS AND MORTALITY RISK
3.4 BLACK COHOSH AND HEPATOTOXICITY

4 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE

4.2 QUARTERLY REPORTS FROM CARM AS 30 JUNE 2009

4.3 HUMAN PAPILLOMAVIRUS VACCINE (HPV) REPORTS

5 PHARMACOVIGILANCE ISSUES FOR INFORMATION ONLY

6 NEW ZEALAND PHARMACOVIGILANCE-RELATED ACTIVITIES

7  INTERNATIONAL PHARMACOVIGILANCE-RELATED ACTIVITIES

7.1 AUSTRALIA
7.2 CANADA
7.3 SINGAPORE
7.4 UNITED KINGDOM
7.5 UNITED STATES

8 SUMMARY LISTINGS OF CASE REPORTS CONSIDERED BY THE MARC (1997- 2009)


Preface:

In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.

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 OF THE 139th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING
10 September 2009

The one hundred and thirty ninth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 10 September 2009 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9 am and closed at 2.30 pm.

MARC Members Present

Associate Professor M Rademaker (Chair)
Dr L Bryant
Professor P Ellis
Associate Professor C Frampton
Dr F McClure
Dr H Kingston
Associate Professor D Reith
Dr R Savage
Dr S Sime
Dr M Tatley

MARC Secretariat Present

A Kerridge (Acting MARC Secretary)

MEDSAFE STAFF IN ATTENDANCE FOR PARTS OF THE MEETING

A Cutfield (Advisor, Pharmacovigilance)
J Hart (Manager, Clinical Risk Management)
C James (Advisor, Pharmacy)
S Kenyon (Senior Advisor, Pharmacovigilance)
K Sheehy (Senior Advisor, Medical)
E Yousuf (Principal Clinical Advisor)

1. Matters of Administration

1.1 Welcome and Apologies

The Acting Chair welcomed the attendees to the meeting.

1.2 Minutes of the 138th MARC Meeting

The minutes of the 138th 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 next MARC meeting was confirmed as being 10 December 2009. The dates for the MARC meetings for 2010 were proposed as 25 February, 20 May, 12 August, and 4 November.

Secretary's note: the date of the December 2009 meeting was subsequently amended to 3 December 2009.

1.4 Potential Conflicts of Interest

Committee members submitted their Conflict 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.

The conflicts of interest were discussed but were not considered to influence the discussions or decisions.

1.5 Prescriber Update

1.5.1 Schedule of Planned Prescriber Update Articles

Discussion

The Committee noted the schedule of planned Prescriber Update articles and agreed that the new format enabled a decrease in the time period between the identification of a safety issue and the communication of this to healthcare professionals.

The Committee noted that the Singaporean Health Sciences Authority has recently published an article on herbal medicines that had been found to have been adulterated with steroids. The Committee recommended that a similar article be published in Prescriber Update to raise awareness in this country.

Recommendation

The Committee recommended that an article be published in Prescriber Update on the issue of herbal medicines adulterated with steroids.

1.5.2 Prescriber Update. Volume 30, Number 3. August 2009

Discussion

The Committee noted the latest edition of Prescriber Update.

2. STANDING AGENDA ITEMS

The Committee considered the list of issues monitored by MARC, Medsafe and NZPhvC.

2.1 Report on Standing Agenda Items from previous meetings of the MARC

Background information on these issues is available on the Medsafe web site at www.medsafe.govt.nz/profs/MARC/Minutes.asp.

2.1.1 Paracetamol associated with childhood asthma
June 2009 minute item 2.1.1, March 2009 minute item 2.1.6, December 2008 minute item 3.4

MARC Recommendation

In December 2008 the Committee recommended that Medsafe write to sponsors of paracetamol and require them to include a warning about the possible risk of paracetamol use in pregnancy leading to asthma in the infant.

Outcome

The sponsors have thus far declined to put the warning in their data sheets, including in their replies that there is no causal association proven.

Discussion

The Committee noted the above, and that Medsafe will continue to monitor this issue as new information becomes available.

2.1.2 Clozapine and neutropenia, lymphopenia, anaemia [death] (76419)
June 2009 minute item 2.1.2, March 2009 minute item 2.1.23, December 2008 minute item 2.1.14, September 2008 minute item 2.1.11, May 2008 minute item 2.1.2, March 2008 minute item 2.1.9, December 2007 minute item 4.1.1.7

MARC Recommendation

In June 2009, the Committee recommended that Medsafe approach the College of Psychiatrists to undertake an audit of clozapine prescribing in elderly patients in New Zealand.

Outcome

Medsafe approached the College of Psychiatrists, which advised that the RANZCP's Faculty of Psychiatry of Old Age is able to support a clozapine audit for older New Zealanders but is not able to lead such an audit. The College indicated that the Psychiatry of Old Age Academic Unit within the CDHB would be able to carry out a formal audit but that the faculty has no budget for such a task and requested that Medsafe contribute funding for the project.

Given the low usage of clozapine in this age group, the restrictions around prescribing and the monitoring requirements that are in place, Medsafe does not consider commissioning such a piece of work to be a priority for funding.

Discussion

The Committee noted the above.

2.1.3 Methylphenidate SR (Rubifen SR) brand switch-aggressive and defiant behavioural reactions- Scheduled Review
June 2009 minute item 2.1.5, March 2009 minute item 3.4

MARC Recommendation

In March 2009 the Committee recommended that Medsafe review the CHMP risk-benefit review for methylphenidate-containing medicines and report back to the MARC.

Outcome

Medsafe has received a summary of the CHMP risk-benefit review from the MHRA and from the innovator, and this will be presented to the MARC at the December 2009 meeting.

Discussion

The Committee noted the above.

2.1.4 Diclofenac and intestinal perforation, sepsis, multiple organ failure [death] (82166)
June 2009 minute item 2.1.7, March 2009 minute item 4.1.1.5

MARC Recommendation

In March 2009 the Committee recommended that NZPhvC seek further details about this case.

Outcome

The NZPhvC will bring back any further information to the MARC when received.

Discussion

NZPhvC confirmed that this case had been followed up and more information will become available.

2.1.5 Infanrix-hexa, Prevenar and sudden death [death] (82290)
June 2009 minute item 2.1.9, March 2009 minute item 4.1.1.9

MARC Recommendation

In March 2009 the Committee recommended that NZPhvC bring further information to the MARC when the Coroner's report has been received.

Outcome

The NZPhvC will bring back any further information to the MARC when received.

Discussion

The Committee noted the above.

2.1.6 Trastuzumab, tamoxifen and renal disorder not-otherwise-specified (NOS), respiratory infection, oligohydramnios (mother), pregnancy exposure (mother) [death] (81237)
June 2009 minute item 2.1.10, March 2009 minute item 4.1.1.10

MARC Recommendation

In March 2009 the Committee recommended that NZPhvC seek further information, including ultrasound information if available.

Outcome

The NZPhvC will bring back any further information to the MARC when received.

Discussion

NZPhvC confirmed that this case had been followed up and more information will become available.

2.1.7 Sodium valproate, topiramate, levetiracetam and hyponatraemia, cerebral infarction, peripheral oedema (81286)
June 2009 minute item 2.1.11, March 2009 minute item 4.1.3.1

MARC Recommendation

In March 2009 the Committee recommended that an article be published in Prescriber Update alerting prescribers to the problem of drug-induced hyponatraemia.

