Revised: 21 May 2013

Committees

Minutes of the 110th Medicines Adverse Reactions Committee Meeting - 20 June 2002

In the Sunderland Room 2, Wellington Airport Conference Centre, commencing at 9:00am.

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In order to protect the privacy of those involved, descriptions of unpublished case reports are not included in these minutes.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

Note relevant to these minutes: The recommendations arising from this meeting have been accepted by the Delegate of the Minister of Health.

MARC MEMBERS PRESENT

Associate Professor T.J.B. Maling (Chair)
Professor P. Ellis
Dr J. Goldsmith
Dr H. Kingston
Dr F. McClure
Dr M. Rademaker
Dr N. Rafter
Dr D. Coulter
Dr K. Ronaldson (Secretary)

PARTICIPATING ATTENDEES

Ms S. Von Afehlt (Editor, Prescriber Update)
Dr K. Maclennan (Advisor, Pharmacovigilance)
Dr M. Tatley (Medical Assessor and Director of CARM)
Dr M. Harrison-Woolrych (Senior Research Fellow, CARM)
Dr S. Martindale (Team Leader, Business Development & Support, Medsafe) (morning only)

1. MATTERS OF ADMINISTRATION

1.1 Welcome and apologies

The Chair welcomed Karyn Maclennan who will take over as MARC Secretary at the end of June. The Committee farewelled Kathlyn Ronaldson and thanked her for her excellent work as MARC Secretary.

Apologies had been received from Professor D.C.G. Skegg, Dr R. Savage and Dr S. Jessamine.

1.2 Minutes of the 109th meeting

The minutes of the 109th meeting were signed by the Chair as a true and accurate record of the meeting.

1.3 Dates of the next meetings

Wednesday 11 September and Thursday 5 December were confirmed as the dates for the next meetings.

1.4 Conflict of interest

Committee members with undeclared conflicts of interest submitted these to the Secretary.

1.5 Prescriber Update

M. Rademaker. Isotretinoin and pregnancy precautions. Draft article.

Members were requested to provide any comment on the above article to S. von Afehlt outside of the meeting.

M. Rademaker expressed concern regarding patient confidentiality in Prescriber Update articles. The Committee agreed that this was an important issue to consider when writing articles.

1.6 Trans-Tasman Agency Discussion Paper

S. Martindale discussed the recently released proposal for a trans-Tasman agency to regulate therapeutic products. She invited the MARC members to make submissions as a Committee or as individuals. Members were very interested in the proposal and expressed their desire to maintain communication with Medsafe regarding this issue. After reading the Discussion Paper, members are to forward their comments to the Chair, who will then report to Medsafe on behalf of the MARC. Members may also submit comments as individuals.

2. MATTERS ARISING

2.1 Report on the outcome of previous MARC requests and recommendations

2.1.1 Correspondence with Pharmac (agenda item 2.1.2, MARC March 2002)

- T. Maling. Funding of adrenaline syringes for self-administration. Letter to Minister of Health, 23 May 2002.

The Committee noted the aforementioned letter.

2.1.2 Isotretinoin and pregnancy (agenda item 2.1.4, MARC March 2002)

- Douglas Pharmaceuticals. Pregnancy prevention in women taking isotretinoin. Dear Doctor letter, May 2002
- Roche Pharmaceuticals. Roaccutane - reminder - isotretinoin contraindicated in pregnancy. Dear Doctor letter 6 May 2002

The Committee noted that both companies have issued a Dear Doctor letter, reminding dermatologists and GPs that isotretinoin is contraindicated in pregnancy.

2.1.3 Estelle 35/Diane 35 (agenda item 2.1.7, MARC March 2002)

- K Ronaldson. Advertising for Estelle-35/35 ED. Letter to Douglas Pharmaceuticals. 24 May 2002

The Committee noted that the indication for Estelle-35 has been strengthened (i.e., second line therapy for only severe acne, and contraception for those requiring treatment for androgenic diseases), and that Schering are intending to put in an application to change Diane-35 in June 2002. The MARC also noted that Douglas Pharmaceuticals are to bring their advertising in line with this new indication.

The entry for Estelle-35 in the Pharmaceutical Schedule was discussed at the Medsafe/Pharmac liaison meeting on 6 June. Pharmac indicated that it would consider Medsafe's comments and recognised that, with the change to the indications, it would not be appropriate to suggest that Estelle-35 could be regarded primarily as a contraceptive. Pharmac will consider putting Estelle-35 under the "dermatologicals" section in the Schedule. The Committee requested that Medsafe follow the scheduling issue up with Pharmac and report back to the MARC at the September 2002 meeting.

2.1.4 Progestogen-only pills (POPs) and VTE (agenda item 2.1.9, MARC March 2002)

- .., Organon. Cerazette and VTE. Letter 7 May 2002.
- .., Microlut. Schering e-mail 29 May 2002
- Microlut data sheet extracts

At the September 2001 MARC meeting, the Committee recommended changes to the wording in the Contraindications and the Warnings and Precautions sections of POP data sheets. The changes to the Warnings and Precautions section related to POPs being considered as an option for contraception in women who have experienced DVT or PE with a COC, provided the thromboembolic process has resolved. In addition, it was recommended that the contraindication of a history of DVT be removed.

The Committee noted that Pharmacia has made the requested changes to its Noriday and Femulen data sheets. Due to the limited amount of data available on POPs and VTE, both Schering and Organon have objected to the requested data sheet changes. The Committee agreed with Organon and Schering that data on POPs and VTE are limited. In light of this, no further action is to be taken at this time.

Wyeth has recently updated the data sheet for Microval, without removing a history of DVT from the Contraindications section. S Von Afehlt has recently written to Wyeth in order to request that this issue be addressed. The Committee requested that Medsafe report on the outcome of this letter at the September 2002 meeting.

2.1.5 Isotretinoin and suicide (agenda item 3.1.1.4, MARC March 2002)

The Committee noted that the Oratane data sheet is being updated with regard to suicide.

2.1.6 Monofeme and DVT/pulmonary embolism (agenda item 3.1.2.2, MARC March 2002)

A letter was to be written by CARM to the Royal Australasian College of Physicians and the Australasian College for Emergency Medicine, citing the above case and highlighting the need to discontinue oral contraceptives at the time of diagnosis of DVT/PE. The Committee asked Medsafe to ensure that this letter has been sent, and requested that the letter be also sent to the Royal NZ College of GPs.

