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Committees

Updated 20 May 2013

Minutes of the 140th Medicines Adverse Reactions Committee Meeting - 3 December 2009

MARC MEMBERS PRESENT

MARC SECRETARIAT PRESENT

MEDSAFE STAFF PRESENT

1 MATTERS OF ADMINISTRATION

1.1 WELCOME AND APOLOGIES

1.2 MINUTES OF THE 139TH MARC MEETING

1.3 DATES OF FUTURE MARC MEETINGS

1.4 POTENTIAL CONFLICTS OF INTEREST

1.5 PRESCRIBER UPDATE

1.5.1 Schedule of Planned Prescriber Update Articles
1.5.2 Prescriber Update. Volume 30, Number 4. November 2009

2 STANDING AGENDA ITEMS

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

2.1.1 Prescriber Update
2.1.2 Risk of cancer in association with insulin glargine (Lantus) treatment
2.1.3 Conventional antipsychotics and mortality risk
2.1.4 Black cohosh and hepatotoxicity
2.1.5 Lamotrigine, valproate sodium and Stevens Johnson syndrome, incorrect dose prescribed, drug interaction [death] (83869)
2.1.6 Methotrexate, hydroxychloroquine, venlafaxine, and myocarditis, cardiac arrest [death] (84033)
2.1.7 Diclofenac and convulsions, numbness localised (84488)
2.1.8 Ziprasidone and arrhythmia, dyskinesia, dehydration, tremor (84310)
2.1.9 Black cohosh, nitrofurantoin and hepatic necrosis (85273)
2.1.10 Fatalities Listing
2.1.11 Quarterly Reports from CARM as at 30 June 2009
2.1.12 Pharmacovigilance issues for information only
2.1.13 Abuse of ibuprofen/codeine combination products
2.1.14 Methylphenidate SR (Rubifen SR) brand switch-aggressive and defiant behavioural reactions- Scheduled Review
2.1.15 Diclofenac and intestinal perforation, sepsis, multiple organ failure [death] (82166)
2.1.16 Infanrix-hexa, Prevenar and sudden death [death] (82290)
2.1.17 Trastuzumab, tamoxifen and renal disorder not-otherwise-specified (NOS), respiratory infection, oligohydramnios (mother), pregnancy exposure (mother) [death] (81237)
2.1.18 Sodium valproate, topiramate, levetiracetam and hyponatraemia, cerebral infarction, peripheral oedema (81286)
2.1.19 Vitamin D and renal failure, hypervitaminosis D, medication error (81804)
2.1.20 Oral bisphosphonates and the risk of atrial fibrillation
2.1.21 Ropivacaine and convulsion grand mal, cardiac arrest, drug overdose [death] (80093)
2.1.22 SSRI antidepressants
2.1.23 Removal of specialist prescribing restriction from retinoids
2.1.24 Dextropropoxyphene/ paracetamol combination products and the risk of overdose
2.1.25 Sodium valproate and foetal valproate syndrome, drug exposure during pregnancy (82615)
2.1.26 Influenza virus vaccine and cardiac arrest, bradycardia, diarrhoea, abdominal pain, gastrointestinal disorder NOS (83046)
2.1.27 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)
2.1.28 Lamotrigine and convulsion [death] (74826)
2.1.29 Clozapine and neutropenia, lymphopenia, anaemia [death] (76419)

3 PHARMACOVIGILANCE ISSUES

3.1 CONSIDERATION OF DEXTROPROPOXYPHENE- CONTAINING MEDICINES UNDER SECTION 36 OF THE MEDICINES ACT 1981

3.2 DROSPIRENONE/ETHINYLOESTRADIOL: RISK OF VENOUS THROMBOEMBOLISM COMPARED TO OTHER COMBINED ORAL CONTRACEPTIVES

3.3 BISPHOSPHONATES AND ATRIAL FIBRILLATION

3.4 MONITORING OF VARENICLINE (CHAMPIX)

4 MATTERS ARISING FROM THE NEW ZEALAND PHARMACOVIGILANCE CENTRE 19
4.1 CENTRE FOR ADVERSE REACTIONS MONITORING (CARM) SPONTANEOUS CASE REPORTS

4.1.1 Case reports
4.1.2 Fatalities Listing
4.1.3 Dianeal death reports
4.1.4 List reports

4.2 QUARTERLY REPORTS FROM CARM AS AT 30 JUNE 2009

4.3 FURTHER DETAILS OF CARM REPORTS REQUESTED AT PREVIOUS MEETINGS OF THE MARC

4.4 HUMAN PAPILLOMAVIRUS VACCINE (HPV) REPORTS

4.5 PROTON PUMP INHIBITORS (PPI) REPORT

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

8 OTHER BUSINESS

8.1 The use of low-dose aspirin for primary prevention
8.2 Continuing Medical Education


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 140th MEDICINES ADVERSE REACTIONS COMMITTEE MEETING,
3 December 2009

The one hundred and fortieth meeting of the Medicines Adverse Reactions Committee (MARC) was held on 3 December 2009 in the Board Room, Medsafe, Wellington, New Zealand. The meeting commenced at 9 am and closed at 3.30 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 M Tatley

MARC Secretariat Present

J McNee (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)
E Jamison (Advisor)
S Kenyon (Senior Advisor, Pharmacovigilance)
S Martindale (Principal Advisor, Regulation)
M Miller (Advisor, Science)
M Prescott (Advisor, Science)
E Yousuf (Principal Clinical Advisor)

1. Matters of Administration

1.1 Welcome and Apologies

The Acting Chair welcomed the attendees to the meeting. Dr S Jessamine (Group Manager, Medsafe) attended the meeting during the discussion of minute item 3.1. Apologies were received from Dr S Sime.

1.2 Minutes of the 139th MARC Meeting

The minutes of the 139th meeting of the Committee were accepted as a true and accurate record of the meeting.

1.3 Dates of Future MARC Meetings

The dates for the MARC meetings for 2010 were proposed as 11 March, 10 June, 9 September, and 2 December.

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.

Two members declared they had received industry funding through the NZPhvC to undertake a Paradex utilization study. The Committee agreed it was appropriate that they be absent from the meeting during the discussion of agenda item 3.1.

There were no other potential conflicts of interest which were 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.

1.5.2 Prescriber Update. Volume 30, Number 4. November 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 Prescriber Update
September 2009 minute item 1.5.1

MARC Recommendation

In September 2009, the Committee recommended that an article be published in Prescriber Update on the issue of herbal medicines adulterated with steroids.

Outcome

This information was included in the Complementary Medicine Corner of the November 2009 edition of Prescriber Update.

Discussion

The Committee noted the above.

2.1.2 Risk of cancer in association with insulin glargine (Lantus) treatment
September 2009 minute item 3.1

MARC Recommendation

In September 2009, the Committee recommended that Medsafe disseminate information to Healthcare Professionals advising that the MARC had reviewed the recently published studies and concluded that there were significant problems with these studies; that 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.

Outcome

Medsafe issued a press release and Dear Healthcare Professional letter in September 2009. These were included in the December dossier. This information was also included in the November 2009 edition of Prescriber Update.

On 9 November 2009, PHARMAC advised that the proposal to widen access to insulin glargine had been declined.

Discussion

The Committee noted the above.

