National Drugs and Poisons Schedule Committee...arising from the meeting. Please note that the Record of the Reasons includes extracts from the NDPSC minutes which have been edited

NationalDrugs and

Poisons ScheduleCommittee

Record of Reasons

41st Meeting22-23 June 2004

Section 52D(2) of the Therapeutic Goods Act 1989 (the Act) provides the power for theNDPSC to amend the Poisons Standard or prepare a new Standard. The NDPSC takes intoaccount relevant matters mentioned in Section 52E of the Act when making a schedulingdecision.The Record of the Reasons contains the basis of scheduling decisions and other outcomesarising from the meeting. Please note that the Record of the Reasons includes extracts fromthe NDPSC minutes which have been edited to remove confidential information.

National Drugs and Poisons Schedule CommitteeRecord of Reasons 41 � June 2004 i

TABLE OF CONTENTS

GLOSSARY.................................................................................................................................................. IV

1.5 ADMINISTRATION ............................................................................................................................... 91.5.1 Correction to the Minutes of the NDPSC 38th Meeting – Melaleuca Oil ................................ 91.5.2 Correction to the Minutes of the NDPSC 39th (October 2003) & 40th (February 2004)Meetings – Hyoscyamus niger ............................................................................................................. 10

1.8 TRANS-TASMAN HARMONISATION WORKING PARTY...................................................................... 111.8.1 Minutes from the 10th (October 2003) TTHWP Meeting....................................................... 11

1.8.1.1 Phenylephrine .......................................................................................................................111.8.1.4 Propantheline ........................................................................................................................12

1.8.2 Matters arising from previous consideration of TTHWP items............................................. 131.8.2.1 Meclozine.............................................................................................................................131.8.2.2 Amphotericin ........................................................................................................................151.8.2.3 Definition for �Day-Night� Preparations..................................................................................171.8.2.4 Injectable Preparations...........................................................................................................17

AGRICULTURAL/VETERINARY, INDUSTRIAL AND DOMESTIC CHEMICALS...................... 18

3. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUS MEETING(CONSIDERATION OF POST-MEETING SUBMISSIONS UNDER 42ZCZ) ................................... 18

3.1 10,10�-OXYDIPHENOXARSINE (OBPA) .............................................................................................. 183.2 CHILD-RESISTANT PACKAGING DEFINITION...................................................................................... 22

4. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS................................... 26

4.1 EYELASH AND EYEBROWN TINTING PRODUCTS ............................................................................... 264.2 METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL............................................................. 284.3 CREOSOTE......................................................................................................................................... 304.4 ALKALINE SALTS.............................................................................................................................. 344.5 VINCLOZOLIN.................................................................................................................................... 37

5. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FOR THE UNIFORMSCHEDULING OF DRUGS AND POISONS. .......................................................................................... 39

5.1 SUSDP, PART 4.............................................................................................................................. 395.2 SUSDP, PART 5................................................................................................................................ 40

5.2.1 Bifluorides.............................................................................................................................. 40

6. MATTERS REFERRED BY THE AUSTRALIAN PESTICIDES AND VETERINARYMEDICINES AUTHORITY....................................................................................................................... 41

6.1 MOLINATE........................................................................................................................................ 416.2 GONADOTROPHIN RELEASING HORMONE ........................................................................................ 446.3 POTASSIUM BICARBONATE............................................................................................................... 446.4 OCTENOL .......................................................................................................................................... 466.5 FIROCOXIB........................................................................................................................................ 486.6 QUINCLORAC.................................................................................................................................... 506.7 FLUMICLORAC PENTYL ESTER .......................................................................................................... 516.8 PERMETHRIN .................................................................................................................................... 52

7. MATTERS REFERRED BY THE OFFICE OF CHEMICAL SAFETY (OCS)......................... 55

7.1 ANDROSTENEDIONE ALBUMEN CONJUGATE WITH DEA DEXTRAN ADJUVANT.................................. 55

National Drugs and Poisons Schedule CommitteeRecord of Reasons 41 � June 2004 ii

8. ANTIBIOTICS FOR CONSIDERATION FOLLOWING RECOMMENDATIONS OF THEJOINT EXPERT TECHNICAL ADVISORY COMMITTEE ON ANTIBIOTIC RESISTANCE(JETACAR) .................................................................................................................................................. 57

8.1-8.7 SULFONAMIDES....................................................................................................................... 588.8 TIAMULIN ......................................................................................................................................... 61

9. OTHER MATTERS FOR CONSIDERATION .............................................................................. 61

9.1 SODIUM HYPOCHLORITE .................................................................................................................. 619.2 SODIUM FLUOROACETATE................................................................................................................ 64

10. INITIAL REVIEW AND/OR FORMAL OPINIONS (AG/VET, INDUSTRIAL & DOMESTICCHEMICALS).............................................................................................................................................. 65

11. INFORMATION ITEMS (AG/VET, INDUSTRIAL & DOMESTIC CHEMICALS)................ 66

PHARMACEUTICALS .............................................................................................................................. 67

12. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUS MEETING(CONSIDERATION OF POST-MEETING SUBMISSIONS UNDER 42ZCZ) ................................... 67

12.1 TRIAMCINOLONE ......................................................................................................................... 6712.2 SODIUM FLUORIDE ...................................................................................................................... 6812.3 MITRAGYNA SPECIOSA................................................................................................................ 72

13. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS................................... 76

13.1 MELIA AZEDARACH..................................................................................................................... 7613.2 PANCREATIC ENZYMES................................................................................................................ 7913.3 PSEUDOEPHEDRINE...................................................................................................................... 8113.4 MEDICAL DEVICES ...................................................................................................................... 8613.5 KAVA AND KAVALACTONES........................................................................................................ 8813.6 ARIPIPRAZOLE............................................................................................................................. 9013. 7-13.9 [ITEMS DELETED ] ..................................................................................................................... 9113.10 IBUPROFEN .................................................................................................................................. 91

14. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FOR THE UNIFORMSCHEDULING OF DRUGS AND POISONS. ........................................................................................ 100

14.1 SUSDP, PART 4......................................................................................................................... 10014.1.1 Diclofenac............................................................................................................................ 10014.1.2 Nicotine................................................................................................................................ 104

14.2 SUSDP, PART 5......................................................................................................................... 108

15. MATTERS REFERRED BY THE AUSTRALIAN DRUG EVALUATION COMMITTEE(ADEC)........................................................................................................................................................ 108

15.1 NEW SUBSTANCES..................................................................................................................... 10815.1.1 Atomoxetine.......................................................................................................................... 10815.1.2 Atazanavir ............................................................................................................................ 10915.1.3 Treprostinil .......................................................................................................................... 11015.1.4 Amotosalen........................................................................................................................... 11115.1.5 Ciclesonide........................................................................................................................... 11215.1.6 Rosuvastatin......................................................................................................................... 11315.1.7 Alefacept .............................................................................................................................. 11415.1.8 Aprepitant ............................................................................................................................ 115

16. OTHER MATTERS FOR CONSIDERATION ............................................................................ 116

National Drugs and Poisons Schedule CommitteeRecord of Reasons 41 � June 2004 iii

16.1 KETAMINE ................................................................................................................................. 116

17. MATTERS REFERRED BY THE MEDICINES EVALUATION COMMITTEE (MEC) ..... 117

17.1 ASPIRIN ..................................................................................................................................... 117

18. MATTERS REFERRED BY THE MEDICINES CLASSIFICATION COMMITTEE (MCC)OF NEW ZEALAND ................................................................................................................................. 123

18.1 ZINC IN DIETARY SUPPLEMENTS ............................................................................................... 123

19. INITIAL REVIEW/FORMAL OPINIONS (PHARMACEUTICALS) ...................................... 124

22. AMENDMENTS TO THE SUSDP................................................................................................. 124

22.1 EDITORIAL CHANGES AND ERRATA........................................................................................... 124

National Drugs and Poisons Schedule CommitteeRecord of Reasons 41 � June 2004 iv

GLOSSARY

ABBREVIATION NAME

AAN Australian Approved Name

AC Active Constituent

ACSPA Australian Consumer and Specialty Products Association

ADEC Australian Drug Evaluation Committee

ADI Acceptable Daily Intake

ADRAC Adverse Drug Reactions Advisory Committee

AGRD Australian Guidelines for the Registration of Drugs

AHMAC Australian Health Ministers' Advisory Council

APMF Australian Paint Manufacturers Federation

APVMA Australian Pesticides and Veterinary Medicines Authority

AQIS Australian Quarantine and Inspection Service

ARfD Acute Reference Dose

ASMI Australian Self-Medication Industry

ARTG Australian Register of Therapeutic Goods

BAN British Approved Name

CAS Chemical Abstract Service

CHC Complementary Healthcare Council of Australia

CMEC Complementary Medicine Evaluation Committee

CMI Consumer Medicine Information

COAG Councils Of Australian Governments

National Drugs and Poisons Schedule CommitteeRecord of Reasons 41 � June 2004 v

CPAS Chemical Product Assessment Section

CRC Child-Resistant Closure

CRIH Chemical Review and International Harmonisation

CTFAA Cosmetic, Toiletry & Fragrance Association of Australia

DAFF Department of Agriculture, Forestry and Fisheries

DAP Drafting Advisory Panel

DSEB Drug Safety and Evaluation Branch

EAGAR Expert Advisory Group on Antimicrobial Resistance

ECRP Existing Chemicals Review Program

EPA Environment Protection Authority

ERMA Environmental Risk Management Authority

FAISD First Aid Instructions and Safety Directions

FDA Food and Drug Administration (US)

FOI Freedom of Information

FSANZ Food Standards Australia New Zealand

GHS Globally Harmonised System for Classification and Labelling ofChemicals.

GIT Gastro-intestinal tract

GP General Practitioner

HCN Health Communication Network

HSNO NZ Hazardous Substances and New Organisms Act

INN International Non-proprietary Name

ISO International Standards Organization

National Drugs and Poisons Schedule CommitteeRecord of Reasons 41 � June 2004 vi

JETACAR Joint Expert Advisory Committee on Antibiotic Resistance

LC50 The concentration of a substance that produces death in 50% of apopulation of experimental organisms. Usually expressed as mgper litre (mg/L) as a concentration in air.

LD50 The concentration of a substance that produces death in 50% of apopulation of experimental organisms. Usually expressed asmilligrams per kilogram (mg/kg) of body weight

MCC Medicines Classification Committee

MEC Medicines Evaluation Committee

MODA NZ Misuse of Drugs Act

MOH Ministry of Health (NZ)

NCCTG National Coordinating Committee of Therapeutic Goods

NDPSC National Drugs and Poisons Schedule Committee

NHMRC National Health and Medical Research Council

NICNAS National Industrial Chemicals Notification & Assessment Scheme

NOEL No Observable Effect Level

NOHSC National Occupational Health & Safety Commission

NPMB Non-Prescription Medicines Branch

NZ New Zealand

OCM Office of Complementary Medicines

OCS Office of Chemical Safety

ODBT Office of Devices, Blood and Tissues

OOS Out of Session

OTC Over the Counter

PACIA Plastics And Chemicals Industries Association

National Drugs and Poisons Schedule CommitteeRecord of Reasons 41 � June 2004 vii

PAR Prescription Animal Remedy

PBAC Pharmaceutical Benefits Advisory Committee

PEC Priority Existing Chemical

PGA Pharmaceutical Guild of Australia

PHARM Pharmaceutical Health and Rational Use of Medicines

PI Product Information

PIC Poisons Information Centre

PSA Pharmaceutical Society of Australia

PSIC DAFF Product Safety and Integrity Committee

RCP Restricted Chemical Product

RFI Restricted Flow Insert

RLC APVMA Registration Liaison Committee

SUSDP Standard for the Uniform Scheduling of Drugs and Poisons

SVT First aid for the solvent prevails

TCM Traditional Chinese Medicine

TGA Therapeutic Goods Administration

TGC Therapeutic Goods Committee

TGO Therapeutic Goods Order

TTHWP Trans-Tasman Harmonisation Working Party

TTMRA Trans-Tasman Mutual Recognition Agreement

UK United Kingdom

USA United States of America

National Drugs and Poisons Schedule CommitteeRecord of Reasons 41 � June 2004 viii

WHO World Health Organization

WP Working Party

WS Warning statement

National Drugs and Poisons Schedule CommitteeRecord of Reasons 41 � June 2004

9

1.5 ADMINISTRATION

1.5.1 CORRECTION TO THE MINUTES OF THE NDPSC 38TH

MEETING – MELALEUCA OIL

PURPOSE

The Committee considered correspondence dated 26 August 2003 fromXXXXXXXXXXXX which sought clarification over references and quotations includedin the Minutes of the NDPSC 38th Meeting (June 2003) relating to Item 2.4.1 eucalyptusoil and melaleuca oil.

BACKGROUND

The NDPSC 38th Meeting (June 2003) considered a proposal to amend the StandardStatements in Appendix E, Part 2 required for eucalyptus oil and melaleuca oil.

DISCUSSION

The Committee noted the correspondence from XXXXXXXXXXXX and the NDPSCSecretariat�s response. The Committee noted that the Minutes of the NDPSC 38th

Meeting contained uncited references and transcription errors.

The Committee agreed that the fourth dot point under melaleuca oil of Item 2.4.1 whichreads:

… However, lower literature LD50 values for eucalyptus oil such as 1560 mg/kg (oral/ratand probable lethal dose of 0.05 mL/lg to 0.5 mL/kg (human, adult) were not referred to.

should include cited references, to read:

… However, lower literature LD50 values for eucalyptus oil such as 1560 mg/kg(oral/rat) (Brownlee G, 1940. Q Jl Pharm. Pharmac, 13,130) and probable lethal dose of0.05 mL/lg to 0.5 mL/kg (human, adult) (Hindle RC, 1994, Eucalyptus oil ingestion. NZMed. J, May: 185-186) were not referred to.

The Committee noted the transcription errors in relation to the words symptomatic andasymptomatic as contained in the fifth dot point under melaleuca oil of Item 2.4.1, whichcurrently reads:

The submission quoted Webb and Pitt (1993) "Seventy seven per cent of children weresymptomatic despite several large ingestions….The authors consider that prudentmanagement of cases where estimated volume ingested is large…..should includegastrointestinal decontamination using charcoal and sorbitol…". This suggested that23% were asymptomatic and that a number of these would require medicalassessment/management.


10

should be amended to read:

The submission quoted Webb and Pitt (1993) "Seventy seven per cent of children wereasymptomatic despite several large ingestions….The authors consider that prudentmanagement of cases where estimated volume ingested is large…..should includegastrointestinal decontamination using charcoal and sorbitol…". This suggested that23% were symptomatic and that a number of these would require medicalassessment/management.

OUTCOME

The Secretariat was asked to amend the Record of Reasons and Ratified Minutes of theNDPSC 38th Meeting (June 2003) by including a footnote highlighting the error and thatthis matter had been corrected at the June 2004 meeting.

1.5.2 CORRECTION TO THE MINUTES OF THE NDPSC 39TH

(OCTOBER 2003) & 40TH (FEBRUARY 2004) MEETINGS – HYOSCYAMUSNIGER

PURPOSE

The Committee considered correspondence dated 3 May 2003 from XXXXXXXXXXXXseeking a correction to the Minutes of the NDPSC 39th (October 2003) and 40th(February 2004) Meetings in relation to Hyoscyamus niger.

BACKGROUND

Following consideration of a recommendation of the NZ MCC 29th Meeting (May 2003)and a submission from the applicant XXXXXXXXXXXX, the NDPSC 39th Meeting(October 2003) foreshadowed an amendment to the Schedule 2 entry for Hyoscyamusniger to exempt preparations containing 30 micrograms or less of total solanaceousalkaloids from the requirements of scheduling. The amendment was agreed to by theNDPCS 40th Meeting (February 2004).

DISCUSSION

The Committee noted the XXXXXXXXXXXX correspondence and that there had been atranscription error whereby 30 micrograms had been incorrectly recorded as 300micrograms per pack size in the Record of Reasons of the 39th (October 2003) and 40th

(February 2004) Meetings.

NDPSC 39th Meeting (October 2003) Record of ReasonsAgenda Item 13.9, third paragraph


11

“The 29th (May 2003) MCC meeting considered a submission from XXXXXXXXXXseeking reclassification of Hyoscyamus niger from pharmacy only medicine to generalsale medicine when in packs containing 300µg or less of total solanaceous alkaloids …”

NDPSC 40th Meeting (February 2004) Record of ReasonsAgenda 13.3, third paragraph

“The 29th (May 2003) MCC meeting considered a submission from XXXXXXXXXXXXseeking reclassification of Hyoscyamus niger from a pharmacy only medicine to ageneral sale medicine when in packs containing 300µg or less of total solanaceousalkaloids ...”

OUTCOME

The Committee agreed to amend the Record of Reasons and Ratified Minutes of theNDPSC 39th (October 2003) and 40th (February 2004) Meetings by including a footnotehighlighting the error and that this matter had been corrected at the NDPSC 41st Meeting(June 2004).

1.8 TRANS-TASMAN HARMONISATION WORKING PARTY

1.8.1 MINUTES FROM THE 10TH (OCTOBER 2003) TTHWP MEETING

The Committee noted the Minutes of the TTHWP 10th Meeting (October 2003) andconsidered the following items arising from that meeting.

1.8.1.1 PHENYLEPHRINE

PURPOSE

The Committee considered the TTHWP Decision 10/4 to remove phenylephrine from the2-year list.

BACKGROUND

The Committee noted that phenylephrine was considered for harmonisation at theNDPSC 20th Meeting (February 1999) where the entries in the Schedules forphenylephrine in the SUSDP were amended to harmonise with New Zealand. Whilst thescheduling of phenylephrine became harmonised, the supply of nasal preparationsremained unharmonised as such products in New Zealand could be sold at airports.

The TTHWP 10th Meeting (October 2003) meeting discussed this matter and agreed thatthere was no further action required as the regulatory outcomes in terms of schedulingwere already harmonised. To this end, the TTHWP 10th Meeting made a


12

recommendation (Decision 10/4) that the NDPSC remove phenylephrine from the 2-yearlist.

DISCUSSION

The Committee noted that harmonisation efforts were focused on the schedulingprovisions and that differences in supply arrangements within both countries couldoccasionally lead to an unharmonised approach in respect to supply. This was the casewith phenylephrine where, despite consistency in the scheduling provisions, nasalpreparations would continue to remain unharmonised in that such products wouldcontinue to be permitted to be sold at airports in New Zealand.