Outcome

This is part of a wider picture of increasing reports of hyponatraemia to CARM as indicated in the case report assessment. NZPhvC are to present data on valproate and omeprazole and combinations of hyponatraemic medicines to the RNZCGP annual scientific meeting in September and write a publication. A synopsis of this will be included in Prescriber Update.

Discussion

The Committee noted the above.

2.1.8 Vitamin D and renal failure, hypervitaminosis D, medication error (81804)
June 2009 minute item 2.1.12, March 2009 minute item 4.1.4.1

MARC Recommendation

In March 2009 the Committee recommended that this event be followed up through Medsafe.

In March 2009 the Committee recommended that renal failure and hypervitaminosis D be removed from the list of suspect reactions.

In June 2009 the NZPhvC requested that the ADR terms renal failure and hypervitaminosis D be retained in the list of suspect reactions. The NZPhvC acknowledged that medication error was the prime adverse event and the outcomes were secondary to this. However, the CARM database needs to be searchable for specific adverse reactions related to particular medicines or to particular circumstances e.g. medication error and this would not be possible if specific terms are not included.

In June 2009 the Committee recommended that the ADR terms renal failure and hypervitaminosis D be retained in the list of suspect reactions in case report 81804.

Outcome

Medsafe has begun the follow up process and will inform the MARC of the outcome.

NZPhvC has retained the ADR terms renal failure and hypervitaminosis D in the list of suspect reactions in case report 81804.

Discussion

The Committee noted the above.

2.1.9 Etanercept and uveitis (76978, 76980)
June 2009 minute item 2.1.16, March 2009 minute item 2.1.2, December 2008 minute item 2.1.19, September 2008 minute item 2.1.19, May 2008 minute item 2.1.16, March 2008 minute item 4.1.5.2

MARC Recommendation

In September 2008 the Committee recommended that a paragraph be published in Prescriber Update advising prescribers of the risk of uveitis in association with TNF inhibitors, and this information be disseminated to the Ophthalmologists Society.

In June 2009 the Committee recommended that this information also be distributed to the optometrists via their professional body.

Outcome

A paragraph was published in the August 2009 edition of Prescriber Update, which was distributed to opthalmologists and optometrists via the Ophthalmologists Society.

Discussion

The Committee noted the above.

2.1.10 Oral bisphosphonates and the risk of atrial fibrillation
June 2009 minute item 2.1.17, March 2009 minute item 2.1.5, December 2008 minute item 3.3

MARC Recommendation

In December 2008 the Committee recommended that [..] be asked to provide an opinion on the risk of AF in association with oral bisphosphonates.

Outcome

[..] has received a copy of the Medsafe paper prepared for the December 2008 MARC meeting on the risk of atrial fibrillation in association with oral bisphosphonates. [..] also received a Medsafe review of the evidence for an association between long-term use of alendronic acid with an increased risk of atypical stress fractures.

[..] opinion was included in the September 2009 dossier.

Safety of bisphosphonates

A paper on the issue of oral bisphosphonates and the risk of atrial fibrillation will be presented at the December 2009 MARC meeting.

Bisphosphonates and atypical fractures

In this review, Medsafe considered that there was sufficient evidence to support the inclusion of a statement about atypical stress fractures in the datasheet for oral bisphosphonates.

[..] agreed with this opinion.

The following statement has been included in the Warnings and Precautions section of the datasheets for the alendronic acid products currently on the market in New Zealand:

"Stress fractures (also known as insufficiency fractures) of the proximal femoral shaft have been reported in patients treated long-term with alendronic acid (time to onset in the majority of cases ranged from 18 months to 10 years). The fractures occurred after minimal or no trauma and some patients experienced thigh pain, often associated with imaging features of stress fractures, weeks to months before presenting with a completed femoral fracture. Fractures were often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture. Poor healing of these fractures was also reported. Discontinuation of bisphosphonate therapy in patients with stress fracture is advisable pending evaluation of the patient, based on an individual benefit risk assessment."

This statement is in line with wording recommended by the European CHMP and that present in the innovator's data sheet.

The Adverse Effects sections of the datasheets have also been updated to list stress fractures of the proximal femoral shaft as a possible adverse drug reaction.

Discussion

The Committee noted the above.

2.1.11 Ropivacaine and convulsion grand mal, cardiac arrest, drug overdose [death] (80093)
June 2009 minute item 2.1.18, March 2009 minute item 2.1.7, December 2008 minute item 4.1.1.1

MARC Recommendation

In December 2008 the Committee recommended that NZPhvC provide a follow-up report to the MARC when the Coroner's report has been received.

Outcome

NZPhvC will provide a follow-up report to the MARC when the Coroner's report has been received.

Discussion

The Committee noted the above.

2.1.12 SSRI antidepressants
June 2009 minute item 2.1.10, March 2009 minute item 2.1.12, December 2008 minute item 9.2

MARC Recommendation

In December 2008 the Committee recommended that a formal request be made to the Coroner's Office to forward decisions regarding medication related cases directly to the NZPhvC.

Outcome

The Waikato Coroner has agreed to forward his decisions regarding medication related cases to the MARC and NZPhvC.

A similar request will be made to the other Coroner's Offices throughout the country.

Discussion

The Committee noted the above. The Committee noted that the number of Coroner's reports received by CARM had increased, and requested that their appreciation be passed on to the Coroner's Offices.

2.1.13 Removal of specialist prescribing restriction from retinoids
June 2009 minute item 2.1.21, March 2009 minute item 2.1.13, December 2008 minute item 9.4

MARC Recommendation

In March 2009, the Committee noted that PHARMAC had communicated its final decision to broaden access to oral retinoid treatments. Medsafe is currently in the process of requiring the sponsors of oral retinoids to develop a Risk Management Plan. Details of the Risk Management Plans will be communicated to the MARC at a later stage.

Outcome

PHARMAC has announced that the Oratane brand of isotretinoin will be the Sole Supply brand from 1 February 2010.

Medsafe will provide details of the Risk Management Plans to the MARC when available.

Discussion

[..]

Medsafe advised that it is currently working with the product sponsor to develop a risk-management plan, including the monitoring of both usage and adverse reaction data. The Committee recommended that Medsafe obtain prescribing data for both oral retinoids currently funded and present this to the Committee at its December meeting.

Recommendation

The Committee recommended that Medsafe obtain prescribing data for both oral retinoids currently funded and present this to the Committee at its December meeting.

2.1.14 Reporting of patient allergies to the Centre for Adverse Reactions Monitoring (CARM)
June 2009 minute item 2.1.22, March 2009 minute item 2.1.14, December 2008 minute item 9.5

MARC Recommendation

At the June 2009 meeting, a member informed the committee that they had become aware that redevelopments to the NHI system presently underway would result in the Medical Warning Module which is an integral part of the existing NHI, ceasing to operate by June 2010. The Committee recommended that a letter be drafted, expressing their concerns about the potential loss of the medical warning system.

Outcome

A letter has been drafted to the appropriate Directorate.

Discussion

Medsafe advised that at a working party meeting they were advised that the current NHI software platform would not be replaced until such time as an alternative to the Medical Warning System had been scoped and developed and was fully functional for release.