2.1.3 Conventional antipsychotics and mortality risk
September 2009 minute item 3.3

MARC Recommendation

In September 2009, the Committee recommended that the issue of conventional antipsychotics and mortality risk be removed from the Scheduled Review list.

Outcome

The issue of conventional antipsychotics and mortality risk has been removed from the Scheduled Review list.

Discussion

The Committee noted the above.

2.1.4 Black cohosh and hepatotoxicity
September 2009 minute item 3.4

MARC Recommendation

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 [..] 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.

Outcome

An article providing guidance to prescribers when reporting suspected adverse reactions to complementary medicines was published in the November 2009 edition of Prescriber Update. An article focusing on black cohosh was published in the May 2009 edition of Prescriber Update.

[..] has advised that the topic of black cohosh is scheduled for [..] next column in the New Zealand Journal of Primary Health Care, to be published in March 2010.

The issue of black cohosh and hepatotoxicity has been removed from the Scheduled Review list.

Discussion

The Committee noted the above.

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

September 2009 minute item 4.1.1.1

MARC Recommendation

In September 2009, 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.

Outcome

An article was published in the November 2009 edition of Prescriber Update.

Discussion

The Committee noted the above.

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

September 2009 minute item 4.1.1.2

MARC Recommendation

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

Outcome

Medsafe has requested a review of QT prolongation from the New Zealand sponsor. The review is expected to be submitted in time for the next MARC meeting.

Discussion

The Committee noted the above.

2.1.7 Diclofenac and convulsions, numbness localised (84488)

September 2009 minute item 4.1.1.3

MARC Recommendation

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

Outcome

The NZPhvC has been asked to provide a review of the case reports suggesting that patients taking higher doses of diclofenac may be at increased risk of renal failure. If there is sufficient evidence based on the NZPhvC's review to suggest there is an increased risk of renal failure with high, short-term exposures to 200 mg/day diclofenac, a formal review will be requested from product sponsors. It is important to note that because this is to some extent an efficacy issue, any review of the efficacy of 200 mg/day would require a formal risk-benefit review initiated under s36 of the Medicines Act 1981.

Medsafe has noted the data sheet discrepancy between different diclofenac products and is investigating this.

Discussion

The Committee noted the above.

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

September 2009 minute item 4.1.1.4

MARC Recommendation

In September 2009, the Committee recommended that a Prescriber Update article be written reminding prescribers of the effect of antipsychotics in general on the QT interval.

Outcome

Medsafe is in the process of updating product datasheets and will communicate this information to healthcare practitioners.

Discussion

The Committee noted the above. A member advised a recent paper had been published on this topic in the Lancet.

2.1.9 Black cohosh, nitrofurantoin and hepatic necrosis (85273)
September 2009 minute item 4.1.1.6

MARC Recommendation

In September 2009, the Committee recommended that guidance be requested from relevant specialists on the treatment of recurrent urinary tract infections (UTIs).

Outcome

The urologist consulted by CARM stated that she uses low dose nitrofurantoin for three months to prevent recurrent uncomplicated UTIs in women. She understood that there was a risk of pneumonitis at any time during treatment and does warn patients about symptoms. After three months she discontinues treatment as often it is no longer needed. If there is relapse she restarts it. As stated at the last meeting the nephrologist consulted would use nitrofurantoin for six months and then discontinue. If there is rapid relapse he would give trimethoprim but would use nitrofurantoin again if there was later relapse. Both agreed that nitrofurantoin is the most appropriate antibiotic in this situation as it had a low potential to cause resistance. Neither knew of any guidelines on its use.

Discussion

The Committee noted the above and recommended that the Best Practice Advocacy Centre (BPAC) be asked to consider publishing an article on the treatment of recurrent urinary tract infections.

Recommendation

The Committee recommended that the Best Practice Advocacy Centre (BPAC) be asked to consider publishing an article on the treatment of recurrent urinary tract infections.

2.1.10 Fatalities Listing
September 2009 minute item 4.1.2

MARC Recommendation

In September 2009, the Committee recommended that further details be provided for case reports:

Olanzapine (83748)

Olanzapine, risperidone, clonazepam, metoprolol (84713)

Outcome

Further details of these reports were included in the December 2009 dossier.

Discussion

The Committee noted the further details provided on the above case reports and determined that no further action was indicated.

2.1.11 Quarterly Reports from CARM as at 30 June 2009
September 2009 minute item 4.2

MARC 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.

Outcome

A report on Drospirenone/ethinyloestradiol: Risk of venous thromboembolism compared to other combined oral contraceptives was included in the December 2009 dossier.

Discussion

Refer to minute item 3.2.

2.1.12 Pharmacovigilance issues for information only
September 2009 minute item 5

MARC Recommendation

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

Outcome

Medsafe will continue to monitor the literature for similar published papers as part of its ongoing signal detection activities.

Discussion

The Committee noted the above.

2.1.13 Abuse of ibuprofen/codeine combination products
September 2009 minute item 8.1

MARC 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.

Outcome

Medsafe is attempting to obtain a copy of this presentation.

Discussion

The Committee noted the above.

2.1.14 Methylphenidate SR (Rubifen SR) brand switch-aggressive and defiant behavioural reactions- Scheduled Review
September 2009 minute item 2.1.3, 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 Committee for Medicinal Products of Human Use (CHMP) risk-benefit review for methylphenidate-containing medicines and reports back to the MARC.

Outcome

Medsafe's summary of the CHMP risk-benefit review was included in the December dossier.

The CHMP concluded that the benefit/risk ratio for methylphenidate containing products in the treatment of ADHD in children aged six and above was favourable. Medsafe concurred with this conclusion. The risk management plan (RMP) is an accurate reflection of the known safety profile and contains adequate risk minimisation activities. The CHMP have recommended several amendments to the product information for methylphenidate medicines. The MARC was asked to comment on whether all or some of these amendments should be included in the New Zealand data sheet.

Discussion

The Committee noted the November 2009 Medsafe report. They discussed the proposed amendments to the European methylphenidate product information and recommended this information be included in the New Zealand methylphenidate data sheets.

Recommendation

The Committee recommended that the proposed amendments to the European methylphenidate product information be included in the New Zealand methylphenidate data sheets.

2.1.15 Diclofenac and intestinal perforation, sepsis, multiple organ failure [death] (82166)
September 2009 minute item 2.1.4, June 2009 minute item 2.1.7, March 2009 minute item 4.1.1.2

MARC Recommendation

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

Outcome

Further information

[..]

Discussion

The Committee noted the above.

2.1.16 Infanrix-hexa, Prevenar and sudden death [death] (82290)
September 2009 minute item 2.1.5, 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.

2.1.17 Trastuzumab, tamoxifen and renal disorder not-otherwise-specified (NOS), respiratory infection, oligohydramnios (mother), pregnancy exposure (mother) [death] (81237)
September 2009 minute item 2.1.5, 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

CARM has been informed that early pregnancy ultrasound scans for both babies were normal.

Discussion

The Committee noted the above.

2.1.18 Sodium valproate, topiramate, levetiracetam and hyponatraemia, cerebral infarction, peripheral oedema (81286)
September 2009 minute item 2.1.7, 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

A short article regarding medicine-related hyponatraemia has been published in the November 2009 edition of Prescriber Update. A presentation of this data was made to the Royal New Zealand College of General Practitioner's annual scientific conference.

Discussion

The Committee noted the above.