Given that controls on supply were administered through State and Territory legislation,the Committee was advised that the TTHWP agreed to consider substances where thescheduling was harmonised but the provisions on supply between the countries varied tobe �essentially harmonised� with New Zealand. The Committee noted that harmonisationof supply mechanisms were yet to be addressed in the overall trans-Tasmanharmonisation process and the issue was to be referred to the NCCTG for advice.

OUTCOME

The Committee agreed to remove phenylephrine from the 2-year list.

1.8.1.4 PROPANTHELINE

PURPOSE

The Committee considered a proposal to delete the Schedule 2 entry for propantheline inorder to achieve harmonisation of scheduling with New Zealand.

BACKGROUND

The NDPSC 21st Meeting (May 1999) considered harmonisation of the S2 entry forpropantheline but agreed that the existing S4 entry in Australia remained appropriate atthe time. This decision was made on the grounds that there was one existing product inAustralia containing propantheline which was indicated for adjunctive therapy in thetreatment of peptic ulcer, neurogenic bladder, urinary incontinence in patients withdetrusor hyperactivity and hyperhidrosis.

In the context of trans-Tasman harmonisation the TTHWP 10th Meeting (October 2003)(Item 2.3.3) reviewed the scheduling of propantheline and noted that it was listed inSchedule 4 of the SUSDP except in preparations for topical use which were Schedule 2.However, propantheline was a prescription medicine in New Zealand with no provisionfor a less restrictive classification. The TTHWP 10th Meeting had also noted that the oralpreparation containing propantheline bromide for use as an adjunctive therapy in thetreatment of peptic ulcer (gastric and duodenal), neurogenic bladder, urinary incontinence


13

in patients with detrusor hyperactivity and hyperhidrosis was still registered in Australia.There were no other registered products for human topical use or veterinary usecontaining propantheline.

DISCUSSION

The Committee agreed that, as there were no topical human or veterinary preparationscontaining propantheline registered in Australia, harmonisation of scheduling could beachieved by deletion of the Schedule 2 entry.

OUTCOME

On the grounds of harmonisation, the Committee agreed to foreshadow for the NDPSC42nd Meeting (October 2004), deletion of the Schedule 2 entry for propantheline.

FORESHADOWED DECISION(for consideration at the NDPSC 42nd Meeting of October 2004)

Schedule 4 – Amendment

PROPANTHELINE � amend the entry to read

PROPANTHELINE.

Schedule 2 � Amendment

PROPANTHELINE � delete entry.

1.8.2 MATTERS ARISING FROM PREVIOUS CONSIDERATION OFTTHWP ITEMS

The Committee considered the following matters which had arisen from previousmeetings of the TTHWP.

1.8.2.1 MECLOZINE

PURPOSE

The Committee considered the scheduling of meclozine for the purpose of harmonisationwith New Zealand.

BACKGROUND

The TTHWP 8th Meeting (October 2002) recommended that the NDPSC considerexempting from scheduling, small packs of meclozine for the prevention or treatment of


14

motion sickness. The TTHWP had advised that small packs of travel sicknesspreparations containing meclozine were allowed to be sold in New Zealand as generalsales medicines (unscheduled) through specified outlets such as transport terminals oraboard a ship or plane. NDPSC members noted that there was one such product on themarket in New Zealand but none in Australia.

The NDPSC 40th Meeting (February 2004) noted that meclozine was included inSchedule 4 of the SUSDP and that this classification was possibly due to meclozine�spotential teratogenicity. NDPSC Members recalled that the last time the teratogenicity ofmeclozine was discussed was in December 1969 when the Australian Drug EvaluationCommittee (ADEC) had noted that there was no evidence of teratogenicity in humans atthe recommended dosage. A number of submissions were received at the NDPSC 40th

Meeting including submissions from XXXXXXXXXXXX expressing concern that theproposal to include small packs of meclozine in Schedule 2 would increase the level ofabuse of meclozine products.

The NDPSC 40th Meeting foreshadowed agreement to the TTHWP�s proposal toreschedule meclozine from Schedule 4 to Schedule 2 for the treatment or prevention ofmotion sickness and requested that advice from the ADEC be sought about theteratogenicity of meclozine for consideration at the NDPSC 41st Meeting (June 2004).

DISCUSSION

The Committee was informed that advice from the ADEC had raised the followingpoints:

• meclozine was last considered in 1971 and since that time, the ADEC has not hadcause to review meclozine or to conduct a systematic literature review.

• the Adverse Drugs Reactions Advisory Committee (ADRAC) had advised ADEC thatfour adverse reaction reports of congenital abnormalities associated with meclozinehad been identified but these had occurred over a long time. ADRAC had notreceived any recent adverse reports.

• in the 2nd edition of the publication �Medicines in Pregnancy�, for which ADEC wasresponsible, meclozine had been included in Category A � �Drugs which had beentaken by a large number of pregnant women and women of childbearing age withoutany proven increase in the frequency of malformations or other direct or indirectharmful effects on the foetus having been observed.� However, in the 3rd edition,meclozine had been deleted from the text on the basis of discontinuation of supplyand its omission from the PP Guide and MIMS.

• any future application to register meclozine as a Schedule 4 product to be referred tothe ADEC for comment.

A pre-meeting submission was received from XXXXXXXXXXXX advisingXXXXXXXXXXXX was now in agreement with the scheduling proposal.


15

The Committee noted that to fully harmonise with New Zealand would require aSchedule 2 entry for meclozine exempting small packs containing 12 or less tablets orcapsules as well as the deletion of the Schedule 4 entry. Members recalled that theNDPSC 40th Meeting noted that there was no Schedule 4 product containing meclozine inAustralia and that any proposed new product would be fully evaluated by the TGA forregistration prior to sale to the public. On this basis, the Committee agreed that it couldachieve a common regulatory outcome between Australia and New Zealand by includingsmall pack sizes of meclozine in Schedule 2. Retaining the Schedule 4 entry in theSUSDP for meclozine would not alter the harmonised outcome given that there were no�prescription only� medicines containing meclozine in New Zealand.

Retaining the Schedule 4 entry would ensure that if products were presented forregistration in the future, then they would be subjected to an appropriate level ofevaluation.

DECISION 2004/41 - 1

On the grounds of harmonisation, the Committee confirmed the foreshadowedamendments to include meclozine in primary packs containing 12 or less tablets orcapsules for the prevention or treatment of motion sickness in Schedule 2 of the SUSDP.

Schedule 2 – New Entry

MECLOZINE in primary packs containing 12 or less tablets or capsules of meclozine forthe prevention or treatment of motion sickness, except in preparations for thetreatment of children under two years of age.

Schedule 4 - Amendment

MECLOZINE � amend entry to read:

MECLOZINE except when included in Schedule 2.

1.8.2.2 AMPHOTERICIN

PURPOSE

The Committee considered the foreshadowed inclusion in Schedule 3 of topicalpreparations containing amphotericin for the treatment of oral candidiasis followingadvice from the Expert Advisory Group on Antimicrobial Resistance (EAGAR) on thepotential for the development of resistance.

BACKGROUND

The Committee recalled that the TTHWP 8th Meeting (October 2002) recommended thattopical preparations containing amphotericin for the treatment of oral candidiasis be


16

included in Schedule 3 of the SUSDP (Recommendation 8.11). This change wouldharmonise the scheduling with New Zealand.

The item was considered at the NDPSC 39th Meeting (October 2003). A pre-meetingsubmission from XXXXXXXXXXXX submitted that amphotericin should not berescheduled to Schedule 3. XXXXXXXXXXXX noted that amphotericin was thetreatment of choice for the most serious systemic fungal infections and was thereforeconcerned that more widespread use could lead to the development of resistance andtherefore reduced effectiveness. Further discussion was deferred to allow advice to besought from the ADEC on the potential for resistance to develop with topical use ofamphotericin. The ADEC subsequently advised that the matter should be referred toEAGAR.

The NDPSC 40th Meeting (February 2004) agreed to refer the matter to EAGAR, notingthat, should EAGAR consider that the issue was outside its terms of reference, EAGARbe asked to convene a special advisory panel to provide advice to NDPSC on thepotential for resistance development with amphotericin. A decision on the harmonisationproposals was deferred pending advice from EAGAR. The Chair of EAGAR undertookto table the information provided by NDPSC at the EAGAR April 2004 meeting.

DISCUSSION

The Committee received advice that EAGAR saw the issue of potential resistance toamphotericin as being of critical importance and therefore requested that a detailed riskassessment should be compiled before further advice could be given. EAGARrecommended that there be no change in the scheduling of amphotericin pending a broadranging review of antifungals.

The Committee noted that EAGAR had been more concerned with antibiotic resistancerather than fungal resistance. The Committee also noted that the NHMRC had recentlyadvised that in future, EAGAR would not undertake primary reviews but would reviewthe outcome of reviews of the potential for antibiotic resistance undertaken by regulatoryauthorities. As a result, an assessment of the potential for resistance developmentassociated with more widespread use of products containing amphotericin would need tobe arranged by the NDPSC and the outcome submitted to the EAGAR for review.

The Committee also noted pre-meeting advice from the XXXXXXXXXXXX agreeing tothe placement of amphotericin topical products in Schedule 3.

OUTCOME

The Committee agreed to defer further consideration of this matter until the NDPSC 42nd

Meeting (October 2004). In the meantime the Committee requested that the Secretariatarrange for a review of amphotericin for possible resistance development arising frommore widespread use should there be a relaxation of the scheduling.


17

1.8.2.3 DEFINITION FOR “DAY-NIGHT” PREPARATIONS

This item was inadvertently included on the agenda and was therefore withdrawn.

1.8.2.4 INJECTABLE PREPARATIONS

PURPOSE

The Committee considered harmonisation of the scheduling of injectable preparations.

BACKGROUND

The NDPSC 38th Meeting (June 2003) considered a number of policy questions relatingto the possible abuse, misuse and regulatory controls over injectable preparations with aview to harmonising the regulation of injectable preparations between Australia and NewZealand.

The NDPSC 38th Meeting was advised that, on the basis of an extensive literature reviewthat there was no evidence of any problem associated with the legitimate use of injectablepreparations in developed countries including Australia and New Zealand. On this basisthe Committee agreed that there was no need to control such preparations throughscheduling and that should future evidence to the contrary come to light, the matter wouldbe considered on a case-by-case basis. The working party was asked to reconsider thescheduling of �injectable medicines� with a view to recommending harmonisation on theleast restrictive schedule, that is �unscheduled� and removal of the Part III entry forinjectables in the New Zealand medicines classification category.

The issue was again raised at the NDPSC 39th Meeting (October 2003) when Memberswere advised that removal of the class entry for injectable medicines from Part III wasnot likely to have a negative impact on public health outcomes in New Zealand ascontrols on injectable medicines would still be covered by the scheduling of the activeingredient (s) as was the case in Australia. The NDPSC 39th Meeting agreed torecommend to the NZ Ministry of Health (MOH) that, in the absence of evidenceassociated with abuse or misuse of injectable dose forms in either country, harmonisationwith Australia should be achieved by deleting the Part III class entry (Schedule 2) forinjectable medicines.

DISCUSSION

The Committee noted that at the TTHWP 10th Meeting (October 2003, it was agreed(Decision 10/3) to recommend that New Zealand not only delete its Part III entry forinjectable medicines, but recognising their safety record in both countries and in order toachieve a common regulatory outcome, injectable medicines containing vitamins (e.gfolic acid and vitamin K), multivitamins, potassium chloride and other salts, dextrose andother sugars, and homeopathic injections be exempt from scheduling. Advice was


18

received from NZ Medsafe that as from 29 April 2004, injectable preparations becameexempt from scheduling unless specified elsewhere in the Schedules.

The Committee noted that the scheduling status of injectable preparations was nowharmonised between Australia and New Zealand, ie injectable preparations areunscheduled except when separately specified in the Schedules.

The Committee agreed to consider further, the proposal to exempt from schedulinginjectable preparations containing vitamins, multivitamins, potassium chloride and othersalts, dextrose and other sugars, and homeopathic injections. The Committee also notedthe need to first examine the regulatory impact of the decision on individual products andto seek public comment on the proposal. The regulatory impact assessment would bepresented to the TTHWP 12th Meeting (October 2004).

OUTCOME

The committee endorsed decision 10/3 of the TTHWP noting that this decision had sincebeen accepted by NZMOH.

The NDPSC agreed to consider exempting injectable preparations containing vitamins,multivitamins, potassium chloride and other salts, dextrose and other sugars, andhomeopathic injections from scheduling.

AGRICULTURAL/VETERINARY, INDUSTRIAL AND DOMESTICCHEMICALS

3. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUSMEETING (CONSIDERATION OF POST-MEETINGSUBMISSIONS UNDER 42ZCZ)

3.1 10,10’-OXYDIPHENOXARSINE (OBPA)

PURPOSE

The Committee considered post-meeting comment regarding the initial schedulingdecision for 10,10′-oxydiphenoxarsine (OBPA).

BACKGROUND

The NDPSC 40th Meeting (February 2004) considered an application to down-schedulepreparations containing 5.25% w/w or less of OBPA from Schedule 7 to Schedule 6 onthe basis that they would not be supplied to the public and would only be used by trainedindustrial polymer/plastic processors. The applicant also sought to have OBPA exemptfrom the requirements of scheduling when contained in polymer/plastic articles


19

containing a maximum OBPA concentration of 525 ppm (or expressed as arsenic content,156 mg/kg of polymer).

The Committee received advice at the NDPSC 40th Meeting that if OBPA was to beincluded in Schedule 6 limiting its supply to industrial users through the inclusion of thefollowing warning statements �WARNING - For industrial use only� and �WARNING -Not to be supplied for domestic use� may not be enforceable in the States and Territories.Therefore, the Committee agreed that, as a Schedule 6 poison, it would be difficult tolimit the availability OBPA to industrial users and did not support the inclusion of OBPApreparations in Schedule 6. The Committee did, however, agree that OBPA polyvinylchloride and polyurethane extruded and moulded articles did not pose an unreasonablerisk to human health where OBPA particles from these articles did not come into contactwith food, drinking water, peoples� skin or animal feeds. The Schedule 7 entry for arsenicwas amended accordingly. This decision was made after consideration of a NICNASassessment of a submission received from XXXXXXXXXXXX.

DISCUSSION

The Committee was informed that post-meeting comment had been received fromXXXXXXXXXXXX in regard to the scheduling decisions made at the NDPSC 40th

Meeting. The Members were advised that the applicant�s submission was forwarded toNICNAS for evaluation. The sponsor raised the following two issues for theconsideration of Members:

The Committee’s decision not to reschedule preparations containing 5.25% or lessof OBPA is not based on the toxicity profile of OBPA. The applicant was of the viewthat the Committee�s decision not to down-schedule preparations containing 5.25% w/wor less of OBPA on the grounds that limiting the availability of OBPA to industrial userswould be difficult when classified as a Schedule 6 poison. The applicant sought areconsideration of the decision on the grounds that the toxicity profile of OBPApreparations with a concentration of 5.25% or less fits with in the definition of a Schedule6 poison.The NICNAS assessment reported that no significant new data had been presented by theapplicant. Data summarising the results of an acute oral LD50 study in rats, acute dermalLD50 study in rabbits, and a skin irritation test in rabbits for XXXXXXXXXXXX hadbeen provided. The acute toxicology of XXXXXXXXXXXX is consistent with low acuteoral and dermal toxicity, however, there was insufficient data to evaluate the potentialdermal irritancy of XXXXXXXXXXXX. The acute toxicology of XXXXXXXXXXXXis consistent with moderate acute oral and dermal toxicity, and high dermal and eyeirritancy. No chronic toxicity data was available for the 5% OBPA preparationsXXXXXXXXXXXX or XXXXXXXXXXXX. No toxicity data was provided for otherXXXXXXXXXXXX preparations. However, the assessment considered it unlikely thatthere would be significant differences in toxicity given the carriers specified by theapplicant. The potential for preparations containing 5.25% OBPA to be source ofelemental arsenic cannot be discounted. The lowest NOEL in studies submitted on OBPA


20

pertains to foetal toxicity following dermal application: NOEL = 0.3 mg/kg bw. Anequivalent oral dose study was not available. The assessment highlighted that theXXXXXXXXXXXX range of preparations are intended solely for industrial use andwould be subject to relevant State and Territory occupational, health and safetylegislation.

The Committee’s decision to exempt only polyvinyl chloride and polyurethaneextruded and moulded articles is too restrictive. The applicant proposed twoalternatives for the Committee�s consideration. Firstly, that the Schedule 7 entry forarsenic be amended to include an exemption for �plastic� extruded and moulded articlescontaining 160 mg/kg or less of arsenic citing alkyl-tin compounds in Schedule 7 as aprecedent. Alternatively, the Schedule 7 entry for arsenic could be amended to include anexemption for �water-insoluble polymers�. The applicant proposed that alternativebecause �water-soluble polymers� may release OBPA more readily thus increasing thebioavailability of the substance. Should the Committee choose to reject these proposals,the applicant suggested that the current exemption be expanded to include polyethylene,polypropylene, ethylene vinyl acetate, thermoplastic polymer elastomer and natural andsynthetic rubber.

In response, the NICNAS assessment reported that the main risks associated with the useof OBPA related to the potential leaching or dislodgment of OBPA from plastic articles.Based on expected exposure scenarios, it was appropriate to exclude OBPA treated PVCand PU articles containing not more than 525 ppm OBPA from the SUSDP. However,additional information about potential leach and dislodgment rates should be sought fromthe applicant to support an extension of the exclusion to other specific polymersrequested. The assessment also drew to the Committee�s attention that it was unknownwhether plastic toys were an intended application for OBPA. The present Schedule entrystates OBPA-treated plastics will not be used for contact with food stuffs, animal feeds orpotable water; clothing and footwear in contact with the skin; in infant wear; orpackaging materials. Due to concerns over potential for arsenic accumulation, theexemption from the schedule for such articles should not be applied to OBPA treatedtoys.

On the basis of these considerations, the NICNAS assessment made the followingrecommendations:

• That the Committee re-confirm Decision 2004/40 � 8. That is reject the applicant�srequest for the rescheduling of preparations containing 5.25% or less of OBPA fromSchedule 7 to Schedule 6.

• Amend Schedule 7 such that PVC and PU extruded and moulded articles containingno more than 160 mg/kg of arsenic as OBPA be exempt from the Schedule exceptwhen included in articles intended as children�s toys.

• Request that the applicant provide information regarding potential leach anddislodgment rates of OBPA from plastics other than PVC and PU in order todetermine whether an exemption beyond PVC and PU is appropriate.


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The Committee noted that no significant new data had been presented by the applicantthat warranted a change to Decision 2004/40 � 8. Furthermore, Members were still of theopinion that an amendment to the Schedule 6 entry form arsenic to include OBPA did notlimit its availability exclusively to industrial users.