2.1.15 All adverse reactions to complementary and alternative medicines
June 2009 minute item 3.1

MARC Recommendation

In June 2009 the Committee recommended that NZPhvC continue to report serious and/or unusual events to each MARC meeting, and provide an annual ARCC submission of a summary/listing of all reports.

Outcome

The issue of all adverse reactions to complementary and alternative medicines has been retained on the 'Scheduled Review' list.

Discussion

The Committee noted the above.

2.1.16 Dextropropoxyphene/ paracetamol combination products and the risk of overdose
June 2009 minute item 3.2

MARC Recommendation

In June 2009 the Committee recommended that Medsafe write to the sponsors of Paradex and Capadex under Section 36 of the Medicines Act 1981 requesting that they provide further data for a full risk-benefit review.

Outcome

Medsafe has written to the sponsors of Paradex and Capadex under Section 36 of the Medicines Act 1981 and requested that they provide further data for a full risk-benefit review before 30 September 2009.

Discussion

The Committee noted the above.

2.1.17 The safety and efficacy of cough and cold medicines for use in children
June 2009 minute item 3.2

MARC Recommendation

At the June 2009 meeting, Medsafe advised that a Working Group (Cough and Cold Review Group) has been formed to advise on the safety and efficacy of cough and cold medicines in children over two years of age. The Working Group will include representatives from community, industry, pharmacy, paediatrics, general practice and other healthcare professions. The Working Group will investigate options for disseminating advice to healthcare professionals and the public regarding the use of cough and cold products in children.

In June 2009 the Committee recommended that the Cough and Cold Review Group be advised that, after consideration of the evidence provided at the MARC meeting, the MARC considered that cough and cold medicines be contraindicated in children under six years and the sale restricted to pharmacist-only.

Outcome

A verbal update was provided to the Committee at the meeting. The minutes of the 1st Cough and Cold Review Group meeting were included in the September dossier.

At the 1st Review Group meeting, the Group noted that cough and cold medicines are already contraindicated for use in children under 2 years of age. The majority of members considered that it would be appropriate to extend the contraindication to children under 6 years of age, with the exception of bromhexine and topical nasal decongestants, which required further review by the Group.

The Group considered the reclassification of cough and cold medicines to a pharmacy-based classification (Pharmacy-only medicine or Restricted medicine) was appropriate, with the exception of bromhexine and topical nasal decongestants, which required further review by the Group. The Group noted that such a reclassification would need to be assessed by the Medicines Classification Committee, and that this process involves a public consultation.

The purpose of the 2nd Review Group meeting was to assess the risk-benefit profile of bromhexine and topical nasal decongestants for use in children in the treatment of the common cold, and to make a final recommendation on the risk-benefit balance of all cough and cold medicines in children.

The Group considered that the lack of evidence of toxicity of bromhexine in overdose provided a case for making a recommendation separate from that for other cough and cold medicines as discussed at the previous meeting. The Group considered that bromhexine-containing medicines indicated for treatment of the symptoms of the common cold should remain contraindicated in children under 2 years of age. Due to less evidence of harm, the Group concluded that these medicines could be considered for use in children 2 years of age and above.

The Group considered that the small number of reported adverse reactions and enquiries to poisons centres involving topical nasal decongestants compared to oral decongestants also provided a case for making a recommendation separate from that for other cough and cold medicines, as discussed at the previous meeting. The Group considered that topical nasal decongestants (oxymetazoline/ xylometazoline/ intra-nasal phenylephrine) indicated for treatment of the symptoms of the common cold should remain contraindicated in children under 2 years of age. Due to less evidence of harm, the Group concluded that these medicines could be considered for use in children 2 years of age and above.

The Group also discussed and recommended possible risk management options and appropriate implementation, communication and education strategies to improve the safety profile of cough and cold medicines in children.

Discussion

The Committee noted the above.

2.1.18 Ornidazole and vertigo, somnolence, vision disorder (83131)
June 2009 minute item 4.1.2.1

MARC Recommendation

In June 2009 the Committee recommended that NZPhvC change the causality from 'probable' to 'possible' for vertigo, somnolence, vision disorder.

In June 2009 the Committee recommended that an article be published in Prescriber Update reminding prescribers of the adverse effects of ornidazole.

Outcome

NZPhvC has amended the causality as above.

Discussion

The Committee noted the above.

2.1.19 Entanercept and meningoencephalitis (82750)
June 2009 minute item 4.1.4.1

MARC Recommendation

In June 2009 the Committee recommended that NZPhvC obtain further details about this case (82750).

Outcome

The NZPhvC will bring back any further information to the MARC when received.

Discussion

The Committee noted the above.

2.1.20 Sodium valproate and foetal valproate syndrome, drug exposure during pregnancy (82615)
June 2009 minute item 4.1.6.1

MARC Recommendation

In June 2009 the Committee recommended that NZPhvC change the causality from 'possible' to 'certain' for foetal valproate syndrome.

In June 2009 the Committee recommended that the datasheet for sodium valproate be reviewed to determine if the warning information should be strengthened.

In June 2009, the Committee noted that both babies had been diagnosed with foetal valproate syndrome, and recommended that NZPhvC create a second report to reflect this.

Outcome

NZPhvC has amended the causality as above.

Medsafe will review the datasheet for sodium valproate to determine if the warning information should be strengthened.

Discussion

The Committee noted the above.

2.1.21 Infanrix-hexa (DTaP-IPV & HepB-Hib) (83019)
June 2009 minute item 4.1.7.1

MARC Recommendation

In June 2009 the Committee recommended that NZPhvC change the causality from 'possible' to 'unclassifiable' for cerebral oedema.

Outcome

NZPhvC has amended the causality as above.

Discussion

The Committee noted the above.

2.1.22 Influenza virus vaccine and cardiac arrest, bradycardia, diarrhoea, abdominal pain, gastrointestinal disorder NOS (83046)
June 2009 minute item 4.1.7.2

MARC Recommendation

In June 2009 the Committee recommended that the influenza virus vaccine datasheets be reviewed and strengthened regarding the potential gastrointestinal adverse effects.

Outcome

Medsafe will review the influenza virus vaccine datasheets and determine if the information regarding the potential gastrointestinal adverse effects requires strengthening.

Discussion

The Committee noted the above.

2.1.23 Atorvastatin and rhabdomyolysis [death] (77591), Simvastatin and abdominal pain, rhabdomyolysis, acute renal failure, respiratory failure [death] (76185) Simvastatin and rhabdomyolysis [death] (77669) Simvastatin and rhabdomyolysis, creatine kinase increased, hepatic function abnormal, hyperkalaemia, cardiac arrest [death] (78076)
June 2009 minute item 2.1.29, March 2009 minute item 2.1.22, December 2008 minute item 2.1.12, September 2008 minute item 2.1.8, May 2008 minute items 4.1.1.3, 4.1.1.4, 4.1.1.5, 4.1.1.6

MARC Recommendation

The Committee recommended that a sub group of two Committee members review the dose response data and report back to the MARC at the next meeting.

Outcome

A report is being prepared by [..].

Discussion

The Committee recommended that [..] be invited to the December meeting of the MARC to present her report.

Recommendation

The Committee recommended that [..] be invited to the December meeting of the MARC to present her report.