2.1.19 Vitamin D and renal failure, hypervitaminosis D, medication error (81804)
September 2009 minute item 2.1.8, 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.

Outcome

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

Discussion

The Committee noted the above.

2.1.20 Oral bisphosphonates and the risk of atrial fibrillation
September 2009 minute item 2.1.10, 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 Professor Ian Reid be asked to provide an opinion on the risk of atrial fibrillation in association with oral bisphosphonates.

Outcome

A report on bisphosphonates and atrial fibrillation was included in the December dossier.

Discussion

Refer to minute item 3.3.

2.1.21 Ropivacaine and convulsion grand mal, cardiac arrest, drug overdose [death] (80093)
September 2009 minute item 2.1.11, 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.

2.1.22 SSRI antidepressants
September 2009 minute item 2.1.12, 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 the decisions relating to medication related cases directly to the NZPhvC.

Outcome

The Waikato Coroner has agreed to forward his decisions related to 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.

2.1.23 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 September 2009, the Committee recommended that Medsafe obtain prescribing data for both oral retinoids currently funded and present this to the Committee at its December meeting.

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

Medsafe has obtained prescribing data from PHARMAC for isotretinoin and acitretin.

A formal Risk Management Plan is expected to be submitted by the New Zealand sponsor of Oratane (isotretinoin) shortly. Medsafe will provide details of the Risk Management Plans to the MARC when available.

Discussion

The Committee noted that there had been no substantial change in usage over the past 12 months.

2.1.24 Dextropropoxyphene/ paracetamol combination products and the risk of overdose
September 2009 minute item 2.1.16, 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

A report on Dextropropoxyphene containing medicines: Risk Benefit Review under section 36 of the Medicines Act was included in the December dossier.

Discussion

Refer to minute item 3.1.

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

References

Meador K., et al. (2009). Cognitive function at 3 years of age after fetal exposure to antiepileptic drugs. New England Journal of Medicine. 360(16): 1597 - 1605.

Medsafe. (2009). Anticonvulsants and congenital malformations. Prescriber Update. 30(1): 4.

Review of wording in New Zealand Epilim data sheet regarding pregnancy.

MARC Recommendation

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

Outcome

Medsafe's report was included in the December 2009 dossier.

The report included details of the information contained in the New Zealand Epilim (sodium valproate) data sheet regarding use in pregnancy. Medsafe advised that this information is identical to that contained in the Australian Prescribing Information, and noted that the Epilim data sheets are set out in a very similar way to the data sheets for other antiepileptic medicines with multiple indications.

The Committee was asked to consider whether the Precautions section of the Epilim data sheet contains sufficient information regarding exposure during pregnancy for both the epilepsy and bipolar indications, and if not, how the information could be strengthened and the readability improved.

Discussion

The Committee noted the November 2009 Medsafe report. They agreed that while the recent article published in the New England Journal of Medicine (reference 1 above) was an interim analysis, it was important that this information be published in the product data sheet.

The Committee recommended that the Precautions section of the Epilim data sheet be revised to ensure that the risk-benefit statement is clear at the beginning of the section. The Committee also recommended that the sponsor be requested to include information in the data sheet from the Meador et al paper.

Recommendation

The Committee recommended that the Precautions section of the Epilim data sheet be revised to ensure that the risk-benefit statement is clear at the beginning of the section. The Committee also recommended that the sponsor be requested to include information from the Meador paper in the Epilim data sheet.

2.1.26 Influenza virus vaccine and cardiac arrest, bradycardia, diarrhoea, abdominal pain, gastrointestinal disorder NOS (83046)

September 2009 minute item 2.1.22, 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 has reviewed the influenza virus vaccine datasheets and found that they are consistent with Australian and UK product information.

Discussion

The Committee noted the above.

2.1.27 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)

September 2009 minute item 2.1.23, 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

In September 20090, the Committee recommended that [..] be invited to the December 2009 meeting of the MARC to present [..] report on statins and dose response data.

Outcome

[..] is unable to attend the December 2009 meeting, but has agreed to present [..] report at the March 2010 meeting of the MARC.

Discussion

The Committee noted the above.

2.1.28 Lamotrigine and convulsion [death] (74826)

September 2009 minute item 2.1.24, 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.

2.1.29 Clozapine and neutropenia, lymphopenia, anaemia [death] (76419)

September 2009 2.1.2, 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

A member advised that the College had not yet had a response from Medsafe. Medsafe agreed to follow up on this.

3 Pharmacovigilance Issues

3.1 CONSIDERATION OF DEXTROPROPOXYPHENE- CONTAINING MEDICINES UNDER SECTION 36 OF THE MEDICINES ACT 1981

The two members who declared a possible conflict of interest left the room before this agenda item was discussed.

References
  1. Relevant Legislation: Section 36, Medicines Act 1981, Regulation 35, Misuse of Drugs Regulations 1977.
  2. 2. Minutes of previous MARC discussions on dextropropoxyphene (June 2009 minute item 3.2; December 2005 minute item 2.2.7; September 2005 minute item 2.1.2; June 2005 minute item 3.1).
  3. Response to Section 36 notice for Capadex. Sigma Pharmaceuticals Limited.
    1. Response to Section 36 notice for Paradex. API Consumer Brands.
    2. Personal communication. 20 October 2009. Arthritis New Zealand.
    3. FDA. 7 July 2009. Letter to Public Citizen.
    4. IMMP. Paradex Drug Utilisation Study, Phase 2 Report. November 2008.
  4. Medsafe. November 2009. Review of benefits and risks for dextropropoxyphene-containing medicines.
  5. Pharmacy Retailing (NZ) Limited. 22 March 2006. Dextropropoxyphene/ paracetamol (Capadex) data sheet.
  6. PSM Healthcare Limited. 6 April 2006. Dextropropoxyphene/ paracetamol (Paradex) data sheet.
  7. Xanodyne Pharmaceuticals inc. Propoxyphene (Darvon-N). United States Product Information.
  8. Moore RA et al. 2008. Single dose oral dextropropoxyphene, alone and with paracetamol (acetaminophen) for postoperative pain (Review). The Cochrane Library 2009 (3).
  9. Po ALW & Zhang WY. 1997. Systemic overview of co-proxamol to assess analgesic effects of addition of dextropropoxyphene to paracetamol. BMJ 315: 1565-71.
  10. Simkin et al. 2005. Co-proxamol and suicide: preventing the continuing toll of overdose deaths. QJ Med 98:159-170.
  11. Tavassoli et al. 2009. Reporting rate of adverse drug reactions to the French Pharmacovigilance system with three step 2 analgesic drugs: dextropropoxyphene, tramadol and codeine (in combination with paracetamol). Br J Clin Pharmacol 68: 422-426.
  12. Hawton et al. 2009. Effect of withdrawal of co-proxamol on prescribing and deaths from drug poisoning in England and Wales: time series analysis. BMJ 338: 62270.
Background

there are two products containing dextropropoxyphene approved for use in New Zealand:

In May 2005, the MARC reviewed the balance of benefits and risks for dextropropoxyphene-containing medicines following the UK announcement that these medicines were being withdrawn.

At that time, the MARC considered there was evidence that the risk of dose-related adverse effects was greater in patients taking dextropropoxyphene-containing medicines for the treatment of acute pain than in patients taking these medicines for chronic pain, who were likely to have developed tolerance to the opioid-related adverse effects. It was also noted that there were limited treatment options for chronic pain.

