Revised: 21 May 2013

Committees

Minutes of the 103rd Medicines Adverse Reactions Committee Meeting - 6 September 2000

Preface:

The material listed as being considered on an issue is not intended to be exhaustive.

Descriptions of unpublished case reports have not been included to protect the privacy of those involved.

Names of individuals have been deleted where the contribution is not in the public domain and will not shortly be so. For example the names of those to be approached to write an article are deleted, but not usually the names of those who have contributed a draft article. Names are not usually deleted when a contribution has been made in an official capacity.

The recommendations of the Committee are in bold typeface.

MINUTES OF THE 103^RD MEETING OF THE
MEDICINES ADVERSE REACTIONS COMMITTEE
HELD 6 SEPTEMBER 2000 IN MEDSAFE MEETING ROOMS, 18^th FLOOR, GRAND PLIMMER TOWER COMMENCING AT 9.30AM

PRESENT

Associate Professor TJB Maling (Chairperson)
Dr M Tatley (Medical Assessor)
Dr D Coulter
Professor P Ellis
Dr J Goldsmith
Dr S Jessamine
Dr H Kingston
Dr F McClure
Dr M Rademaker
Dr N Rafter (Medical Advisor, Medsafe)
Dr K Ronaldson (Secretary)

1. WELCOME AND APOLOGIES

The Chairperson welcomed members to the meeting. Apologies had been received from Professor Skegg and Dr Savage

2. MINUTES OF THE 102^nd MEETING

After making one correction, the minutes of the 102^nd meeting were signed by the Chairperson, indicating that they were accepted as a true and accurate record of the meeting.

3. DATES OF THE NEXT MEETING

22 November (Wed) was confirmed as the date of the next meeting.

4. MATTERS OF ADMINISTRATION

4.1 Conflict of interest

- Conflict of interest response form
- Conflict of Interest Protocols. Letters, 27 July, 2 Aug, 8 Aug 2000
- MHN Tattersall, IN Olver. Conflict of interests and advisory committees. Intern J Pharmaceutical Med 13:325-8, 1999
- Ministry of Health. Conflict of interest protocol for statutory bodies and other committees. 17 Apr 2000
- State Services Commission. Identifying and dealing with conflicts of interest, Annex 2
- State Services Commission. Duties of Board Members. Annex 3

The issue of conflict of interest was raised because of a recently updated Ministry of Health guideline on the subject and because of a query from a Committee member who had recently inherited pharmaceutical company shares. It was agreed that a tightening of the handling of conflict of interest issues by the Committee was required.

Several possibilities were discussed including:

• the Secretary maintaining a running list of conflicts of interests by Committee members and bringing the list to each meeting;
• the Committee members advising the Secretary at least 3 days before the meeting of conflicts of interest with agenda items, so that a decision could be made before the meeting on how the issue should be handled.

Members asked that the Secretary prepare new guidelines for discussion at the next meeting.

Concerning conflict of interest declarations presented at the current meeting, no interests were considered to be in conflict with items on the current agenda.

4.2 MARC minutes on the Medsafe web site

- K Ronaldson. MARC minutes on the Medsafe web site. Discussion paper prepared for MARC. 16 Aug 2000
- J Wise. CSM takes small step towards openness. BMJ 319:939, 9 Oct 2000
- J Jones. CSM attacked over delay in reducing secrecy. BMJ 321:135, 15 July 2000
- Summary of the minutes of the Sub-Committee on Pharmacovigilance meeting, 24 Feb 1998. Sub-Committee of the Committee on Safety of Medicines. http://www.open.gov.uk/mca/csmhome.html

At the previous meeting the Secretary had advised the members that Medsafe was planning to publish the minutes of the Committee on its web site. Members had objected, and had requested that the issue be on the agenda for discussion at the present meeting.

The Secretary had prepared a report responding to each of the Committee's objections.

• As far as Medsafe is aware, publication of articles about adverse reactions on the web site has not resulted in any adverse consequences in terms of alarm by members of the public. The minutes are equally well balanced
• Misinformation in the recent past has resulted from third parties obtaining versions of the minutes, but not the entire minutes. Having the entire minutes available on the web site may reduce the risk of misinformation circulating.
• In relation to case reports, the privacy of patients and medical practitioners could be protected by modifying the presentation of case reports. However, knowledge that an expert committee is discussing and taking these cases seriously may be gratifying and reassuring to those who have been seriously affected by an adverse reaction.

The items from the British Medical Journal described criticism of the UK Medicines Control Agency for its tardiness over putting the minutes of the Committee on Safety Medicines on its web site, and its apparent lack of commitment to openness. Members agreed that similar pressure for openness would eventually be forthcoming in New Zealand.

Dr ... mentioned the Ericé Declaration and the discussion surrounding it. All delegates at that important meeting in 1997 had agreed openness in regulatory decision making regarding medicines is important. Members suggested that if the minutes are tailored at all for the web site, the Committee might be accused of hiding information. Because of the openness, the Committee need not feel compelled to recommend action on each issue. In situations where no action is recommended on an issue, an explanation can be included in the minutes.

There was discussion surrounding the privacy issues associated with case reports. It was suggested that if details of case reports were presented showing that a medical practitioner had behaved inappropriately, e.g. continuation of therapy in a patient with a medicine-related adverse reaction, medical practitioners may cease to report these types of cases. However, all agreed that it is essential to receive reports of cases such as these, because they often highlight an inadequacy in information available to medical practitioners.

Members agreed that the details of the individual case reports should not be included in the version of the minutes that goes on the web site, but the title and number of the report should be included along with the comment and recommendation.

5. MATTERS ARISING

5.1 Report on the recommendations

- K Ronaldson. Secretary's report
- Report to the Minister's delegate on the minutes and recommendations of the 102^nd meeting of MARC, 25 Aug 2000
- Recommendations of the 102^nd meeting of the MARC

5.1.1 Tramadol adverse effects (5.5.14, June 2000)

- S Schug, A Lim. Tramadol - not simply a new opioid analgesic. Draft Prescriber Update article. (tabled)

Members recommended the following changes be made to the article:

• The title be changed to simply "Tramadol"
• Mention be made of the funding status in New Zealand
• The sentence on the use of naloxone in overdose be clarified.

5.1.2 Medicines for use during lactation (6.9.7, June 2000)

- S Ito. Drug therapy for breast-feeding women. NEJM 343:118-126, 13 July 2000.
- SL Clark, et al. Coumarin derivatives and breast-feeding. Obstet & Gynecol 95:938-40, Part 1, Jun 2000. Reactions abstract

At the previous meeting members had recommended publishing an article on medicine use during lactation. Subsequently the review article by Ito had been published. It contained 2 lists of medicines, one included those medicines that should be used only after careful risk-benefit assessment and the other list was of medicines that could be safely used. The article indicated that most medicines are secreted in breast milk, and there is very little information available on possible adverse reactions in breast-feeding infants.

There was some discussion by the Committee about what advice could usefully be given about use of medicines during lactation. It was noted that Dr ... had done some work on secretion of medicines in human milk.

The Committee recommended that Dr ... be invited to write an article for publication in Prescriber Update on medicines that can be safely used during lactation. The article should indicate the strength of evidence on which the recommendations are made and it should outline basic principles.

5.1.3 Doxazosin - discontinuation of arm of the ALLHAT trial (12.1, June 2000)

- N Rafter. Doxazosin and ALLHAT. "Paragraph" for MARC, 31 Aug 2000

Members recommended that after the "paragraph" had been finalised in consultation with the Chairperson, it should be published on the Medsafe web site and in Prescriber Update.

5.1.4 Safety issues with clozapine (12.5, June 2000)

- K Ronaldson. Potentially fatal complications of clozapine therapy: myo-carditis, venous thromboembolism and constipation. Draft Prescriber Update article

Members were advised that the article had been peer reviewed by Professor ... and Dr ... Members recommended making a few specified changes before publishing the article.

Members were advised that clozapine was being considered by the IMMP Panel for monitoring on the IMMP along with risperidone and olanzapine.

5.1.5 Thrombotic thrombocytopenic purpura and antiplatelet agents (12.6, June 2000)

- M Tatley. Ticlopidine, clopidogrel and thrombocytopenic purpura. Draft Prescriber Update article

Dr Tatley's article had been peer reviewed by Dr ..., but comment was awaited from Dr ..., a cardiologist.