2.1.24 Lamotrigine and convulsion [death] (74826)
June 2009 minute item 2.1.31, March 2009 minute item 2.1.21, December 2008 minute item 2.1.21, September 2008 minute item 2.1.21, May 2008 minute item 2.1.14, March 2008 minute item 2.1.18, December 2007 minute item 2.1.17, September 2007 minute item 2.1.9, June 2007 minute item 4.1.1.3

MARC Recommendation

In June 2007, the Committee recommended that NZPhvC should provide a follow up report to the MARC when the Coroner's report or further information that facilitates assessment becomes available.

Outcome

The NZPhvC will bring any further information to a future MARC when received.

Discussion

The Committee noted the above.

2.1.25 Clozapine and haematological malignancies
June 2009 minute item 2.1.32, March 2009 minute item 2.1.22, December 2008 minute item 2.1.22, September 2008 minute item 2.1.22, May 2008 minute item 2.1.28, March 2008 minute item 2.1.20, December 2007 minute item 2.1.20, September 2007 minute item 2.2.1, June 2007 minute item 2.1.1; March 2007 minute item 2.1.2; December 2006 minute item 2.2.3

MARC Recommendation

The Committee recommended that Medsafe, in consultation with Assoc. Prof. Frampton, explore a protocol for obtaining age-standardised data on the frequency of haematological events with clozapine.

Outcome

When the literature search was performed in May 2008, there were no published studies examining the relationship between clozapine exposure and haematological malignancies. The incidence of haematological malignancies in NZ is about 0.03%. The types of haematological malignancies reported with clozapine in NZ (7 cases as at April 2008) are varied and it seems implausible that one medicine could be responsible.

Discussion

The Committee noted the above.

3. pharmacovigilance issues

3.1 RISK OF CANCER IN ASSOCIATION WITH INSULIN GLARGINE (LANTUS) TREATMENT

References
  1. Summary of epidemiology studies investigating the risk between human insulin use and cancer
  2. Overview of recent epidemiology studies investigating insulin glargine use and cancer risk
  3. Hemkens et al 2009 Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia DOI 10.1007/s00125-009-1418-4
  4. Currie et al 2009 The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia DOI.1007/s00125-009-1440-6
  5. Jonasson et al 2009 Insulin glargine use and short-term incidence of malignancies - a population based follow up study in Sweden Diabetologia DOI 10.1007/s00125-009-1444-2
  6. SDRN Epidemiology Group 2009 Use of insulin glargine and cancer incidence in Scotland: A study from the Scottish Diabetes Research Network Epidemiology Group Diabetologia DOI 10.1007/s00125-009-1453-1
  7. Smith and Gale 2009 Does diabetes therapy influence the risk of cancer? Diabetologia DOI 10.1007/s00125-009-1441-5
  8. [..]
Issue

Medsafe provided a report for the MARC on the issue of the risk of cancer in association with insulin glargine (Lantus) treatment. Medsafe was alerted by the sponsor for Lantus (Sanofi-aventis) that four studies had been published in Diabetologia in July 2009 concerning a possible increased risk of cancer associated with Lantus treatment. The initial study was submitted by Hemkens and colleagues in 2008. However, because the interpretation of the study was controversial it was agreed that it would be premature to publish these findings in isolation and three other studies were commissioned. All four studies were published together.

Lantus is approved for use in New Zealand for once-daily subcutaneous administration in the treatment of patients with type 1 or type 2 diabetes mellitus who require insulin for the control of hyperglycaemia. Lantus is provided as 100IU/ml in 10ml injection solution, 100IU/ml in 3ml cartridge and as a pre-filled pen (Lantus SoloStar). PHARMAC have consulted on widening access to Lantus by removing the current special authority criteria from 1 August 2009. The Diabetes Subcommittee of PTAC has reviewed the Special Authority criteria for Lantus on several occasions. The Subcommittee recommended that access to insulin glargine be widened to include patients with type 2 diabetes who are receiving an intensive regimen of insulin, because these patients carry the same risk of severe hypoglycaemia as patients with type 1 diabetes on intensive insulin regimens. However, this decision has been deferred. Following review of all available information on a possible relationship between insulin analogues, in particular insulin glargine, and the risk of cancer, the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) concluded that the available data does not provide a cause for concern and that changes to the prescribing advice are therefore not necessary. Because of the limitations of the existing evidence the CHMP has requested the marketing authorisation holder, Sanofi-aventis, to develop a strategy for generation of further research in this area. In addition, the CHMP is exploring possibilities for cooperation with academia to generate further information. The FDA is currently reviewing many sources of safety data for Lantus, including these newly published observational studies, data from all completed controlled clinical trials, and information about ongoing controlled clinical trials, to better understand the risk, if any, for cancer associated with use of Lantus. Discussions are also ongoing between the FDA and the manufacturer of Lantus as to whether any additional studies evaluating the safety and efficacy of this drug need to be performed. The Committee were asked to advise on:

Discussion
The Committee noted the August 2009 Medsafe report.

The MARC noted that some preclinical studies suggested that insulin glargine may have greater potential to stimulate cell division than human insulin in vitro. However, studies in rats and mice did not confirm this finding.

The Committee reviewed data from controlled clinical trials and spontaneous reports and noted that the numbers involved in these clinical trials and the time period studied were not sufficient to be able to detect or evaluate a safety signal for malignancy. The Committee agreed that this data did not provide evidence for an increased risk of cancer with insulin glargine.

The Committee noted that due to the high background rate of cancer in diabetics it is difficult to determine the contribution made by treatment, therefore any epidemiological study needs to be well designed and include a large population with sufficient follow up to enable the strength of the association, if any, to be determined.

The Committee reviewed the four epidemiological studies (references 3 to 6 above). They noted that there were significant differences in methodology between the studies and additionally significant differences in the populations included in the cohorts, both in terms of the type of diabetes and disease stage. Since the studies were observational in nature, it was not clear that all the confounding factors had been taken into account, or that any significant results are not spurious due to the number of statistical comparisons made. All the studies had short follow up periods which were not sufficient to detect a signal for cancer induction. All the studies had significant differences in baseline characteristics between comparator groups.

The MARC considered that the methodological problems and the inconsistency in the results between studies meant that the MARC could not determine if there was an increased risk of cancer with insulin glargine.

The MARC considered that until more information is available, prescribers should inform their patients that there is less safety information available for newer insulins such as insulin glargine. The newer insulins should only be used when there is a potential benefit, such as management of nocturnal hypoglycaemia.

The Committee recommended that Medsafe disseminate information to healthcare professionals advising that the MARC had reviewed the recently published studies, concluded that there were significant problems with these studies, the Committee could not determine whether there was an increased risk of cancer in patients taking glargine, and reminding of the increased cancer risk in patients with diabetes.

The Committee noted that Medsafe will continue to closely monitor this issue and will work with the MARC to review new information when it becomes available.

Recommendation

The Committee recommended that Medsafe disseminate information to Healthcare Professionals advising that the MARC had reviewed the recently published studies, concluded that there were significant problems with these studies, the Committee could not determine whether there was an increased risk of cancer in patients taking glargine, and reminding of the increased cancer risk in patients with diabetes.