2.1.7 Oxytocin and inadequate therapeutic effect (agenda item 3.1.2.3, MARC March 2002)

At the March 2002 meeting, a case was presented of oxytocin (Syntocinon) not stored at 2-8(C being ineffective. Product used directly from the fridge however, had the desired therapeutic effect. As a result, the Committee recommended contacting professional bodies for those in obstetric practice, to advise on the appropriate storage of oxytocin.

In the interim, Medsafe has received and approved a Changed Medicine Notification (CMN) from Novartis. The CMN requested a change to the storage conditions to allow Syntocinon to be stored for up to 3 months below 30(C. The data sheet also states that Syntocinon should not be frozen.

The storage details for the ineffective ampoule in the aforementioned case report were not described. It is possible that, rather than having been left out at room temperature, the ampoule may have been frozen. As a result, the proposed letters to the professional organisations will not be sent.

2.1.8 Selective COX-2 inhibitors (agenda item 3.2.1, MARC March 2002)

The Committee noted a finalised article on the psychiatric events with COX-2 inhibitors that have been reported through the IMMP. The article is to be published in the July 2002 issue of Prescriber Update.

2.1.9 Intensive Vaccine Monitoring Programme (agenda item 3.3, MARC March 2002)

- T Maling. Monitoring the safety of the meningococcal B vaccine. Letter to the Minister of Health, 23 May 2002

Members noted the letter, which asked the Minister to support the IVMP for the meningococcal B vaccine.

2.1.10 Quarterly report (agenda item 3.4, MARC March 2002)

The Committee noted that the request to include fatalities for the 12-month period ending with the quarter to which the report applies has been overlooked. It will be addressed for the next quarterly report.

2.1.11 Bupropion (agenda item 4.1, MARC March 2002)

- S Jessamine. Safety of Zyban (bupropion). Letter to Glaxo SmithKline, 18 Apr 2002

Members noted the letter sent to Glaxo SmithKline as a result of the Committee's review of the safety of bupropion.

2.1.12 Antipsychotic/antiepileptics and sudden death (agenda item 4.2-4.3, MARC March 2002)

The Committee noted that material regarding this issue is to be held over for the September meeting.

2.1.13 Funding for oral contraceptives (agenda item 4.4.3, MARC March 2002)

- K Ronaldson. Funding of third generation oral contraceptives. Letter to Pharmac, 7 May 2002

Members noted that Pharmac has indicated it is favourably disposed towards the suggestion of having third generation pills fully-funded only when the script is endorsed "certified condition".

2.1.14 NSAIAs and cardiovascular effects (agenda item 4.6, MARC March 2002)

The Committee noted that no correspondence regarding the editorial by Cleland (questioning the value of aspirin in preventing mortality) have been published to date.

2.1.15 Selective COX-2 inhibitors and renal disease (agenda item 4.7, MARC March 2002)

The presentation on IC values will be made at the September meeting.

2.1.16 Sibutramine (agenda item 4.8, MARC March 2002)

The Committee noted that material on sibutramine had been included in the 110th meeting agenda, as requested.

2.1.17 Oral contraceptives and cervical cancer (agenda item 4.9, MARC March 2002)

The Committee noted that Medsafe is publishing an article on oral contraceptives, human papillovirus and cervical cancer in the November issue of Prescriber Update.

2.2 Outstanding matters

2.2.1 Hyperglycaemia & atypical antipsychotics (agenda item 3.2.2, MARC December 2001)

  • K Ronaldson. Atypical antipsychotics and hyperglycaemia. Report on the WHO data. March 2002
  • K Ronaldson. Risperidone and hyperglycaemia. Janssen-Cilag report. 17 Apr 2002
  • Seroquel and hyperglycaemia. Correspondence with AstraZeneca 10 May & 21 May 2002

The data sheets for risperidone and quetiapine have been updated by Janssen-Cilag and AstraZeneca, respectively, to include the association with hyperglycaemia and diabetes mellitus. While the Clopine data sheet has also been updated, the process is yet to be completed for Clozaril. Novartis is prepared to include advice about monitoring 'at risk' patients for hyperglycaemia, however, it is not prepared to delete the statement that a causal relationship has not been established. At a meeting between Medsafe and Eli Lilly on 12 June, data were presented by Eli Lilly indicating that hyperglycaemia is a class effect of atypical antipsychotics and is not specific to olanzapine. Eli Lilly was concerned that olanzapine may be being singled out. Following discussion, Eli Lilly is prepared to update the olanzapine data sheet as requested, with additional statements regarding the incidence of diabetes mellitus in schizophrenics, and the atypical antipsychotic class effect. Eli-Lilly is to propose a statement to Medsafe.

Members noted the above and agreed that no further action was necessary at this time.

2.2.2 HRT and cardiovascular /cerebral disease (agenda item 4.2, MARC December 2001)

At the December 2001 meeting, the MARC recommended that statements regarding cardiovascular and cerebrovascular disease be included in HRT data sheets. The Committee noted that a range of responses from pharmaceutical companies has been received. Members requested that these responses be processed for evaluation at the September 2002 meeting.

2.2.3 SSRIs and haemorrhage (agenda item 4.3, MARC December 2001)

  • Cipramil and abnormal bleeding. Correspondence with Lundbeck, 29 Apr, 8 May, 23 May 2002
  • K Ronaldson. Paroxetine and gastrointestinal bleeding. Report on GSK submission, 22 Apr 2002
  • SSRIs and haemorrhage. Item 4.3, minutes of MARC, 11 Dec 2002

At the December 2001 MARC meeting, it was recommended that gastrointestinal haemorrhage be included as a possible adverse reaction in SSRI data sheets. As clomipramine is also a potent serotonin reuptake inhibitor, this recommendation extended to Anafranil and Clopress. The data sheets for Fluox and Zoloft have been updated as requested. Replies have not been received concerning Lovan, Plinzene, Anafranil, Prozac, Luvox and Clopress. Replies have been received from Lundbeck concerning citalopram, and Glaxo SmithKline concerning paroxetine. Both companies have requested permission to use alternative statements which cover abnormal bleeding, particularly ecchymosis. Glaxo SmithKline and Lundbeck consider there is insufficient evidence of an association between SSRIs and gastrointestinal haemorrhage to warrant specific mention in the data sheet.