Comparison of the data sheets for dextropropoxyphene-containing medicines had highlighted some inconsistencies. The Committee recommended that:

In September 2005 the MARC was provided with feedback on progress in the implementation of these recommendations. The Committee was disappointed to find that there was no mechanism available to restrict the period of supply to 30 days for dextropropoxyphene-containing medicines. The Committee agreed to further assess the issue at its next meeting.

In December 2005, the MARC noted that:

The Committee recommended that:

The industry census of patient use (medicine utilisation study) was subsequently undertaken and the results of the Paradex Utilisation Study were presented to the MARC at its June 2009 meeting. The study showed that more than half of the prescriptions issued for Paradex during the course of the study were not consistent with the indication in the data sheet.

In June 2009, the Committee recommended that the sponsors of Paradex and Capadex be issued with notices under section 36 of the Medicines Act 1981, requesting that they provide further data in support of the safety and efficacy of their respective medicines in order to allow a full risk-benefit review to be conducted.

Section 36 notices were issued to the sponsors of Capadex and Paradex in June 2009, following the MARC meeting. Responses were received from both sponsors within the agreed time frame. Medsafe considered the responses and found them to be inadequate. Neither sponsor provided a comprehensive review of all the available literature on efficacy and safety for dextropropoxyphene-containing medicines.

Medsafe, acting under powers delegated by the Director General of Health, therefore informed the sponsors (in a letter dated 9 November 2009) that this matter had been referred to the appropriate committee (the MARC).

Since the Section 36 notice was issued, regulatory action with regard to dextropropoxyphene-containing medicines has been taken in Europe and the US.

On 25 June 2009, the Committee for Medicinal Products for Human Use (CHMP) concluded that the benefits of dextropropoxyphene do not outweigh its risks. The CHMP recommended that all marketing authorisations for dextropropoxyphene-containing medicines should be withdrawn throughout the European Union. The withdrawal will be gradual to allow the safe transfer of patients to alternative therapies in line with national recommendations.

The FDA is not, at this stage, withdrawing (dextro)propoxyphene-containing medicines. However, the FDA is requiring manufacturers of propoxyphene-containing products to strengthen the label, including the boxed warning, emphasising the potential for overdose when using these products. The manufacturers will also be required to provide a medication guide to patients stressing the importance of using the drugs as directed. In addition, the FDA is requiring the following studies to be conducted:

Medsafe Review

Medsafe presented a review of the benefits and risks of medicines containing dextropropoxyphene.

Usage data

It was noted that there appeared to have been a steady decline in the use of dextropropoxyphene-containing medicines since the 2005 MARC review. However, usage remains significant.

Pharmacokinetics

The major pathway of dextropropoxyphene is metabolism by cytochrome P450 3A4 in the liver to an active metabolite, norpropoxyphene. Dextropropoxyphene has a half-life (T½) of 6-12 h, while norpropoxyphene has a T½ of 30-36 h. The potential for norpropoxyphene accumulation with repeat dosing (usually given 6 hourly) is apparent from its longer half-life relative to dextropropoxyphene, particularly in renal and hepatic impairment and in the elderly. There is limited information on the potential for pharmacokinetic interactions to occur with dextropropoxyphene. However, there is an interaction with alcohol, which is problematic.

Published clinical efficacy profile

Capadex and Paradex are indicated for the relief of chronic pain of moderate severity. The data sheets for these medicines do not contain clinical study data in support of clinical efficacy. Due to the age of dextropropoxyphene and the regulatory requirements in the past there is a paucity of information on efficacy. A number of other small clinical trials were reviewed but various problems with these studies mean that the data are not reliable.

The evidence for efficacy relies on two major systemic reviews. In a Cochrane Review (Moore et al. 2008) the authors concluded that the combination of dextropropoxyphene 65 mg with paracetamol 650 mg showed similar efficacy to tramadol 100 mg for single dose studies in post-operative pain (but with a lower incidence of adverse effects). The same dose of paracetamol combined with 60 mg codeine appeared more effective, however, the authors considered this was not a robust conclusion. Ibuprofen (400 mg) was concluded as having a lower (better) NNT than both dextropropoxyphene 65 mg plus paracetamol 650 mg, and tramadol 100 mg.

The authors concluded that single dose dextropropoxyphene on its own is not particularly effective in relieving post-operative pain. The results of the review support the view that dextropropoxyphene used in combination with paracetamol provides more effective analgesia than placebo, but ibuprofen (400 mg) provides better analgesia than the dextropropoxyphene/paracetamol combination.

A meta-analysis by Po and Zhang (1997) reached a similar conclusion. The authors concluded that there was no statistically significant difference in efficacy between dextropropoxyphene plus paracetamol and paracetamol alone. The meta-analyses support the efficacy of single doses of dextropropoxyphene-paracetamol combinations for the relief of moderate pain. However, this combination did not demonstrate superiority over paracetamol alone. There is no data to support the indication for chronic use.

Safety profile in therapeutic use

The Committee noted that although the current data sheets are consistent with the UK SPC at the time of co-proxamol withdrawal (co-proxamol is a dextropropoxyphene/paracetamol combination), they do not contain as much information as the newly updated product information in the US.

Examination of New Zealand spontaneous adverse reaction reports showed that the first report for Paradex was received in February 1999. By May 2007 CARM had a total of 24 reports. After Paradex was put on IMMP there were a further 14 reports over a period of one month.

Adverse reactions associated with dextropropoxyphene in the literature includes: skin reactions; hypersensitivity reactions; liver reactions; hypoglycaemia; hip fracture risk; and dependence in addition to the expected opioid effects.

There does not appear to be any published evidence of cardiotoxicity at therapeutic dose of these medicines.

Overdose data

Reith et al 2005 analysed opioid poisoning deaths in New Zealand between 2001 and 2002. There were 92 poisoning deaths involving opioids, of which 16 were due to dextropropoxyphene (12 were due to codeine/dihydrocodeine). The rate of deaths per 100,000 prescriptions was 2.5 (95% CI 1.45 to 4.12) for dextropropoxyphene.

There appears to have been a reduction in deaths due to dextropropoxyphene since 2001-2002. However, it is not clear how reliable this information is.

The New Zealand data reflects the greater lethality of dextropropoxyphene compared with codeine since the ratio of deaths to hospitalisations is higher for dextropropoxyphene than for codeine. It was noted that some of the hospitalisations due to dextropropoxyphene ingestion occurred in children, most likely due to exploratory behaviour. This reflects the published data showing that not all deaths due to dextropropoxyphene occur in patients for whom the medicine is prescribed.

The published literature on the toxic effects of dextropropoxyphene indicates that dextropropoxyphene is more dangerous in overdose than other analgesics used for mild to moderate pain. Dextropropoxyphene and its metabolite norpropoxyphene cause respiratory depression and cardiotoxicity - specifically QT prolongation which can result in sudden death. The actual lethal dose varies with the individual, and so cannot be calculated. There appears to be a tolerance effect which may change the response in an individual over time. The lethal dose is also affected by alcohol intake and concomitant use of other medicines. In addition the elderly may be more susceptible.

It has also been noted that many of the people who died did so before they reached hospital, some within one hour of taking the overdose. Whilst the opiate effects of dextropropoxyphene on respiration can be reversed by naloxone, the cardiac effects cannot.