3.2 STIMULANT USE AND SUDDEN DEATH IN CHILDREN WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER

References
  1. Gould M., et al. (2009). Sudden death and use of stimulant medications in youths. American Journal of Psychiatry. Published online June 15, 2009; doi:10.1176/appi.ajp.2009.09040472
  2. Vitiello B. and Towbin K. (2009). Stimulant treatment of ADHD and risk of sudden death in children (Editorial). American Journal of Psychiatry. Published online June 15, 2009; doi:10.1176/appi.ajp.2009.09050619
Issue

Medsafe provided a report for the MARC on the issue of stimulant use and sudden death in children with attention deficit hyperactivity disorder (ADHD). This followed the publication of a recent paper in the American Journal of Psychiatry which identified a potential signal of sudden death in children associated with stimulant medication use.

In recent years, the use of ADHD medicines at therapeutic doses has been associated with a number of cases of serious cardiovascular adverse events including hypertension, myocardial infarction and stroke in both paediatric and adult populations, and more recently, cardiac arrest and sudden death.

To determine whether a significant association exists between the use of stimulants and the rare event of sudden unexplained death in children and adolescents, a matched case-control study was undertaken (Gould, 2009). The study was funded by the United States Food and Drug Administration (FDA) and the National Institute of Mental Health (NIMH). The authors of the study noted that no cardiac sudden deaths occurred during the 42,612 patient-years of clinical trials, however due to the rarity of sudden death in children aged 7 to 19 years of age (estimated at 0.8-8.5 cases per 100,000 patient-years), a sample size 16 times larger (2,000,000 patent-years) would be required to detect a significant difference between the stimulant use and non-use groups.

In June 2009, the FDA provided its perspective on the potential risks of stimulant medicines used to treat ADHD in children based on the data published in the Gould paper. Given the limitations of the study's methodology, the FDA was unable to conclude that these data affected the overall risk-benefit profile of stimulant medicines used to treat ADHD in children. The FDA therefore advised that the study should not serve as a basis for parents to stop a child's stimulant medicine. The FDA recommended that healthcare professionals follow all the current prescribing information for use of these medicines.

The FDA is continuing its review of the strengths and limitations of this and other epidemiological studies that evaluate the risks of stimulant medicines used to treat ADHD in children. The US Agency for Healthcare Research and Quality and the FDA are joint sponsors of a large epidemiological study investigating the potential for increased risk of heart attack, stroke or other cardiovascular problems associated with stimulant medicine use in children. The data collection for this study will be complete later in 2009. The FDA will update its advice when additional information or analyses become available.

The Committee was asked to consider the value of the Gould paper in assessing whether a significant association exists between the use of stimulants and the rare event of sudden unexplained death in children and adolescents.

The Committee was also asked to consider whether the results of the Gould paper alter the risk-benefit profile of ADHD medicines in children and whether any regulatory action or communication is warranted in New Zealand at this time.

Discussion
The Committee noted the August 2009 Medsafe report.

The Committee discussed the Gould paper. They noted that it had a retrospective, case-control design, in which the investigators matched children who had died of sudden unexplained death to children who had died as passengers in motor vehicle accidents. Medical and treatment information was collected from autopsy reports, toxicology results, and direct interviews with the parents.

The Committee noted that the matching of cases to controls occurred after the data was collected. The Committee considered this to be an unusual approach.

The Committee noted that although the investigators went to great lengths to reduce possible sources of bias, important confounders remained.

The Committee noted the following limitations of the study:

The sudden unexplained death of a child, in comparison to the death of a child from a motor vehicle accident, may have increased the likelihood of a post-mortem inquiry into medicine use.

The difference in cause of death could have influenced the family or caregiver's recall of information on stimulant medicine use at the time of death, creating an elevated rate of stimulant medicine use in the group of children who died suddenly.

The significant time lag between the dates of deaths and collection of the data may have resulted in reporting errors.

The dose and duration of stimulant medicine use was not identified.

Sudden death could have occurred as a result of an undiagnosed cardiac structural abnormality, rather than stimulant use.

The Committee noted that the methods of the study did not allow the investigators to establish whether ADHD itself increases the risk of sudden unexplained death, independent of stimulant treatment.

The Committee considered that the results of the study demonstrated a weak association between stimulant use and sudden death, with a wide confidence interval. The results were only significant when all information sources were considered (autopsy reports, toxicology results, and information from parents and caregivers).

The Committee agreed that the Gould conclusions suggesting a link between stimulant use and sudden unexplained death cannot be dismissed because the sympathomimetic activity of stimulants provides biological plausibility for adverse cardiovascular effects.

Based on the available evidence, the Committee considered the current NZ data sheets for methylphenidate-containing ADHD medicines to be adequate in addressing the risk of sudden death associated with stimulant use in children with ADHD.

The Committee noted that Medsafe will await the completion of the US epidemiological study investigating the potential for increased risk of heart attack, stroke or other cardiovascular problems associated with the use of stimulant medicines in children. They agreed that Medsafe review the results of the epidemiological study when they become available and report back to the MARC.

The Committee considered that no regulatory action was required at this time.

3.3 CONVENTIONAL ANTIPSYCHOTICS AND MORTALITY RISK

References
  1. Medsafe (2009) Conventional antipsychotics and mortality risk, Prescriber Update 30(1):1
  2. FDA (2008) Conventional Antipsychotics - Healthcare professional sheet FDA Alert
  3. Faculty of Psychiatry of Old Age, Committee for Therapeutic Interventions and Evidence-Based Practice (2009) Antipsychotic medications as a treatment of behavioural and psychological symptoms in dementia, Royal Australia New Zealand College of Psychiatrists (RANZCP)
  4. Greve M, O'Connor D (2005) A survey of Australian and New Zealand old age psychiatrists' preferred medications to treat behavioural and psychological symptoms of dementia (BPSD), International Psychogeriatrics, 17(2): 195 - 205
  5. Setoguchi S, Wang P, Brookhart A, Canning C, Kaci L, Schneeweiss S, (2008) Potential causes of higher mortality in elderly users of conventional and atypical antipsychotic medications. Journal of the American Geriatrics Society 56: 1644 - 1650
Issue

Medsafe provided a report for the MARC on the issue of conventional antipsychotics and mortality risk.

In 2005, regulatory warnings were issued about the risk of death associated with atypical antipsychotics. This warning excluded conventional antipsychotics, largely due to an absence of data showing such a risk in this group of medicines. Subsequently a similar risk of death has been shown to be associated with the use of conventional antipsychotics in elderly patients with dementia.

The increased risk of mortality associated with the use of conventional antipsychotics was first discussed by the MARC at the September 2008 meeting. The Committee agreed that the recently published studies concluded that the risk of death associated with conventional antipsychotics in elderly patients with dementia may be greater than that with atypical antipsychotics. They recommended that product sponsors for all antipsychotic medicines be required to update their New Zealand datasheets to include information about the increased risk of mortality in elderly patients with dementia. The majority of the datasheets have now been updated and the remainder are being processed and will be published on the Medsafe website in the near future.

At the 2008 review, the Committee also recommended that the opinions of psychogeriatricians about the risks and benefits of antipsychotics for elderly patients with dementia be sought. The recent publication of comprehensive guidelines by BPAC and the RANZCP and the Greve and O'Connor article have addressed this recommendation.