Members agreed to keep a watching brief on this issue. The Committee asked P Ellis to reconsider the data surrounding SSRIs and haemorrhage, and to liase with S Von Afehlt as to whether a Prescriber Update article should still be written (as per the December 2001 MARC meeting).

2.2.4 Mometasone furorate and dermatitis (agenda item 6.8.2, MARC September 2001)

Members noted that the data sheet for Elocon has now been updated and that it is available on the Medsafe web site.

2.2.5 Risk factors for VTE (agenda item 12.2.5, MARC September 2001)

Assoc. Prof. Charlotte Paul's report on risk factors for VTE with OCs is now out of date and she does not wish to update it. The report has been, and will continue to be, a valuable resource for the Committee's consideration of VTE with OC's.

In light of the above, the Committee recommended to Medsafe that the outdated report not be published in any form. A letter of appreciation of her contribution and effort is to be sent to Assoc. Prof. Paul.

2.2.6 Suicidal ideation/suicide with SSRIs (agenda item 12.7, MARC June 2001)

P Ellis's article on agitation with SSRIs is to be published in the November issue of Prescriber Update. The Committee on Proprietary Medicinal Products (CPMP) has recently considered this issue in Europe. P Ellis advised that, before he finalises the article on SSRIs and self-harm, he would like to obtain the outcome of the CPMP's discussion about the possible inclusion of akathisia in the data sheets for SSRIs. Members supported this action.

3. ISSUES ARISING FROM SPONTANEOUS Reporting AND IMMP

3.1 Spontaneous reporting programme

All spontaneous reports presented to the MARC meeting have been assessed by CARM and replies 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 entry of the reaction into the National Health Index against the patient's name, presenting the reaction to the MARC, including it in an article to be published, etc.


Note: In the comment associated with each report, the case has been given a causality designation using terms and definitions developed by the WHO. The precise definitions are available on the website of the WHO Collaborating Centre 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 the terms used by CARM and MARC can be accessed by hyperlink at each causality designation.

3.1.1 Reports in which death occurred

3.1.1.1 Carbamazepine/Rifampicin/Pyrazinamide and hepatic failure/hepatic coma, 50911

Discussion

Of a total of 369 reports with carbamazepine in the CARM database, there have been 69 reports of hepatic reaction and 1 of hepatic failure. CARM has received 63 reports for isoniazid, 3 of hepatic reactions and 1 of hepatic coma. The Committee considered that all of the suspected medicines, along with valproate, could be hepatotoxic and it is difficult to predict which may have been involved in this case. The causal association was designated "possible" and no further action was recommended.

3.1.1.2 Amoxycillin + Clavulanic acid/Erythromycin and colitis pseudomembranous, 49802

Discussion

The CARM database holds 609 reports for amoxycillin/clavulanic acid, 5 of which involve any form of colitis. In addition, the WHO database holds 382 reports of amoxycillin/clavulanic acid and pseudomembranous colitis (out of a total of 22129 reports for amoxycillin/clavulanic acid). CARM has received 2 reports of pseudomembranous colitis with erythromycin (of a total of 505 erythromycin reports). The WHO database holds 25726 reports for erythromycin, 163 of which involve colitis. The Committee considered the causal association "possible" and noted that while amoxycillin/clavulanic acid data sheets make reference to pseudomembranous colitis, this is not always the case for erythromycin.

Action

The Committee recommended that erythromycin data sheets that do not already include pseudomembranous colitis as a potential adverse effect be updated to do so.

3.1.1.3 Streptokinase / heparin / acetylsalicylic acid and cerebral haemorrhage, 50380

Discussion

Of a total of 80 reports with streptokinase in the CARM database, there have been 6 reports of cerebral haemorrhage. The Committee noted the case report and considered a causal association to be "probable". No further action was required.

3.1.1.4 Flecainide and sudden death, 46833

Discussion

The CARM database holds 38 reports for flecainide. Of these, there is 1 of sudden death, 1 of fatal arrhythmias, and 1 of cardiac arrest. Given the lack of information regarding sampling and potential post-mortem redistribution of flecainide, members had concerns with respect to the reliance of the post-mortem blood and liver flecainide levels.

Action

The Committee requested that CARM write to the National Poisons Centre asking if they have further information on flecainide toxicology. In addition, members requested that the Ministry of Health communicate the view of MARC in a letter of feedback to the coroner. The Committee also recommended that 3M Pharmaceuticals be asked to prepare a CMI sheet for this medicine.

3.1.1.5 Paroxetine and suicide, 50795 Discussion

The WHO database holds a total of 22821 reports for paroxetine, 418 of which involve attempted suicide. CARM has received 218 reports for paroxetine, 2 of which involve suicide. CARM has written to the reporter of this case requesting more substantial information, however, they have not yet received a reply. Members agreed that more information was required for a proper assessment and considered the report to be "unclassified". Members noted that an article addressing the issue of SSRIs and suicidal ideation is soon to be published in Prescriber Update.

3.1.2 Antiepileptic-related reports

3.1.2.1 Phenytoin and hypersensitivity syndrome, 50535

Discussion

The CARM database holds no reports of hypersensitivity syndrome, 14 reports of fever, 4 reports of eosinophilia and 58 reports of various rashes with phenytoin (out of a total of 200 reports). The WHO database holds 177 reports of eosinophilia with phenytoin (of a total of 14263 phenytoin reports). The Committee noted that while this is the first report of hypersensitivity to this medicine, hypersensitivity syndrome has been associated with anticonvulsant medications in general. The causal association was designated "possible".

Action

Members recommended that a Prescriber Update article, communicating the key diagnostic features of a drug hypersensitivity syndrome, be prepared. It was recommended that such an article should include a list of possible causative medicines, and should encourage the reporting of such incidents to CARM.