5.1.6 Oral contraceptives and RANZCOG (12.8.3, June 2000)

- T Maling. Letter to Dr JR Doig, Chairman, New Zealand Committee, RANZCOG, 10 July 2000

Members noted Associate Professor Maling's letter to Dr Doig. The letter corrected some misconceptions and explained that the Committee had not decided to exclude the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) from the project on risk factors for venous thromboembolism (VTE) in women taking oral contraceptives, and that the project had not yet proceeded.

Members commented that they considered that the Dear Doctor/Midwife/Pharmacist letter Medsafe had sent out plus the accompanying prescribing guidelines and the consumer leaflet were very good.

See 12.4 for more on oral contraceptives and VTE.

5.1.7 Necrotising fasciitis and NSAIAs (5.3, March 2000)

- L Voss. Necrotising fasciitis and non-steroidal anti-inflammatory drugs. Mark I
- L Voss. Necrotising fasciitis and non-steroidal anti-inflammatory drugs. Mark II
- Comments by and on L Voss's article

Members' preference was that the text of the first article and the conclusion of the second be published with one exception. They considered that the third sentence of the conclusion should be changed to the following:

The implications of these findings to the use of ibuprofen, and other NSAIDs, in situations where there is no varicella infection are not clear.

The Committee recommended that the article on necrotising fasciitis and NSAIAs be published amended as indicated.

In addition, the Committee recommended that "any serious soft-tissue infection following an NSAIA" be added to the list of adverse reactions of current concern.

5.1.8 Omeprazole-induced interstitial nephritis (6.2.1, March 2000)

- R Savage. Omeprazole-induced interstitial nephritis. Draft Prescriber Update article

Members noted the article on omeprazole-induced interstitial nephritis and that it was to be peer reviewed by Dr .... No changes were recommended.

5.1.9 Phentermine and amfepramone (12.6, March 2000)

Members were advised that the UK authorities had put phentermine and amfepramone back on the market, and stated that the Committee on Safety of Medicines believes that there are no public health safety issues with these products.

In response to notices under s.36 of the Medicines Act, Medsafe had received submissions from the sponsor companies providing information on the safety and efficacy of these products. Medsafe was obtaining an expert review of the material. The review may include advice on how these products can be appropriately used.

6. General Reporting

- Adverse reaction reports reviewed by MARC since Nov 97, by medicine class
- Adverse reaction reports reviewed by MARC since Nov 97, by recommendation
- Glossary of terms

This section covers significant adverse reactions recently reported to CARM. The boxed statement describes the action already taken in response to these reports.

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.

6.1 Deaths

Note: These deaths were discussed under the therapeutic group of the medicine involved. Each of the deaths has an associated report number which is also a hyperlink to the comment on that case. To access the comment click on the hyperlink.

Cisapride and aspiration, 44746
Abacavir/efavirenz and vomiting, abnormal hepatic function, prothrombin increased, gastrointestinal haemorrhage, anorexia, 44356
Nitrofurantoin and interstitial pneumonia, 44115
Pethidine and seizure, 44258
Warfarin and cerebral haemorrhage, 44175
Enoxaparin/acetylsalicylic acid and haemorrhage, circulatory failure, 45051
Amiodarone and epidermal necrolysis, Stevens Johnson syndrome, 44298
Amiodarone and toxic epidermal necrolysis, pneumonia, sepsis, 44506
Nifedipine and myocardial infarction, 44636
Cyproterone acetate and abnormal hepatic function, 44349
Clozapine and neutropenia, death by suicide, 44550
Clozapine and lymphopenia, 44888
Clozapine and death, 44890
Clozapine and carcinoma, 45012
Clozapine and myocardial infarction, hypotension, 45013
Clozapine and myocardial infarction, cardiac arrest, 45048
Clozapine and death, 45112
Iopramide and pruritus, bradycardia, respiratory arrest, hypertension, 44345
Ciclosporin and tuberculosis miliary, oesophagitis, immunosuppression, 44267
DTPH, Hepatitis B vaccine, OPV and haematoma, vomiting, diarrhoea, somnolence, crying abnormal, 44838

6.2 Alimentary

6.2.1 Cisapride and aspiration (death), 44746

Comment: Members wondered about the content of the eye drops given to the infant and whether they may have caused arrhythmias. However, the relationship between aspiration of milk and cisapride was considered to be unlikely. No additional action was recommended.

6.2.2 Omeprazole and confusion, dementia, 44265

Comment: While omeprazole was being monitored in the IMMP, 9 reports of confusion with omeprazole had been received. Of these cases, 3 were recorded as probable. All of these patients were older than 65 years. The present case is very clear-cut, both because of the younger age of the patient and because of the rapid return to normal after withdrawal of omeprazole. The causal association was designated probable. Confusion is listed as an adverse reaction in the data sheet for Losec (omeprazole) and it was mentioned in an article published in New Zealand Family Physician. No further action was recommended.

6.2.3 Sulphasalazine and aseptic meningitis, rash, malaise, 45011

Comment: The WHO database holds 9 reports of meningitis and 3 of meningism with sulphasalazine. Members commented that the woman's adverse event might have been viral despite the negative viral screen. Members asked that the causal association be changed from probable to possible. The Committee recommended no additional action.

6.3 Antiepileptics

6.3.1 Phenytoin/Coca Cola and therapeutic response decreased, food-drug interaction, 44257

Comment: Members commented that the effect may have been caused by the sweetener of diet Coke. Because of the number of possible contributing factors and incomplete documentation in this case, members asked that the causal association be changed from possible to unclassifiable. No additional action was recommended.

6.3.2 Carbamazepine and hypersensitivity reactions

6.3.2.1 Carbamazepine and macular erythematous rash, fever, 44925 6.3.2.2 Carbamazepine and hypersensitivity syndrome, 45070 6.3.2.3 Comment

Erythematous maculo-papular rashes and multi-system hypersensitivity reactions are known to occur with carbamazepine. The first of these cases was designated possible, and the second probable. A Prescriber Update article was published on hypersensitivity reactions in June 1998, and another on skin reactions with carbamazepine in June 1999. Skin reactions have been adverse reactions of current concern up until this meeting (see 9.2). No further action was recommended at this time.

6.4 Antiinfectives

6.4.1 Minocycline and benign intracranial hypertension, hemiplegia, 44351

Comment: There is one previous report of intracranial hypertension with minocycline among 172 reports associated with this medicine in the CARM database. Because of the positive rechallenge, the causal association for the patient's intracranial hypertension was rated certain. The Committee recommended publishing a Prescriber Update article on benign intracranial hypertension with the tetracycline antibiotics. It was suggested that Dr ... write the article.

6.4.2 Trimethoprim/methotrexate interaction and bone marrow depression, neutro-penia, 44084

Comment: Bone marrow suppression from an interaction between trimethoprim and methotrexate is a recognised but rare adverse reaction, with 3 case reports published in the literature. Methotrexate alone in high doses is known to cause this adverse reaction. One other haematological reaction in the CARM database with metho-trexate was in a patient also taking trimethoprim. In the present case the causality for the adverse reaction was considered to be possible. The Committee recommended writing to a haematologist to obtain comment on this adverse reaction and interaction.

6.4.3 Abacavir/efavirenz and vomiting, abnormal hepatic function, prothrombin increased, gastrointestinal haemorrhage, anorexia (death), 44356

Comment: The causal associations for gastrointestinal haemorrhage and increased prothrombin were designated unlikely. Because of the number of possible causative factors, members asked that the causal association for vomiting, abnormal hepatic function and anorexia be changed from probable to possible. No other action was recommended.

6.4.4 Interferon alpha-2B/ribavirin and mouth dry, polydipsia, anorexia, weight decrease, diabetes, 44140

Comment: It was noted that Intron A (interferon alpha-2B) is known to cause diabetes mellitus or hyperglycaemia rarely. The condition can be managed with antidiabetic therapy. The causal associations for each of the adverse events were designated probable for each of the medications the patient was taking. No additional action was recommended.

6.4.5 Nitrofurantoin and interstitial pneumonia (death), 44115

Comment: The CARM database holds 3 reports of interstitial pneumonia, 5 of pneumonitis, 6 of pulmonary fibrosis and 5 of pulmonary infiltration. Pulmonary damage with nitrofurantoin may occur if nitrofurantoin use is continued for > 6 months, and pulmonary function may be permanently impaired if the problem is not identified early and nitrofurantoin stopped. In the present case, the causal association was designated possible. The post-mortem report had been requested to ascertain whether it was possible to be more certain about causality. The Committee recommended publishing a Prescriber Update article on the risk of interstitial pneumonitis with long term nitrofurantoin and advising of the need to monitor the lung function of patients.