Not all of the fatal and non-fatal overdoses appear to have been intentional. This may highlight a difficulty in taking the medicine safely, perhaps due to the interactions with alcohol and other medicines.

The dangers of prescribing dextropropoxyphene-containing medicines to patients with high alcohol consumption or a history of self harm, or to those under psychiatric care or taking concomitant medicines that interact with dextropropoxyphene are highlighted by this information.

Comparison with alternative analgesics

A study has been undertaken which compared the reporting rate of adverse reactions to the French pharmacovigilance system for dextropropoxyphene, tramadol and codeine (in combination with paracetamol). The study concluded that the rate and seriousness of reported ADRs were significantly higher with dextropropoxyphene than codeine (+paracetamol), but appeared to be less unsafe than tramadol. Gastrointestinal, neurological, hepatobiliary, cutaneous and metabolic ADRs were significantly more frequent with dextropropoxyphene.

Effect of dextropropoxyphene restrictions and withdrawal

Published information indicates that withdrawal of these medicines, either at a local level or national level, has been shown to reduce analgesic use and have a beneficial effect on suicide rates. The data published to date (from the UK) shows that most patients on dextropropoxyphene were successfully switched to other analgesics, most commonly paracetamol alone, codeine alone or a codeine/paracetamol combination. Overall there was a decrease in suicide deaths.

Paradex drug utilisation study

This study was commissioned by the sponsor for Paradex and performed by the independent New Zealand Pharmacovigilance Centre. Paradex was placed on the Intensive Medicines Monitoring Programme (IMMP) during the month of July 2007.

It was highlighted that the evaluable questionnaires represented less than 50% of the questionnaires sent.

Whilst the majority of prescribers had three patients or less taking Paradex, a significant number were prescribing Paradex for more than 20 patients. In addition, a number of prescriptions were recorded for children. The study concluded that less than half of all the prescriptions issued in July 2007 were in line with the indications listed in the data sheet.

Discussions and conclusions of other regulators

In the United Kingdom in 2004, the MRHA concluded that the risk-benefit ratio of co-proxamol (usually dextropropoxyphene 32.5mg/paracetamol 325mg) was negative. A phased withdrawal of the marketing authorisations for co-proxamol started in 2005. In June 2009, the Committee for Medicinal Products for Human Use (CHMP) recommended that all marketing authorisations for dextropropoxyphene-containing medicines should be withdrawn throughout the European Union.

In the United States, following the latest review of propoxyphene-containing medicines, the expert Committee voted 14 to 12 to remove propoxyphene-containing products from the market. The FDA has not withdrawn the product at this time, but has imposed conditions on use and required further studies to be undertaken.

Committee considerations

The Committee was asked to consider the following questions:

The Committee was then asked to make a recommendation, based on its assessment of the risk benefit profile for dextropropoxyphene-containing medicines, on the regulatory and non-regulatory actions (if any) that should be undertaken.

Discussion

The Committee discussed and agreed with the Medsafe report, as summarised above.

The Committee noted that dextropropoxyphene and dextropropoxyphene/paracetamol combinations were developed in the 1950s and 1960s and have therefore not been required to demonstrate the same level of clinical efficacy as would be required for a new medicine approved today.

The Committee agreed unanimously that:

The Committee discussed various regulatory options. The Committee considered whether restrictions could be imposed on the use of these medicines which could improve the benefit-risk balance. It was decided that there was an absence of regulatory options available to ensure that these medicines could only be prescribed by specialists and for restricted quantities.

The Committee therefore recommended that consent to distribute dextropropoxyphene-containing medicines in New Zealand be revoked.

The Committee noted that revocation will affect patients and their doctors. Various issues of importance to patients and prescribers were discussed such as dependency and alternative treatments. The Committee noted that dependency to dextropropoxyphene was an insidious dose dependency which happened gradually with chronic use and possibly went unrecognised, similar to dependency to benzodiazepines.

Studies examining prescribing practices following the withdrawal/restriction of dextropropoxyphene containing medicines have shown that for a number of patients pain has been controlled with paracetamol, or a paracetamol/codeine combination.

The Committee noted that there was a significant usage of dextropropoxyphene products in New Zealand and agreed that it was important that a transition period be allowed to enable patients to be withdrawn in a safe manner. The Committee emphasised the importance that in the transition period, a multi-pronged communication plan should be implemented by Medsafe. The Committee requested that Medsafe present its plan for the withdrawal of dextropropoxyphene at its next meeting as an information item for the Committee.

Recommendations

The Committee recommended that consent to distribute dextropropoxyphene-containing medicines in New Zealand be revoked.

The Committee recommended that Medsafe implement a transition plan for the withdrawal of dextropropoxyphene, incorporating into the plan a multi-pronged communication strategy.

The Committee recommended that Medsafe inform the Committee of its transition plan at its next meeting.

3.2 DROSPIRENONE/ETHINYLOESTRADIOL: RISK OF VENOUS THROMBOEMBOLISM COMPARED TO OTHER COMBINED ORAL CONTRACEPTIVES

References
  1. Dinger J, et al. 2007. The safety of a drospirenone-containing oral contraceptive: final results from the European Active Surveillance study on Oral Contraceptives based on 142,475 women-years of observation. Contraception. 75: 344-354.
  2. van Hylckama Vlieg A. et al. 2009. The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study. British Medical Journal. 339(7720): 561.
  3. Lidegaard Ø. et al. 2009. Hormonal contraception and risk of venous thromboembolism: national follow-up study. British Medical Journal. 339(7720): 557-560.
  4. Dunn N. 2009. Editorial: Oral contraceptives and venous thromboembolism. British Medical Journal. 339(7720): 521-522.
  5. Amy J. and Tripathi V. 2009. Contraception for women: an evidence based overview. British Medical Journal. 339(7720): 563-568
  6. Seeger J. et al. 2007. Risk of thromboembolism in women taking ethinyloestradiol/drospirenone and other oral contraceptives. Obstetrics & Gynecology. 110(3): 587-593.
  7. Cronin M. and Korner P. 2008. Editorial: The safety profile of Yasmin is similar to other combined oral contraceptives. Clinical and Applied Thrombosis/Hemostasis. 14(2): 245-246.
  8. Heinemann L. and Dinger J. 2004. Safety of a new oral contraceptive containing drospirenone. Drug Safety. 27(13): 1001-1018.
  9. Pearce H. et al. 2005. Deep vein thrombosis and pulmonary embolism reported in the Prescription Event Monitoring study of Yasmin. British Journal of Clinical Pharmacology. 60(1): 98-102.
  10. Excerpts from New Zealand data sheets, Australian PI and European SPC for Yasmin and Yaz.
  11. MHRA. 2004. Combined oral contraceptives: venous thromboembolism. Current Problems in Pharmacovigilance. 30: page 7.
  12. SwissMedic. 2009. Risks associated with the contraceptive pill: SwissMedic reported on cases of fatal pulmonary embolism. http://www.swissmedic.ch/aktuell/00003/01095/index.html?lang=fr
Issue

Medsafe provided a report for the MARC on the issue of drospirenone/ethinyloestradiol: risk of venous thromboembolism (VTE) compared to other combined oral contraceptives.