The Committee recommended that a Prescriber Update article be published, and an article entitled 'Conventional antipsychotics and mortality risk - carefully assess risks and benefits before use in elderly dementia patients' was published in February 2009.

The purpose of the 2009 report was to:

Discussion

The MARC noted the August 2009 Medsafe report.

The Committee discussed the study by Greve and O'Connor, which consisted of a survey of a random sample of members of the Royal Australian and New Zealand College of Psychiatrists, asking about their preferred treatments for behavioural and psychological symptoms of dementia (BPSD). The Committee noted that the methodology of the study did not allow for combining ratings of all conventional antipsychotics and thus did not allow for a direct comparison of ratings between conventional and atypical antipsychotics.

The Committee discussed the study by Setoguchi et al, a Canadian database cohort study which assessed rates and major causes of deaths for new users of conventional antipsychotics compared to new users of atypical antipsychotics. The study aimed to identify the specific causes of death responsible for the increased risk seen with antipsychotics. The Committee agreed that it is unlikely that this study offers sufficient evidence that the risk of death is different for conventional compared to atypical antipsychotics. They considered that this study therefore does not justify any recommendation to change patients from conventional to atypical antipsychotics.

The Royal Australian and New Zealand College of Psychiatrists (RANZCP) have recently issued guidelines on 'Antipsychotic medications as a treatment of behavioural and psychological symptoms of dementia'. The guidelines state that traditional antipsychotics are modestly effective in treating behavioural and psychological symptoms of dementia (BPSD), and that newer atypical preparations are possibly more effective, but not to a striking degree. The guidelines advised that the evidence base supporting pharmacological and non-pharmacological management strategies for BPSD was modest in quality and quantity, and clinicians were recommended to familiarise themselves with summaries of available information. The Best Practice Advocacy Centre (BPAC) has also issued a Best Practice Guide on the use of antipsychotics in dementia in September 2008, along with clinical recommendations prepared in conjunction with the RANZCP.

The Committee noted that in the period under review, there has been further information supporting the presence of an increased risk of death in elderly dementia patients using conventional and atypical antipsychotics. The Committee agreed that this information was adequately addressed in the product datasheets and in the recently published guidelines, and therefore this new information did not alter the risk-benefit profile of antipsychotic medicines compared with when the MARC last reviewed the issue in September 2008.

The MARC noted that Medsafe will continue to monitor and evaluate international regulatory action and safety-related data as it arises, and will report back to the MARC as necessary. The Committee recommended that the issue of conventional antipsychotics and mortality risk be removed from the 'Scheduled Review' list.

Recommendation

The Committee recommended that the issue of conventional antipsychotics and mortality risk be removed from the 'Scheduled Review' list.

3.4 BLACK COHOSH AND HEPATOTOXICITY

  1. WHO VigiSearch results (received date ≥1 August 2008)
  2. Mahady GB, Low Dog T, Barrett ML, Chavez ML, Gardiner P, Ko R, Marles RJ, Pellicore LS, Giancaspro GI, Sarma DN. United States Pharmacopeia review of the black cohosh case reports of hepatotoxicity. Menopause. 2008 Jul-Aug;15(4 Pt 1):628-38. Review
  3. Teschke R, Schwarzenboeck A. Suspected hepatotoxicity by Cimicifugae racemosae rhizoma (black cohosh, root): critical analysis and structured causality assessment. Phytomedicine. 2009 Jan;16(1):72-84. Epub 2008 Nov 17
  4. Teschke R, Bahre R, Genthner A, Fuchs J, Schmidt-Taenzer W, Wolff A. Suspected black cohosh hepatotoxicity-Challenges and pitfalls of causality assessment. Maturitas. 2009 Jul 6. [Epub ahead of print]
  5. Borrelli F, Ernst E. Black cohosh (Cimicifuga racemosa): a systematic review of adverse events. Am J Obstet Gynecol. 2008 Nov; 199(5): 455-66. Review
  6. Vannacci A, Lapi F, Gallo E, Vietri M, Toti M, Menniti-Ippolito F, Raschetti, R, Firenzuoli F, Mugelli A. A case of hepatitis associated with long-term use of Cimicifuga racemosa. Altern Ther Health Med. 2009 May-Jun;15(3):62-3
  7. Pierard S, Coche JC, Lanthier P, Dekoninck X, Lanthier N, Rahier J, Geubel AP. Severe hepatitis associated with the use of black cohosh: a report of two cases and an advice for caution. Eur J Gastroenterol Hepatol. 2009 Aug; 21(8):941-5
  8. Joy D, Joy J, Duane P. Black cohosh: a cause of abnormal postmenopausal liver function tests Climacteric 2008; 11:84-8
  9. Nasr A, Nafeh H. Influence of black cohosh (Cimicifuga racemosa) use by postmenopausal women on total hepatic perfusion and liver functions. Fertil Steril. 2009 Jun 17. [Epub ahead of print]
Issue

Medsafe provided a report for the MARC's 'Scheduled Review' on the issue of black cohosh and hepatotoxicity. This issue was placed on the 'Scheduled Review' list in September 2008 following the publication of a paper by Chow et al. This paper described an Australian case report of a patient who developed liver failure after taking black cohosh to treat menopausal symptoms.

In September 2008, the Committee agreed that while the risk of hepatotoxicity with black cohosh appeared to be very rare, they considered that the risk:benefit ratio to be such that it was worthwhile disseminating information regarding this risk. They acknowledged that many of these products contain several different ingredients and are self-selected by the consumer, rather than following consultation with a practitioner. They recommended that Medsafe consider ways to disseminate this information as widely as possible.

An article entitled 'Black cohosh and hepatotoxicity - ask about use and look for signs' was published in the February 2009 edition of Prescriber Update.

Discussion

The Committee noted the 2009 Medsafe report. The Committee noted that there had been no further regulatory action in other countries since September 2008 when the Committee first considered this issue.

The Committee considered that the most interesting information obtained from a review of the literature since September 2008 was contained in the five case reports, noting the cases where improvement occurred upon dechallenge. The Committee considered these reports provide a strong case for a causal association between black cohosh and hepatotoxicity.

The Committee's attention was also drawn to a recent New Zealand case report of hepatic necrosis in a 53-year-old woman taking black cohosh and nitrofurantoin. This report is discussed in section 4.1.1.6.

The Committee noted that Medsafe had notified the New Zealand Food Safety Authority (NZFSA) of the Committee's recommendations from September 2008 as products containing black cohosh were under NZFSA's jurisdiction as dietary supplements. Medsafe agreed to keep the Committee informed of any actions taken by NZFSA in respect of dietary supplements containing black cohosh.

The Committee noted that one way of providing information to GPs about black cohosh and its association with hepatotoxicity was through the new journal of the RNZCGP: New Zealand Journal of Primary Health Care. The Committee noted that [..] has a regular column on complementary medicines in this journal. The Committee therefore recommended that Medsafe write to [..] to request that she consider including an article about black cohosh and hepatotoxicity in her regular column.

The Committee agreed that it would be helpful to include an article in Prescriber Update providing guidance to prescribers on the information to include when reporting suspected adverse reactions to complementary medicines, including giving consideration to obtaining a sample of the suspect complementary medicine in the case of serious adverse reactions.