6.5 Analgesics

6.5.1 Pethidine and seizure (death), 44258

Comment: The CARM database holds only 1 report of convulsions within an hour of administration of pethidine. Members found the present report impossible to interpret and asked that the causality designation be changed to "unclassified" pending receipt of the post-mortem report. No additional action was recommended.

6.6 Antithrombotics

6.6.1 Warfarin and cerebral haemorrhage (death), 44175

Comment: Members noted the high INR and considered that the causality designation should be probable. No further action was recommended.

6.6.2 Enoxaparin/acetylsalicylic acid and haemorrhage, circulatory failure (death), 45051

Comment: The patient's haemorrhage and circulatory failure were both thought to be probably related to enoxaparin and aspirin. Since haemorrhage with low molecular weight heparins and aspirin are known adverse reactions, the Committee recommended no further action.

6.7 Cardiovascular

6.7.1 Amiodarone and severe skin reactions

6.7.1.1 Amiodarone and epidermal necrolysis, Stevens Johnson syndrome (death), 44298

6.7.1.2 Amiodarone and toxic epidermal necrolysis, pneumonia, sepsis (death), 44506

6.7.1.3 Comment

Toxic epidermal necrolysis and Stevens Johnson syndrome appear to be very rare in association with amiodarone, with 6 and 5 reports, respectively in the WHO database. The association with the skin reaction in each of these cases was thought to be possible. In the second case, members considered that the patient's concomitant sulindac may also have played a role in the development of the adverse effect. No further action was recommended.

6.7.2 Nifedipine and myocardial infarction (death), 44636

Comment: Because of the doubts concerning the medication used (nifedipine or placebo) in this report, the causality was designated unclassified. No additional action was recommended.

6.8 Hormones

6.8.1 Cyproterone acetate and abnormal hepatic function (death), 44349

Comment: Members observed that it was impossible to assess this adverse reaction in the absence of details of duration of therapy and information on other possible causative factors. However, it was noted that liver toxicity is a known adverse reaction of cyproterone acetate. CARM staff had requested further information. The Committee recommended no additional action.

6.8.2 Depo-Provera and abortion, 44405

Comment: The CARM database holds no previous reports of stillbirth with Depo-Provera, and this is not thought to be an adverse effect of Depo-Provera. The causal association was designated unclassifiable. No additional action was recommended by the Committee.

6.8.3 Combined oral contraceptives and venous thromboembolism

6.8.3.1 Diane-35 and pulmonary embolism, 44343

Comment: It was noted that the report might be a duplicate of one already reported to CARM. In the absence of details of duration of therapy, risk factors and patient age, the report was designated unclassifiable and no further action was recommended.

6.8.3.2 Femodene and pulmonary embolism, 44701

Comment: The Committee noted the apparent lack of risk factors in this case. The causal association was designated possible, consistent with other cases of venous thrombosis with oral contraceptives.

6.8.3.3 Marvelon and pulmonary embolism, deep vein thrombosis, 44709

Comment: The reporter had been advised by CARM staff that combined oral contraceptives should be contraindicated in this woman because of her heart failure. The causal association was designated possible.

6.8.3.4 Microgynon 30 and deep vein thrombosis, 44502

Comment: The association with the recent injury and immobilisation was noted. The causal association of this case with Microgynon 30 was designated possible.

6.8.3.5 Comment

It was noted that Medsafe had sent out a dear doctor letter on venous thromboembolism with combined oral contraceptives in June. The Committee recommended no further action at this time, except as outlined in 12.4.5.

6.8.4 Hormone replacement therapy and brand switches

6.8.4.1 Menoprem Continuous/Premia 5 Continuous and postmenopausal bleeding, 44525 6.8.4.2 Premia 5 Continuous and migraine, 44494

Comment: Members had no explanations for these adverse reactions. The causal association of the first was designated possible and for the second it was designated probable. No action further was recommended.

6.8.5 Oral contraceptives and St John's wort interaction

6.8.5.1 Microgynon 30/St John's Wort interaction and intermenstrual bleeding, 44346 6.8.5.2 Femulen/St John's wort interaction and intermenstrual bleeding, 44609 6.8.5.3 Comment

St John's wort is known to interact with combined oral contraceptives with a reduction in contraceptive efficacy. To date the only reported manifestation has been intermenstrual bleeding. It is thought to be associated with an interaction with the oestrogen. There is no known interaction with the progestogen, or with progestogen-only oral contraceptives, such as in the second case above. The causality of the first report was designated certain, because of the results of rechallenge, but the second report was designated unclassified, until such a time as information should be obtained on whether such an interaction is possible. Medsafe had published material on interactions between St John's wort and prescribed medicines, including combined oral contraceptives, early in 2000. No additional action was recommended.

6.9 Psychiatric

6.9.1 Clozapine and death

6.9.1.1 Clozapine and neutropenia, death by suicide (death), 44550

Comment: The causality assessment for suicide attempt was rated unlikely in this case.

6.9.1.2 Clozapine and lymphopenia (death), 44888

Comment: The causality for lymphopenia was designated possible, but the outcome was coded "death - cause unknown".

6.9.1.3 Clozapine and death (death), 44890

Comment: In the absence of any information on cause of death, the causal relationship of this case to use of clozapine was designated unclassified.

6.9.1.4 Clozapine and carcinoma (death), 45012

Comment: It was considered that this adverse reaction was unlikely to be related to clozapine.

6.9.1.5 Clozapine and myocardial infarction, hypotension (death), 45013

Comment: Members considered these events to be unrelated to the use of clozapine.

6.9.1.6 Clozapine and myocardial infarction, cardiac arrest (death), 45048

Comment: The reporter considered there to be no causal relationship between clozapine and the adverse reaction. Because of the lack of information about the case it was rated unclassified.

6.9.1.7 Clozapine and death (death), 45112

Comment: The causal relationship of this case was rated unclassified, because of the lack of data on cause of death.

6.9.1.8 Comment

For each of the above cases of death in patients taking clozapine further information had been requested. Each of these reports had been sent in by the sponsor company. A Prescriber Update article on myocarditis, venous thromboembolism and constipation with clozapine was in draft form (see 5.1.4). The Committee recommended no additional action.

6.9.2 Trimeprazine and dental caries, 44327

Comment: This child's dental caries were considered to be probably causally associated with the nightly use of Vallergan syrup. Although the use of the word "syrup" is indicative of the presence of significant amounts of sugar, the reporter had complained about the lack of warning about the sugar content of the syrup on the product label. Members discussed the labelling issue and decided there was little that could sensibly be done that would ensure the bottle dispensed carried additional information about the high concentration of sugar in the product. No action was recommended.

6.10 Diagnostics

6.10.1 Iopramide and pruritus, bradycardia, respiratory arrest, hypotension (death), 44345

Comment: Because of the time course of the events, this adverse reaction was considered to be probably causally related. The post-mortem report had been requested but no further action was recommended.

6.10.2 Meglumine ioxaglate and toxic nephropathy, 44664

Comment: It was noted that toxic nephropathy may occur with contrast media, and that ACE inhibitors which impair renal response may increase the risk. There are no previous reports of nephropathy in the CARM database. This patient had previously experienced a mild adverse reaction to another contrast medium (iodixanol). The association of the patient's toxic nephropathy with the use of meglumine was considered to be possible. The Committee recommended no additional action.

6.11 Immunosuppressive agents

6.11.1 Thalidomide and hepatocellular damage, 44114

Comment: There are only 2 reports of liver function abnormalities with thalidomide in the WHO database. In one of these the patient recovered without discontinuation of the medication. The details were incomplete for the other case. The causal association in this case was rated possible. The Committee recommended no other action.

6.11.2 Ciclosporin and miliary tuberculosis, oesophagitis, immunosuppression (death), 44267

Comment: The association was thought to be probable for each of the infections and for increased susceptibility. The WHO database holds no reports specifically of immune system disorder with ciclosporin, but there are 7 reports of Pneumocystis carnii infection. No further action was recommended.