The Centre for Adverse Reactions Monitoring (CARM) brought this issue to the attention of the MARC in September 2008 following local reports of thromboembolic events associated with drospirenone-containing oral contraceptives (drospirenone/ethinyloestradiol combination).

At that time, the Committee considered a paper (Dinger, 2007) which concluded that the risk of VTE in users of drospirenone-containing oral contraceptives was similar to the risks associated with the use of other combined oral contraceptives.

CARM returned the issue to the MARC in September 2009 following additional local reports of thromboembolic events associated with drospirenone-containing oral contraceptives. Of the 17 reports of adverse events that CARM has received since introduction into the New Zealand market, 11 reports detail VTE (5 reports of deep vein thrombosis and 7 of pulmonary embolism with both diagnoses recorded for one patient).

The Committee noted two recently published papers describing the results of studies investigating the risk of venous thromboembolism (VTE) associated with drospirenone/ethinyloestradiol compared with other combined oral contraceptives. These two papers (Lidegaard, 2009 ; van Hylckama Vlieg, 2009) concluded that drospirenone-containing oral contraceptives were associated with a significantly higher risk of venous thrombosis than combined oral contraceptives containing levonorgestrel (2nd generation).

The Committee was provided with Medsafe's analysis of the risk of VTE associated with drospirenone-containing oral contraceptives compared to that with other combined oral contraceptives and was asked to advise whether members concurred with this analysis. If not, the Committee was asked to advise on suitable regulatory action and recommend appropriate risk management strategies for drospirenone-containing oral contraceptives.

Discussion

The Committee noted the November 2009 Medsafe report.

There are two drospirenone-containing oral contraceptives with ministerial consent for distribution in New Zealand, Yasmin (drospirenone 3mg/ ethinyloestradiol 0.03mg) and Yaz (drospirenone 3mg/ ethinyloestradiol 0.02mg). Neither product is funded by PHARMAC.

The MARC reviewed the three recent studies (references 1 to 3 above). They noted the limitations of each study. The Committee considered that due to the fundamental differences between the three trials, it was difficult to compare baseline rates and a conclusion on the relative safety on drospirenone could not be drawn from this information.

The current New Zealand data sheets for Yasmin (dated 23 June 2009) and Yaz (dated 10 February 2009) contain information regarding the risk of VTE in the Contraindications and Warnings and Precautions sections. The Committee noted that the Yasmin and Yaz data sheets are consistent with the data sheets for 2nd and 3rd generation oral contraceptives. That is, all data sheets for combined oral contraceptives (irrespective of progestogen type) contain a generic warning regarding the risk of VTE.

The Committee agreed that no regulatory action was required at this time but considered that more information on the risk-benefit profile of these products would be valuable. The Committee recommended that Medsafe write to the sponsors of drospirenone-containing medicines requesting that they review the risk of venous thromboembolism in association with their products (including preclinical, clinical, postmarket and observational studies) and report back to the MARC. Following the outcome of this review, Medsafe will review data sheets to determine if they require amending.

Recommendation

The Committee recommended that Medsafe write to the sponsor of drospirenone-containing medicines requesting that they review the risk of venous thromboembolism in association with their products (including preclinical, clinical, postmarket and observational studies) and report back to the MARC.

3.3 BISPHOSPHONATES AND ATRIAL FIBRILLATION

References
  1. Bunch TJ, et al. 2009 Relation of bisphosphonate therapies and risk of developing atrial fibrillation. Am J Cardiol 103: 824-828.
  2. Grosso A, et al. 2009 Oral bisphosphonates and risk of atrial fibrillation and flutter in women: A self-controlled case-series safety analysis PLoS ONE 4: e4720.
  3. Abrahamsen B, Eiken P, and Brixen K. 2009. Atrial fibrillation in fracture patients treated with oral bisphosphonates J Intern. Med. 265: 581-592.
  4. Mak A, et al. 2009. Bisphosphonates and atrial fibrillation: Bayesian meta-analyses of randomized controlled trials and observational studies' BMC Musculoskeletal Disorders. 10: 113
  5. Loke YK, Jeevananthan V, and Singh S. 2009 Bisphosphonates and Atrial Fibrillation Drug Safety 32: 219-228
Issue

Medsafe provided a follow up report for the MARC on the issue of bisphosphonates and atrial fibrillation. This issue was first presented to the MARC at the December 2008 meeting. Prescribers were informed of the potential risk in a Prescriber Update article (Feb 2009; 30 (1): 3).

At the 2008 review, the MARC recommended that this issue be put on the scheduled review list and further data be requested from the sponsors.

The 2009 report reviewed data supplied by the sponsors of bisphosphonate containing medicines and relevant papers published since the last review of this issue by MARC.

The Committee was asked to advise whether:

Discussion

The Committee discussed the data provided by the sponsors of alendronate, etidronate, risedronate, and tiludronate. Medsafe reviewed this data, which included a meta-analysis of alendronate data and concluded that it did not indicate an association between bisphosphonate treatment and a risk of atrial fibrillation for any of these products.

The Committee agreed with Medsafe's conclusions. The Committee discussed five epidemiology studies and two meta-analyses published since the last review. Of the five observational studies, only one found a positive association between bisphosphonate treatment and atrial fibrillation. The authors attributed this result to exposure bias, i.e. patients with risk factors for atrial fibrillation were more likely to be prescribed a bisphosphonate after experiencing a fracture.

The results of the meta-analyses were conflicting - one study showed no association and one study reported an association. However it was noted that the meta-analysis with the positive result included less information and the result was only just statistically significant.

The Committee agreed with Medsafe's conclusion that the available evidence does not support an increase in risk of atrial fibrillation with bisphosphonate treatment.

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 bisphosphonates and atrial fibrillation be removed from the Scheduled Review list.

Recommendation

The Committee recommended that the issue of bisphosphonates and atrial fibrillation risk be removed from the Scheduled Review list.

3.4 MONITORING OF VARENICLINE (CHAMPIX)

  1. IMMP. September 2009. Intensive monitoring of varenicline (Champix).
  2. Medsafe. November 2009. Champix safety profile (varenicline) update. Supporting information to IMMP report
  3. Pfizer New Zealand Limited. 31 July 2009. Varenicline (Champix) New Zealand data sheet.
Issue

Varenicline has been monitored on the Intensive Medicines Monitoring Programme (IMMP) since April 2007.

An interim report was presented to the MARC at the March 2009 meeting. The most common adverse effects reported at that time were psychiatric events, including depression, suicidal ideation, sleep disorders, anxiety disorders and withdrawal symptoms. With the exception of withdrawal symptoms, this was consistent with the emerging international safety profile of varenicline.

A Prescriber Update article, as recommended by the Committee, was published in May 2009 describing the psychiatric adverse events, including withdrawal symptoms that have been reported in association with varenicline use, and reminding prescribers to continue reporting adverse drug reactions.

NZPhvC provided a report for the MARC following the completion of follow-up of the first year IMMP varenicline cohort (April 2007 to 31 March 2008). Medsafe provided an update of the varenicline safety profile, including a summary of the latest Champix Periodic Safety Update Report (PSUR) and interim results from the United Kingdom Prescription Event Monitoring study (PEM).

Discussion

NZPhvC advised that psychiatric events were the most common adverse effects reported, particularly depression and sleep disturbance. Psychiatric events accounted for about one third of all adverse events identified in the IMMP study. The majority of these psychiatric side effects are now listed in the Champix New Zealand data sheet.