Similarly, the Committee did not favour expanding the exemption for extruded andmoulded articles to include plastics other than PVC and PU in the absence of informationon dislodgment rates from these other plastics. Accordingly, Members asked that furtherdata be sought from the applicant regarding the potential leach and dislodgment rates ofOBPA from plastics other than PVC and PU.

Members also expressed concern that OBPA may be incorporated into children�s toysand asked that further information be sought from the applicant regarding the likelihoodof this use before any consideration could be given to the inclusion of toys under part (e)of the Schedule 7 entry for arsenic.

DECISION 2004/41 – 2 (Confirmation of Decision 2004/40 – 8)

In accordance with sub-regulation 42ZCZ(3) the Committee agreed to confirm theamendment (Decision 2004/40 � 8) to the Schedule 7 entry for arsenic exempting fromthe requirements of scheduling polyvinyl chloride and polyurethane extruded andmoulded articles containing a maximum of 525 mg/kg OBPA (equivalent to 160 mg/kgarsenic).


ARSENIC – amend entry to read:

ARSENIC except:

(a) when separately specified in this Schedule;

(b) when included in Schedule 4 or 6;

(c) as selenium arsenide in photocopier drums;

(d) as 10,10'-oxydiphenoxarsine in silicone rubber masticcontaining120 mg/kg or less of arsenic;

(e) as 10,10′-oxydiphenoxarsine contained in polyvinylchloride and polyurethane extruded and moulded articlescontaining 160 mg/kg or less of arsenic other than whenincluded in articles:


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(i) in contact with food stuffs, animal feeds or potablewater;

(ii) of clothing and footwear in contact with the skin;

(iii) used as infant wear; or

(iv) intended for use as packaging materials;

(f) in animal feeds containing 75 g/tonne or less of arsenic; or

(g) in paints containing 0.1 per cent or less of arsenic calculatedon the non-volatile content of the paint.

3.2 CHILD-RESISTANT PACKAGING DEFINITION

PURPOSE

The Committee considered post-meeting comment regarding the proposed definitions forchild-resistant packaging and child-resistant closure for inclusion in Part 1 of the SUSDP.

BACKGROUND

At the NDPSC 39th Meeting (October 2003), the Committee decided that the definition ofchild-resistant closure/packaging in the SUSDP was too narrow for the purposes ofpoisons regulation. Specifically, the current definitions did not account for packaging andclosures which were sufficient to render their contents inaccessible to children but wouldfail to meet the strict definition of CRP or CRC according to AS1928-2001. TheCommittee agreed to adopt the definition for child-resistant packaging from the DraftTherapeutic Good Order (TGO) 65 and considered the foreshadowed amendment at theNDPSC 40th Meeting (February 2004).

DISCUSSION

The Committee was informed that a post-meeting comment had been received fromXXXXXXXXXXXX. XXXXXXXXXXXX highlighted the following four issues hewished the Committee to consider in regard to the definitions for CRP and CRC.

Currency of Compliance: XXXXXXXXXXXX considered that the Committee did notfully discuss his recommendation that CRC and CRP be compliant with the currentversion of a Standard, or in the absence of a version change then the product itself befield-tested every three to five years.

Members noted that in response to XXXXXXXXXXXX�s earlier submission, theCommittee did amend the SUSDP to include the phrase �as specified or amended fromtime to time� in relation to the Standards specified. The Committee was of the opinionthat any change to a standard should incorporate an adequate lead time to ensure that after


23

the implementation date all product at all points of the supply chain should comply withthe incoming standard. Consequently, mandatory field testing of products after a changeto a standard would not be necessary. Furthermore, spot inspections by State andTerritory health authorities would ensure that non-compliant products would be removedfrom sale.

Non-reclosable Packaging: XXXXXXXXXXXX contended that Section 3 of AS1928-2001 is not really about �child-resistance� but more about leakage for blister packing. Hehighlighted that those products which only comply with AS4710-2001 cannot claim to be�child-resistant� despite AS4710 & AS1928 being essentially similar Standards withsimilar aims. In his opinion the three options proposed by the XXXXXXXXXXXX at theFebruary meeting all have merit, however, he would support amending AS1928-2001 toinclude child-testing for non-reclosable packaging or modifying AS4710-2001. In orderto facilitate this recommendation, XXXXXXXXXXXX suggested that the Committeeseek the assistance of Standards Australia.XXXXXXXXXXXX also considered that the deliberations of Committee seem to bestrongly influenced by medical and veterinary considerations over those of industry.XXXXXXXXXXXX suggested that perhaps the Minister could nominate arepresentative from the packaging or plastics industries to join the Committee thusallowing their points of view in relation to child-resistant packaging to be expressed.The Committee noted that Section 42ZCD of the Therapeutic Goods Regulations 1990allows for only one representative from industry on the NDPSC and consequentlyXXXXXXXXXXXX proposal to include a representative from the packaging or plasticsindustries would require legislative change. Members also noted that at the NDPSC 40th

Meeting (February 2004), the Committee considered the inclusion of AS4710-2001 in thedefinition of CRP but agreed that it was inappropriate on the grounds that the Standardtests for packaging that is designed not to be opened.

The XXXXXXXXXXXX suggested that perhaps this issue should be referred to the soonto be formed Therapeutic Good Committee�s (TGC) expert committee on child-resistantcontainers. The Committee was of the view that it was inappropriate to refer an issueregarding an Australian standard to a subcommittee concerned only with the packaging ofmedicines. However, the Committee agreed to refer the matter to Standards Australia andto brief the TGC of its consideration of this issue and course of action.

Different Requirements in Different Australian Jurisdictions: XXXXXXXXXXXXhighlighted that there are significant differences between the States & Territories in theirlegislation in regard to CRC and CRP resulting in a burden to industry. He urged theCommittee to work towards national criteria so that acceptance of a CRC or CRP in onejurisdiction results in acceptance in every other jurisdiction.

The Committee agreed to refer XXXXXXXXXXXX comments on this issue to NCCTG.

Additionally, XXXXXXXXXXXX pointed out that there are differences between theJurisdictions in the requirements for retail storage of Schedule 5 (and Schedule 6)


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poisons. The Committee agreed that this matter should be referred toXXXXXXXXXXXX with a view to the development of uniform approach to the storageof these substances.

Organisations Seeking to Go Beyond the Minimum Requirements:XXXXXXXXXXXX expressed concern that there did not appear to be a clear policyposition on whether industry should be encouraged to voluntarily package more productsin child resistant packaging or whether this practice diluted the effectiveness of childresistant packages. XXXXXXXXXXXX supported improvements to policies andprocedures and recommended that a full public discussion be undertaken with consumergroups, parent groups, child care representatives as well as industry groups andgovernment representatives being invited to participate.The Committee was advised that there was no evidence that the use of CRCs or CRPs onproducts which did not require these measures diluted their effectiveness. Furthermore,the Member believed that there were not a large number of products unnecessarily fittedwith CRCs or packaged in CRPs and that the storage of these products did not differ fromthose not packaged in this manner. The Committee agreed that it should not discouragethe non-mandated use of CRCs and CRPs on public health grounds.

Members noted that, after the Secretariat reviewed the four international Standards(International Organization for Standardization Standard ISO 8317:1989, BritishStandards Institution Standard BS EN 28317:1993, Canadian Standards AssociationStandard CSA Z76.1-99 and the United States Code of Federal Regulations, Title 16,Sections 1700.15 and 1700.20) referred to in the proposed definition for �Child-resistantClosure�, none actually define CRCs and reference to them was subsequently removedfrom the definition.

DECISION 2004/41 – 3 (Variation of Decision 2004/40-4)

The Committee agreed to delete the current definitions for child-resistant closure andchild-resistant packaging and replace these with the following definitions and to include adefinition for non-reclosable packaging in the SUSDP. The Committee also agreed tovary the 40th Meeting (February 2004) Decision 2004/40-4 by deleting reference to thefour international standards from the CRC definition. It was noted that these changeswould be included in the SUSDP 19 Amendment 1, which is planned to come into effectthrough State and Territory legislation on 1 September 2004.

Part 1 – Interpretation - Amendment

Sub-paragraph 1.(1)

�Child-resistant closure� � amend entry to read:

“Child-resistant closure” means:


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(a) a closure that complies with the requirements for a child-resistant closure in the Australian Standard AS1928-2001entitled Child-resistant packages as specified or amendedfrom time to time;

(b) a closure approved by any order made under section 10(3)of the Commonwealth Therapeutic Goods Act 1989; or

(c) in the case of a can fitted with a press-on lid, a lid of thedesign known as �double tight� or �triple tight�.

�Child-resistant packaging� � amend entry to read:

“Child-resistant packaging” means packaging that:(a) complies with the requirements of the Australian Standard

AS1928-2001 entitled Child-resistant packages as specifiedor amended from time to time;

(b) is reclosable and complies with the requirements of at leastone of the following standards as specified or amendedfrom time to time.

(i) the International Organization for StandardizationStandard ISO 8317:1989 entitled Child-resistantpackaging - Requirements and testing proceduresfor reclosable packages;

(ii) the British Standards Institution Standard BS EN28317:1993 entitled Child-resistant packaging -Requirements and testing procedures for reclosablepackages;

(iii) the Canadian Standards Association Standard CSAZ76.1-99 entitled Reclosable Child-ResistantPackages;

(iv) the United States Code of Federal Regulations,Title 16, Section 1700.15, entitled Poisonprevention packaging standards and Section1700.20, entitled Testing procedure for specialpackaging;

(c) is approved as child-resistant by any order made undersection 10(3) of the Commonwealth Therapeutic Goods Act1989; or


26

(d) is in the form of blister or strip packaging in which a unit ofuse is individually protected until the time of release andthat complies with Section 3 (Requirements for non-Reclosable Packages) of Australian Standard AS 1928-2001Child-resistant packages.

Part 1 – Interpretation – New Entry

Sub-paragraph 1.(1)

“Non-access packaging� is packaging that complies with the requirements ofAustralian Standard AS4710-2001 entitled Packages for chemicals not intendedfor access or contact with their contents by humans, in relation to products thatare not intended for human therapeutic use.

4. OTHER OUTSTANDING MATTERS FROM PREVIOUSMEETINGS

4.1 EYELASH AND EYEBROWN TINTING PRODUCTS

PURPOSE

The Committee noted updates from the XXXXXXXXXXXX regarding the NICNASreview on hair dyes and the progress of a compliance and education program withindustry on the regulatory requirements under NICNAS facilitated byXXXXXXXXXXXX.

BACKGROUND

At the NDPSC 40th Meeting (February 2004) the Committee was updated on the progressof investigations being separately conducted by XXXXXXXXXXXX andXXXXXXXXXXXX on incorrectly packed and labelled eyelash and eyebrow tinting andhair care products. The XXXXXXXXXXXX Member advised the Committee that alllash/brow tinting products on the Australian market are imported from either Austria,Germany or Switzerland and contain similar ingredients. Consequently,XXXXXXXXXXXX recommended that advice regarding this matter be sought from theXXXXXXXXXXXX. Given this evidence of incorrectly packed and labelled products,the XXXXXXXXXXXX Member agreed to facilitate a compliance and educationprogram with industry on the regulatory requirements under NICNAS. The Committeealso considered a public submission from the XXXXXXXXXXXX seeking an exemptionfrom scheduling for eyelash/eyebrow tinting products containing paraphenylenediamineand toluenediamine on the grounds that application by professional beauty therapistswould minimises the risk associated with their use. The Committee was of the view that itdid not have enough data to determine the potential danger posed to the eye byparaphenylenediamine and toluenediamine should the use of eyelash and eyebrow tintingproducts be permitted by a change to the label requirements. Given that NICNAS was at


27

that time in the process of conducting a major review of all hair dye ingredients currentlyused in Australia, the Committee agreed to defer this matter to a future meeting to allowconsideration of the final NICNAS review.

DISCUSSION

The Committee noted updates on the progress of investigations being separatelyconducted by XXXXXXXXXXXX and XXXXXXXXXXXX on incorrectly packed andlabelled eyelash and eyebrow tinting and hair care products.

The XXXXXXXXXXXX Member advised the Committee that XXXXXXXXXXXX hadinvestigated recent claims of the inappropriate retail sale of several hair dye products.The distributors (one in XXXXXXXXXXXX and three in XXXXXXXXXXXX) werecontacted and asked to remove the products from retail sale. The XXXXXXXXXXXXMember advised the Committee that the XXXXXXXXXXXX has informed companiesthat, until the labelling of eyelash and eyebrow tinting products issue is resolved,XXXXXXXXXXXX will only allow salon use of these products. Companies have alsobeen warned that, if such a product were to be found on retail sale, action may be takenagainst a company. The XXXXXXXXXXXX Member indicated that for there to be asuccessful resolution to this issue the Committee would need to assess the potential foreye damage resulting from exposure to eyelash and eyebrow tinting products containingparaphenylenediamine and toluenediamine. The XXXXXXXXXXXX advised theCommittee that paraphenylenediamine and toluenediamine are included in the list ofchemicals being reviewed in Europe and agreed to seek the toxicity profiles andclassifications on skin/eye irritancy and report to the next meeting.

The XXXXXXXXXXXX submitted the following comments regarding the NICNAS hairdye review for the information of the Committee:

• [Paragraphs deleted].

The XXXXXXXXXXXX Member submitted the following update for the information ofthe Committee:

• XXXXXXXXXXXX from the XXXXXXXXXXXX has confirmed that generally itwould not be his member companies that are importing or supplying products foreyelash/eyebrow tinting either for retail or salon use.

• During a recent meeting with the beauty therapists representatives in Brisbane, theyindicated that their interest is apparently in the sale of salon only eyelash and eyebrowtinting products. They contend that the formulations of these products are different tothat of other hair dyes, and hence demonstrate a different safety profile. Confirmationof this has been requested, together with other relevant information for the Committeeto subsequently consider (at the October 2004 meeting) the appropriate labelling ofthese products eg. safety experience locally (and possibly internationally).


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• A consultant to a company has expressed interested in retail sale of eyelash andeyebrow tinting products (NB: these have been currently withdrawn from the market)and discussed with the XXXXXXXXXXXX Member the nature of the informationthat would be necessary to compile a submission to the NDPSC. Presumably asubmission will be provided to the Secretariat in due course.

OUTCOME

The Committee noted the updates given by Members and agreed to include this matter onthe agenda for the next meeting.

4.2 METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL

PURPOSE

The Committee considered comment regarding the proposed scheduling ofmethylcyclopentadienyl manganese tricarbonyl (MMT).

BACKGROUND

The NDPSC 39th Meeting (October 2003) considered the scheduling of MMT where itwas proposed that this substance be included in Schedule 7 with a cut-off to Schedule 6for fuel additive preparations containing 10% or less of MMT when fitted with a child-resistant closure. The Committee based its decision on the acute toxicological profile ofMMT and that the use pattern of consumer products fitted with a child-resistant closurewould limit the exposure direct to the public. The scheduling of MMT was consideredfollowing the completion of a Priority Existing Chemical (PEC) Assessment Report byNICNAS. The Committee noted that the companies producing MMT products who hadprovided information to NICNAS for assessment had not taken the opportunity to make asubmission to the NDPSC with regard to the scheduling of MMT. The Committee agreedto foreshadow the proposed scheduling of MMT to allow interested parties to commentprior to a decision being made.

At the NDPSC 40th Meeting (February 2004) the Committee noted that a number ofpublic submissions were received from companies and industry groups involved in theimportation, reformulation and manufacture of MMT or products containing thesubstance. However, the consensus of opinion regarding the foreshadowed schedulingproposal was that industry had not had sufficient time to fully assess the regulatory andcommercial impact of the Committee�s decision. Consequently, the Committee deferredthe matter to allow for industry to complete an adequate assessment of the implicationsresulting from the scheduling decision.

MMT is an anti-valve seat recession additive in automotive lead replacement petrol.MMT is also an octane enhancer. It is either pre-blended at the refinery or added tounleaded petrol by the vehicle owner and acts as a lubricating agent to prevent excessivevalve seat wear and recession of the valve seat into the automotive cylinder head.


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DISCUSSION

The Committee was advised that public submissions had been received fromXXXXXXXXXXXX, XXXXXXXXXXXX XXXXXXXXXXXX,XXXXXXXXXXXX, XXXXXXXXXXXX, XXXXXXXXXXXX,XXXXXXXXXXXX and XXXXXXXXXXXX.

The Committee noted that the consensus of opinion from industry was that the schedulingof MMT for industrial use was unnecessary and would result in limited public healthbenefits. Furthermore, the inclusion of MMT in Schedule 7 would subject industrial usersto additional regulatory burden. Given that the scheduling was targeted at the regulationof consumer sized containers, industry was of the view that an exemption from therequirements of scheduling was appropriate for industrial use and may be achievedthrough a pack size limit. It was proposed by XXXXXXXXXXXX and others that MMTand all preparations containing MMT be exempt from the requirements of schedulingwhen in pack sizes greater than 20 litres or when used in laboratory analysis. For packsizes less than 20 litres, MMT be included in Schedule 7 with a cut-off to Schedule 6 forpreparations containing 10% or less and a cut-off to Schedule 5 for preparationscontaining 5% or less when fitted with a child-resistant closure.

Members noted that the concerns raised by the public submissions relate to the varyingcontrols flowing from the inclusion of MMT in Schedule 7 and posed questions regardingthe need for such controls in the industrial setting. XXXXXXXXXXXX highlighted that�HSE requirements for the use of MMT in these oil industry contexts is already coveredfully by the requirements of the various National and State Dangerous Goods andOccupational Health and Safety Regulations and Codes of Practice�.

The Committee was advised that MMT is only imported into Australia, mostly in bulk(10000 L isotanks) as a 62% MMT petroleum distillate solution for use in leadreplacement petrol at refineries. A relatively small quantity of MMT is imported in 205 Lsteel drums for formulation into after market fuel additives containing less than 10% w/wMMT and less commonly in 450 L steel cylinders. MMT is also imported in pre-formulated, pre-packaged fuel additives that are available for sale through petrol stationsand retail outlets. MMT (as Mn) is currently listed in the NOHSC List of DesignatedHazardous Substances with no classification. Therefore, preparations intended solely forindustrial use would be subject to State and Territory occupational, health and safetylegislation.

The Committee was advised that several jurisdictions had the capacity to allowexemptions for the industrial use of Schedule 7 substances through their respectivelegislation. The Committee did not consider it appropriate to exempt a Schedule 7 poisonfrom the requirements of scheduling for industrial use on the basis of pack size,particularly when there is a mechanism in place to exempt industrial use through Stateand Territory legislation. Furthermore, the Committee did not agree that a further cut-offto Schedule 5 for preparations containing 5% or less of MMT was warranted in theabsence of specific toxicological data.