6.12 Musculoskeletal

6.12.1 Quinine/celecoxib and thrombocytopenia, epistaxis, 44503

Comment: The patient's thrombocytopenia was thought to be possibly related to the use of quinine and celecoxib. CARM holds 31 reports of thrombocytopenia with quinine, and on the WHO database there are 5 reports of thrombocytopenia with celecoxib. It was not known whether the effects of the 2 agents may have been additive or synergistic. This adverse reaction is well known for quinine. It was noted that a Prescriber Update article on the adverse reactions of celecoxib is in preparation. No further action was recommended.

6.13 Urologicals

6.13.1 Sildenafil/diltiazem interaction and pulmonary oedema, hypotension, 44358

Comment: The WHO database holds one report of pulmonary oedema and 14 of hypotension with sildenafil. Members were uncertain of the causality of the patient's reaction, and agreed that, with the present information available about sildenafil, it was appropriate to designate each of the reaction terms, pulmonary oedema, hypotension and drug interaction, as possible. Members asked that the designations be changed from probable. No further action was recommended.

6.14 Alternative medicines

6.14.1 Bee pollen and anaphylactic shock, 44724

Comment: The CARM database holds 5 previous reports of serious allergic reactions with bee products. Members observed that the report was short on details, but considered that the causality designation should be probable. No additional action was recommended.

6.14.2 Kava kava/triazolam and pruritus, urticaria, maculopapular rash, tachypnoea, 44316

Comment: Members commented that kava kava is known to cause skin rash. It was considered that the adverse event was unrelated to the triazolam, but was probably associated with kava kava. No action was recommended on this adverse reaction to a food.

6.15 Quarterly reports

Members discussed how the quarterly reports prepared by CARM could have enhanced value. Members requested that an executive summary, highlighting important features, be prepared for each report.

Dr Tatley reported that although ACC had undertaken to supply to CARM copies of accepted cases of medical misadventure, no reports had yet been received. The Committee recommended that enquiries be made of ACC to check the situation.

7. Vaccines

- Vaccine adverse reaction reports reviewed by MARC since Nov 97

7.1 New Zealand adverse reaction reports

7.1.1 BCG and jaundice, respiratory failure, pneumonitis, hepatitis, 44474

Comment: The WHO database holds 5 reports of pneumonia and 2 of pulmonary infiltration with BCG vaccine. Members considered that the association should be designated probable for each of the adverse events in this case in which BCG vaccine was administered for bladder cancer. The Committee recommended no further action.

7.1.2 DTPH, Hepatitis B vaccine, OPV and haematoma, vomiting, diarrhoea, somnolence, abnormal crying (death), 44838

Comment: Members considered that the vomiting, diarrhoea and somnolence were possibly associated with the vaccination received, but considered that there was not enough information about the cause of death for the designation for that event to be other than unclassified. It was noted that CARM staff had requested further information including a copy of the postmortem report.

7.1.3 Vaccine consent for being circulated by Immunisation Awareness

One of the Committee members had had a copy of a consent form being distributed by Immunisation Awareness given to her by a patient. The consent form was about liability should an adverse event occur following vaccination, and sought the vaccinator's signature. Members considered it to be misleading. Nevertheless to recommend action related to the consent form was outside of the Committee's area of responsibility. The Secretary advised that the form had been passed to the public health section of the Ministry of Health.

7.2 Articles from the literature

- M Hotopf, et al. Role of vaccinations as risk factors for ill health in veterans of the Gulf War: cross sectional study. BMJ 320:1363-1367, 20 May 2000.

The study by Hotopf et al found that Gulf War veterans who had received multiple vaccinations during deployment were more likely to suffer long-term ill health. Multiple vaccination by itself did not result in adverse outcomes.

8. IMMP

8.1 Sumatriptan

8.1.1 Vascular effects possibly related to sumatriptan

- DM Coulter. Cerebrovascular events associated with Sumatriptan. Comment for MARC, 2 June 2000
- Reports of cerebral events with sumatriptan
- Table showing age/sex frequency of patients at first prescription
- WHO listing
- Extracts from Imigran data sheet
- W Luman, RS Gray. Adverse reactions associated with sumatriptan. Lancet 341:1091-2, 1993

While sumatriptan was monitored in the IMMP and subsequently, 15 reports of cerebrovascular reactions possibly associated with sumatriptan have been received. The timeframe was specified in 7 of the cases, and the event occurred within hours of administration of sumatriptan in 6 of the cases. In 2 of the cases the patient was older than the recommended age for use (65 years). One patient had a cerebrovascular accident, following sumatriptan, but continued use without further incident. Two others had a history of transient ischaemic attack and developed hemiplegia or hemiparesis following use of sumatriptan. A previous cerebrovascular accident or transient ischaemic attack is a contraindication for sumatriptan. In one case the event occurred a week after the last dose in a series of 5 doses taken for a migraine attack. In another case the patient's migraines involved becoming dysarthric prior to development of severe headache. The patient had been treated with oral sumatriptan 4 times in the past 2 weeks. On the occasion of interest sumatriptan was taken before retiring for the night, at which time he was dysarthric. In the morning he had complete aphasia and no movement in the right side of his body.

Luman and Gray reported 2 cases of hemiparesis with sumatriptan. One case occurred 12 hours after a single dose in a 25-year-old woman. The other case was in a 46-year-old man and occurred a week after he had received the last of 5 subcutaneous 6mg doses over a period of a week. This patient also had no risk factors. The authors proposed the possibility of sumatriptan binding to cerebral vascular receptors after frequently repeated doses.

Members agreed that these cases were not sufficient to establish a causal association between sumatriptan and cerebrovacular events. Nevertheless, members recommended that a short article be published in Prescriber Update alerting medical practitioners to the possibility of this reaction occurring, emphasising the need to adhere to contraindications, advising that sumatriptan is not recommended for those aged > 65 years, warning that sumatriptan should be prescribed only on a clear diagnosis of migraine, and drawing attention to the recommendation in the data sheet of not exceeding 2 doses within 24 hours.

8.1.2 Sumatriptan and radial artery occlusion, 42863

Comment: The causal association for this case was considered to be possible. No further action was recommended.

8.1.3 Sumatriptan and atrial fibrillation

- DR Morgan, et al. Atrial fibrillation associated with sumatriptan. BMJ 321:275, 29 Jul 2000

Morgan et al reported a case of a 34-year-old man going into atrial fibrillation (130 beats/min) after taking sumatriptan. The man recalled having a fast irregular pulse after previous use of sumatriptan. Sinus rhythm was restored spontaneously 12 hours after admission. This published case was noted, but no action was recommended.

8.2 Nefazodone

8.2.1 Nefazodone and hepatic reactions

8.2.1.1 Nefazodone and hepatocellular liver injury/damage, 44859, 43234, 44317 8.2.1.2 Comment

- WHO printout of hepatic reactions with nefazodone
- Extracts from the New Zealand data sheet for Serzone

A rate of hepatic reactions of 3.6/1000 for nefazodone has been found to date with the IMMP monitoring. 235 reports of hepatic reactions with nefazodone are held by the WHO database, including 9 reports of hepatic failure and 4 of hepatic necrosis. Hepatic dysfunction with nefazodone has been discussed by the Committee previously (see 11.5, September 1999).

The data sheet for Serzone (nefazodone) states that a causal association between nefazodone and increased liver enzymes and hepatitis has not been established. This statement was regarded by the Committee to be inconsistent with the evidence. The Committee recommended asking the sponsor company to update the data sheet by dropping the comment that the causal association had not been established.

8.2.2 Nefazodone and withdrawal reactions

8.2.2.1 Nefazodone and withdrawal symptoms, 45156, 44310 8.2.2.2 Published case reports

- M Rajagopalan, J Little. Discontinuation symptoms with nefazodone. Aust NZ J Psychiatry 33:594-7, 1999
- M Kotlyar, et al. Possible nefazodone withdrawal syndrome. Am J Psychiatry 156:117, Jul 1999
- F Benazzi. Nefazodone withdrawal symptoms. Can J Psychiatry 43:194-5, 1998

Rajagopalan and Little reported a case of withdrawal symptoms involving nausea, vomiting, diarrhoea, ataxia, insomnia, agitation, headache and 'flu-like symptoms developing 2 days after discontinuing nefazodone. The patient recovered completely after 10 days.

A healthy volunteer who had received 9 days of nefazodone experienced electrical sensations down his legs 36 hours after discontinuing nefazodone, according to Kotlyar et al. These symptoms resolved after 12 hours but dizziness with occasional nausea persisted up to 72 days after withdrawal.