3.1.3 Antiinfective-related reports

3.1.3.1 Amoxycillin+ Clavulanic acid/Erythromycin /Cefuroxime /Paracetamol and toxic epidermal necrolysis, 49816

Discussion

The CARM database holds 172 reports for erythromycin and skin reactions (5 for Stevens-Johnson syndrome, and 6 for erythema multiforme), and 61 reports for paracetamol and skin reactions (2 for erythema multiforme). Of a total of 14352 reports for erythromycin in the WHO database, there have been 96 reports of Stevens-Johnson syndrome. The WHO database contains 55 reports of the same syndrome in conjunction with cefuroxime (out of a total of 7189 reports for cefuroxime). The WHO database also holds 107 reports of toxic epidermal necrolysis with paracetamol (out of a total of 10499 reports for paracetamol). Members were concerned about the unusual combination of antibiotics used in this patient and requested additional information pertaining to the patient's medical condition.

Action

The Committee requested that CARM contact the necessary health professionals in order to obtain further information regarding this case.

3.1.3.2 Penicillin and rash, 50518 Discussion

The Committee noted the case report and considered a causal association to be "unlikely". No further action was required.

3.1.4 Cardiovascular medication-related reports

3.1.4.1 Atorvastatin and foetal abnormality, 50966 Discussion

There are 60 reports for atorvastatin held in the CARM database, however, none of these involve congenital abnormalities. Of 25626 atorvastatin reports in the WHO database, there are no instances of chromosomal abnormalities and 1 congenital abnormality. The Committee noted the case report and considered a causal association to be "unlikely". No further action was required.

3.1.4.2 Enalapril / Insulin and hyperglycaemia, 50442 Discussion

The CARM database holds 989 reports for enalapril. Three of these involve hypoglycaemia, and 21 relate to brand-switch problems. On considering the case report, members questioned whether the patient's blood sugar levels normalised upon return to Renitec. CARM has requested this information from the case reporter but has not yet received a reply.

Action

The Committee requested that CARM obtain this information. If a difference between Renitec and the generic is apparent, members recommended that Pharmac be directly informed of this issue.

3.1.5 Dermatological medication-related reports

3.1.5.1 Mometasone and dermatitis, 49852 Discussion

The CARM database holds 11 reports for mometasone. These include two of perioral dermatitis, two of skin striae, two of rosacea, one of skin atrophy, and one of telangiectasia. The Committee noted the case report and considered a causal association to be "possible". No further action was required.

3.1.6 Hormone-related reports

3.1.6.1 Femodene and pulmonary embolism, 50557 Discussion

The CARM database holds 35 reports for Femodene, 12 of pulmonary embolism. On considering the case report, the Committee deemed a causal association to be "possible". Members discussed the case report with respect to the age of the patient. The Committee agreed that there was no need to change the recommendation that oral contraceptives may be taken until menopause, if there are no other risk factors.

3.1.6.2 Marvelon and pulmonary embolism, DVT, 49790

Discussion

The CARM database holds 20 reports of Marvelon and DVT, and 15 of Marvelon and pulmonary embolism. Of 3231 reports for Marvelon in the WHO database, there are 473 of pulmonary embolism (78 of which were fatal). The Committee noted the case report and considered a causal association to be "possible". No further action was required.

3.1.6.3 Postinor-2 and ectopic pregnancy/therapeutic response inadequate/salpingectomy, 50874 Discussion

The CARM database holds seven reports for Postinor-2, three with ectopic pregnancies. The Committee noted the case report and considered a causal association to be "possible". This issue was discussed further in Section 4.1 of the agenda.

3.1.7 Vaccine-related reports

3.1.7.1 MMR and measles/cross infection, 50731 Discussion

The Committee noted the case report and considered a causal association for both measles and cross-infection to be "possible". No further action was required.

3.1.8 Alternative medicine-related reports

3.1.8.1 Cheng Kum and skin fragility/obesity/raised hepatic enzymes/adrenal cortical insufficiency, 50569 Discussion

The Committee noted the case report and that recent testing of Cheng Kum has shown it to contain betamethasone. A causal association was considered to be "possible". No further action was required.

3.1.8.2 Creatine and cerebral infarction/upper motor neurone lesion, 50539 Discussion

The Committee noted the case report and considered a causal association to be "possible". No further action was required.

3.2 Spontaneous reporting programme: Quarterly report (as at 31 March 2002)

3.2.1 Brandswitch-related reports

It was noted that CARM has received eight reports (and close to 20 to date) of diverse reactions with Felodipine. The number of reports for Estelle-35 has increased to nine, with reactions suggesting variations in bioavailability. Fluoxetine continues to be reported, with 10 of the 14 reports this quarter related to reduced therapeutic effect. Reports of diverse reactions with enalapril also continue to be received.

3.2.2 Vaccine reactions

Members noted that 21 injection site reaction reports have been received for the newly introduced IPV. The injection site reactions are typically reported to be significant and already number at a higher rate than with the DTaP alone. Reports of massive, but painless, injection site reactions with DTaP/HiB continue to be received.

3.3.3 Pharmacovigilance literature of interest

The Committee noted the list of pharmacovigilance-related references and were advised that copies of these articles are available on request to CARM.

3.3 IMMP

3.3.1 COX-2 inhibitors

Issue

COX-2 inhibitors and visual effects

  • Visual problems with COX-2 inhibitors, 50707, 50469
  • BC Lund, RF Neiman. Visual disturbance associated with celecoxib. Pharmacotherapy 21:114-115, 2001
  • KM Gehrs. Visual disturbance associated with celecoxib - a comment. Pharmacotherapy 21:101, 2001
Discussion

The Committee noted 2 IMMP case reports of elderly patients who experienced reduced vision with COX-2 inhibitors. The WHO database also holds a number of reports of visual disturbance with celecoxib and rofecoxib.

Action

Members recommended that, in order to alert practitioners to this potential problem, D. Coulter prepare an article regarding visual problems with COX-2 inhibitors for Prescriber Update.

Issue

Events with COX-2 inhibitors

The Committee noted that there have been 11 reported neurological deaths with celecoxib and none with rofecoxib. Similarly, there have been 12 reported respiratory deaths with celecoxib and none with rofecoxib. An important confounding factor, however, is that celecoxib is often prescribed long-term to elderly patients (e.g. for arthritis), whereas rofecoxib is prescribed short-term to younger patients (e.g., for sports injuries).

Members also noted that there was no evidence in the IMMP data to date, to indicate that rofecoxib has a greater prothrombotic effect than celecoxib.