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The Committee asked that the Jurisdictions advise the Secretariat of the requirements forindustrial use exemptions in each State and Territory with a view to providing thisinformation to the companies that import MMT or manufacture products containing thesubstance.

Whilst the Committee appreciated the concerns raised by industry, Members were of theview that the inclusion of MMT in Schedule 7 with a cut-off to Schedule 6 for fueladditive preparations containing 10% or less was justified on the basis of its toxicologicalprofile.

OUTCOME

The Committee agreed to foreshadow the proposal to include MMT in Schedule 7 with acut-off to Schedule 6 for fuel additive preparations containing 10% or less of MMT whenfitted with a child-resistant closure.



METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL except whenincluded in Schedule 6.


METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL in fuel additivepreparations containing 10 per cent or less of methylcyclopentadienylmanganese tricarbonyl when fitted with a child-resistant closure.

4.3 CREOSOTE

PURPOSE

The Committee considered the scheduling of creosotes and related compounds orfractions.

BACKGROUND

The NDPSC 38th Meeting (June 2003) agreed to ask the Office of Chemical Safety (OCS)to review the safety of coal tar creosote. This request was based upon concerns beingraised about the carcinogenic potential of creosote and safety for use as a woodpreservative. At the June 2003 meeting, the Committee considered an overview of thedraft CICAD on coal tar creosote prepared by the OCS. The Committee was asked toconsider:


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• The creation of a specific SUSDP entry for coal tar creosote, with entries if and asnecessary for other coal tar derived mixtures, and wood creosote.

• Whether the marketing of coal-tar creosote as a wood preservative should be limitedto industrial use and to licensed applicators.

• Whether all marketed coal tar creosote preparations should be required to containlimits on specific toxic and carcinogenic contaminants of concern (eg. less than0.005% by weight of benzo[a]pyrene and water-extractable phenols at less than 3%by weight).

• The appropriateness of coal tar preparations being available for the treatment ofpsoriasis (and for any cosmetic uses that may exist).

• The appropriateness of creosote being available in oral pharmaceutical preparations.At the NDPSC 39th Meeting (October 2003) the Committee asked that advice be soughtfrom the APVMA, MEC and OCM regarding the potential impact on existing productsshould creosote and related substances be scheduled. This advice was provided to theNDPSC 40th Meeting (February 2004) for consideration by the Committee.

The APVMA advised that at the time there were 10 products containing creosoteregistered by the APVMA. The majority (7) were for the treatment of timber and timberproducts, but there was also a farm disinfectant product, a liniment product and an anti-fouling paint registered containing creosote with concentrations ranging between 43 g/Lto 1044 g/L. In addition to these products, there are another 11 products containing coaltar or tar acids. These products were registered for use as dog and cat washes, equinegrooming aids, ointments, disinfectants and blowfly strike treatments with concentrationsranging between 3 g/L to 419 g/L.

The Medicines Evaluation Committee (MEC) highlighted the following forconsideration:

• The ARTG includes products containing �creosote�, coal tar, �tar� (pine tar) and cadeoil (juniper tar).

• None of the products containing �creosote� have been evaluated by the TGA; most arelisted and most appear to be indicated for use as expectorants/decongestants forcoughs;

• If described correctly, products containing �creosote� should contain �wood creosote�(as defined by the AAN);

• All the Australian products containing coal tar are registered, with most of theevaluated products indicated for itchy skin and/or scalp conditions (eg. psoriasis,seborrhoeic dermatitis, seborrhoea, dandruff, eczema, dermatitis) � ie. conditionsconsistent with those accepted by the ARGOM policy guideline on �Coal tarpreparations�;


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• At least two of the �grandfathered� products containing coal tar are indicated fornappy rash � ie. these products do not comply with the ARGOM guideline;

• Most of the evaluated registered products containing pine tar are indicated for use onitchy and/or inflamed skin (eg. dermatitis, eczema, dry skin, nappy rash, psoriasis);

• Most of the products containing cade oil are �grandfathered� � all the registeredproducts are intended for inflamed skin/scalp conditions; and

• A number of the products contain more than one tar.The Office of Complementary Medicines (OCM) advised that, as creosote is regulated asan over-the-counter registrable, they are unable to provide comment.

The Committee expressed concern that there appeared to be no uniformity in the use ofthe terms �creosote�, �wood creosote�, �coal tar creosote� and �coal tar BP�. Similarly,the type of the creosote present in the registered and listed medicines identified by theMEC and the products registered by the APVMA were also poorly defined. Accordingly,the Committee asked that the nature and percentage of the creosote present in theregistered and listed medicines and agricultural and veterinary products be determined inconsultation with the TGA and the APVMA and that �coal tar creosote� be clearlydefined. The Committee deferred its consideration of creosote to the 41st Meeting (June2004) to allow further information and advice to be obtained.

DISCUSSION

The Committee noted that advice had been received from the APVMA and the OTCMedicines Section of the TGA.

The APVMA provided the information it had available on the specifications andchemical composition of the coal derivative/s in certain agricultural and veterinaryproducts and advised that:

• Approximately half of the products containing creosote, coal tar and tar acids (andsynonyms) were registered under previous State-based registration systems and thatthe APVMA did not hold detailed chemical specifications of the coal derivatives.

• In a number of cases, general information on the nature of the coal derivative isavailable (eg. complies with a particular Australian Standard or pharmacopeialmonograph). However in some cases, the cited pharmacopeial monographs are out ofdate.

• Information regarding composition and general specifications were found for somecoal derived active constituents. However, detailed chemical specifications and CASnumbers were generally not available.

The OTC Medicines Section of the TGA advised that the AAN 'creosote' refers tocreosote as defined by Martindale - ie. wood creosote. Therefore, all products stated ascontaining creosote should contain wood creosote. The five registered products


33

containing creosote identified in their previous advice were �grandfathered� and have notbeen evaluated by the TGA. As such, no information is available on these products, andthe type of creosote present has never been required to be characterised. Four of theseproducts would be regulated by the OTC Medicines Section if marketed and the fifthregistered product (also �grandfathered�) would to be regulated by the Office ofComplementary Medicines (OCM). The listed products containing creosote for supply inAustralia are the responsibility of the OCM and, as such, further information would needto be obtained on those products from them.

The OTC Medicines Section further advised that the TGA requires coal tar (any relevantAAN) or tar (ie. pine tar) in registered products to meet the requirements of the BPmonographs for 'Coal tar' or 'Tar', respectively. No further information is currentlyavailable on products containing tars, as the OTC Medicines Section has not evaluatedany of these products.

The Committee expressed disappointment that more information could not be gathered onthe nature of the creosote present in the �grandfathered� products identified by the TGA.

A Member advised the Committee that MEC had recently reviewed their guidelines oncoal tar and that this involved extensive consultation with industry. The Membersuggested that perhaps the Committee could seek advice from MEC on this matter. TheCommittee agreed to seek the MEC coal tar guidelines for consideration at the 42nd

Meeting (October 2004).

Members agreed that the way forward was to publish in the Gazette the Committee�sintention to include entries for creosote derived from coal and creosote derived frombeechwood in Schedule 7 of the SUSDP on the basis of their toxicity and carcinogeniccharacteristics. The Committee would also redefine the current creosote entries inSchedules 2 and 6 to specify creosote derived from wood other than beechwood. It washoped that in doing so sponsors of human therapeutic and veterinary products,particularly those �grandfathered� into their respective regulatory schemes, would beencouraged to provide data on the nature of the creosote present thus allowing theCommittee to draft schedule entries for these creosotes and to set cut-offs whereappropriate.

OUTCOME

The Committee agreed to defer this agenda item to the 42nd Meeting (October 2004) toallow further information and advice to be obtained.


Schedule 7 – New entry

CREOSOTE derived from coal.


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CREOSOTE derived from beechwood.


CREOSOTE � amend entry to read:

CREOSOTE derived from wood other than beechwood except:

(a) when included in Schedule 2;

(b) in preparations for human therapeutic use containing 10 percent or less of creosote (derived from wood other thanbeechwood); or

(c) in other preparations containing 3 per cent or less ofphenols and homologues of phenol boiling below 220°C.


CREOSOTE � amend entry to read:

CREOSOTE derived from wood other than beechwood for human therapeutic use,except in preparations containing 10 per cent or less of creosote derived fromwood other than beechwood.

4.4 ALKALINE SALTS

PURPOSE

The Committee considered the scheduling of alkaline salts.

BACKGROUND

At the NDPSC 40th Meeting (February 2004) the Committee considered a review ofalkaline salts prepared by the Hazardous Substances Section of XXXXXXXXXXXX.The alkaline salts review addressed issues relating to the cut-off pH for scheduling, totalalkalinity, the concentration at which the pH of a product should be measured, and thegreater accessibility of automatic dishwasher detergents compared with laundrydetergents in the home.

The review proposed the following options with regard to the scheduling of alkaline salts:

• Change the cut-off pH for inclusion in Schedule 5 to �more than 11.0�;

• Take the alkali reserve into account, as well as the pH, in determining whether aproduct is scheduled;


35

• Specify performance criteria when considering the scheduling of products containingalkaline salts, eg. results of Draize test, OECD test methods 404 (skin irritation), 405(eye irritation);

• Have a subcategory in Schedule 5 for irritant products; and

• Change the concentration at which the pH is measured for scheduling purposes to50% for laundry detergent (if the pH of a 50% solution can be accurately measured,otherwise measure the pH of a 25% solution).

Members were of the view that there was insufficient information to consider amendingthe Schedule 5 entry for alkaline salts in accordance with the options presented by theXXXXXXXXXXXX. Accordingly, the Committee asked that more information beobtained by NICNAS on the control of similar substances in the US, Canada, NZ andEurope and in particular the way the issue of irritancy is addressed.

At its 40th Meeting (February 2004), the Committee also considered a public submissionfrom XXXXXXXXXXXX in which the company expressed concerned that the first aidstatements required for product containing alkaline salts was unnecessary stronger thanthose imposed on a product containing sodium hydroxide, a more corrosive substance.The company proposed that the entry for alkaline salts in Appendix E, Part 2 be revisedto mirror that of sodium hydroxide. Specifically, that the entry for alkaline salts inAppendix E, Part 2 be revised with the following first aid statements � A, G3, E2 and S1.The Committee was of the view that there was insufficient information to support achange to the first aid instructions and agreed to consider this proposal as part of theconsideration of alkaline salts at a future meeting.

DISCUSSION

The Committee was advised that NICNAS had provided a review of the internationalregulation of alkaline salts. In summary, NICNAS submitted the following points for theCommittee�s consideration:

• The regulation of hazardous substances and preparations (products) for consumerswas examined for each of the countries surveyed. No entries were found in thepoisons or hazardous substances regulations in the USA, Canada, New Zealand andEurope pertaining to alkaline salts as a group in consumer products. No controlsincluding first aid instructions were found for this group of substances.

• In hazardous substances regulations for consumer products, performance criteria forclassification of corrosivity and irritancy differed in each country. In the USA,consumer products are regulated by the Consumer Product Safety Commission withthe Federal Hazardous Substances Act. Regulations provide for separate Corrosiveand Irritant categories and labelling requirements based on the results of animal testsspecified in the regulations. There are no criteria for corrosivity or irritation based onphysicochemical properties such as pH alone.


36

• In Canada, consumer chemical products are regulated by the Consumer Chemicalsand Containers Regulations, 2001. Separate categories of Very Corrosive, Corrosiveand Irritant exist. The category of Very Corrosive is reserved for ethyl bromoacetateand fluoride. The categories of both Corrosive and Irritant are based on strictlyprescribed pH and alkali reserve criteria or the results from animal testing or humanexperience. These categories have separate labelling requirements.

• In New Zealand, hazardous substances including household products are regulated bythe Hazardous Substances and New Organisms (HSNO) Act 1996. The thresholds andclassification scheme are based on the OECD Global Harmonisation System (GHS).Separate Corrosive and Irritant categories exist based on the results from animaltesting or on limited pH and acidic/alkaline reserve criteria. A substance is deemed askin corrosive at pH ≤ 2 or ≤ 11.5. The exact criteria for alkali reserve are not stated.There are no pH and acid/alkali reserve criteria for irritation. These categories haveseparate specified labelling requirements.

• Several regulatory instruments are used in the European Union for hazardoussubstances and preparations (products). Separate Corrosive and Irritant categoriesexist based on the results from animal testing and for irritation, on human experience.A corrosivity classification can also be applied based on pH (≤ 2 or ≥ 11.5) andalkaline or acidic reserves alone. The criteria for acidic or alkaline reserve are notstated. For irritation, classification is based on animal data or human experience only.There are no pH and acidic/alkaline reserve criteria for irritation. These categorieshave separate labelling requirements.

The Committee noted that XXXXXXXXXXXX had advised that they have an interest inthe Committee�s consideration of alkaline salts and sought the right to make post-meetingcomment.

Members were of the view that to reduce the current pH cut-off for alkaline salts inSchedule 5 to pH 11 the Committee would need to know the number of productscurrently marketed with a pH between 11 and 11.5 and the number of harmful exposuresattributed to the use of these product. Accordingly, the Committee asked that theXXXXXXXXXXXX Member determine the number of products currently on theAustralian market with a pH between 11 and 11.5 and that the XXXXXXXXXXXX andXXXXXXXXXXXX Members seek from their respective Poisons Information Centresinformation regarding the number of poisonings attributed to these products and theidentity of the products involved. The Members were asked to report to the 42nd Meeting(October 2004).

The Committee also considered the 40th Meeting (February 2004) submission fromXXXXXXXXXXXX in which they highlighted their concerns over inconsistencies in thefirst aid statements required for alkaline salts and sodium hydroxide. The Committeeagreed that it was appropriate to amend the Appendix E, Part 2 entry for alkaline salts tomirror that of sodium hydroxide.


37


The Committee agreed to further review the current scheduling of alkaline salts at theNDPSC 42nd Meeting (October 2004). The Committee also agreed to amend theAppendix E, Part 2 entry for alkaline salts to mirror that of sodium hydroxide inaccordance with XXXXXXXXXXXX submission to the NDPSC 40th Meeting (February2004).

Appendix E, Part 2 - Amendment

ALKALINE SALTS � Amend to read:

ALKALINE SALTS A, G3, E2, S1

4.5 VINCLOZOLIN

PURPOSE

The Committee considered the scheduling of vinclozolin.

BACKGROUND

At the NDPSC 40th Meeting (February 2004) the Committee considered the scheduling ofa procymidone, a dichlorophenyl dicarboximide fungicide closely related to vinclozolin.The Committee agreed that there was sufficient information regarding the teratogenicpotential of procymidone to warrant inclusion in Schedule 7.

The Committee noted that vinclozolin and procymidone are closely related chemicallyand toxicologically and have similar hazard profiles. Consequently, Members thought itappropriate to foreshadow a reconsideration of the scheduling of vinclozolin.

The Committee asked that the Secretariat review the previous considerations ofvinclozolin relating to the teratogenicity and endocrine disrupting potential of thissubstance and report to the 41st Meeting (June 2004).

DISCUSSION

The Committee noted the following advice from the Secretariat regarding the previousconsiderations of the scheduling of Vinclozolin:

• Vinclozolin was first considered by the Committee in February 1979. The Committeenoted that the acute toxicity of vinclozolin was very low. However, some concern wasexpressed over the formation of 3,5-dichloroaniline in strawberries and grapes treatedwith the compound. The Committee deferred its consideration of vinclozolin to allowmore information regarding the carcinogenic/mutagenic potential of 3,5-dichloroaniline to be obtained. At the August 1979 meeting the Committee was


38

advised that several literature searches had failed to yield any evidence ofcarcinogenic or mutagenic activity associated with 3,5-dichloroaniline. The matterwas referred to the Carcinogenic Substances Committee. Vinclozolin was exemptedfrom the requirements of scheduling and included in Appendix B.

• At the August 1988 meeting the Committee considered a review of toxicological datasubmitted in support a TGAC clearance of vinclozolin. The data reviewed suggestedthat vinclozolin exhibited low acute oral, dermal and inhalational toxicity in rats andguinea pigs. It was considered to be a mild skin and eye irritant in rabbits, a moderateskin sensitiser in guinea pigs and did not exhibit systemic toxicity in a 21-day rabbitdermal study. Chronic studies in mice and rats showed no carcinogenic potential. A 3-generation rat reproduction study showed no dose related effects and the teratologypackage, containing a mouse and rabbit study, indicated that vinclozolin was notconsidered to be teratogenic. Based on this data, the Committee considered that theentry for vinclozolin in Appendix B remained appropriate.

• At the NDPSC 7th Meeting (November 1995) the Committee considered additionaltoxicological data relating to a review undertaken by the then Chemicals Policy andReview Section of Environmental Health and Safety Unit. The mechanistic studiesindicated that in the rat vinclozolin acted as an anti-androgen through several of itsmetabolites binding preferentially on androgen receptors, thus preventing testosteronefrom activating the receptor. This produces serious reproductive and teratogenicadverse effects in both adult and developing animals. The Committee assumed that, inthe absence of pharmacokinetic data in humans, the human is as sensitive as the rat tothis effect. Serious reproductive effects across a range of doses (gross alteration ofmale reproduction organs rendering F1 males incapable of reproduction andaccompanied by absence or underdevelopment of the prostate, testes and epididymes)were seen in Wistar rats but not in Sprague-Dawley rats.

• On the basis of this data the Committee considered that vinclozolin posed a potentialrisk to humans because of the following:

! Vinclozolin is a teratogen that could cause irreversible damage to the foetus.! Vinclozolin is an anti-androgen with a well defined mechanism of action.

Furthermore, the anti-androgenic effects were seen across a range of animalspecies (rat, mouse, dog) and at various dose levels, including low doses.

! Vinclozolin exerts chronic effects at relatively low doses and has a very steepdose-response.

! In-vitro evidence that vinclozolin preferentially binds to human androgenreceptors, and exposure studies showing that humans could be exposed to toxiclevels in the course of daily activities involving contact with vinclozolin.

! The potential of ingestion of minimally processed food containing of significantamounts of vinclozolin.