Benazzi reported a case of 27-year-old man who was taking clomipramine and alprazolam and abruptly stopped nefazodone. The following day he experienced dizziness, nausea, vomiting, sweating, anxiety, insomnia and restlessness. The symptoms resolved within 3 days.

8.2.2.3 Comment

- Extract from the New Zealand data sheet for Serzone

The data sheet for Serzone states that nefazodone has not been systematically studied for withdrawal emergent symptoms. No further information was supplied. Members recommended writing to the company to ask whether it holds information on withdrawal and whether it may be appropriate to indicate in the data sheet that discontinuation symptoms have been reported rarely.

8.2.3 Nefazodone and urinary retention, hypotension, 43938

Comment: Dr Coulter commented that various anticholinergic type adverse reactions such as dry mouth, constipation and blurred vision had been reported with nefazodone (and are noted in the data sheet for Serzone), although it is said to have no affinity for cholinergic receptors. The WHO holds 15 reports of urinary retention with nefazodone. The Committee considered that there were insufficient data on anticholinergic effects with nefazodone to recommend any action at present, but asked that any further information be brought to its attention.

8.3 Patient and prescription numbers

- Patient and prescription numbers

At the end of June the IMMP had recorded 830 patients on montelukast, 3069 on nefazodone, 1878 on olanzapine, 74 on quetiapine and 345 on tolcapone. For salmeterol and eformoterol the number of scripts has more than doubled from 31 March 1999 to 30 June 2000: from 21,949 to 46,176 for salmeterol and from 4618 to 9428 for eformoterol.

9. Other NZ activities

9.1 Minutes of PTAC (PHARMAC)

- Minutes of Pharmacology and Therapeutics Advisory Committee meeting, 25 May 2000

9.2 Adverse reactions of current concern

- K Ronaldson. Evaluation of adverse reactions of current concern, May 2000

The following is the current list of adverse reactions of current concern:

Medicine	Adverse reactions	Prescriber Update reference
Alendronate	oesophagitis	No. 16, Apr 1998
Carbamazepine	skin and haematological reactions	No. 17, Dec 1998
Cisapride	cardiac arrhythmias	No. 18, Jun 1999 & No.14, Feb 1997
Clozapine	hyperglycaemia	No.18, Jun 1999
Colchicine	serious toxicity	No. 16, Apr 1998
Herbal medicines	all adverse reactions	No. 13, Oct 1996
Hormone replacement therapy	venous thromboembolism	No. 16, Apr 1998
Nefazodone	hepatic reactions	This issue
NSAIAs	renal damage	No. 13, Oct 1996 & No. 16, Apr 1998
Mefloquine	neuropsychiatric reactions	No. 15, Aug 1997
Oral contraceptives	venous thromboembolism	No. 11, Feb 1996
Ticlopidine	neutropenia and thrombocytopenia	No. 17, Dec 1998 & No. 14, Feb 1997

The Committee recommended deleting the following adverse reactions from the list:

• Alendronate and oesophagitis
• Carbamazepine and skin and haematological reactions
• Colchicine and serious toxicity
• NSAIAs and renal damage
• Mefloquine and neuropsychiatric reactions

The possibility of removing cardiac arrhythmias with cisapride from the list was discussed. Because of the current concern about QT-prolongation with cisapride it was considered preferable to leave it on the list at present (see 12.1). See also 5.1.7 and 12.2 for additions to the list.

9.3 Adverse reactions to be reported

- DM Coulter. Adverse reaction reporting. What to report? 31 May 2000
- Statements regarding adverse reactions to be reported in Australia, Canada and the United Kingdom

Dr Coulter had prepared for the Committee a new statement concerning what adverse reactions should be reported. The statement encouraged the reporting of adverse reactions of clinical concern.

The Committee requested the following changes to the statement:

• Drop the word "prescribing" from "highlight a widespread prescribing problem" and
• Indicate the reason for the request to report serious allergic reactions - to allow entry against the patient's name in the national health database.

9.4 Harmonisation with Australia

- Consultation paper for the Joint Agency Project, 22 June 2000

10. Other countries

10.1 Australia

- Aust Adv Drug Reactions Bulletin 19(3), Aug 2000

10.2 Canada

- Canadian Adv Drug React Newsletter 10(3), July 2000

11. Publications

- D Coulter, A Bate, R Meyboom, M Lindquist, IR Edwards. Antipsychotics and heart muscle disorder in international pharmacovigilance. Draft article.

12 Current topics

12.1 Cisapride and cardiac arrythmias

- N Rafter. Cisapride report (Section 36). Report for MARC 21 Aug 2000
- New Zealand data sheet for Prepulsid (cisapride)
- Interactions section of Australian product information for Prepulsid
- E Wager, PJH Tooley, et al. A comparison of two cohort studies evaluating the safety of cisapride: prescription event monitoring and a large phase IV study. Eur J Clin Pharmacol 52:87-94, 1997
- A Walker, et al. The risk of serious cardiac arrhythmias among cisapride users in the United Kingdom and Canada. Am J Med 107:356-62, 1999
- Table: Number of reports of QT-prolongation, serious VA and sudden death by year.
- Cisapride: Periodic Safety Update Report, 1 April 1998 to 31 March 1999. Extract from report, 6.4.4 to the end, p.21-66.
- Nine case reports of QT-prolongation without reported cofactors
- Prepulsid. Therapeutic Goods Administration, Australia. Media release, 18 Aug 2000
- Review of cisapride, item 10. Minute of ADRAC, June 2000
- Changed recommendations for use of cisapride, ADRAC, July 2000
- .... Cisapride. Comment for the NZ Society of Gastroenterology Incorporated. 26 Aug 2000

12.1.1 Background

Because of the risk of QT-prolongation and death as a result, cisapride has been withdrawn from the market or restrictive action has been taken in several countries. In the United Kingdom and Germany it has been withdrawn from the market pending a review by the CPMP. In the US and Canada it is available only under special access schemes. In Australia, the indications have been restricted and its use is subsidised only if it is prescribed for one of the specified indications (gastroparesis, reflux oesophagitis).

In New Zealand, Janssen-Cilag was sent a notice (dated 14 April) by the Delegate of the Director-General of Health under s.36(1) of the Medicines Act 1981 asking it to supply evidence of the safety of cisapride (Prepulsid). The Company had responded with documentation and the matter had been referred to this Committee for its assessment of the data provided.

12.1.2 Data supplied by Janssen-Cilag

Janssen-Cilag had conducted a review of cases of QT-prolongation with cisapride (471 cases), and concluded that QT-prolongation with cisapride is a very rare event in the absence of recognised cofactors (other agents known to prolong the QT-interval, agents inhibiting metabolism of cisapride, hypokalaemia and hypomagnesaemia, pre-existing QT-prolongation, excessive dose of cisapride).

Walker et al conducted a study of QT-prolongation with cisapride using the Saskatchewan database and the General Practice Research Database (GPRD) in the UK. They identified 52 cases of arrhythmias. 18 of these were associated with recent use of cisapride. The relative risk of serious arrhythmias associated with the use of cisapride was 1.6 (95% CI 0.9-2.9). When adjustment was made for cofactors the relative risk fell to 1.0 (0.3-3.7).

The Drug Safety Research Unit (DSRU) in Southampton had conducted a study of cisapride by prescription event monitoring. The study included 13,000 patients aged 3 months to 99 years. The study found 5 reports of arrhythmias, giving a rate of 0.4 reports per 1000 patients. This figure is slightly lower than the average for the 33 medicines monitored by the DSRU. 96 of the patients taking cisapride were on concomitant interacting medication without any recorded adverse effects.

12.1.3 Discussion

Most of the cases of QT-prolongation with cisapride have been reported in the US (291 US cases vs 180 non-US cases). In New Zealand only 1 (non-fatal) case of serious arrhythmia has been reported. This was a case of supraventricular tachycardia in a patient who was also taking grapefruit juice and quinine, both of which would have increased the risk.

The recommended maximum dose of cisapride in New Zealand is 40mg, while the recommended maximum in the US is 80mg. In addition, there is no paediatric indication and hence no approved paediatric dosage instructions in the US (and no product for paediatric use with dropper for administration), and the adult indication in the US is very broad compared with very specific indications in New Zealand. These factors may have led to wider use and unnecessarily high dosage in the US, increasing the rate of QT-prolongation.

Medsafe had sought comment from the Gastroenterology Society on the value of cisapride as a therapeutic agent. The Society had put a request for reports of any adverse reactions on its web site for members' response. None had reported adverse reactions but several had reported that they had had no problems using cisapride.