The Committee noted that the latest Champix PSUR covered the period of 10 November 2008 - 9 May 2009. No action has been taken for safety reasons during this period, either by the company or by regulatory action. The events most commonly reported during this period were depression, nausea, and suicidal ideation.

The Committee noted the 2009 NZPhvC and Medsafe reports. They agreed that no regulatory action was required at this time and noted that Medsafe will continue to monitor and evaluate international regulatory activity and safety-related data as it arises, and will report back to the MARC as necessary. Varenicline will continue to be monitored by the NZPhvC on the IMMP.

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 Case reports

4.1.1.1 Cabergoline and mitral insufficiency, cardiac failure left, intestinal obstruction, cerebral infarction [death] (85242)

Discussion

NZPhvC advised that the CARM database includes one report of valve disorders in association with cabergoline. The WHO database includes a variety of heart valve disorders which are statistically prominent.

The product data sheet lists valvular effects as an adverse reaction but notes that these are predominantly seen at doses exceeding the maximum recommended dose for the treatment of hyper prolactinaemic disorders, and may be associated with cumulative dose.

NZPhvC advised that this case report had been published. The authors comment that the cabergoline dose that this patient received was below the level of exposure to cabergoline that has previously been associated with valvulopathy. The accompanying editorial to the case report notes that small cohort studies of treated hyperprolactinemia patients have not demonstrated to have an increased risk of valvulopathy. Prescribing recommendations in the editorial are to keep cabergoline dose and duration to a minimum, and discontinue whenever appropriate.

The MARC noted that there is little evidence at present that low dose cabergoline used to treat pituitary prolactinomas may cause valvulopathy similar to that caused when it is used at higher doses for Parkinson's disease in older patients. They noted that patients with prolactinomas are often young and may need to take dopamine agonists for many years. The Committee recommended that NZPhvC approach the appropriate specialist prescribing groups of cabergoline, advising them of this case report and requesting that members report any similar events in order to obtain further information about this possible association.

The causal association with cabergoline was considered to be 'possible' for mitral insufficiency, and cardiac failure left, and 'unlikely' for intestinal obstruction, and cerebral infarction.

Recommendation

The Committee recommended that NZPhvC approach the appropriate specialist prescribing groups of cabergoline, advising them of this case report and requesting that members report any similar events.

4.1.1.2 Gabapentin and renal failure acute, hyperkalaemia, cardiac arrest (85589)

Discussion

NZPhvC advised that the terms chronic renal failure, renal failure abnormal, creatinine clearance decreased, and acute renal failure are all associated with positive IC values in the WHO database. Four published case reports have been identified in the literature.

The Neurontin (gabapentin) data sheet includes acute kidney failure and renal impairment in a list of post-marketing reports, with a comment that the data is insufficient to support an estimate of their incidence or to establish causation.

The Committee considered that there is now increasing evidence that gabapentin can cause renal failure. They noted that while this is likely to be rare, gabapentin is becoming more widely used and recommended that a Prescriber Update article be published to alert healthcare professionals.

The causal association with gabapentin was considered to be 'certain' for renal failure acute, and 'probable' for hyperkalaemia, and cardiac arrest.

Recommendation

The Committee recommended that a Prescriber Update article be published to alert healthcare professionals of the risk of renal failure in association with gabapentin.

4.1.1.3 Sibutramine and cardiac arrhythmia [death] (85606)

Discussion

NZPhvC advised that sibutramine has been monitored on the Intensive Medicines Monitoring Programme (IMMP). The IMMP cohort includes cases of heart rate and rhythm disorders which were considered causal in association with sibutramine. Reports of QT prolonged, sudden death and ventricular fibrillation are statistically prominent in the WHO database.

Cardiovascular adverse effects are included in the product data sheet, along with details of monitoring blood pressure and heart rate. NZPhvC advised that the US Product Information includes information regarding sudden unexplained death, ventricular arrhythmias and Torsades de Pointes. These adverse events are not included in the New Zealand data sheet for Reductil (sibutramine).

The Committee noted that the FDA is reviewing preliminary data from a recent study that suggested there is an increased rate of adverse cardiovascular outcomes in association with sibutramine, when compared with placebo. Analysis of data from the Sibutramine Cardiovascular Morbidity/Mortality Outcomes in Overweight or Obese Subjects at Risk of a Cardiovascular Event (SCOUT) is ongoing. The Committee recommended that Medsafe review this study, and the New Zealand Reductil data sheet, and report back to the MARC.

The causal association with sibutramine was considered to be 'possible' for cardiac arrhythmia.

Recommendation

The Committee recommended that Medsafe review the SCOUT study and the New Zealand Reductil data sheet and report back to the MARC.

4.1.1.4 Flutamide and hepatic failure, hepatitis (86193)

Discussion

NZPhvC advised that the CARM database includes reports of hepatic reactions in association with flutamide.

The Committee noted that in NZ, flutamide is indicated for the palliative treatment of advanced prostate cancer in previously untreated patients or those who have not responded or have become refractory to hormonal manipulation, or as a component of the treatment of locally advanced prostatic carcinoma.

The flutamide data sheet contains strong warnings and precautions on the use of flutamide in patients with hepatic injury. The product data sheet recommends that all patients have periodic liver function tests while being treated with flutamide. In addition, therapy should be discontinued if the patient develops jaundice or if serum transaminase levels rise to two to three times the upper limit of normal.

The Committee considered it would be helpful to remind prescribers to advise patients of the possibility of flutamide causing hepatic reactions and to consult a health care professional if symptoms of hepatic dysfunction occur.

The Committee considered the causal association with flutamide to be 'possible' for hepatic failure, and hepatitis.

Recommendation

The Committee recommended that this case report form the basis of a Prescriber Update article to remind prescribers to advise patients of the possibility of flutamide causing hepatic reactions and to consult a health care professional if symptoms of hepatic dysfunction occur.

4.1.1.5 Isotretinoin and suicide [death] (86236)

Discussion

NZPhvC advised that the CARM database includes reports of suicide and depression in association with isotretinoin, and that both of these terms have very significant IC values in the WHO database. The Committee has previously considered the issue of depression and suicide with isotretinoin and the roles of acne itself and adolescence as significant factors for depression have been considered more likely to be contributory.

NZPhvC advised that the Coroner has raised the issue of prescribing isotretinoin to persons of this age without parental consent. Medsafe advised that the Care of Children Act 2004 states the consent, or refusal to consent, to medical procedures, if given by a child of or over the age of 16 years, has effect as if the child were of full age. The powers of the Minister of Health under the Medicines Act 1981 are limited to placing restrictions on the manufacturing, selling, supplying, distributing, and advertising of medicines. The Minister may declare certain medicines to be prescription medicines. However, this only means that those medicines can only be administered in accordance to a prescription given by a practitioner. They do not extend to how medicines are to be administered or to whom.

The Committee considered the causal association with isotretinoin was 'unclassifiable' for suicide.

4.1.1.6 Drospirenone/ethinyloestradiol (Yasmin) and pulmonary embolism (86246)

Discussion

This case report was considered in the discussion of the risk of drospirenone/ethinyloestradiol of venous thromboembolism (VTE) compared to other combined oral contraceptives, minute item 3.2.