The Committee recommended an entry in Schedule 6 on the basis of chronic,developmental and reproductive adverse effects. Several Members suggested Schedule 7


39

as an option. However, the Committee, noting that there was a threshold for the effectsand that its uses were to be restricted in order to minimise human exposure as well asapplying more stringent safety directions, were of the view that Schedule 6 wasappropriate. Consequently, the Committee also recommended Warning Statement 46 ofAppendix F, because of the potential of vinclozolin for teratogenicity and adversereproductive effects.The then National Registration Authority for Agricultural and Veterinary Chemicals(NRA) undertook a special review of vinclozolin due to toxicological and workerexposure concerns and cancelled all vinclozolin registrations effective 31 December1996.

Members noted that that the Organisation for Economic Co-operation and Development(OECD) had recently validated the Hershberger Assay, a Test Guideline designed toscreen potential endocrine disruptors in which procymidone and vinclozolin are used aspositive controls.

The Committee noted that as a consequence of the NRA review, there are currently noproducts containing vinclozolin registered with the APVMA. Therefore, any change inthe scheduling of vinclozolin will have no regulatory impact.

DECISION 2004/41 – 5

The Committee agreed to include vinclozolin in Schedule 7 on the basis of its teratogenicpotential and in order to maintain consistency with its previous decision regarding thescheduling of procymidone.


VINCLOZOLIN - delete entry


VINCLOZOLIN.

5. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FORTHE UNIFORM SCHEDULING OF DRUGS AND POISONS.

5.1 SUSDP, PART 4

There were no items considered.


40

5.2 SUSDP, PART 5

5.2.1 BIFLUORIDES

PURPOSE

The Committee considered the inclusion of entries for Schedule 7 bifluorides inAppendices E and F.

BACKGROUND

At the NDPSC 31st Meeting (May 2001) the Committee considered the scheduling ofcorrosive fluorides following the release of the NICNAS Priority Existing Chemical(PEC) Report for hydrofluoric acid. After further consideration of corrosive fluorides atthe 32nd (August 2001), the 33rd (November 2001) and the 34th (February 2002)Meetings, the Committee agreed that the corrosive fluorides including the bifluoridesshould be more restrictively scheduled in a like fashion to hydrofluoric acid on achemically equivalent basis. And that appropriate amendments should also be made toAppendices E and F to mirror the entries for hydrofluoric acid.

Amendments to the Appendix E, Part 2 and Appendix F, Part 3 entries for bifluorides inSchedule 7 intended to mirror those for hydrofluoric acid had been omitted from theSUSDP.

DISCUSSION

The Committee considered it appropriate to include:

• A, G3, E2 and S5 to the Appendix E, Part 2 entry for bifluorides when included inSchedule 7; and

• Warning Statements 1, 17, and 93 and Safety Directions 1, 3, 4, 5, 8, 29 and 35 to theAppendix F, Part 3 entry for bifluorides when included in Schedule 7.


Members agreed to amend Appendix E, Part 2 and Appendix F, Part 3 entries forbifluorides in Schedule 7 to mirror those of hydrofluoric acid.

Appendix E, Part 2 - Amendment

BIFLUORIDES (including ammonium, potassium and sodium salts) � Amend to read:

BIFLUORIDES (including ammonium potassium and sodium salts)


41

when included in Schedule 5 A

when included in Schedule 6 or 7 A,G3,E2,S5

Appendix F, Part 3 - Amendment

BIFLUORIDES � Amend to read:

BIFLUORIDES (including ammonium, potassium and sodium salts)

(a) when included in Schedule 5

Warning statements .............................2Safety directions ..................................1,4

(b) when included in Schedule 6 or 7

Warning statements .............................1,17,93Safety directions�� 1,3,4,5,8,29,35

6. MATTERS REFERRED BY THE AUSTRALIAN PESTICIDESAND VETERINARY MEDICINES AUTHORITY.

6.1 MOLINATE

PURPOSE

The Committee considered the scheduling of molinate.

BACKGROUND

Molinate was nominated for review under the APVMA Chemicals Review Program(CRP) following recent reports that low doses of the chemical could cause irreversibledamage to nerves (neuropathy) and interfere with the development of the foetus and theyoung (developmental toxicity).

Molinate was last reviewed in 1986. The Acceptable Daily Intake (ADI) of 0.002 mg/kgbw established at that time was based on the No Observed Effect Level (NOEL) of 0.2mg/kg bw for adverse effects on fertility in male rats. The database reviewed in 1986 didnot contain any studies which indicated that molinate could cause neuropathy anddevelopmental toxicity.


42

Molinate is a thiocarbamate herbicide which has been used to control barnyard grass andsilver top or brown beetle grass in rice crops in Australia for over 30 years. Currentlythere are four products containing molinate registered by the APVMA.

DISCUSSION

The Committee noted the following points raised in the OCS evaluation report forconsideration:

• In rats, molinate has low to moderate oral toxicity (LD50 = 549 mg/kg bw) and lowdermal toxicity (LD50 ~ 4350 mg/kg bw). Data evaluated in 1986 indicated thatmolinate has moderate inhalational toxicity (the LC50 in rats was 830 mg/m3).Molinate was a slight skin and eye irritant in rabbits and was classified as a skinsensitiser in the guinea pig maximisation test.

• Molinate is formulated as an emulsifiable concentrate at 960 g/L, and is used solely asa herbicide in rice cultivation. It is applied as a spray, either on-ground or aerially, todry rice bays, rice in permanent water or to inflowing water. Molinate can be usedundiluted when applied to inflowing water, or diluted in water for other applications.The on-ground use rate per hectare is 3.75 L in 200 L water for dry bays and 3.75 L in5-10 L for permanent water. For aerial application, the use rate per hectare is 3.75 Lin 10-100 L.

• Certain aspects of the reproductive toxicity of molinate were recognised when thechemical underwent a public health assessment in Australia in 1980 and 1986. TheADI established at the time (0.002 mg/kg bw/d) was based on the NOEL of 0.2 mg/kgbw/d, for testicular degeneration in male rats, and a 100-fold safety factor.

• New data submitted to the US EPA, as part of their re-registration program, indicatedthat molinate caused neuropathy and developmental toxicity in experimental animalsat low doses. The potential relevance of the neuropathy findings to humans isconsidered high because the lesions developed in four species and there was noevidence that they were reversible. The major issues raised by the EPA assessmentwere:! The high dermal absorption of molinate (40%).

! NOAELs were not established in acute and 90-day neurotoxicity studies in rats.The Low Observable Adverse Effect Level (LOAEL) in the acute study was 25mg/kg bw (decreased motor activity, increased time to tail flick). The LOAEL inthe 90-day study was 4 mg/kg bw/d (decreased brain cholinesterase activity andneuropathy target esterase activity), while nerve fibre degeneration in the sciaticand sural nerves occurred in males at 35.5 mg/kg bw/d.

! A NOAEL was not established in a rat developmental neurotoxicity study(LOAEL = 1.8 mg/kg bw/d; reduction in startle amplitude in pups). Reductions inmorphometric measurements of certain areas of the cerebellum also occurred inpups at the maternal NOAEL (6.9 mg/kg bw/d).


43

! The NOAEL for developmental toxicity (2.2 mg/kg bw/d; increased runting) wasbelow the NOAEL for maternotoxicity in rats (35 mg/kg bw/d).

! In a 2-generation reproduction study, a NOAEL was not determined for decreasedbrain weight in adults and pups of all generations (LOAEL = 0.4 mg/kg bw/d).Effects on the reproductive organs and delayed vaginal opening occurred at lowdoses (0.8 mg/kg bw/d).

! The absence of NOAELs for neuropathy in chronic rat and dog studies. TheLOAEL in rats was 0.4 mg/kg bw/d based on the increased incidence ofdegeneration or demyelination in the sciatic nerve, and muscle atrophy. In dogs,the LOAEL was 1 mg/kg bw/d based on demyelination of the sciatic nerve and inthe lumbar, sacral and thoracic regions of the spinal cord.

• The OCS evaluator indicated that none of the data underpinning the EPA�sassessment were submitted for evaluation as part of the current Australian review onmolinate. Furthermore, other studies submitted to the OCS for evaluation did notaddress concerns relating to the potential neuropathy and developmental toxicity ofmolinate.

In the absence of data to address these serious toxicological concerns the OCSrecommended that approval of molinate active constituent and the registration ofmolinate products no longer be supported. Additionally, the Committee was asked toconsider the inclusion of entries for molinate in Schedule 7 and Appendix J of theSUSDP.

The Committee was advised that Nufarm Australia Limited, Farmoz Pty Ltd, Crop CareAustralasia Pty Ltd and Sipcam Pacific Australia Pty Ltd market Nufarm Molinate 960Herbicide, Farmoz Molinate 960 Herbicide, Ordram Herbicide and Sirion Herbicide,respectively. According to the PUBCRIS database, all 4 products (containing molinate ata concentration of 960 g/L) are currently labelled as Schedule 6 substances and usedexclusively in rice crops.

The Committee was informed that the scheduling consideration of molinate was includedin the pre-June 2004 meeting gazette notice and no public submissions were received.

A Member informed the Committee that the neurotoxicity and developmental effectsexhibited by molinate warranted a reconsideration of its Schedule 6 entry.

The Committee was informed that the sponsor of molinate in the USA no longersupported its continued registration and that its use would be phased out over a five yearperiod. The evaluator further advised that the sponsor no longer supported the registrationof molinate in Australia and that this was the justification for the non-submission of thedata referred to above.

The XXXXXXXXXXXX Member reminded the Committee that molinate was currentlyunder review by the XXXXXXXXXXXX and sought support amongst Members for adelayed implementation date in order to allow the review to be completed. The Member


44

advised that, in the absence of further data, the XXXXXXXXXXXX could be in aposition to make a decision by early 2005. Should further data be provided by thesponsor, time would be needed to assess this information, thus delaying the decision byseveral months.

A Member reminded the Committee that molinate had clearly been implicated inneurotoxicity in humans and that such a delay may not be justified as the Committee mustbe seen to take appropriate regulatory action. Members also noted that any decision madeat the NDPSC 41st Meeting (June 2004) meeting would not come into effect until 1January 2005.


The Committee agreed to include molinate in Schedule 7 and Appendix J.


MOLINATE � delete entry


MOLINATE.

Appendix J – New entry

Poison Conditions

Molinate 1

6.2 GONADOTROPHIN RELEASING HORMONE

Item withdrawn following advice from the sponsor.

6.3 POTASSIUM BICARBONATE

PURPOSE

The Committee considered the scheduling of potassium (and sodium) bicarbonate.

BACKGROUND

XXXXXXXXXXXX applied for registration of a new product, XXXXXXXXXXXX,which is a soluble powder formulation and contains an active constituent, potassiumbicarbonate (950 g/kg). XXXXXXXXXXXX will be used for the control of powderymildew on grapes, cucurbits, strawberries, tomatoes, ornamentals and black spot in roses.


45

A similar product, XXXXXXXXXXXX for control of powdery mildew is currentlyregistered in USA.

Potassium bicarbonate is found throughout nature in living systems and in non-livingenvironments. It is also found in human food. According to the US EPA, no adversehealth effects are expected when potassium bicarbonate is used as pesticides. The USFood and Drug Administration (FDA) also considers that potassium bicarbonate isgenerally recognised as safe.

Currently there are no products containing potassium bicarbonate registered by theAPVMA. However, there are 24 products containing sodium bicarbonate currentlyregistered with the APVMA for such uses as anti-scour treatments, electrolytereplacements, digestive and mineral supplements and tick fever vaccines.

DISCUSSION


• Potassium bicarbonate has low acute oral, dermal and inhalation toxicity, is a slighteye irritant, but not a skin sensitiser or skin irritant. The acute oral LD50 forpotassium bicarbonate of 2825 mg/kg bw, is consistent with the NDPSC guidelinesfor inclusion in Schedule 5 of the SUSDP.

• Sodium bicarbonate also exhibits low acute oral toxicity (LD50 4220 mg/kg bw in therat) and is a slight eye irritant but not a skin irritant or skin sensitiser.

• Given that potassium bicarbonate is of low toxicity, widely used in human food, anormal constituent of human tissues and generally recognised as safe by the FDA, theOCS recommended the inclusion of potassium bicarbonate in Appendix B of SUSDP.Furthermore, given its similar toxicological profile and uses, the OCS recommendedthat the Committee also consider exempting sodium bicarbonate from therequirements of scheduling.

Members were advised that according to the PUBCRIS database, all 24 productscontaining sodium bicarbonate are currently labelled as unscheduled substances. TheCommittee noted that if it were to decide that the inclusion of an entry in Schedule 5 forpotassium bicarbonate was warranted, there would be no regulatory impact foragricultural and veterinary chemicals as there are no products containing potassiumbicarbonate currently registered with the APVMA. However, the inclusion of potassiumbicarbonate in Schedule 5 was likely to have a significant regulatory impact on humantherapeutics as there are currently 66 products listed on the ARTG containing potassiumbicarbonate, most of which would be either unscheduled or in a lower schedule than thatproposed. There would also be a significant regulatory impact on certain food products ifpotassium bicarbonate were to be included in Schedule 5.


46

The Committee was informed that a public submission had been received fromXXXXXXXXXXXX. The company advised that it has an interest in potassiumbicarbonate and sought to reserve the right to make post-meeting comment.

A Member expressed the opinion that in light of their low toxicities, exemptingpotassium bicarbonate and sodium bicarbonate from the requirements of scheduling wasnot unreasonable.


The Committee agreed to exempt potassium bicarbonate and sodium bicarbonate for therequirements of scheduling on the basis of its low toxicity.

Appendix B – New entries

SUBSTANCE DATE OFENTRY

REASONFOR

LISTING

AREAOF

USE

POTASSIUM BICARBONATE June 2004 a 1SODIUM BICARBONATE June 2004 a 1

6.4 OCTENOL

PURPOSE

The Committee considered the scheduling of octenol.

BACKGROUND

XXXXXXXXXXXX applied for the registration of a new product, containing 100%(1000 ml/L) octenol (1-Octen-3-ol, CAS 3391-86-4). The octenol will be used as anattractant, luring mosquitoes and biting midges into a trap where they are dehydrated anddie within 24 hours. This product has been registered in USA as a pesticide.

1-Octen-3-ol is a naturally occurring compound found in plants, animals, edible fruits andvegetables. Furthermore, it is widely used as a flavouring ingredient in foods and isapproved by the US FDA as a direct food additive and the Council of Europe as anartificial flavouring agent. The US FDA considers that octenol is generally recognised assafe (GRAS).


47

DISCUSSION


• XXXXXXXXXXXX will be sold in a package which has 1, 3, 6 or 10 child resistant,crush proof, cartridges with each cartridge containing 1.66 g of octenol. Eachcartridge is contained within a PET tray with a plastic cover over the top. Theoperator does not need to touch the cartridge in use of the product as the tray isplaced, intact, into the trapping device.

• Octenol has moderate acute oral toxicity (LD50) of 340 mg/kg bw, low dermaltoxicity (LD50) of 3300 mg/kg bw and an inhalation toxicity (LC50) of 3720 mg/m3.It may be an irritant to the eye, but is not a skin irritant or a skin sensitiser.

• [Paragraph deleted]On the basis of the above considerations, the OCS recommended that an entry for octenolbe included in Schedule 6 of the SUSDP with a cut off to Schedule 5 when packed in biteand crush resistant cartridges containing 2 g or less of octenol.

The Committee was informed that the scheduling consideration of octenol was includedin the pre-June 2004 meeting gazette notice and no public submissions were received.

A Member expressed the opinion that based on the toxicological information submittedan entry for octenol in Schedule 6 was appropriate. However, the Member was concernedthat there did not appear to be a recognised standard to test whether the packaging is �biteand crush resistant� as the sponsor had claimed. Members agreed that it was difficult toconsider the suitability of non-standard packaging in the absence of a sample to assess.Members agreed that the actual product packaging would need to be seen by theCommittee before any decision regarding a cut-off to Schedule 5 could be considered.Accordingly, the evaluator was asked to obtain an example of the product packaging forconsideration by the Committee at the 42nd Meeting (October 2004).

The Committee further agreed that, in order to assist Members in making futurescheduling decisions regarding domestic, agricultural and veterinary chemicals, examplesof product packaging should be provided with the evaluation report in situations wherethe packaging proposed did not conform to a recognised standard. Furthermore, theevaulator should also provide specific comment in the evaluation report on the packagingand presentation of the product, particularly in regard to public safety.

The XXXXXXXXXXXX advised the Committee that octanol is used in perfumes andsoaps at low concentrations (up to 1.5%) and that it may also be used in food additives.The Committee agreed that information regarding its use in cosmetics and food additiveswould also need to be obtained for consideration at the 42nd Meeting (October 2004).


48

The Committee was reluctant to defer the consideration of octenol to the 42nd Meeting(October 2004) as this would delay the implementation date and thus delay theregistration of the sponsor�s product. As an alternative the Committee agree to consideran entry for octenol in Schedule 6 and then subsequently consider the proposal for a cut-off to Schedule 5 at the 42nd Meeting (October 2004) after assessing the product�spackaging. This would also allow time to determine the regulatory impact on cosmeticsand food additives resulting from the proposed scheduling of octenol.


The Committee agreed to include an entry for 1-octen-3-ol in Schedule 6 on the basis ofits acute oral toxicity.


1-OCTEN-3-OL when packed and labelled for use as an insect attractant.

6.5 FIROCOXIB

PURPOSE

The Committee considered the scheduling of firocoxib.

BACKGROUND

XXXXXXXXXXXX submitted an application for the registration of XXXXXXXXXXX.The product consists of flavoured, chewable tablets formulated in two sizes, 57 mg and227 mg of the active ingredient firocoxib. The company advises that the product is likelyto be used in older dogs to relieve inflammation and pain from ailments such asosteoarthritis and other age-related conditions. The product may also be used to treatother musculo-skeletal disorders and post-operative pain in dogs.

Firocoxib is an anti-inflammatory, analgesic and anti-pyretic drug of the �coxib� class,which selectivity inhibits cyclooxygenase-2 (COX-2) isozyme. COX-2 is an immediateearly response gene product in inflammatory and immune cells. COX-2 also plays aphysiological role in a number of tissues including the female reproductive tract, thekidney and vascular endothelium.

DISCUSSION


• [Paragraphs deleted]


49

Based on firocoxib�s low acute toxicity, its intended use as a therapeutic agent, whichrequires professional veterinary advice and management prior to use, the OCSrecommended inclusion in Schedule 4.

[sentences deleted] The OCS thus recommended that the committee consider restrictingthe product pack size to blister packs containing 10-30 tablets to ensure that the productwas dispensed in its original packaging displaying the appropriate safety directions to theconsumer. The Committee was advised that Part 2 � Labels and Containers stipulates thata person must not sell or supply a poison unless it is labelled in accordance withparagraphs 3 to 19 of this Standard. Furthermore, paragraphs 7(n) and 7(o) specificallyrequire that, if a poison may be harmful to the user, the label must carry appropriatesafety directions and warning statements.