The Committee recommended that the issue of black cohosh and hepatotoxicity be removed from the Scheduled Review list.

Recommendations

The Committee recommended that an article be published in Prescriber Update providing guidance to prescribers when reporting suspected adverse reactions to complementary medicines.

The Committee recommended that Medsafe write to [..] to request that she include an article in her regular column in the New Zealand Journal of Primary Health Care on the issue of black cohosh and hepatotoxicity.

The Committee recommended that the issue of black cohosh and hepatotoxicity be removed from the Scheduled Review list.

4. Matters arising from the New Zealand Pharmacovigilance Centre

4.1 Centre for Adverse Reactions Monitoring (CARM) Spontaneous Case Reports

Spontaneous reporting programme

All spontaneous reports presented at the MARC meeting have been assessed by the Centre for Adverse Reactions Monitoring (CARM) and responses have been sent to the reporters. The purpose of these responses is to assist the practitioner to discharge his/her responsibility to patients. These individual replies include as appropriate:

  • comment about causality;
  • information about similar suspected adverse reactions reported with the same or related medicines;
  • prescribing advice;
  • advice related to the care of the patient, including information that may assist the practitioner to make a risk:benefit assessment for future treatment; and
  • any specific action being taken by the Centre, including entering the reaction into the National Health Index against the patient's name, presenting the case report to the MARC, etc.

Note: In the discussion notes for each report, the case has been given a causality designation using terms and definitions developed by the World Health Organisation. The precise definitions are available on the website of the The Uppsala Monitoring Centre, which is the WHO Collaborating Centre for International Drug Monitoring - http://www.who-umc.org/

These designations (certain, probable, possible, unlikely, unclassified and unclassifiable) refer to the degree of certainty about the relationship between the medicine and the adverse event. The terms should not be understood literally. For example, "certain" means that the appropriate elements are present to match the international definition. It does not mean there is absolute certainty that the medicine caused the adverse event. Explanations of these terms can be found on the Medsafe website via the hyperlink at each causality designation.

The Committee was advised that the way in which the spontaneous case reports were presented to the MARC had been refined, with the focus of cases presented to the Committee being on advice and signal detection. The remainder of case reports are included as list reports, with an expanded section for relevant comments.

4.1.1 Deaths

4.1.1.1 Lamotrigine, valproate sodium and Stevens Johnson syndrome, incorrect dose prescribed, drug interaction [death] (83869)

Discussion

NZPhvC advised that the CARM database includes reports of Stevens Johnson syndrome and toxic epidermal necrolysis in association with lamotrigine.

NZPhvC advised that the product datasheet contains dosing guidelines when commencing Lamictal therapy with and without any other anti-epileptic drug therapy. The datasheet includes warnings of adverse skin reactions, the majority of which are mild and self-limiting, but may be serious. These serious skin reactions, which have included Stevens-Johnson syndrome and toxic epidermal necrolysis, appear to be associated with high initial doses of lamotrigine and exceeding the recommended dose escalation of lamotrigine therapy, along with concomitant use of valproate.

The Committee recommended that a paragraph be published in Prescriber Update to remind prescribers to adhere to the recommended dose guidelines in the product datasheet for lamotrigine, both alone, and in combination, particularly with valproate.

The causal association with lamotrigine, valproate sodium was considered to be 'possible' for Stevens Johnson syndrome, and for drug interaction.

The causal association with lamotrigine, valproate sodium was considered to be 'certain' for incorrect dose prescribed.

Recommendation

The Committee recommended that a paragraph be published in Prescriber Update to remind prescribers to adhere to the recommended dose guidelines for lamotrigine, for lamotrigine alone and in combination particularly with valproate sodium, as outlined in the product datasheet.

4.1.1.2 Methotrexate, hydroxychloroquine, venlafaxine, and myocarditis, cardiac arrest [death] (84033)

Discussion

NZPhvC advised that there were reports in the WHO database of myocarditis, cardiomyopathy, ventricular arrhythmias, and cardiac arrest with both methotrexate and hydroxychloroquine. QT interval increased and Torsade de Pointes have been reported in association with hydroxychloroquine only.

The product datasheet for methotrexate includes a warning that it be used with extreme caution in the presence of active infection, and includes sudden death in the 'Adverse Reactions' section. The hydrochloroquine (Plaquenil) datasheet includes cardiomyopathy as a rare adverse reaction, and lists cardiac symptoms occurring in overdose. QT prolongation is not listed as an adverse reaction. The Committee recommended that Medsafe request a review of QT prolongation in association with hydrochloroquine from the product sponsor.

The causal association with methotrexate, hydroxychloroquine, and venlafaxine was considered to be 'possible' for myocarditis, and cardiac arrest.

Recommendation

The Committee recommended that Medsafe request a review of QT prolongation in association with hydrochloroquine from the product sponsor.

4.1.1.3 Diclofenac and convulsions, numbness localised (84488)

Discussion

NZPhvC advised that the CARM database includes reports of convulsions in association with diclofenac. The product datasheet lists seizures and paraesthesias as very rare adverse reactions.

NZPhvC commented on the dose of diclofenac prescribed. An analysis of the CARM database showed a high proportion of patients taking 150mg daily or more of diclofenac in reports of acute renal failure, and a higher proportion of renal failure with diclofenac than with two other commonly prescribed NSAIDs in the CARM database.

NZPhvC noted that there were inconsistencies across the product information for the different brands of diclofenac in NZ. Some product datasheets stated the maximum daily dose of diclofenac to be 150mg, except for dysmenorrhoea, for which the dose may be increased over several menstrual cycles to 200mg daily. The Voltaren Dispersible brand included a dose of 200mg daily for the treatment of migraine. Diclax did not include any exceptions to the maximum recommended daily dose of 150 mg.

The Committee recommended that Medsafe request a review of the 200mg dose recommendations for diclofenac from the product sponsors.

The causal association with diclofenac was considered to be 'possible' for convulsions, numbness localised.

Recommendation

The Committee recommended that Medsafe request a review of the 200mg dose recommendations for diclofenac from the product sponsors.

4.1.1.4 Ziprasidone and arrhythmia, dyskinesia, dehydration, tremor (84310)

Discussion

NZPhvC advised that the CARM database includes reports of QT prolonged, dystonia, oculogyric crisis, akathisia, and hyperkinesia in association with ziprasidone. In the WHO database, the terms cardiac arrest, QT prolonged, and Torsade de Pointes in association with ziprasidone have positive IC values.

The product datasheet lists known QT-interval prolongation as a contraindication to the use of ziprasidone, along with other cardiac abnormalities. It states that the safety and efficacy of ziprasidone in children under 18 years of age has not been established.

The Committee noted that concerns about a connection between QT prolongation, Torsade de Pointes, and sudden death had led to the withdrawal of, or datasheet changes, for other anti-psychotics. They recommended that a Prescriber Update article be written reminding prescribers of the effect of anti-psychotics in general on the QT interval.

The Committee considered the causal association with ziprasidone to be 'unclassified' for arrhythmia, and 'possible' for dyskinesia, dehydration, tremor.

Recommendation

The Committee recommended that a Prescriber Update article be written reminding prescribers of the effect of anti-psychotics in general on the QT interval.