The Committee considered the causal association with drospirenone/ethinyloestradiol to be 'possible' for pulmonary embolism.

4.1.1.7 Digoxin and sudden death, drug level increased [death] (86454)

Discussion

The Committee noted that there were no concomitant medications reported. They considered this information would be helpful, particularly to assess if any interactions were possible. The Committee recommended that NZPhvC request further information about this case.

NZPhvC advised that the Coroner raised the issue of whether the current recommendations for monitoring digoxin levels are adequate.

The product data sheet states that serum electrolytes and renal function should be assessed periodically, depending on the clinical setting. In a paper published in the New Zealand Medical Journal by Sidwell et al recommends the following indications for monitoring digoxin - to confirm toxicity, to assess pharmacokinetic factors, therapeutic failure, and to determine medication compliance. The Committee recommended that the Coroner be sent a copy of this article.

Recommendations

The Committee recommended that NZPhvC request further information about this case, specifically regarding anti-psychotic medicines.

The Committee recommended that the Coroner be sent a copy of the NZMJ article regarding digoxin monitoring.

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:

4.1.2.1 Caspofungin/ dextrose (85321)
4.1.2.2 Albumin (86333)
4.1.2.3 Bortezomib (85078)
4.1.2.4 Clozapine (85434)
4.1.2.5 Clozapine (86334)
4.1.2.6 Diclofenac, erythropoietin, ferrous sulphate, acetylsalicylic acid (85677)
4.1.2.7 Erlotinib (85647)
4.1.2.8 Heparin - LMW- enoxaparin (85105)
4.1.2.9 Iloprost-trometamol (85998)
4.1.2.10 Insulin aspart (863338)
4.1.2.11 Iohexol (85327)
4.1.2.12 Methylphenidate SR, methadone, morphine sulphate, oxycodone (85891)
4.1.2.13 Orphenadrine citrate (86336)
4.1.2.14 Risperidone (85076)
4.1.2.15 Risperidone (85965)
4.1.2.16 Risperidone, opioids unspecified (85989)
4.1.2.17 Sertraline (86239)
4.1.2.18 Simvastatin, fluconazole, erythromycin (86356)
4.1.2.19 Sorafenib (85074)
4.1.2.20 Trastuzumab (85664)

Recommendation

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

4.1.3 Dianeal death reports

These reports originate from the Marketing Authorisation Holder (MAH) and identify the death of the patient when the reporting nurse informed the MAH that no further solution was required because the patient had since died in the context of end-stage renal failure. The reason for reporting to the MAH was not due to concern that the death may be related to exposure to the solution, but for supply management purposes. Discussion with the MAH established that these cases were recorded and passed on as under ICH regulations, it is a requirement for the MAH to report all cases of death identified whether or not the death is related to the medicine.

Reports of a similar nature were considered at the December 2008 meeting. These reports, which were received subsequently, are of the same nature, and are reported here following the recommendation of the MARC.

4.1.3.1 Dianeal (85330)
4.1.3.2 Dianeal (85331)
4.1.3.3 Dianeal (85332)
4.1.3.4 Dianeal (85333)
4.1.3.5 Dianeal (85334)
4.1.3.6 Dianeal (85336)
4.1.3.7 Dianeal, icodextrin (85337)
4.1.3.8 Dianeal, icodextrin (85338)
4.1.3.9 Dianeal, icodextrin (85339)
4.1.3.10 Dianeal (85340)
4.1.3.11 Dianeal (85341)
4.1.3.12 Dianeal (85342)
4.1.3.13 Dianeal (85343)
4.1.3.14 Dianeal (85344)
4.1.3.15 Dianeal (85345)
4.1.3.16 Dianeal (85346)
4.1.3.17 Dianeal (85347)
4.1.3.18 Dianeal (85348)
4.1.3.19 Dianeal, icodextrin (85349)
4.1.3.20 Dianeal, icodextrin (85352)
4.1.3.21 Dianeal, icodextrin (86427)
4.1.3.22 Dianeal, icodextrin (86428)
4.1.3.23 Dianeal (86429)
4.1.3.24 Dianeal, icodextrin (86430)

4.1.4 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:

4.1.4.1 Glutathion (85146)
4.1.4.2 Infliximab (85808)
4.1.4.3 Lamotrigine (85829)
4.1.4.4 Leflunomide, adalimumab (85103)
4.1.4.5 Leflunomide (85153)
4.1.4.6 Leflunomide, naproxen (85382)
4.1.4.7 Leflunomide (86437)
4.1.4.8 Methotrexate, leflunomide (86181)
4.1.4.9 Pioglitazone (86366)
4.1.4.10 Pioglitazone (86460)
4.1.4.11 Quetiapine, venlafaxine (85262)
4.1.4.12 Risperidone (85081)
4.1.4.13 Rosiglitazone(86378)
4.1.4.14 Simvastatin, amiodarone (86289)
4.1.4.15 Zopiclone (86436)

4.2 Quarterly Reports from CARM as at 30 June 2009

Discussion

The Committee noted the quarterly reports from CARM as at 30 September 2009. They discussed the changes to the format of the report and considered it was timely to review how, and which data, are presented to the MARC. The Committee recommended that NZPhvC and Medsafe undertake this review.

NZPhvC advised that they have received three reports in the last quarter each of withdrawal syndrome in association with paroxetine and also with venlafaxine, which will continue to be monitored and brought to the MARC's attention as required.

Recommendation

The Committee recommended that NZPhvC and Medsafe review the format of the quarterly report.

4.3 Further details of CARM reports requested at previous meetings of the MARC

Discussion

The Committee noted the further details provided for case reports:

4.4 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 October 2009.

The Committee noted that reports were similar to the pattern of adverse reaction reports received in other countries where the HPV vaccination programme is operating. The NZPhvC was asked whether there were any reports of concern and were informed of one report which would be brought to the next meeting.

4.5 Proton Pump Inhibitors (PPI) report

Discussion

The Committee noted the CARM report of adverse reactions to PPIs for the period 1 June 1990 to 31 October 2009.

The Committee noted that these brand switch reports continue to be reported in similar numbers as in the last quarter, and continue to reflect a similar pattern. NZPhvC advised that respiratory adverse reactions appeared to be more prominent with Dr Reddy's omeprazole, compared with Losec.

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 Medsafe Signal Detection and Evaluation paper be included in each agenda as an Annex to the Standing Agenda report.

6 New Zealand pharmacovigilance-related activities

7 international pharmacovigilance-related Activities

7.1 Australia

7.2 Canada

7.3 Singapore

7.4 United Kingdom

8 OTHER BUSINESS

8.1 The use of low-dose aspirin for primary prevention

A member informed the Committee that two recent studies have been published looking at the use of low-dose aspirin in the prevention of heart attacks and strokes in people without a history of vascular disease. Both studies found that the risk of a major gastrointestinal bleed outweighed any vascular benefit. The Committee recommended that Medsafe review these papers and report back to the MARC.

Recommendation

The Committee recommended that Medsafe review the recently published studies on the use of low-dose aspirin in primary prevention and report back to the MARC.

8.2 Continuing Medical Education

The Acting Chair gave a presentation on allergy/skin reactions including current thinking about dose response.

The Acting Chair thanked members and the secretariat for their attendance and closed the meeting at 3.30pm.

Associate Professor M. Rademaker
Acting Chair
Medicines Adverse Reactions Committee

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