The Committee noted that XXXXXXXXXXXX had subsequently advised thatXXXXXXXXXXXX XXXXXXXXXXXX. XXXXXXXXXXXX contended that theavailability of the 60 tablet bottle to veterinarians was important for use in veterinaryhospitals and that there would be little motivation to dispense from the 60 tablet bottlegiven the ready availability of a 10 tablet blister pack.

The Committee was advised that the draft label provided in the submission stated underPrecautions that �Safe use in breeding, pregnant or lactating dogs has not beenestablished� and thus did not highlight the teratogenic potential of firocoxib. It wasrecommended that the Committee consider drawing this issue to the attention of theAPVMA.

The Committee was informed that the scheduling consideration of firocoxib was includedin the pre-June 2004 meeting gazette notice and no public submissions were received.

A Member agreed that pack size restrictions should be applied so that veterinarians werediscouraged from dispensing small numbers of tablets to clients without appropriatelabels. Furthermore, advising the APVMA that warning statements be included in theproduct statement regarding the effect of the substance on breeding animals would alsobe appropriate.

Accordingly, the Committee agreed to recommend that the APVMA consider that theproduct only be available to the consumer in blister packs with the 60 tablet bottlerestricted to veterinary hospitals and that appropriate warnings regarding the potential forteratogenic effects in female dogs intended from breeding purposes be included in theproduct information and on product packaging.

DECISION 2004/41 - 10

The Committee agreed to include an entry for firocoxib in Schedule 4 on the grounds thatthe condition being treated necessitates appropriate veterinary diagnosis and the safe useof this medicine requires management and monitoring of the treated dog by a veterinaryprofessional.


50


FIROCOXIB.

6.6 QUINCLORAC

PURPOSE

The Committee considered the scheduling of quinclorac.

BACKGROUND

XXXXXXXXXXXX submitted an application for new active constituent, quinclorac, andthe registration of a new product XXXXXXXXXXXX containing 750 g/kg quinclorac.XXXXXXXXXXXX is intended for the post-emergence control of summer grass andwhite clover and the suppression of kikuyu in turf. XXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXX XXXXXXXXXXXX .

Quinclorac is a carboxylic acid type chemical that mimics the natural plant hormone,indoleacetic acid and brings about its herbicidal activity by acting as an enzyme/cell walldisruptor.

DISCUSSION


• [Paragraphs deleted]The Committee was informed that the scheduling consideration of quinclorac wasincluded in the pre-June 2004 meeting gazette notice and no public submissions werereceived.

A Member advised the Committee that, in addition to exhibiting relatively low toxicity,quinclorac�s mode of biochemical action is specific to plants and that consequently, anentry in Schedule 5 was appropriate.

A Member expressed concern that the product containing quinclorac would be marketedto home gardeners in pack sizes greater than 1 kg. Members agreed that pack size was notan issue for concern in this case given the low toxicity exhibited by the substance.

DECISION 2004/41 - 11

The Committee agreed to include an entry for quinclorac in Schedule 5 on the basis of itsacute oral toxicity and skin sensitisation potential.


51


QUINCLORAC.

6.7 FLUMICLORAC PENTYL ESTER

PURPOSE

The Committee considered the scheduling of flumiclorac pentyl.

BACKGROUND

XXXXXXXXXXXX submitted an application for the approval of a new active,flumiclorac pentyl and the registration of the new product XXXXXXXXXXXX. Theproduct will contain 100 g/L flumiclorac pentyl as the active ingredient in a formulationcontaining hydrocarbon solvent.

Flumiclorac pentyl is a N-phenylimide herbicide and a porphyrin biosynthesis pathwayinhibitor, proposed to act by reducing the enzyme activity of protoporphyrinogen oxidase.The product is an emulsifiable concentrate and will be used as a defoliant in cottonplants.

DISCUSSION


• [Paragraphs deleted]Based on the above data, the OCS recommended that flumiclorac pentyl be exempt fromthe requirements of scheduling.

The Committee was informed that the scheduling consideration of flumiclorac pentyl wasincluded in the pre-June 2004 meeting gazette notice and no public submissions werereceived.

A Member expressed the opinion that the data presented was deficient in informationregarding flumiclorac pentyl�s primary mode of action in biosynthesis. The Memberadvised that in previous considerations of similar substances these had been included inSchedule 7. In particular, concern was expressed that protoporphyrinogen oxidase is thepenultimate enzyme in both chlorophyll and heme biosynthesis and should a susceptibleperson to porphyria come in contact with flumiclorac pentyl, it may trigger an attack. Theevaluator informed Members that the assessment did not identify any significanthaematological concerns in the mammalian studies evaluated and that this may resultfrom flumiclorac pentyl exhibiting a greater plant specificity than other analoguespreviously considered by the Committee. The Member acknowledged that flumicloracpentyl did exhibit a lower toxicity profile and produced less porphyrin when compared


52

with other compounds in its class, however, in his view the sponsor failed to supply dataon this matter for the Committee�s consideration.

A Member noted that flumiclorac pentyl had been identified as a potential skin sensitiseron the basis of tests conducted in the late 1980�s and early 1990�s. The Member wasconcerned that perhaps there may be more recent experiences since 1992 with thesubstance�s skin sensitiser potential that have not been made available to the Committeefor consideration. The evaluator advised the Committee that, given the time lag betweenproduct registration and product sale, there was unlikely to be any significant exposureand epidemiological monitoring to produce such information. Furthermore, the evaluatorreminded the Committee that the sponsor is obliged to provide all known data to the OCSfor evaluation including any monitoring data, however, in this case the sponsor hadindicated that there were no findings to report. The XXXXXXXXXXXX advised theCommittee that flumiclorac pentyl would be considered to be a skin sensitiser in theworkplace on the basis of the tests submitted.

OUTCOME

The Committee agreed to defer consideration of the scheduling of flumiclorac pentyl inorder to seek more information regarding porphyrin metabolism and its potential totrigger an attack of porphyria. Furthermore, the Committee asked that the sponsorconfirm that there is no evidence of skin sensitisation or the onset of acute porphyricattacks associated with the use of flumiclorac pentyl.

6.8 PERMETHRIN

PURPOSE

The Committee considered the scheduling of permethrin.

BACKGROUND

XXXXXXXXXXXX submitted an application for the registration of a productXXXXXXXXXXXX for dogs (0.4 - 4 mL tubes to suit dogs of various body weights)containing two active constituents, permethrin (500 g/L, cis:trans isomers 40:60) andimidacloprid (100 g/L). The applicant proposed a change to the scheduling for permethrinto allow inclusion in Schedule 5 when packed in single use containers having a capacityof 4 mL or less. Currently, the product would be labelled as a Schedule 6 poison on thebasis of its permethrin content.

XXXXXXXXXXXX is intended for home use on dogs and will be applied (up to 8 mL)on the skin every two weeks for the control of paralysis ticks (Ixodes holocyclus) ormonthly for the control of all other ticks and/or fleas, and for mosquitoes and midges.

Permethrin is a synthetic pyrethroid insecticide while imidacloprid is an ectoparasiticidebelonging to the chloronicotinyl group of compounds.


53

Permethrin was first considered at the May 1977 meeting where it was exempted fromthe requirements of scheduling on the grounds of low toxicity. At the NDPSC 2nd

Meeting (August 1994) the Committee considered new data suggesting that permethrinexhibited moderate acute oral toxicity but delayed making a decision until a list ofregistered products containing permethrin was obtained from the NRA. A decision todelete permethrin from Appendix B and include an entry in Schedule 6 with a cut-off toSchedule 5 for preparations containing 25% or less was made at the NDPSC 3rd Meeting(November 1994). Preparations containing 2% or less of permethrin remained exemptfrom the requirements of scheduling.

DISCUSSION



• The ADI for permethrin is 0.05 mg/kg/day based on a NOEL of 5 mg/kg/day inchronic studies in rats and dogs. Imidacloprid has an ADI of 0.06 mg/kg bw/daybased on a NOEL of 6 mg/kg bw/day in a 2 year rat study. Target organs for toxicitywere liver (permethrin) and thyroid (imidacloprid). There is no ARfD established foreither permethrin or imidacloprid.

• In animal studies, permethrin was not carcinogenic, and it did not show anyreproductive or developmental toxicity. Imidacloprid was not carcinogenic and didnot show reproductive toxicity, but showed embryofetal effects (wavy ribs in rats;increased post-implantation loss, and decreased fetal weights and development inrabbits) but the changes were associated with maternal toxicity (NOEL: 10 and 30mg/kg bw/d for maternal and fetal toxicity in rats, respectively; 8 and 24 mg/kg bw/dfor maternal and fetal toxicity in rabbits, respectively).

Based on the acute toxicity profile of XXXXXXXXXXXX, the OCS recommended aSchedule 5 entry for preparations containing 26-50% permethrin when packed in singleuse containers having a capacity of 4 mL or less.

The Committee was advised that, according to the PUBCRIS database, there are 269products containing permethrin of which 63 are veterinary pesticides and 5 are veterinarymedicines. The Committee noted that an amendment to the Schedule 5 entry forpermethrin to include preparations containing 50% or less when packed in single usecontainers having a capacity of 4 mL or less would result in 9 products currentlyregistered with the APVMA being down-scheduled from Schedule 6 to Schedule 5. Theseproducts, containing 40% permethrin, are all used to control fleas and ticks on dogs andare available in single dosage units of 2 and 4 mL.

The Committee was informed that public submissions were receivedXXXXXXXXXXXX, XXXXXXXXXXXX, and XXXXXXXXXXXX.


54

XXXXXXXXXXXX advised that it holds the registration for XXXXXXXXXXXXcontaining permethrin currently labelled as Schedule 5. The company also provided acopy of their product�s registered label and sought the right to make post-meetingcomment.

XXXXXXXXXXXX advised that it has an interest in permethrin and sought the right tomake post-meeting comment.

XXXXXXXXXXXX advised that, in its opinion, permethrin poses a significanttoxicological risk to cats. Specifically, the company expressed concern that this non-target species would be exposed to the substance through contact with dogs and productmisuse. Therefore, XXXXXXXXXXXX recommended that permethrin remain inSchedule 6 and that the Committee consider lowering the 25% cut-off to Schedule 5. TheCommittee was advised that the submission was forwarded to the OCS for assessment. Inresponse, the OCS advised the Committee that while there are genuine concerns, theissues identified primarily relates to off label use or inappropriate use and as such were anissue for the APVMA to consider during deliberations on label directions. In the OCS�sview, scheduling is not an appropriate mechanism for controlling the use of products incontravention of the label directions. The OCS considered that the possible use on orexposure to cats was an issue of off-label use and as such a matter for the APVMA andrecommended that Committee refer these issues to the APVMA.

A Member expressed concern over the possibility of exposure to non-target animals suchas cats, not only through off label use but also through exposure to treated dogs in thesame household. The Member advised the Committee that while permethrin is non-toxicto dogs at the dosage rates recommended by the sponsor, it is extremely toxic to cats atthe same levels. The Member considered it inappropriate to remove the �Poisons� labelrequirement by down-scheduling the sponsor�s product because the consumer should bemade aware of the risks to non-target animals such as cats.

A Member also expressed the opinion that a product that exhibited severe eye irritationwhich was not reversible within 7 days should remain in Schedule 6.

A Member highlighted the issue of accidental ingestion by children. Specifically, thestatement in the OCS report referring to a child safety study in which up to 19% ofchildren successfully opened the product packaging and thereby could ingest thecontents. The Member expressed the opinion that ingestion of the product by a child mayresult in exposure to permethrin approaching a possibly toxic level and that moving aproduct such as this into Schedule 5 was inappropriate.

The Committee was concerned that down-scheduling of permethrin may increase thepossibility of accidental ingestion by children and the poisoning of non-target species,however, acknowledged that the latter may be dealt with by appropriate label warnings.

In light of the Committee�s decision, the OCS evaluator drew to the attention of Membersthat there were products currently labelled as Schedule 5 containing 25% or less of


55

permethrin in pack sizes with a volume of much greater than 4 mL that would pose agreater risk of exposure if accessed by children. The Committee acknowledged that thereappeared to be an inconsistency in the approach to the scheduling of these products giventheir decision regarding the sponsor�s product and asked the Secretariat to review theexisting Schedule 5 entry for premethrin and report to the 42nd Meeting (October 2004).

OUTCOME

The Committee noted that the OCS assessment reported a child safety study whichindicated that a significant proportion of children could gain access to the sponsor�sproduct packaging and thus potentially ingest the contents. The Committee wasconcerned that agreeing to the company�s request to increase the Schedule 5 cut-off forpermethrin to 50% would result in the product being more readily available in homes andthus increasing the potential for permethrin exposure to children. Similarly, Memberswere concerned that a change to the Schedule 5 entry for permethrin in accordance withthe company�s proposal may also result in an increase in the poisoning of non-targetspecies such as cats. Accordingly, the Committee agreed that the current scheduling ofpermethrin remained appropriate.

7. MATTERS REFERRED BY THE OFFICE OF CHEMICALSAFETY (OCS)

7.1 ANDROSTENEDIONE ALBUMEN CONJUGATE WITH DEADEXTRAN ADJUVANT

PURPOSE

The Committee considered the scheduling of androstenedione albumen conjugate withDEA dextran adjunct.

BACKGROUND

Androstenedione albumin conjugate with DEA Dextran adjuvant (AAC), also known aspolyandroalbumin, is a vaccine intended for use in sheep to increase the frequency oftwins born to breeding ewes. The active has previously been marketed in Australia asXXXXXXXXXXXX but was removed from the market for commercial reasons.

Androstenedione albumen conjugate with DEA dextran adjunct was first considered atthe February 1983 meeting. The Committee noted that no data regarding acute, sub-acute,chronic or human toxicity were submitted in support of the application. The Committeesupported the view that due to the nature of the product, AAC should be exempt from therequirements of scheduling. Accordingly, an entry for AAC was included in Appendix Bof the SUSDP.


56

Appendix B was removed from SUSDP 11 and subsequent editions because of concernsthat it may be misinterpreted, particularly as reasons for the inclusion of many substanceson the list were unclear.

Appendix B was reinstated at the NDPSC 37th Meeting (February 2003). AAC was notincluded in the list at this time due to there being no or limited toxicological informationand the understanding that there were no AAC products registered with the NRA(APVMA) at the time. In 2000, the OCS reviewed a registration application forXXXXXXXXXXXX containing AAC at a concentration of 600 mg/L. The OCSrecommended that the product be labelled as an exempt product on the basis of the earlierAppendix B entry. The application was not referred to the NDPSC as no newtoxicological data was submitted.

In response to a question raised by Industry regarding the scheduling of AAC, theSecretariat sought advice for OCS on whether there was sufficient toxicological dataavailable to allow the reinstatement of ACC in Appendix B.

DISCUSSION

In response to the Secretariat�s request, the Committee noted that the OCS provided itsXXXXXXXXXXXX evaluation report and a summary of their principle conclusions.Members noted that the OCS report identified the following two issues for theCommittee�s consideration:

• The primary hazards associated with the occupational use of XXXXXXXXXXXXare the potential for allergic reaction following acute exposure and a potential fortemporary disturbance of reproduction in women that may result in multiple births ortemporary infertility. The limited evidence available suggests that these effects wouldbe of limited duration and dependent on the attainment of substantial antibody titres.Under most circumstances of accidental self-injection the exposure is likely to beinsufficient for the necessary antibody levels to result. However, these conclusionsare drawn from minimal information, and whilst the hazards associated withaccidental self-administration appear likely to be low, some, slight, potential existsfor reproductive disturbance to result.

• The key conclusion from the toxicological assessment was that AAC was found to beinactive both anabolically and androgenically in castrated male rats.

On the basis of their evaluation, the OCS expressed the view that there are notoxicological hazards inconsistent with the inclusion of AAC in Appendix B of theSUSDP.

A Member expressed concern that the products steroidal content may encourage misuseshould the product remain unscheduled. The evaluator advised the Committee that thesteroidal component of the product was present at a very low concentration such that itwas unlikely that enough could be injected into the body to aid muscle growth.


57

Furthermore, the Committee was reminded that studies in rats had shown that ACC didnot exhibit any anabolic or androgenic effects.

DECISION 2004/41 - 12The Committee agreed to exempt androstenedione albumen conjugate with DEA dextranadjunct from the requirements of scheduling on the basis of its low toxicity.

Appendix B – New entry

SUBSTANCE DATE OFENTRY

REASONFOR

LISTING

AREAOF

USE

ANDROSTENEDIONE ALBUMENCONJUGATE WITH DEA DEXTRANADJUNCT

June 2004 a 2.1

8. ANTIBIOTICS FOR CONSIDERATION FOLLOWINGRECOMMENDATIONS OF THE JOINT EXPERT TECHNICALADVISORY COMMITTEE ON ANTIBIOTIC RESISTANCE(JETACAR)

BACKGROUND

In 1999, the Joint Expert Advisory Committee on Antibiotic Resistance (JETACAR)recommended:

�That all antibiotics for use in humans and animals (including fish) be classified as S4(prescription only)� (Recommendation 6).

The Commonwealth Government�s response to the JETACAR Report accepted �theconcept that all antibiotics for use in humans and animals (including fish) be classified asS4 (prescription only)�. However, the Government�s acceptance was qualified byhighlighting that �� certain antibiotic products might be exempted from this schedulingclass where the Australian Pesticides and Veterinary Medicines Authority (APVMA), theTherapeutic Goods Administration (TGA) and the NDPSC assess the antibiotic productsas having a low and acceptable risk of promoting antibiotic resistance�.

The Committee agreed at the 35th Meeting (June 2002) that the scheduling of antibioticscurrently registered with the APVMA and listed outside of Schedule 4 in the SUSDPwould be reviewed. This intention was included in the post - October 2002 meetingnotice published in the Commonwealth of Australia Gazette No GN 49, 11 December2002.


58

The Committee agreed to consider each substance gazetted for consideration at the 42nd

Meeting (June 2004) collectively. These were sulfonamides (class entry), sulfacetamide,sulfadiazine, sulfadimidine, sulfamerazine, sulfaquinoxaline and sulfathiazole (8.1-8.7).Additionally, the Committee also agreed to consider tiamulin (8.8) which was initiallyconsidered at the 40th Meeting (February 2004).

8.1-8.7 SULFONAMIDES

PURPOSE

The Committee considered the scheduling of the sulfonamides.