In addition, the Society commented that the low maximum recommended dose and the funding only on specialist endorsement might have resulted in safer use in New Zealand. Cisapride is used as a second- or third-line agent for gastroparesis, non-ulcer dyspepsia and gastrointestinal reflux. These conditions are not usually life threatening, but lack of symptom control affects quality of life. The only alternative in these patients is surgery which is associated with its own mortality and morbidity. The Society advised that it would be preferable for cisapride to be available "in some way for some of our patients."

The Committee noted that in Australia the indications had been restricted, and a dear doctor letter advising of the change had been sent out.

The Committee recommended adopting the indications now used in Australia and requiring diagnosis by a specialist, but dropping the word "proven" from the indication for children (because of the difficulty of diagnosis in children):

Adults
For the treatment of:

• severe reflux oesophagitis where other treatment, including acid suppression with proton pump inhibitors, has failed; and
• gastroparesis;

where the diagnosis has been made or confirmed by a specialist physician.

Children
Use should be restricted to children with severe gastro-oesophageal reflux, where the diagnosis has been made or confirmed by a specialist physician.

In addition, the Committee recommended dropping mention of "refractory constipation" and the paragraph on the treatment of constipation in children from the dosage instructions. Refractory constipation is not an indication.

The Committee recommended that Medsafe send out a dear doctor letter outlining this change in indication and advising about the risk of QT-prolongation and the predisposing factors for this event.

The Committee also recommended asking the sponsor to include a patient education card in each carton of Prepulsid (cisapride) suspension and tablets. The card would warn patients about the predisposing factors which increase the risk of QT-prolongation with cisapride.

12.2 Diane-35 and venous thromboembolism

- RDT Farmer, et al. Oral contraceptives and venous thromboembolic disease. Analyses of the UK GPRD and the UK MediPlus Database. Human Reproduction 5:688-706, Nov/Dec 1999
- L Parkin, DCG Skegg, et al. Oral contraceptives and fatal pulmonary embolism. Lancet 355:2133-4, 17 June 2000
- World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Effect of different progestagens in low oestrogen oral contraceptives on venous thromboembolic disease. Lancet 346:1582-8, 16 Dec 1995
- Printout of thrombotic events associated with Diane (includes Diane, and Diane-35) and recorded on the WHO database
- Schering AG. 6.1.1.1 Serious ADRs associated with the use of Diane-35. Periodic Safety Update Report for Diane-35, Oct 1998 to Oct 1999
- Schering AG. Diane-35 and venous thromboembolism. 22 Aug 2000
- K Ronaldson. Diane-35 and venous thromboembolism. Report for MARC, 29 Aug 2000
- CARM case reports of pulmonary embolism with Diane-35 considered at the MARC meetings from June 1999 to March 2000

12.2.1 Background

On the basis of the 8 reports of pulmonary embolism (PE) and 3 of VTE with Diane-35 (none fatal), and the high odds ratio for death from PE in women taking Diane-35 in Professor Skegg's study using New Zealand data, members had asked that data on the rate of VTE with Diane-35 be brought to the present meeting.

12.2.2 Published data

Only 3 published epidemiological studies provide data on the incidence or relative risk of VTE with Diane-35. In each of these studies the numbers of cases and controls taking Diane-35 were small. The studies are as follows:

• The New Zealand study by Parkin and Skegg et al included only 2 women aged 15-49 years who had died of PE while taking Diane-35. The adjusted odds ratio for death from PE in current users of Diane-35, compared with non-users of an oral contraceptive (OC) was 17.7 (95% CI 2.7-113). The calculated relative risk was slightly above that for third generation OCs.
• The WHO study included 9 cases and 3 controls who were current users of Diane-35. The adjusted odds ratio for VTE compared with non-users of an OC was 14.9 (3.7-59.4). In the same study, Diane (with a oestrogen content of 50(g) was associated with a lower odds ratio of 1.3 (0.5-3.8).
• A recent study by Farmer et al included cases with idiopathic VTE and controls from the GPRD and MediPlus in the UK. The GPRD included 16 cases (27 controls) and MediPlus 4 cases (11 controls). The adjusted odds ratio for Diane-35 from the GPRD data, relative to a combined OC containing levonorgestrel and 30µg ethinyloestradiol, was 2.3 (1.1-4.8), which was statistically significant. Other odds ratios for OCs were not significantly different from unity.

It was observed that because of the low case and control numbers, none of these studies can be said to provide a reliable estimate of the incidence or relative risk of VTE with Diane-35.

12.2.3 Considerations

There are some usage factors which may be increasing the observed incidence of VTE with Diane-35:

• Because of its indications, Diane-35 tends to be used for shorter periods than OCs. The risk of VTE with OCs is known to be higher during the first 12-months of treatment.
• The indications of Diane-35 are different from those for OCs, which means that the characteristics of users will differ. In NZ, Diane-35 is approved for polycystic ovary syndrome (PCOS) (since 1992). In 1 study,¹ 41% of cases of 1079 biopsy-proven cases of PCOS were obese. Obesity is a risk factor for VTE.

12.2.4 Case reports

The WHO database holds 156 reports of thrombotic events with Diane (Diane-35 and Diane). Of these reports 98 were of PE and 14 of thrombosis. Details were not obtained on the number of cases that were fatal.

CARM holds 8 reports of PE and 3 of deep vein thrombosis with Diane-35. None of these cases was fatal. Of the 4 most recently reported cases of PE, the only identified risk factor was temporary immobility in the week prior to the event.

In the Periodic Safety Update for Diane-35 for Oct 98 to Oct 99, 12 cases of PE (3 fatal) and 4 of DVT were included. The duration of use was unknown in 6 cases. It was 2-3 months in 3 cases, 5-8 months in 2, and > 1 year in 5 cases. Risk factors were said to be present in all except 1 of the cases of PE, but they were stated in only 2 (personal history and immobilisation with a plaster cast on the leg).

12.2.5 Conclusion

Members agreed that there were insufficient data to reach a conclusion on the relative risk of VTE with Diane-35.

The Committee recommended:

• Including VTE with Diane-35 among the adverse reactions of current concern
• Seeking an opinion on the risk of VTE with Diane-35 from the Medicines Control Agency

In addition, the Committee asked that any new information on this topic be put on the agenda of subsequent meetings.

12.3 Paracetamol use and asthma

- I Town, Medical Director, Asthma and Respiratory Foundation. Correspondence, 27 June and 14 July 2000
- S O Shaheen, et al. Frequent paracetamol use and asthma in adults. Thorax 55:266-270. 2000.
- SL Nuttall, et al. Frequent paracetamol use linked to asthma. Lancet 355:1648-9, 6 May 2000

Shaheen et al compared the use of paracetamol in 664 individuals with asthma and 910 without and found a positive association with asthma. The adjusted odds ratio for infrequent users was 1.06 (0.77-1.45), for monthly users 1.22 (0.87-1.72), for weekly users 1.79 (1.21-2.65) and for daily users 2.38 (1.22-4.64) (p (trend) = 0.0002). This association was present in users and non-users of aspirin, and frequent aspirin use was not associated with greater severity of asthma. The authors concluded that because of the risks associated with NSAIAs, particularly hypersensitivity reactions in asthmatics, gastrointestinal effects in adults and Reye's syndrome in children, paracetamol should remain the analgesic of choice in asthmatics.

The Committee found the results of the study to be puzzling. The authors had proposed a mechanism: paracetamol reduces the availability of the antioxidant glutathione in the lungs.

Dr Ian Town, Medical Director, Asthma and Respiratory Foundation NZ (Inc) had written to Dr Moodie, Medical Director, PHARMAC indicating that he considers there may be substance to the study results and suggesting that there be a review of data sheets for products containing asthma and television advertisements promoting the use of paracetamol in asthma. The letter had been passed on to Medsafe.

The Committee asked that the Chairperson seek the opinion of Dr ..., Thoracic Society, before determining a suitable response to Dr Town.

12.4 Safety of oral contraceptives

- Oral contraceptives and cardiovascular risk. Drug and Therapeutics Bulletin 38(1):1-5, Jan 2000
- DCG Skegg. Third generation oral contraceptives. BMJ 321:190-1, 22 Jul 2000
- K Ronaldson. Safety of oral contraceptives. Report for MARC, 31 Aug 2000

See also 5.1.6 and 6.8.3 for more on this issue.