D Coulter pointed out that the duration of onset to death (as a result of circulatory events or malignant neoplasm) appears to be shorter for patients on rofecoxib compared with celecoxib. Members agreed that, while this may be seen as a signal, more data (which are stratified according to age and indication) are required.

Action

The Committee requested that CARM report back to the MARC if more data relating to the duration of onset to death become available.

Issue

COX-2 inhibitors and psoriasis

- D Clark, D Coulter. Psoriasis with a COX-2 inhibitor: first case report.

Discussion

The Committee noted the case report and agreed with D. Coulter that it was important to document the report.

Action

Members recommended that the case report be submitted for publication.

3.3.2 Atypical antipsychotics

Issue

Risperidone and QT-prolongation

  • Risperidone and QT-prolongation, 49851
  • C Gury, et al. Antipsychotics, risk of QT prolongation and torsades de pointes. Enceph-Rev Psychiatr Clin Biol Ther 26:62-72, 2000
Discussion

The Committee noted the case report of prolonged QT interval with risperidone.

Issue

Events with atypical antipsychotics

Discussion

D. Coulter highlighted the fact that olanzapine has a predominance of weight increase and extrapyramidal events, whereas risperidone has a predominance of skin reactions. In addition, members noted that parotid enlargement, nocturnal enuresis, and possible interactions with valproate and proton pump inhibitors have been seen with clozapine.

In particular, D. Coulter highlighted the fact that 13 reports of fever associated with clozapine have been received. The fever, which can take a number of days to subside, is spiking and is associated with respiratory or alimentary symptoms. Members agreed that there is a need to alert practitioners to this issue. It was also agreed that clozapine could not be withdrawn without considering adequate control of the psychiatric condition.

Action

The Committee requested that Medsafe conduct a literature search for other reports regarding fever with clozapine, and report back to the MARC at the September 2002 meeting. In addition, members asked that this issue be included on the agenda for the June Australia/New Zealand teleconference.

3.3.3 Sibutramine

Issue
  • Sibutramine and manic reaction, 51494
  • Review of IMMP data for sibutramine
  • Table of age and gender distribution
  • Table of regional distribution
Discussion

Members noted the IMMP case report of manic reaction with sibutramine, and that the WHO database holds 3 reports of manic reaction and 2 of manic depressive psychosis. D. Coulter also advised that the sibutramine data sheet states that sibutramine has been shown to have potential antidepressant effects in animal studies. The Committee agreed that this could be a potential problem in obese patients with psychiatric disorders.

Action

The Committee recommended that Medsafe contact PreMec with regard to writing a bulletin on sibutramine. It was recommended that PreMec liaise with CARM about potential adverse reactions with sibutramine.

3.3.4 Nefazodone

Issue
  • Nefazodone interaction with magnesium, therapeutic response decreased, 50802
Discussion

The Committee noted the above IMMP case report in which the therapeutic response to nefazodone was decreased in a patient concurrently taking magnesium. No further action was required.

3.3.5 Mirena

D. Coulter advised the Committee that a dissertation on Mirena has recently been completed and is available to members if they are interested. It was also noted that a significant number of reports of adverse progestogenic effects has been received by CARM.

3.3.6 Multiload Cu 375

Issue

- M Harrison-Woolrych, J Ashton, D Coulter. Uterine perforation with the Multiload Cu 375 intrauterine device: a prospective study of over 17,000 insertions. To be submitted.

Discussion

M Harrison-Woolrych highlighted an IMMP study, which investigated uterine perforation with the multiload Cu375 intra-uterine device. It was noted that the IMMP cohort now includes 17,469 insertions, and that the study confirms a higher incidence of perforation than has been reported in clinical trials. Members commented that it was a good paper and noted that it is to be submitted for publication in an international journal.

3.4 "IC" values

Due to time constraints, members agreed that the presentation by CARM on this topic be deferred to the September 2002 meeting.

3.5 Systems currently proposed to monitor adverse events following immunisation with the Group B meningococcal vaccine.

A seminar on this topic was presented by Jane O'Hallahan (Director, Meningococcal Vaccine Strategy Team, Ministry of Health) and Anne McNicholas (Senior Advisor, Meningococcal Vaccine Strategy Team, Ministry of Health). The following monitoring strategies were noted:

  • Routine passive post-marketing surveillance by CARM
  • Additional health professional reporting of vaccinee visits to CARM
  • CARM monitoring of vaccinations given as part of the routine childhood schedule
  • Parental/vaccinee reporting of adverse events following immunisation to CARM
  • Post-vaccination diary cards
  • Hospital-based monitoring of RARE serious adverse events
  • Hospital-based monitoring of ALL events
  • Retrospective database matching (using the hospital discharge database and the national immunisation register)

4. Pharmacovigilance Issues

4.1 Emergency contraceptive pill and ectopic pregnancy

Reference material
  • M Harrison-Woolrych. Hormonal emergency contraceptive pills and risk of ectopic pregnancy. Report for MARC, May 2002
  • Task Force on Postovulatory Methods of Fertility Regulation. Randomised controlled trial of levonorgestrel versus the Yuzpe regimen of combined oral contraceptives for emergency contraception. Lancet 352:428-33, Aug 1998
  • CARM reports of ectopic pregnancy with Postinor-2, 46420, 50874, 51152
  • Postinor-2 (levonorgestrel 750mg). NZ data sheet.
  • Levonelle (levonorgestrel 750mcg). NZ data sheet.
Issue

It is generally accepted that pregnancies occurring in women taking the progesterone-only pill (POP) are more likely to be ectopic than pregnancies occurring in the general population. In New Zealand, CARM has now received 3 reports of ectopic pregnancy related to the use of the progestogen-only emergency contraceptive pill (ECP), Postinor-2.

Discussion

Members noted that, in addition to the CARM case reports, there are 12 reports of ectopic pregnancy associated with 0.75 mg levonorgestrel used for emergency contraception held in the WHO database. Given that levonorgestrel can interfere with smooth muscle contraction, the Committee agreed that there is biological plausibility for the progestogen-only ECP to increase the likelihood of ectopic pregnancy. It was agreed that, while the Committee did not want to discourage the use of the ECP, it was important that doctors are aware of the possible association with ectopic pregnancy.