BACKGROUND

Sulfonamides inhibit the growth of bacteria by interfering in the biosynthesis of folicacid, essential for the production of amino acids and nucleotides. Within the folic acidpathway, dihydropteroate synthase (DHPS) catalyses the synthesis of 7,8-dihydropteroatefrom pterin pyrophosphate and para-aminobenzoate (PABA); sulfonamides compete withPABA for this enzyme and inhibit its activity.

A search of the PUBCRIS database revealed that there are approximately 90 productsregistered with the APVMA containing sulfacetamide, sulfadiazine, sulfadimidine,sulfamerazine, sulfaquinoxaline, sulfadoxine, sulfathiazole, sulfatroxazole andtrimethoprim. Of these products containing these sulfonamides, 13 are labelled as eitherSchedule 5 or Schedule 6 products and their uses include the treatment of aquarium fishor caged ornamental birds or for the for treatment of coccidiosis in poultry. With theexception of one product that is available in a 25 kg pack, all other products are availablein pack sizes of less that 1 kg/L or 100 tablets.

The following sulfonamides are currently listed in the SUSDP: mafenide,phthalylsulfathiazole, sulfadoxine, sulfamerazine, sulfametrole, sulfamonomethoxine,sulfaquinoxaline, sulfatroxazole, sulfacetamide, sulfadiazine, sulfadimethoxine,sulfadimidine, sulfafurazole, sulfaguanidine, sulfamethizole, sulfamethoxazole,sulfamethoxypyridazine, sulfamoxole, sulfapyridine, sulfathiazole, tetroxoprim andtrimethoprim. Of these the following have entries outside Schedule 4: mafenide (S6 fortreatment of aquarium fish), sulfamerazine (S5 for ornamental fish), sulfaquinoxaline (S5as a coccidiostat in poultry, exempt in animal feeds and vermin baits), sulfacetamide (S3for ophthalmic use, S5 for ornamental fish and birds), sulfadiazine (S5 for ornamentalfish and birds), sulfadimidine (S5 for ornamental fish and birds) and sulfathiazole (S5 forornamental fish and birds).

DISCUSSION

The Committee was informed that XXXXXXXXXXXX had made a public submission.The company advised that it markets XXXXXXXXXXXX which contains 10%sulfacetamide and is currently labelled as a Schedule 3 human therapeutic product. The


59

company further stated that the product is a topical preparation indicated for the treatmentof minor ocular infections such as mild to moderate conjunctivitis. The Committee wasadvised that the covering letter and submission were forwarded to EAGAR for theirconsideration.

The Committee noted advice from EAGAR which recommended that, as the potential forand realisation of resistance to agents in the same class as sulfonamides and to thedevelopment of cross resistance to other antibiotics, all sulfonamides currently registeredfor use in humans and food animals should be included in Schedule 4 for all uses.EAGAR further recommended that sulfonamides in preparations registered for use inaquariums, for ornamental fish and for caged ornamental birds need not be included inSchedule 4 on the basis that the exposure of bacteria to the sulfonamides resulting fromthese uses would be insignificant and, consequently, there would be minimal potential forthe development of resistance transferable to humans. The scheduling of these productsoutside Schedule 4 was recommended by EAGAR on the condition that:

• Pack sizes are such that would preclude the use of these products for commercialpoultry or aquaculture; and

• The products contain a restraint on the label that the product is not to be used on foodanimals.

The Committee noted advice from the APVMA that supported the recommendationsmade by EAGAR. The APVMA advised that all sulfonamides used in food producinganimals, except sulfaquinoxaline when packed and labelled for use as a coccidiostat inpoultry, are currently only available under veterinary prescription. Furthermore, of the 5products containing sulfaquinoxaline, 3 products also contain diveridine and areconsequently labelled as Schedule 4 products. The APVMA further advised that thepoultry industry has access to two other coccidostats currently labelled outside Schedule4 and as such the regulatory impact resulting from the inclusion of the sulfaquinoxaline inSchedule 4 would be minimal.

The Committee noted that the Schedule 4 sulfonamide entry currently included anexemption for sulfaquinoxaline when incorporated into baits for the destruction of verminand for sulfonamides when packed and labelled solely for use as a herbicide. TheCommittee was advised that, according to PUBCRIS, no such products were currentlyregistered with the APVMA.

Members noted that the majority of products containing sulfonamides for the treatment offood animals were available in packs sizes of less that 1 kg/L, and expressed concern thatit would be difficult to limit their availability to domestic use through scheduling. AMember suggested that appropriate pack size limits for products for aquariums,ornamental fish and caged ornamental birds were a matter for the APVMA and could becontrolled during the product registration process.

Members also noted that a decision to reschedule sulfacetamide from Schedule 3 toSchedule 4 in accordance with the EAGAR recommendation would lead to an


60

unharmonised scheduling position with New Zealand. The Committee noted thatconfirmation had been sought from EAGAR that it considered the public submissionfrom XXXXXXXXXXXX before recommending that all sulfonamides used in humanand non-food producing animals be included in Schedule 4. EAGAR advised that theXXXXXXXXXXXX submission had been taken into consideration and that theCommittee should note its initial recommendation regarding the scheduling of thesulfonamides. A Member expressed concerned that there appeared to be no evidence of adetailed review of the XXXXXXXXXXXX submission concerning the 10%sulfacetamide product currently labelled as a Schedule 3. The Committee thought itappropriate that the XXXXXXXXXXXX submission be independently reviewed andadvice obtained on whether maintaining an entry for a 10% sulfacetamide preparation inSchedule 3 presented an unacceptable risk of promoting antibiotic resistance. Thescheduling of sulfacetamide would be further considered at the October 2004 meeting.

DECISION 2004/41 - 13The Committee agreed to include the sulfonamides (except sulfacetamide pendingadvice) when used in humans and food animals in Schedule 4 of the SUSDP.Furthermore, the Committee agreed to limit the use of sulfonamides outside Schedule 4to ornamental fish and for caged ornamental birds. The Committee also agreed to makean editorial amendment to the mafenide Schedule 6 entry for consistency with othersulfonamide entries in Schedule 5.


SULFAQUINOXALINE.


SULFONAMIDES � Amend to read:

SULFONAMIDES except:

(a) when separately specified in this Schedule; or

(b) when included in Schedule 3, 5 or 6.


SULFAQUINOXALINE � delete entry.


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EDITORIAL AMENDMENT


MAFENIDE � Amend entry to read:

MAFENIDE when packed and labelled for treatment of ornamental fish only.

8.8 TIAMULIN

PURPOSE

The Committee considered the final EAGAR report for tiamulin.

BACKGROUND

The rescheduling of tiamulin was considered by the Committee under JETACARrecommendation 6 at the NDPSC 40th Meeting (February 2004). At that time EAGARwas unable to provide a completed assessment report for tiamulin but it provided aninterim recommendation that the substance be included in Schedule 4 for all uses as it is avaluable therapeutic agent in pigs and poultry. The Committee endorsed EAGAR�srecommendation and agreed to include tiamulin for all uses in Schedule 4 of the SUSDPwhich was consistent with the Government response to JETACAR Recommendation 6.

DISCUSSION

The Committee was provided with the EAGAR final assessment for tiamulin thatconfirmed its interim advice to the February 2004 meeting.

It was noted that EAGAR recommended that tiamulin be registered as Schedule 4 to:

• Protect its value in the treatment of mycoplasma and brachyspira in pigs;

• Protect generally the value of tylosin and other macrolides in animals; and

• Protect the value of macrolides in human health.

OUTCOME

The Committee noted the EAGAR report for tiamulin.

9. OTHER MATTERS FOR CONSIDERATION

9.1 SODIUM HYPOCHLORITE

PURPOSE

The Committee considered the scheduling of sodium hypochlorite.


62

BACKGROUND

The scheduling of sodium hypochlorite was considered by the Committee as part of aclass review of chlorinating compounds at the NDPSC 25th (November 1999), 26st

(February 2000), 27nd (May 2000), 29th (November 2000), 34th (February 2002), 35th

(June 2002) and 36th (October 2002) meetings. The Committee agreed to include an entryfor chlorinating compounds in Schedule 6 with a cut-off to Schedule 5 at 20% availablechlorine. During these considerations the Committee noted that sodium hypochloriteexhibited a low acute oral toxicity (LD50 of 8910 mg/kg bw) and agreed to exempt itfrom the requirements of scheduling. These amendments were included in SUSDP 18Amendment 1 and came into effect on 1 September 2003.

DISCUSSION

The Committee was advised that correspondence had been received from Industry(XXXXXXXXXXXX) seeking clarification of the scheduling status of sodiumhypochlorite solutions containing sodium hydroxide. The company highlighted thatsodium hypochlorite is manufactured via a reaction between sodium hydroxide andchlorine gas in water. In order to ensure that the equilibrium reaction is maintained infavour of hypochlorite formation and to prevent the liberation of chlorine gas, a smallexcess of sodium hydroxide is added to maintain the pH between 11 and 13.Consequently, commercially available preparations of sodium hypochlorite contain smallquantities of sodium hydroxide (≤ 1% w/v).

The Committee noted that currently sodium hypochlorite is exempt from therequirements of scheduling. However, the presence of sodium hydroxide would requirethese preparations to be labelled as either Schedule 5 or Schedule 6 poisons depending ofthe percentage of available chlorine and the pH of the particular solution.

Members were informed that the company had sought clarification of this issue fromXXXXXXXXXXXX and was advised that �If a solution of sodium hypochlorite containssodium hydroxide and the pH is above 11.5, it would still be scheduled based on itsalkalinity�. XXXXXXXXXXXX proposed that sodium hypochlorite solutions with a pHof less than 11.5 be exempt from the requirements of scheduling while those with a pHabove 11.5 should remain scheduled. Furthermore, the Committee should ensure that theentry in the SUSDP preclude the intentional adjustment of strong chlorine solutions tobelow pH 11.5 by the addition of sodium hydroxide. The Committee noted that by settinga sodium hydroxide cut-off a 1% w/v, the possibility of the intentional adjustment ofstrong chlorine solutions to below pH 11.5 by the addition of sodium hydroxide would beavoided. Furthermore, allowing for the presence of sodium hydroxide at this level wouldmirror the levels currently available in commercial preparations.

The Committee was of the view that as the presence of sodium hydroxide in sodiumhypochlorite solutions is unavoidable, an exemption from the requirements of schedulingfor preparations containing 1% or less is a reasonable proposition.


63

OUTCOME

The Committee agreed to exempt from the requirements of scheduling all sodiumhypochlorite solutions containing not more than 1% sodium hydroxide and with a pH ofless than 11.5.

FORESHADOWED DECISION(for consideration at NDPSC 42nd Meeting of October 2004)


CHLORINATING COMPOUNDS � Amend to read:

CHLORINATING COMPOUNDS containing 20 per cent or less of available chlorine,except:

(a) when separately specified in these Schedules;

(b) sodium hypochlorite preparations containing not more than1 per cent sodium hydroxide and with a pH of less than11.5;

(c) liquid preparations containing not less than 2 per cent butnot more than 4 per cent of available chlorine when labelledwith the statements:

WARNING � Ensure adequate ventilation when using.Vapour may be harmful. May give off dangerous gas ifmixed with other products;

(d) liquid preparations containing less than 2 per cent ofavailable chlorine; or

(e) other preparations containing 4 per cent or less of availablechlorine.


CHLORINATING COMPOUNDS � Amend to read:

CHLORINATING COMPOUNDS except:


(b) when separately specified in these Schedules;


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(c) sodium hypochlorite preparations containing not more than1 per cent sodium hydroxide and with a pH of less than11.5;

(d) in liquid preparations containing not less than 2 per cent butnot more than 4 per cent of available chlorine when labelledwith the statements:

WARNING � Ensure adequate ventilation when using.Vapour may be harmful. May give off dangerous gas ifmixed with other products;

(e) in liquid preparations containing less than 2 per cent ofavailable chlorine; or

(f) in other preparations containing 4 per cent or less ofavailable chlorine.

9.2 SODIUM FLUOROACETATE

PURPOSE

The Committee considered the scheduling of sodium fluoroacetate.

BACKGROUND

Fluoroacetic acid, its salts and derivatives in all preparations and admixtures wasincluded in Schedule 7 of the Uniform Poisons Schedules in 1955. At the August 1977meeting the Committee also included the amide of fluoroacetic acid in Schedule 7.

DISCUSSION

The Committee noted that the XXXXXXXXXXXX Member raised the following issuesfor the discussion:

• The regulation of sodium fluoroacetate baits (1080 baits) has been raised inXXXXXXXXXXXX following a decision by XXXXXXXXXXXX to requireChemcert training of all purchasers of Schedule 7 pesticides and a proposal byXXXXXXXXXXXX to follow this lead and require Chemcert training for all users ofSchedule 7 poisons. The impact of such requirements on volunteers involved inbiodiversity programs has been raised.

• Sodium fluoroacetate is currently Schedule 7 with no cut off. 1080 baits are thereforenot permitted to be sold for domestic use. It is also included in the list of pesticidesunder XXXXXXXXXXXX legislation which is subject to more stringent controlsincluding licensing requirements.


65

• Sodium fluoroacetate has also been listed in the AgVet Code as a Restricted ChemicalProduct and as such its supply and use is restricted to authorised persons.

! The scheduling of this product raises the following issues:! The criteria considered when determining the scheduling status of a prepared

product.

! The interface between APVMA restricted chemical products (includes someSchedule 6) and Schedule 7 poisons.

The Committee discussed the various controls on the manufacture and use of vermin baitscontaining sodium fluoroacetate in each of the jurisdictions. The Committee was advisedthat currently each of the States and Territories only allows authorised persons who haveundergone prescribed chemical user training to manufacture and use such baits.

The APVMA Member confirmed that both commercially and non-commerciallyproduced vermin baits containing sodium fluoroacetate are registered by the APVMA.Sodium fluoroacetate is a Restricted Chemical Product, however, the AgVet codeprovisions do not allow the APVMA to prescribe the level of competency or the trainingrequired to use this substance.

A Member expressed the opinion that it was not the role of the poisons legislation toprescribe the training necessary for chemicals use but rather its role was as a �broad brushapproach� to the control the availability of substances. Another Member agreed that theissue was beyond the scope of the main focus of the Committee.

The XXXXXXXXXXXX Member sought clarification from the Committee of the issuesthat would be considered when determining the scheduling status of a prepared product.The Committee confirmed that the matters taken into account when making a schedulingdecision would be in accordance with those set out in section 52E of the TherapeuticGood Act 1989.

OUTCOME

The Committee was of the view that, particularly in the case of sodium fluoroacetate,users must be adequately trained and cognisant of the baiting process and risks to non-target animals. The Committee did not support the use of vermin baits containing sodiumfluoroacetate by untrained or unauthorised persons. In the Committee�s view the controlscurrently in place in the jurisdictions achieve the desired outcomes.

10. INITIAL REVIEW AND/OR FORMAL OPINIONS (AG/VET,INDUSTRIAL & DOMESTIC CHEMICALS)

No items were considered.


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11. INFORMATION ITEMS (AG/VET, INDUSTRIAL & DOMESTICCHEMICALS)

No items were considered.


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PHARMACEUTICALS

12. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUSMEETING (CONSIDERATION OF POST-MEETING SUBMISSIONS UNDER42ZCZ)

12.1 TRIAMCINOLONE

PURPOSE

The Committee considered post-meeting comments in relation to the February 2004decision to include intranasal preparations for short term use containing triamcinoloneacetonide in Schedule 2.

BACKGROUND

Triamcinolone is a synthetic fluorinated corticosteroid with mainly glucocorticoidactivity. Intranasal triamcinolone is registered in 64 countries including the UK andUSA. It has been included in the Australian Register of Therapeutic Goods since 1998,but has never been marketed in Australia.

The NDPSC 40th Meeting (February 2004) agreed to reschedule intranasal preparationscontaining triamcinolone acetonide from S3 to S2 for use up to 6 months for thetreatment of allergic rhinitis. In addition, the Committee also agreed to amend thenomenclature used in the S2 entry to reflect the moiety, i.e. triamcinolone, forconsistency with other triamcinolone entries in the SUSDP and the daily dose limit wasalso adjusted accordingly to 200 mcg.

DISCUSSION

Post-meeting comment was received from XXXXXXXXXXXX highlighting that themaximum recommended daily dose in the S2 entry for triamcinolone published in thepost-meeting gazette notice was 200 microgram instead of 220 microgram.XXXXXXXXXXXX also drew attention to the errors in the February 2004 Record ofReasons (RoR) for triamcinolone stating that under �BACKGROUND�, the dosage peractuation of 55 micrograms was erroneously written as 55 g and the maximumrecommended daily dose read �220 g� instead of 220 micrograms. Furthermore, anemail from OTC Medicines Section (OTC) was also received seeking clarification on therecommended daily dose specified in the S2 entry published in the February 2004 RoRfor triamcinolone.

Members noted that whilst the recommended daily dose published in the February 2004post-meeting gazette notice and RoR was adjusted to 200 mcg to reflect the equivalentamount of triamcinolone, the amount per actuation in the Schedule 2 entry was notadjusted accordingly for consistency.


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The Committee agreed to vary Decision 2004/40-33 the Schedule 2 triamcinolone entrypublished in the February 2004 post-meeting gazette notice to amend the amount peractuation to 50 micrograms triamcinolone (equivalent to 55 micrograms triamcinoloneacetonide) for consistency with the revised nomenclature. Members noted that the cut-offs in the new Schedule 2 entry (expressed in terms of the moiety or parent compound)should be equivalent to the cut-offs in the old S3 entry which was expressed in terms oftriamcinolone acetonide.

Members also agreed that the Record of Reasons and ratified minutes for the February2004 meeting published on the NDPSC website should be amended by including afootnote under item 14.1.2 and highlighting that under �BACKGROUND� the dose peractuation had been corrected to read �55 micrograms� instead of 55 g and the maximumrecommended daily dose would read �220 micrograms� instead of 220 g. Furthermore,the amount per actuation to 55 microgram triamcinolone would be corrected to read 50microgram in the S2 entry.


TRIAMCINOLONE in aqueous nasal sprays delivering 50 micrograms or less oftriamcinolone per actuation when the maximum recommended daily dose is nogreater than 200 micrograms and when packed in a primary pack containing 120actuations or less, for prophylaxis or treatment of allergic rhinitis for up to 6months in adults and children 12 years of age and over.


TRIAMCINOLONE ACETONIDE � amend entry to read:

TRIAMCINOLONE for the treatment of mouth ulcers, in preparations containing 0.1 percent or less of triamcinolone in a pack of 5 g or less.


TRIAMCINOLONE � amend entry to read:

TRIAMCINOLONE except when included in Schedule 2 or 3.