12.4.1 Combined oral contraceptives and VTE

- RDT Farmer, et al. Effect of 1995 pill scare on rates of venous thromboembolism among women taking combined oral contraceptives: analysis of General Practice Research Database. BMJ 321:477-9, 19-26 Aug 2000

Farmer et al conducted a study using the GPRD in the UK to evaluate the incidence of VTE before and after the announcement in the UK in October 1995 that there is approximately double the risk of VTE with third versus second generation OCs. The announcement had the effect of reducing the use of third generation pills from 53.4% to 14.0% of use. If the risk is approximately double with the third generation pills, the rate of occurrence VTE should have significantly dropped after the announcement.

The study population was women aged 15-49 years who had taken a combined OC during the period Jan 1993 to Dec 1998. The database was searched for cases of PE and deep vein thrombosis. They were included if there was evidence of prescription with an oral anticoagulant or death from the event. Cases were regarded as exposed if they had a current prescription of a combined OC when the event occurred. Women were excluded if other causes, e.g. fracture, surgery, etc. were present.

The rate of VTE before the announcement (Jan 1993-Oct 1995) was 34.5/100,000 exposed woman-years and after the announcement it was 37.5/100,000 exposed woman-years (Nov 1995-Dec 1998). Hence, there was no reduction in rate of diagnosed VTE with reduction in use of the third generation OCs.

The authors concluded that their results are not consistent with a higher rate of VTE with the third generation OCs. They suggested that if there had been a higher case ascertainment rate after the alert, there would be expected to be an immediate rise in the number of cases. No such effect was observed.

Members commented that, despite the opinion of the authors a change in the rate of case ascertainment may have been a factor in this result. It was agreed that the weight of evidence continues to be in favour of a higher rate of VTE with the third generation OCs compared with second generation products.

12.4.2 Factor V Leiden and VTE

- H Bounameaux. Factor V Leiden paradox: risk of deep-vein thrombosis but not of pulmonary embolism. Lancet 356:182-183, 15 July 2000

Bounameaux conducted a review of the rates of factor V Leiden (or APC resistance) in patients with DVT, PE and DVT with PE, and found that the percentage is low for isolated PE and lower for DVT with PE than for DVT alone. It seems that patients with factor V Leiden or APC resistance are less likely than other members of the population to develop PE, if they develop DVT. Members were uncertain of the significance of this analysis.

12.4.3 Combined oral contraceptives and ischaemic stroke

- L A Gillum. Ischemic stroke risk with oral contraceptives. JAMA 284:72-78, 5 July 2000.

Gillum et al conducted a meta-analysis of case-control and cohort studies which evaluated the relative risk of ischaemic stroke with oral contraceptives. The study included only those studies with > 10 cases, which differentiated between ischaemic and haemorrhagic stroke and controlled for age. 16 studies met the inclusion criteria. The overall relative risk of ischaemic stroke was 2.75 (95% CI 2.24-3.38) in users compared with those not currently using OCs.

The study also found the following:

• The relative risk estimates decreased with the progression of time (year of onset of the study). The relative risk also decreased (non-significantly) with decreasing dose of oestrogen. It was considered that the association with oestrogen dose may account for the association with time.
• No differences were seen between products containing different generations of progestagen at equivalent oestrogen doses.
• Smoking, hypertension, migraine history and age were found to increase the risk of ischaemic stroke, but were found to be independent risk factors.
• The authors estimated that, in the US, treatment of 24,000 women with low-oestrogen dose OCs adds one case of ischaemic stroke each year. If the women are smokers one additional case per year occurs for every 15,000 users.

This meta-analysis of ischaemic stroke found a relative risk estimate that was similar to that in the WHO Collaborative study² which was stated in advice to general practitioners in a Prescriber Update article (Aug 1997). Members considered that no update of the advice was necessary.

12.4.4 Combined oral contraceptives and melanoma

- D Feskanich, et al. Oral contraceptive use and risk of melanoma in premenopausal women. Brit J Cancer 81(5):819-23, 1999

Feskanich et al found 252 cases of melanoma among 183,693 women in the Nurses Health Study. Current use of oral contraceptives was associated with a relative risk of skin cancer of 2.0 (1.2-3.4) compared with never use. The relative risk was increased in current users who had used OCs for ( 10 years (3.4; 1.7-7.0). No elevation of risk was observed among past users, even with a long duration of use. Relative risk estimates were calculated after controlling for various factors which increase the risk of melanoma. The authors commented that further work was required to ascertain whether low-dose oestrogen pills are associated with an elevated risk of melanoma.

Members noted that this is the first study to find such a clear association. No action was recommended at present.

12.4.5 Risk factors project

Members noted that no action had taken place to initiate the project, following on from Professor report, to advise more fully about risk factors for VTE with oral contraceptives. Members considered that the project should proceed and all interested parties should be consulted. These parties included RANZCOG, NZMA, Royal New Zealand College of General Practitioners, Family Planning Association, Women's Health Action, and any other groups that had been consulted previously about VTE with oral contraceptives.

Members recommended that Professor ... report be sent to each of these groups with a covering letter saying:

• This report is to inform you of the current knowledge of risk factors for VTE with combined oral contraceptives;
• Do you consider that your members are adequately informed about risk factors as they have been outlined in this document?
• If you think this information should be disseminated, how do you consider that this should be done? Would your organisation like to be involved in the process of determining how and what to disseminate?
• Please advise if you have additional or contrary data on risk factors.

12.4.6 Usage data for oral contraceptives

- Graph of New Zealand contraceptive usage Jan 1995 to Mar 2000

The graph of contraceptive usage showed that the use of second generation OCs had overtaken the use of third generation OCs during the first quarter of 1999 and that the use of third generation pills had continued to fall gradually from that time so that the ratio of use was now 2:1 with 30,000 prescriptions per month for the second generation pills. Use of progestogen-only pills and spermicides and condoms had increased slightly over this period.

12.5 Safety of calcium antagonists

- C J Maxwell, et al. Nifedipine and mortality risk in the elderly: relevance of drug formulation, dose and duration. Pharmacoepidemiology and Drug Safety 9:11-23, 2000.
- M J Brown, et al. Morbidity and mortality in patients randomised to double-blind treatment with a long-acting calcium-channel blocker or diuretic in the International Nifedipine GITS study: intervention as a goal in hypertension treatment (INSIGHT). Lancet 356:366-372, 29 July 2000.
- L Hansson, et al. Randomised trial of effects of calcium antagonists compared with diuretics and (-blockers on cardiovascular morbidity and mortality in hypertension: the Nordic Diltiazem (NORDIL) study. Lancet 356:359-365, 29 July 2000.

Maxwell et al conducted a population-based prospective study of 837 persons aged > 65 years. They found that the use of nifedipine was associated with an increased risk of all-cause (relative risk 1.85; 1.12-3.05) and cardiac mortality (2.22; 1.02-4.84). Risk increased with average daily dose and with recent initiation of therapy. It was also significantly elevated for long-acting preparations.

Members commented that this study had several methodological difficulties: subjects were all > 65 years; and medicine use was based on recall and no validation was conducted. Smoking was found to have no effect on the risk estimates for any of the categories of medicine examined. The study did not attempt to check for a correlation between blood pressure lowering effectiveness and reduction in mortality.

Brown et al compared nifedipine and amiloride plus hydrochlorothiazide in a randomised double blind trial involving a total of 6321 patients. Primary outcomes occurred in 6.3% of nifedipine recipients and 5.8% of those on amiloride plus hydrochlorothiazide (relative risk 1.10; 0.91-1.34). Members commented that the study was not in keeping with current treatment practices for hypertension.

Hansson et al randomly assigned 10,881 patients with diastolic blood pressure > 100mm Hg to one of two treatment groups, diltiazem or diuretic and/or β-blocker. Effective lowering of blood pressure was achieved in both groups. Primary endpoints occurred in 16.6 vs 16.2 per 1000 person years (relative risk 1.00; 0.87-1.15). Fatal and non-fatal stroke occurred significantly less frequently with diltiazem and fatal and non-fatal myocardial infarction significantly more frequently.

Members commented that the contention that there is a higher risk of fatal and non-fatal cardiovascular endpoints with calcium channel blockers compared with other antihypertensive medication has essentially been resolved in favour of calcium channel blockers. Calcium channel blockers are as effective for primary endpoints (e.g. myocardial infarction and stroke) as other therapy, provided adequate blood pressure control is achieved.