4.1.1.5 Varenicline and suicide [death] (84971)

Discussion

NZPhvC advised that varenicline is currently monitored by the Intensive Medicines Monitoring Programme (IMMP). The IMMP contains six reports of suicidal ideation, one of suicide attempt, one of intentional overdose, and one report of intentional self injury in a patient with a pre-existing problem. The WHO database includes reports of suicide attempt in association with varenicline.

The Committee noted that there was limited information provided in this report, and that further information has been requested. The Committee noted that the next IMMP report for varenicline is due to be presented to the December 2009 MARC meeting.

The Committee considered the causal association with varenicline was 'unclassified' for suicide.

4.1.1.6 Black cohosh, nitrofurantoin and hepatic necrosis (85273)

Discussion

NZPhvC advised that the CARM database holds reports of hepatic reactions in association with nitrofurantoin, including a small number of serious and fatal reactions. The CARM database includes reports for ten complementary medicines which are known to contain black cohosh, with three reports of abnormal hepatic function.

The NZ datasheet for Nifuran includes hepatic reactions in the 'Warnings' section, and states that long-term therapy should be continued beyond six months only when the benefits clearly outweigh the risks.

The Committee discussed the treatment of recurrent urinary tract infections and considered it would be useful to request guidelines from specialists in this area, including nephrologists and urologists.

The Committee considered the causal association with black cohosh and nitrofurantoin to be 'possible' for hepatic necrosis.

Recommendation

The Committee recommended that guidance be requested from relevant specialists on the treatment of recurrent urinary tract infections.

4.1.2 Fatalities Listing

Members were asked to note these reports, with the option of requesting that any particular report/s be discussed at the current, or a subsequent meeting. The Committee noted the following case reports:

Recommendation

The Committee recommended that further details be provided for case reports:

4.1.3 List reports

These reports are typically due to disease progression, or contain insufficient data for an assessment to be made. They also include non-serious or well known reactions to medicines on the Adverse Reactions of Current Concern (ARCC) list. Members were asked to note these reports, with the option of requesting that any particular report/s be discussed at the current, or a subsequent meeting.

The Committee noted the following case reports:

The MARC discussed the new format of the Fatalities and List reports. They suggested that the reports be amended slightly to include the narrative extract from each listed case report that would previously have been a full case report at the meeting, and the indication where available. This would provide a basis for making a decision if more information was required in each particular case.

Members agreed that the NZPhvC comment included for each report was useful.

4.2 Quarterly Reports from CARM as at 30 June 2009

Discussion

The Committee noted the quarterly reports from CARM as at 30 June 2009 and noted that the format of the report had been refined.

The Committee noted that NZPhvC had received one report of deep vein thrombosis and one of pulmonary embolism in association with Yasmin in the first three months of this year. In September 2008, the Committee reviewed the final results from the European Active Post Marketing Surveillance (EURAS) study, which compared the risks of adverse cardiovascular and other events associated with the use of drospirenone-containing oral contraceptives with two groups of established oral contraceptives, and concluded that the risks of cardiovascular and other serious events in users of drospirenone-containing oral contraceptives were similar to those associated with the use of other oral contraceptives. The Committee noted that there had been two papers recently published in the British Medical Journal comparing drospirenone-containing with other oral contraceptives and recommended that these form the basis of a review of drospirenone-containing and the risk of venous thromboembolism, to be presented at the next MARC meeting.

Recommendation

The Committee recommended that the recently published papers in the British Medical Journal comparing drospirenone-containing with other oral contraceptives form the basis of a review of drospirenone-containing and the risk of venous thromboembolism, to be presented at the next MARC meeting.

4.3 Human Papillomavirus Vaccine (HPV) reports

Discussion

The Committee noted the CARM report of reactions to the HPV vaccine for the period 1 May 2007 to 31 July 2009.

The Committee noted that reports continued to be in keeping with the pattern of reports received in the past and were those expected events following any immunisation.

The Committee noted the paper published by Slade et al in JAMA on 19 August 2009, which analysed the adverse reaction reports for the Gardasil vaccine made to the Vaccine Adverse Events Reporting System in the United States. The Committee noted that Medsafe had issued a media release advising that this paper had been reviewed by Medsafe, and the Medicines Advisory Reactions Committee was reviewing adverse event reports associated with the HPV vaccine on an ongoing basis.

5. pharmacovigilance issues for information only

The following information was included in the meeting dossier. However, the Committee did not discuss this material. It included updates on issues already known to the Committee, commentaries, review articles and preliminary information on emerging issues. Members were asked to read this material, with the option of requesting that it be discussed.

Recommendation

The Committee recommended that the literature continue to be monitored for similar papers to that published above by Meador et al in the N Engl J Med entitled 'Cognitive Function at 3 Years of Age after Fetal Exposure to Antiepileptic Drugs'.

6. New Zealand pharmacovigilance-related activities

7. international pharmacovigilance-related Activities

7.1 Australia

7.2 Canada

7.3 Singapore

7.4 United Kingdom

7.5 United States

8. OTHER BUSINESS

8.1 Abuse of ibuprofen/codeine combination products

A member commented that a recent presentation at a Wellington Hospital Grand Round focused on a case series of patients who had been abusing ibuprofen/codeine combination products and experienced gastrointestinal bleeding. The Committee considered it would be useful to obtain a copy of this presentation and recommended that Medsafe review this and determine if further action is required.

Recommendation

The Committee recommended that Medsafe obtain a copy of the recent presentation at Wellington Hospital regarding abuse of ibuprofen/codeine combinations products and determine if further action is required.

8.2 Terms of reference for the MARC

The Committee discussed the proposed new terms of reference for the Committee.

Medsafe advised that a report proposing new terms of reference had been sent to the Minister of Health. The statutory function of the MARC was discussed. Under the Medicines Act 1981, the Minister may refer to an advisory or technical committee to advise him for any of the purposes of the Act. The MARC has been established under this Act, and as such, the terms of reference must fit into this legislative framework. The current terms of reference were last updated and approved by the then Minister in 2000, and it was considered timely to amend these to better reflect the statutory role of the committee and to sharpen the focus of the committee in relation to risk-benefit assessment.

The Acting Chair reported he had expressed his concern to the Minister, that the proposed terms of reference might limit the role of the committee to a technical advisory body, which could only respond to specific material and questions presented to it by Medsafe. The Committee expressed some concern that the new terms of reference could potentially remove any significant role the MARC might have in advising on pharmaco-educational strategies and may also restrict the potential recommendations of the Committee to considering purely legislative regulatory actions. This could preclude the preparation of written materials, such as Prescriber Update articles, BPAC communication and so on. In addition it could remove the pharmaco-surveillance role of reviewing CARM reports. After some discussion, Medsafe reassured the Committee that their role in post-market safety monitoring was valuable, that the proposed changes would not preclude the Committee from participation in the preparation of written materials and other communications, and further discussions on this issue would be carried out.

8.3 Continuing Medical Education

The Committee agreed it would be of benefit for a presentation on a relevant topic to be made at each MARC meeting, and made several suggestions for topics.

The Acting Chair agreed to make a presentation on allergy/skin reactions including current thinking about dose response at the December meeting.

The Acting Chair thanked members and the secretariat for their attendance and closed the meeting at 2.30pm.

Associate Professor M. Rademaker
Acting Chair
Medicines Adverse Reactions Committee