Action

Members recommended that, after checking whether the CMI sheets for these products contain warnings for ectopic pregnancy, Medsafe contact the pharmaceutical companies with regard to what data or reports they may have on this issue. The Committee also recommended that the Family Planning Association be contacted with regard to updating their ECP patient leaflet to include this warning.

4.2 Tiaprofenic acid

Reference material
  • Prescriber Update. (recommendation for s.36 notice) Item 4.2, minutes of MARC, 5 Sep 2001
  • R Savage. Tiaprofenic acid-induced cystitis. Prescriber Update No.22, p.18-21, Oct 2001
  • s.36 notice for Surgam. Correspondence with Aventis Pharma Ltd. 5 Feb, 2 Apr, 24 Apr, 9 May, 15 May 2002
Aventis submission
  • DL Scott, et al. The long-term effects of non-steroidal anti-inflammatory drugs in osteoarthritis of the knee: a randomised placebo-controlled trial. Rheumatology 39:1095-1101, 2000
  • Aventis Pharma. PSUR for tiaprofenic acid, 1 Sep 1998 to 25 Aug 2001 - 4 reports, extracts from these.
Apotex submission
  • .., Apotex NZ Ltd. S.36 notice for Apo-Tiaprofenic. Letter 8 Mar 2002
  • .., Apotex Inc. Tiaprofenic acid indications and safety. Letter 6 Mar 2002.
  • R Buchbinder, et al. Clinical features of tiaprofenic acid associated cystitis and a study of risk factors for its development. J Clin Epidemiol 2000; 53:1013-19.
  • GL Plosker, AJ Wagstaff. Tiaprofenic acid. A reappraisal of its pharmacological properties and use in the management of rheumatic diseases. Drugs 50:1050-75, 1995
  • Pharmac. Tiaprofenic acid usage figures, 1 Feb 2001 to 1 Jan 2002
Issue

Cystitis is a known adverse effect of tiaprofenic acid. In light of this risk, members at the September 2001 MARC meeting recommended that sponsor companies for tiaprofenic acid be asked to justify their medicines remaining on the market. To allow time for a full evaluation of tiaprofenic acid, Aventis has asked for this issue to be held over until the September 2002 MARC meeting. Aventis has also welcomed suggestions from the MARC as to how they can minimise the risk of cystitis going untreated.

Discussion

Members noted that tiaprofenic acid-induced cystitis appears to be relatively uncommon, with 17 such reports received by CARM. It was agreed that this issue requires risk management, rather than removal of the medication from the market. While the Committee decided that it was important to make patients aware that they should seek medical attention if they had any bladder problems while taking this medication (perhaps via a CMI sheet), no specific action was determined.

Action

Members agreed to review this issue at the September 2002 meeting. The Committee requested that Aventis be asked to propose potential initiatives to minimise the risk of untreated/unrecognised cystitis.

4.3 Withdrawal of statins

Reference material

- C. Heeschen, et al. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation 105:1446-52, Mar 2002

Issue

The above report asserts that withdrawal of chronic statin treatment during acute coronary syndromes may impair vascular function and thus, increase cardiac event rate. Medsafe enquired as to whether the MARC believed this was a significant issue.

Discussion

Members agreed that, while this was only one article, withdrawal of statins after the onset of acute coronary symptoms may well be an issue of significance for New Zealand. The Committee also agreed that experts in the cardiovascular field should be consulted as to whether they believe this is a significant clinical problem.

Action

The Committee recommended that Medsafe conduct a literature search before seeking the view of the Cardiac Society on this issue. Members also suggested that, if appropriate, the two bodies could publish a joint article.

4.4 Tamoxifen and uterine sarcoma

Reference material

- L Bergman, et al. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Lancet 356:881-7, 9 Sep 2000
- K Gelmon. One step forward or one step back with tamoxifen? Commentary Lancet 356:868-9, 9 Sep 2000
- C Tempfer, C Atkins, S Narod, C Lasset, FE van Leeuwen, MJ Dickson, F Marsh, et al. Tamoxifen and risk of endometrial cancer. Correspondence. Lancet 357:65-8, 6 Jan 2001
- K Ronaldson. Tamoxifen and endometrial sarcoma. Letter, 1 May 2002
- DK Wysowski, et al. Uterine sarcoma associated with tamoxifen use. NEJM 346:1832-3

Issue

It is accepted that tamoxifen is associated with increased incidence of endometrial hyperplasia and carcinoma. There is recent debate, however, over whether these tumours are more often sarcomas with a poorer prognosis and higher malignant potential than was previously thought. In addition, this risk may be heightened in patients undergoing long-term tamoxifen treatment. Medsafe enquired whether the MARC believed that women taking tamoxifen for more than two years should be actively monitored for endometrial cancer. Medsafe has also sought expert advice from two oncologists on this issue, however only one reply has been received to date.

Discussion

Members agreed that the Bergman et al. (2000) study has an obvious selection bias in that tamoxifen was given only to women with a certain type of breast cancer. The Committee also noted that the FDA is working with AstraZeneca to remind physicians and consumers to the risk of endometrial cancer, and alert them to the possibility of more aggressive uterine sarcoma, with tamoxifen.

Action

The Committee recommended that Medsafe assess the comments of the two oncologists when they have both been received. Members also recommended that pharmaceutical companies be asked to prepare CMI sheets (and to update data sheets if required), which include the need for women experiencing abnormal vaginal bleeding to promptly see a doctor.

4.5 Desogestrel (POP) and venous thromboembolism

Reference material

- Desogestrel (Cerazette). Correspondence with Pharmac, 31 Oct 2000, 11 Dec 2001
- .., Pharmaco. Cerazette and VTE. Letter 7 May 2002
- .., Akzo Nobel. PSUR on Cerazette, July 2001-Dec 2001. Excerpts on VTE with Cerazette
- UH Winkler, et al. A randomised controlled double-blind study of the effects on hemostasis of two progestogen-only pills containing 75mcg desogestrel or 30 mcg levonorgestrel. Contraception 57:385-92, 1998
- Progestogen-only oral contraceptives and VTE. Item 12.2, minutes of MARC, 5 Sep 2001

Issue

Pharmac has asked for MARC comment regarding the safety profile of Cerazette, specifically with regard to the risk of VTE.