12.6 Safety of sildenafil

- N Rafter. Sildenafil - New prescribing guidelines. Report for MARC, 22 Aug 2000
- American College of Cardiology/American Heart Association Expert Consensus Document. VI Recommendations for sildenafil and the cardiac patient. In Use of sildenafil (Viagra) in patients with cardiovascular disease. 1999. http://www.americanheart.org/Scientific/statements/1999/019902.htm
- TF Lue. Erectile dysfunction. NEJM 342:1802-13, 15 Jun 2000, p.1809-10 in dossier
- HC Herrmann, et al. Hemodynamic effects of sildenafil in men with severe coronary artery disease. NEJM 342:1622-6, 1 Jun 2000

At the previous meeting the MARC reviewed a clinical update in the Medical Journal of Australia³ (MJA) regarding the cardiovascular (CV) risks associated with sildenafil (Viagra) use. The update contained advice to avoid nitrates if a patient develops angina within 24 hours of taking sildenafil. The MARC requested further information on the basis of this 24-hour contraindication. It appears that much of the information in the MJA article was based on a summary statement from the American College of Cardiology and the American Heart Association (AHA) on the use of sildenafil in patients at clinical risk from CV effects (10 August 1998).⁴

Around the same time the FDA released post-marketing safety data for a period during which an estimated 6 million prescriptions were dispensed for sildenafil. 130 US patients died after taking the medicine of which 77 deaths were from CV events, and 48 were from unknown cause. In 70% of the total deaths CV risk factors or cerebrovascular disease were present. 16 had used nitrates with the sildenafil and 3 were in possession of a nitrate although use was uncertain. One third died or suffered symptoms of the event which lead to death within 4-5 hours of taking sildenafil. In half the timing in relation to drug taking was unknown.

In studies, under physiological conditions, the effects of sildenafil on blood pressure (BP) were mild to moderate and not dose-related over a range of 25-100mg, causing an average drop in systolic BP of 8-10mmHg and diastolic BP of 5-6mmHg, without significant effects being observed on heart rate. Doses as high as 800mg have been well tolerated in some healthy volunteers.

However, if exogenous nitrates are taken a rise in nitric oxide concentration occurs, potentiating the effect of sildenafil resulting in a significant drop in BP. This potentiating effect on BP reduction has not been observed when sildenafil is used with other vasodilatory agents.

The American College of Cardiology has extrapolated from pharmacokinetic data in an attempt to quantify risk. A single dose of sildenafil results in peak levels of 440 ng/mL in normal volunteers. Plasma concentrations peak within 30 to 120 minutes of oral dosing in the fasted state. After 24 hours the levels drop to 2 ng/mL. In those with reduced clearance of sildenafil (age > 65 years, hepatic impairment, severe renal impairment [creatinine clearance < 30 mL/min], use of cytochrome P450 3A4 inhibitors such as erythromycin), plasma levels at 24 hours are up to 8 times higher.

Hence in treatment of acute angina the American College of Cardiology recommends considering nitrates only after 24 hours (or longer if there is risk of reduced clearance and a prolonged half-life). Use should then occur only with careful monitoring of the initial dosages and the availability of alpha-adrenergic agonists and resuscitation facilities.

Herrman et al measured the haemodynamic effects of sildenafil in men undergoing angiography. The results showed no adverse CV effects were detected in this population with severe coronary artery disease.

Members questioned what would be an appropriate course of action if a man who has taken sildenafil < 24 hours previously presents with angina.

The Committee recommended seeking comment from Dr ... on behalf of the Cardiac Society, prior to asking the sponsor to update its data sheet and publishing an article on this advice to avoid nitrates in the 24 hours following use of sildenafil. Members suggested that Dr ... be asked, in particular, about treatment of angina in a man who has taken sildenafil < 24 hours previously.

12.7 Updates

These items, which were updates on material presented at previous meetings, were noted but not discussed by the Committee.

12.7.1 Change in bone density with inhaled corticosteroids

- T C Medici, et al. Effect of one year treatment with inhaled fluticasone propionate or beclomethasone dipropionate on bone density and bone metabolism: A randomised parallel group study in adult asthmatic subjects. Thorax 55:375-382, 2000.

This study of 69 patients using inhaled corticosteroids over a 1-year period found no significant change in bone density.

12.7.2 Safety of hormone replacement therapy

- D Grady, et al. Postmenopausal hormone therapy increases risk for venous thromboembolic disease. Ann Int Med 132:689-696, 2 May 2000.

12.7.3 SSRIs and gastrointestinal bleeding

- D Williams, et al. Association between SSRIs and upper gastrointestinal bleeding. BMJ 320:1405, 20 May 2000.
- N R Dunn, G L Pearce and S A W Shakir. SSRIs are no more likely than other drugs to cause such bleeding. BMJ 320:1405-1406, 20 May 2000.
- T Dickinson, et al. Self-treatment with non-steroidal drugs may be confounding factor. BMJ 320:1406, 20 May 2000.

12.8 Items of interest

Unless otherwise indicated, these items were noted but not discussed by the Committee.

12.8.1 Warfarin-celecoxib interaction

- T L Mersfelder and L R Stewart. Warfarin and Celecoxib interaction. Ann Pharmacotherapy 34:325-327, March 2000.

12.8.2 Safety issues with herbal products

- L B Moore, et al. St. John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proc Natl Acad Sci 97:7500-7502, 20 June 2000.
- D A Kessler. Cancer and herbs. NEJM 342:1742-1743, 8 June 2000.

12.8.3 Use of paracetamol in children

- P Hewson. Paracetamol: overused in childhood fever. Aust Prescriber 23:60-61, 2000.
- D Horey and H Hopkins. Paracetamol: overused in childhood fever - a consumer perspective. Aust Prescriber 23:61-62, 2000.

12.8.4 Clopidogrel and thrombotic thrombocytopenic purpura

- A J J Wood. Thrombotic thrombocytopenic purpura and clopidogrel - a need for new approaches to drug safety. NEJM 342:1824-1826, 15 June 2000.

12.8.5 NSAIAs and congestive heart failure

- J Page, D Henry. Consumption of NSAIDs and the development of congestive heart failure in elderly patients. Arch Intern Med 160:777-784, 27 March 2000.

12.8.6 Sodium valproate and polycystic ovary syndrome

- .... Sodium valproate and polycystic ovary syndrome. Letter and report for publication in NZMJ, 7 August 2000.

Dr ... had prepared a paper discussing the evidence for an association between sodium valproate and polycystic ovary syndrome. All of the positive evidence was from one group of Finnish women. Dr ... had sent the report to Medsafe in case it was thought appropriate to notify medical practitioners of the evidence. Members considered that the evidence of an association was weak, and recommended not taking any action, except to thank Dr ... for his paper.

12.8.7 Orlistat and hypertension

- M Persson, S Vitols. Orlistat associated with hypertension. BMJ 321:87, 8 Jul 2000

12.8.8 Alendronate and liver damage

- A Halabe, et al. AG Daifotis, et al. Liver damage due to alendronate. NEJM 343:365-6, 3 Aug 2000

12.8.9 Risks versus benefits of low dose aspirin

- T W Meade, PJ Brennan on behalf of the MRC General Practice Research Framework. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. BMJ 321:13-7, 1 July 2000

12.8.10 Use of inhaled corticosteroids in asthma

- P Shirtliffe, S Holt, J Crane, R Beasley. Towards the optimal use of inhaled corticosteroid therapy in adult asthma. Draft article.

12.9 Benefit-risk assessment

- Report of CIOMS Working Group IV. Benefit-Risk Balance for Marketed Drugs: Evaluating Safety Signals. CIOMS, Geneva, 1998

It was agreed that this document would be discussed at a subsequent meeting.

The meeting closed at 5pm

References

1. DS Guzick. Cardiovascular risk in women with polycystic ovarian syndrome. Sem Rep Endocrinal 14:45-9, 1996
2. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. Ischaemic stroke and combined oral contraceptives: result of an international, multicentre, case-control study. Lancet 348:498-505, 24 Aug 1996
3. Chew, K et al. Erectile dysfunction, sildenafil and cardiovascular risk. Medical Journal of Australia 172: 279-283, 2000
4. American Heart Association Advisory: Summary statement of the American College of Cardiology and the American Heart Association on the use of sildenafil (Viagra) in patients at clinical risk from cardiovascular effects. 10 August 1998. http://www.americaheart.org/Whats_News/AHA_Science_Advisories/viagra.html Accessed 21/8/2000.