Discussion

The Committee agreed that there is no evidence to indicate that Cerazette is better, or is more of a problem, than any other POP. Members also commented that they believed the Winkler et al. (1998) study to be unscientific, and they did not want to include it in their consideration of this issue.

It was also brought to the attention of the Committee that, while the New Zealand data sheet for Cerazette gives 12-hour missed-pill advice, the UK has given 3-hour missed-pill advice for this product.

Action

Members agreed that T Maling would contact Pharmac in order to determine the issues behind their request. He will then meet with Medsafe to discuss what advice should be given. The outcome of this will be reported at the September 2002 MARC meeting.

The Committee recommended that Organon be asked to update the Cerazette data sheet to reflect the fact that the risk of VTE with Cerazette is unknown.

The Committee requested that Medsafe investigate the discrepancy in the UK and New Zealand missed-pill advice and report back at the September 2002 meeting.

4.6 Suicide with isotretinoin

Reference material
- D. Wysowski, et al. An analysis of reports of depression and suicide in patients treated with isotretinoin. J Am Acad Dermatol, 45:515-519, Oct 2001
- DK Wysowski, et al. Use of isotretinoin (Accutane) in the United States: rapid increase from 1992 through 2000. J Am Acad Dermatol 46:505-9, Apr 2002
- Roaccutane (isotretinoin) NZ data sheet
- Oratane (isotretinoin) NZ data sheet
- Oratane consent form
- Isotretinoin - safety and usage. Item 12.2, minutes MARC, 14 Mar 2001
- Isotretinoin and suicide (death), 47802. Item 6.8.1, minutes MARC, 5 Sep 2001
- Isotretinoin and multiple malformations, 48737. Item 3.1.2.1, minutes MARC, 11 Dec 2001

- Draft Roaccutane consent forms for male and female users, respectively.

Issue

This issue was considered at the September 2001 MARC meeting, however, it has recently received media attention in New Zealand with the suicide of a person taking isotretinoin. In light of this, Medsafe asked the Committee if it still considers the advice given in the data sheets, and elsewhere, to be adequate.

Discussion

Members agreed that the current advice provided in isotretinoin data sheets is suitable and adequate. The Committee also noted the Roaccutane consent forms, prepared by Roche, for male and female patients.

Action

The Committee recommended that Roche be sent a letter of thanks for the opportunity to view their Roaccutane consent forms.

4.7 Electrolyte disturbance with indapamide

Reference material

- M. Chapman, et al. Hyponatraemia and hypokalaemia due to indapamide. MJA, 176:219-221, Mar 2002
- Natrilix (indapamide) NZ data sheet - extracts
- Naplin (indapamide) NZ data sheet - extracts
- Thiazide usage data Jan 1997 to Mar 2002 (see the 2 graphs)

Issue

ADRAC data indicate that indapamide can cause severe electrolyte disturbances. Usage data from PreMec suggest that indapamide (immediate release) currently has approximately 10% of the thiazide diuretic market in New Zealand.

Discussion

The Committee noted that indapamide use in New Zealand is declining. It was also noted that the data sheets for indapamide cover the risk of electrolyte imbalance in detail. On this basis, the Committee agreed that no further action is necessary at this time.

4.8 Propofol, paediatric sedation

Reference material

- .., AstraZeneca. Diprivan - paediatric ICU sedation indication. Letter, 21 Jan 2002.
- .., AstraZeneca. Diprivan/24 hour paediatric ICU restriction. Letter, 18 Jul 2001
- A Bolotovski, Medsafe. Diprivan/24 hour paediatric ICU restriction. Letter, 3 Jul 2001
- .., AstraZeneca. Diprivan/24 hour paediatric ICU restriction. Letter, 6 Jun 2001
- .., AstraZeneca, US. Diprivan and pediatric sedation. Dear Health Care Provider Letter, 26 Mar 2001
- D Stevens, Medsafe. Consent to distribute a changed medicine. Diprivan and paediatric sedation. Letter, 23 Mar 2001
- .., Clinical Pharmacology Registrar. Diprivan and paediatric ICU sedation. Report Jan 2001

Issue

In 2001, the use of propofol for 24-hour sedation of paediatric ICU patients was approved in New Zealand. Subsequent to this, the FDA directed AstraZeneca to issue a Dear Doctor letter, advising that propofol not be used for paediatric sedation. This advice was based on a clinical trial, which found a higher death rate in patients treated with propofol, as compared to standard sedative agents.

Action

Due to time constraints, members requested that this issue be deferred until the September 2002 meeting.

5. ISSUES FOR INFORMATION ONLY - usually full text supplied

This material was not discussed by the Committee. It includes 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.

5.1 Loratadine and hypospadias

- K Ronaldson. Loratadine and hypospadias. Letter 9 May 2002
- .., Schering-Plough Ltd. Loratadine and hypospadias. Letter 8 May 2002

5.2 Diethylstilbestrol and hypospadias in sons of women exposed in utero

- H. Klip, et al. Hypospadias in sons of women exposed to diethylstilbestrol in utero: a cohort study. Lancet, 359: 1102-1107, Mar 2002.
- S. Hernandez-Diaz. Iatrogenic legacy from diethylstilbestrol exposure. Lancet, 359:1081-1082, Mar 2002.

5.3 Pharmacogenetics of cytochrome P450

- R. Roberts, et al. Molecule-to-Malady, How the pharmacogenetics of cytochrome P450 enzymes may affect prescribing. NZ Med J, 115:137-140, Mar 2002.

5.4 Cyproterone acetate and venous thromboembolism

- A Gompel, et al. Risk of venous thromboembolism and oral contraceptives. Lancet 359:1348, Apr 2002.

5.5 Rofecoxib and aseptic meningitis

- RA Bonnel, et al. Aseptic meningitis with rofecoxib. Arch Intern Med 162:713-5, Mar 2002

5.6 Sibutramine

Submission by Abbott Laboratories to the CPMP, Apr 2002
- Sibutramine. Table of contents. Response Article 31 CPMP referral
Question 3A: Full analysis of all new information available after the 8th PSUR (12 Nov 2001 to 28 Feb 2002)
Question 3B: Risk evaluation: Specific safety reassessment focusing on cardiovascular risk based on all available information.
Question 3C: Risk evaluation: Specific safety reassessment focusing on psychiatric risk based on all available information.

- Sibutramine hydrochloride. Australian Prescriber 25(1), 2002
- Sibutramine, international background
- Comment on sibutramine from WHO Monitoring Centre

5.7 Angiotensin II receptor antagonists after ACE inhibitor angioedema?

- LG Howes, D Tran. Can angiotensin receptor antagonists be used safely in patients with previous ACE inhibitor-induced angioedema? Drug Safety 25:73-6, 2002

5.8 Overwinding of Accuhaler devices

- GR Boyd. S.36 notice for Serevent, Seretide and Flixotide Accuhalers. Letters of 15 Apr & 10 Jun 2002

5.9 Methotrexate and survival advantage

- H. Choi, et al. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet, 359:1173-1177, Apr 2002

5.10 New warnings and withdrawal of medicines

- KE Lasser, et al. Timing of new black box warnings and withdrawals for prescription medications. JAMA 287:2215-20, 1 May 2002
- RJ Temple, MH Himmel. Safety of newly approved drugs. Implications for prescribing. JAMA 287:2273-5, 1 May 2002

5.11 Oral contraceptives and myocardial infarction

- P Hannaford, JP Vandenbroucke, C Kahlenborn, SF Li, S Shapiro, FR Rosendaal, BC Tanis, L Chasan-Taber, MJ Stampfer. Oral contraceptives and the risk of myocardial infarction. NEJM 346:1826-9

6. Other NZ Activities

6.1 Prescriber Update

- July 2002 issue of Prescriber Update - final text
- Schedule of planned Prescriber Update articles

6.2 Pharmac

- Minutes of the Pharmacology and Therapeutics Advisory Committee meeting, 21 Feb 2002

6.3 Publications

- M. Harrison-Woolrych, J. Ashton & D. Coulter. Experience of insertion of a copper intrauterine device in over 16,000 New Zealand women. To be published

6.4 Health Practitioners Competency Assurance Bill

- G Durham. Email. 17 May 2002

7. Other Countries

7.1 Australia

  • Adverse Drug Reactions Advisory Committee, minutes 14 Dec 2001 meeting
  • Adverse Drug Reactions Advisory Committee, minutes 15 Feb 2002 meeting
  • Aust Adv Drug Reactions Bull 21:5-8, June 2002

7.2 Canada

  • Canadian Adv Drug React Newsletter 12(2), Apr 2002

7.3 United Kingdom

  • Current Problems in Pharmacovigilance 28:1-6, Apr 2002
  • Zyban (bupropion hydrochloride) - safety update, CSM, 8 Apr 2002

7.4 Global pharmacovigilance

  • K de Neef. International comparison of pharmacovigilance. Presentation at the First Annual DIA Workshop in Japan for Global pharmacovigilance, Tokyo, 1-2 Nov 2001

8. General Reporting

  • - Case reports considered since Nov 1997, by medicine class
  • - Vaccine adverse reactions since Nov 1997
  • - Case reports for alternative therapies
  • - Glossary of terms

9. ISSUES FOR INTEREST ONLY - abstract or reference only

This material was not discussed by the Committee. It includes updates on issues already known to the Committee and preliminary information on emerging issues. This material differs from that in section 5 in that it is of more peripheral relevance or importance. The material was provided for the interest of the members, and reading it was optional. Members were able to request that the material be discussed at the present, or at a future, meeting.

9.1 Abstract only

- N. Mohan, et al. Demyelination occurring during anti-tumor necrosis factor & therapy for inflammatory arthritides. Arthritis & Rheumatism, 44:2862-2869, Dec 2001
- H. Sorensen, et al. Risk of suicide in users of β-adrenoceptor blockers, calcium channel blockers and angiotensin converting enzyme inhibitors. Br J Clin Pharmacol, 52:313-318, May 2001
- I. Schillevoort, et al. Extrapyramidal syndromes associated with selective serotonin reuptake inhibitors: a case-control study using spontaneous reports. International Clinical Psychopharmacology, 17:75-79, 2002
- The LIPID Study Group. Long-term effectiveness and safety of pravastatin in 9014 patients with coronary heart disease and average cholesterol concentrations: the LIPID trial follow-up. Lancet, 359:1379-1387, Apr 2002
- G. Langman, et al. Non-alcoholic steatohepatitis. Role of non-alcoholic steatohepatitis in methotrexate-induced liver injury. J Gastroenterol Hepatol, 16:1395-1401, 2001.
- G Noroian, D Clive. Cyclo-oxgenase-2 inhibitors and the kidney. Drug Safety 25:165-72, 2002
- Reuters Medical News. Paroxetine use during late pregnancy associated with neonatal complications. Downloaded 22 May 2002.

Prescribing errors

- J. Hafner, et al. Adverse drug events in emergency department patients. Ann Emergency Med 39:258-267, Mar 2002
- B. Dean, et al. Causes of prescribing errors in hospital in patients: a prospective study. Lancet, 359:1373-1378, Apr 2002.
- S. Maxwell, et al. Using drugs safely. Undergraduates must be proficient in basic prescribing. BMJ, 324:930-931, Apr 2002.

Reuse of penicillin following penicillin allergy

- M Rademaker. Penicillin allergy. Letter, 23 Apr 2002
- R. Solensky, et al. Lack of penicillin resensitization in patients with a history of penicillin allergy after receiving repeated penicillin courses. Arch Intern Med, 162:822-826, Apr 2002.
- A. Salkind, et al. Is this patient allergic to penicillin? An evidence-based analysis of likelihood of penicillin allergy. JAMA, 285:2498-2505, May 2001.
- R. Solensky, et al. Penicillin allergy: prevalence of vague history in skin test-positive patients. Ann Allergy, Asthma & Immunol, 85:195-199, Sept 2000.
- MJ Torres, et al. Controlled administration of penicillin to patients with a positive history but negative skin and specific serum IgE tests. Clin Exp All 32:270-276, 2002

9.2 Reference only

J McNeece. Interactions between grapefruit juice and some drugs available in Australia. Australian Prescriber 2002
http://www.australianprescriber.com/magazines/vol25no2/PDFs/p37%20.pdf

The meeting ended at 5pm.

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