12.2 SODIUM FLUORIDE

PURPOSE

The Committee considered post-meeting comments in relation to the decision to exemptfrom scheduling requirements 0.022% fluoride (220 mg/kg or 220 mg/L) in mouth rinsepreparations complying with certain conditions.


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BACKGROUND

The NDPSC 40th Meeting (February 2004) agreed to the proposal byXXXXXXXXXXXX to exempt from scheduling oral mouth rinse preparationscontaining 0.022% fluoride (0.05% sodium fluoride). This exemption was conditionalupon the product complying with the pack size restriction of 120 mg, the requirement fora child-resistant closure (CRC) and label warnings against swallowing the product andusing in children under six years of age. Such preparations were then included inSchedule 2.

DISCUSSION

Post meeting comments were received from XXXXXXXXXXXX, XXXXXXXXXXXX,XXXXXXXXXXXX and XXXXXXXXXXXX. The Committee noted that whilst thedecision to limit the pack size and require certain label warnings on products wassupported in post-meeting submissions received, the main concern raised was therequirement for CRC to be fitted on exempt dental hygiene products, e.g. mouthwashesand rinses. The following reasons were cited:

• Exempt products containing up to 100 mg/L fluoride were not required to be fittedwith CRC and the higher strength S2 products containing 220 mg/L were alreadyavailable on the market without CRCs. The 220 mg/L fluoride product was alreadyavailable on the market without CRC as S2 medicine, and currently being used in thehome setting with no evidence of harm. An exempt status for this product wasunlikely to change the use pattern or how the products would be stored in the home.

• The requirement for CRC was based on the potential for increased fluoride ingestionand subsequent development of fluorosis in children. Literature showed that fluorosiscould occur after continual use of high fluoride preparations, including ingestion offluorides from dietary sources, however there was no evidence of fluorosis occurringfollowing accidental ingestion. Using the most conservative fluoride dose advice of 5mg F/kg, a 10-kg child would need to consume 215 mL of 220 mg fluoridemouthwash to achieve a Probably Toxic Dose. Given that fluorides are powerfulemetics, it is unlikely that a child would absorb all ingested fluoride.

• Many oral hygiene products are packed in unique non-standard packaging which issponsor-specific and part of a particular product feature. To require sponsors todevelop specific closures for their products which are already sold in general saleoutlets without CRCs without evidence-based justification, would create a uniqueAustralian requirement.

The Committee also received a submission from XXXXXXXXXXXX, a privateconsultant working for the TGA, advising that many dental hygiene products wereExcluded Goods under the Therapeutic Goods Act 1989 and therefore were not subject toregulation by the TGA when for human therapeutic use. To resolve this discrepancy, itwas suggested that the lead-in words in the SUSDP fluoride entries be amended whereappropriate to �Fluorides for human use, except��.


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Further, one post-meeting submission suggested that if the amendments proposed were torevise the harmonised meaning and replace it with �pastes, powders or gels for thecleaning of teeth� then NZ should amend their legislation to harmonise with theAustralian fluoride entries given the differing definition for �dentrifice� in the MedicinesAct 1981. Members recalled that the NDPSC 40th Meeting agreed in principle to replacethe term �dentrifice� in the SUSDP with �pastes, powders or gels for the cleaning of teeth�for consistency with the NZ classification and that the resulting amendments to thefluoride entries from this consideration should address this matter.

The Committee noted that the acute toxicity level given for accidental ingestion ofsodium fluoride in children was 5 mg/kg fluoride (Poisindex). For a 10-kg child, thisequated to ingestion of ~227 mL of mouthwash containing 220 mg/L flouride. Membersremained concerned at the risk of toxicity from ingestion of more concentrated fluorideproducts and agreed that CRC on these products should alert consumers to the potentialtoxicity as well as reinforce the message that such products were not appropriate for usein young children.


The Committee agreed to the retention of the CRC requirement on exempt productscontaining up to 220 mg/L or 220 mg/kg fluoride, on the grounds of public health andsafety. In addition, the Committee agreed to vary the NDPSC 40th Meeting (February2004) decision by replacing any reference to �for human therapeutic use� in the Schedule2 and Schedule 4 entries with �for human use�.


FLUORIDES - amend entry to read:

FLUORIDES for human use (except in preparations containing 15 mg/kg or 15 mg/L orless of fluoride ion):

(a) as sodium fluoride, in preparations for ingestion containing2.2 mg or less of sodium fluoride per dosage unit; or

(b) in preparations for topical use containing 2.5 per cent or lessof fluoride ion except:

(i) pastes, powders or gels for the cleaning of teeth,included in Schedule 3;

(ii) pastes, powders or gels for the cleaning of teeth,containing 1000 mg/kg or less of fluoride ion; or

(iii) other dental hygiene products containing 220mg/kg or 220 mg/L or less of fluoride ion, in packs


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containing not more than 120 mg total fluoride,fitted with a child-resistant closure and labelledwith warnings to the following effect:

(A) Do not swallow; and

(B) Do not use [this product/name of product]in children six years of age or less.


FLUORIDES � amend entry to read:

FLUORIDES in pastes, powders and gels containing more than 1000 mg/kg of fluorideion.


FLUORIDES - amend entry to read:

FLUORIDES in preparations for human use except:

(a) when included in Schedule 2 or 3;

(b) pastes, powders or gels for the cleaning of teeth, containing1000 mg/kg or less of fluoride ion;

(c) other dental hygiene products containing 220 mg/kg or 220mg/L or less of fluoride ion, in packs containing not morethan 120 mg total fluoride, fitted with a child-resistantclosure and labelled with warnings to the following effect:

(i) Do not swallow; and

(ii) Do not use [this product/name of product] inchildren six years of age or less; or

(d) in other preparations containing 15 mg/kg or 15 mg/L orless of fluoride ion.


FLUORIDES � amend entry to read:

FLUORIDES in preparations containing 3 per cent or less of fluoride ion except:

(a) when included in Schedule 2, 3 or 4;


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(ii) Do not use [this product/name of product] in children six years ofage or less; or



FLUORIDE � amend entry to read:

FLUORIDES except:

(a) when included in Schedule 2,3,4 or 5;




(ii) Do not use [this product/name of product] in children six years ofage or less; or


12.3 MITRAGYNA SPECIOSA

PURPOSE

The Committee considered post-meeting comments in relation to the February 2004decision to include Mitragyna speciosa (M.speciosa) in Schedule 9 of the SUSDP basedon abuse potential.


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BACKGROUND

M.speciosa (also known as Kratom) is native to Thailand and Malaysia. Mitragynine,one of the alkaloids found in the leaves of M.speciosa, has psychoactive properties and isused as an opium or heroin substitute by Malayans (Burkill 1935). M.speciosa leaves areused extensively in Thailand (also in Malaysia) to increase work output and tolerance todirect sunlight, and are usually chewed, smoked or drunk as tea to achieve the desiredaffect. The leaves are chewed 3 to 10 times a day, with stimulant effects occurring after 5to 10 minutes. M.speciosa was regulated as a narcotic drug in Thailand and carried thesame restrictions and penalties as cocaine.

The NDPSC considered the inclusion of mitragynine and M.speciosa (the plant) inSchedule 9 of the SUSDP over several meetings (February 2003 to February 2004) basedon abuse potential. Subsequently, the NDPSC 39th Meeting (October 2003) agreed toinclude the alkaloid, mitragynine, in Schedule 9 of the SUSDP and foreshadowed toconsider at the February 2004 meeting the inclusion in S9 of the plant, M.speciosa. The40th Meeting (February 2004) then agreed to include M.speciosa in S9 followingconsideration of several public submissions.

DISCUSSION

The Committee noted post-meeting comments from XXXXXXXXXXXX andXXXXXXXXXXXX. The Committee discussed the issues raised in post-meetingsubmissions in relation to matters mentioned in s.52E of the Therapeutic Goods Act1989:

The potential hazards associated with the use of a substance

XXXXXXXXXXXX advised the Committee of the findings of the pre-clinical trialconducted in the 1960s by the then XXXXXXXXXXXX to investigate the possibletherapeutic properties of mitragynine from M. speciosa. The company confirmed thereport that the pre-clinical trial apparently revealed unacceptable acute effects (Raffauf1986) and was discontinued.

People taking Kratom in the �traditional method� (i.e. drinking like tea) could unwittinglybecome addicted based on the evidence showing that habitual chewing of Kratom leavescould lead to gradual addiction and that during early stages of addiction the user may takeonly a few leaves to obtain satisfactory results [United Nations Bulletin on Narcotics(1975 Issue 3)].

The extent and patterns of use of a substance

Post-meeting comment suggested that the only use in Australia had been throughconsumption of the lower-dose tea type preparations and therefore the risk of opiateeffects was correspondingly low. A member raised the issue that given the amount ofinformation available on the Internet about use of this substance and the fact that plants


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were being sold for propagation in Australia, there was no guarantee that this type ofconsumption and pattern of use would remain unchanged.

The Committee was advised that a large number of websites were found on the Internetpromoting the use of M. speciosa as an illicit drug with detailed instructions on how toprepare and use the plant to achieve the �desired� effects. The most common methods ofuse suggested were smoking the leaves, drinking infused water like tea and smoking theresidue (as concentrated resin) from boiling leaf extracts until dry. Members also notedseveral websites on the Internet dedicated to �exposing bogus Kratom Market� suggestinga significant demand for M. speciosa.

The potential for abuse of a substance

Some post-meeting comments received opposed the decision to include M.speciosa in S9based on the claim that there was no evidence to demonstrate harm or abuse and that theplant was beneficial for use as an analgesic, mood-elevating agent or relaxant, andsubstitute for opium or heroin. It was argued that consumption like normal tea of M.speciosa was without any adverse or addictive effects and on this basis the plant shouldnot be restricted.

Members noted that the United Nations Bulletin on Narcotics (1975 Issue 3) stated inrelation to a study conducted on 30 Kratom eaters in Thailand that �In the early stages ofaddiction the user may take only few leaves to obtain satisfactory results. The dosage isthen increased in varying degrees among individual subjects: 10-20 leaves daily (40%);21-30 leaves daily (36.6%); while the remainder of the sample increased its daily use toan indefinite number of leaves. The addicts chew about 3-10 times a day, depending ontheir sensation of weariness to overcome�.

The psychological effects occurring after 5-10 minutes of consuming Kratom weredescribed as feeling happy, strong and active. The UN Bulletin reported that long termKratom addicts became thin, their skin darkened, particularly on the face (on bothcheeks) which gave the appearance similar to that of a hepatic face. Five cases of Kratomaddiction mentioned in the Bulletin revealed psychotic symptoms including convulsions,mental confusion, clouding of consciousness, episodes of delusions and persecutoryideation, hallucinations, dizziness and headaches. Typical withdrawal symptoms noted inKratom addicts included hostility, aggression, flow of tears, wet nose, inability to work,aching muscles and bones, and jerky movement of the limbs.

The Journal of Psychoactive Drugs (Vol 20[4], Oct-Dec 1988) described mitragynine,the major alkaloid of M. speciosa, as a drug with a highly unusual but nevertheless well-documented history of being described as both a depressant and a stimulant, while at thesame time possessing the chemical structure one might expect of a psychedelic.

The Committee noted that almost all the human data published in recognised scientificjournals about the use of M. speciosa related to traditional use in Thailand. A memberindicated that whilst mitragynine is structurally unrelated to other opiates, it appeared to


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act on mu- and delta-opioid receptor subtypes. Since mu-opioid receptors were thoughtto be involved in both the analgesic action, as well as the euphoric and addictiveproperties of opiates, there appeared to be a pharmacological basis for mitragynine tohave similar effects. The action of mitragynine on opiate receptors may also explain theuse of M. speciosa as a substitute for opium and heroin. It was noted that a number ofpost-meeting submissions mentioned the use of M. speciosa for treating opium and heroinwithdrawal symptoms. A member stated that a possible reason for the attenuation ofwithdrawal from opiates by M. speciosa may be compared to the concept of usingmethadone to treat addicts in that, pharmacologically, one opiate was used to replaceanother.

The need for access to a substance, taking into account its toxicity compared withother substances available for a similar purpose

A Member noted that based on the available data there was little evidence to show thatM.speciosa was widely used for therapeutic purposes other than as a substitute for otheraddictive opiates and one other traditional use as an antidiarrhoeal. Although thepharmacology of M. speciosa suggested that analgesic effects were likely given thefindings of studies quoted in several papers [e.g. Journal of Psychoactive Drugs (Vol20[4], Oct-Dec 1988], there was little data to suggest that Kratom was used traditionallyas a pain reliever. On this basis, the Committee noted that despite post-meetingcomments about the usefulness of M.speciosa for treating migraines, there was littleevidence available to support a legitimate therapeutic need for the plant and membersalso noted that a number of other alternatives including complementary medicines werealready available. A Member observed that information on Internet websites referredmainly to the use of Kratom for producing psychoactive effects and in contrast, there waspaucity of information about its therapeutic use.

Any other matters that the Committee considers necessary to protect public health,including the risks (whether imminent or long term) of death, illness or injuryresulting from its use

It was pointed out in post-meeting comment received that emergency scheduling is anoption available to the Committee. However, members contended that in view of theevidence before the Committee on habituation to M.speciosa, as traditionally consumedin Thailand, and anecdotal evidence of abuse from numerous websites, a pro-activeapproach to curb the potential for abuse of M.speciosa was considered necessary toprotect public health and safety.

A jurisdictional Member advised the Committee that M.speciosa had been included in aState�s Prohibited Substances List, on the request of the police force due to �undesirable�activities.


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DECISION 2004/41 – 16 (Confirmation of Decision 2004/40 – 27)

The Committee confirmed the decision made at the NDPSC 40th Meeting (February2004) to include of Mitragyna speciosa in Schedule 9 of the SUSDP based on its abusepotential.

Schedule 9 - New entry

MITRAGYNA SPECIOSA.

13. OTHER OUTSTANDING MATTERS FROM PREVIOUSMEETINGS

13.1 MELIA AZEDARACH

PURPOSE

The Committee considered the scheduling of Melia azedarach.

BACKGROUND

Melia azedarach, also called Chinaberry or White Cedar (also known in Australia as"white mahogany"), is a member of the Meliaceae family (not to be confused with neem,Azadirachta indica) and grows in subtropical areas in Asia, Australia, Hawaii, Africa,South America and parts of the southern United States. The fruit and the bark wereconsidered poisonous and there was great variability in the symptoms seen due to geneticvariation of the plant. The ingestion of as few as 6-8 berries had been fatal in somegeographic locations but in other areas the fruits may be eaten without harm. Ingestion of0.3-0.4 g of the fruit by children was reported to cause toxic reactions and 2-4 g causeddeath (The Complementary and Alternative Healing University website, 2003). Parts ofthe plant that are used for medicinal purposes are the bark, fruits, root bark, leaves andflowers.

The NDPSC 35th Meeting (June 2002) agreed to foreshadow the inclusion of Meliaazedarach or its extracts or its derivatives in Appendix C of the SUSDP, on public healthand safety grounds. Whilst the Committee recognised the need to restrict the use ofMelia azedarach, it agreed to seek additional data from stakeholders on issues such as theappropriate cut-off for exemption, long term safety of Melia azedarach and the nature ofplant extracts in products. The matter had since been considered over several meetingsbut due to the lack of data from the public the NDPSC 38th Meeting (June 2003) agreedto again defer consideration to the June 2004 meeting to allow completion of a safetyreview on Melia azedarach being undertaken by the OCM.

Melia azedarach is the TGA-approved terminology.


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DISCUSSION

There were 19 entries containing Melia azedarach listed on the ARTG. Three of thesecontained M. azedarach as a dried powder of the fruit or seed, ranging from 8.5-129.2mg. Five entries contained a decoction (boiled water extraction) of the stem bark or fruit(dry equivalents ranging from 142-670mg). Six entries contained dried aqueous extractsof the fruit (dry equivalents 105-340mg/tablets), and two entries contained ethanol; waterextracts (~50:50) of the leaf (dry equivalents 135mg/mL and 1.96 g/tablet). Three entriesdid not specify the preparation method, part used or indications. None of the entriesspecified a recommended daily dosage. All products except one were intended for oraluse and the majority of indications related to claims for assisting digestion or as a �livertonic�; six were for cystitis or menstrual symptoms, one was for dry or inflamed skin, andone topical product claimed to be a head lice remedy. There were no reports of adversereactions associated with products containing M. azedarach recorded in the ADRACdatabase or on the WHO database.

The Committee noted the OCM safety review report on Melia azedarach and discussedthe CMEC recommendations (in bold).

Melia azedarach is not suitable for use as an ingredient in Listed medicines

The April 2004 CMEC draft minutes stated that �Toosendanin, a neurotoxin isolatedfrom M. azedarach, was toxic after five doses of 8-10 mg/kg in dogs and rabbits. Ratsfed a diet with 25 % leaf content for more than 14 days showed degeneration of theskeletal muscle and lead to death of most of the animals. However, rabbits fed Meliafruit up to 10 g/kg/day for 35 days showed no apparent toxicity. Relatively minimaltoxicity was seen in male rats given ethanolic extracts of the leaves at 100 mg/kg/day for21 days. Female rats given 500 mg/kg/day of leaf or root extracts for 10 days showedmarked impairment of the reproductive function. At 250 mg/kg/day of ethanolic rootbark extract but not leaf extract, female rats showed adverse effects on reproductiveparameters. This result suggested that root barks are more toxic than leaves for femalereproductive function.�

�An apparent lack of cytotoxicity of leaf extracts at concentrations that have been shownto produce antiviral and immunomodulatory effects in vitro suggests that there appears tobe a safety margin between the therapeutic and toxic concentrations of these preparations.The lack of the animal exposure data with an identified NOAEL dose prevented accurateestablishment of the safe dose level in humans for any herbal preparation of M.azedarach. Even if these data were available for one or a number of animal species,determination of the safe therapeutic dose level for humans would be further complicatedby the fact that the sensitivity to M. azedarach toxins is species-dependent, apparentlyincreasing the higher the species studied.�

Members noted that the acute toxicity (LD50 of 6.4 mg/kg in pigs) of four meliatoxins(A1, A2, B1 and B2) isolated from the fruit of M. azedarach and the was consistent withthe acute toxicity of substances included in Schedule 7 of the SUSDP. In addition, a


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study by Chang and But (1986) mentioned in the OCM safety review report on the barkand root bark of M. azedarach also found that at doses of 0.8 mg/kg in adults, severereactions such as peripheral neuritis, arrhythmia, hypotension, and dypsnoea wereobserved. The report also noted that the enteric toxin responsible for the gastrointestinaltract symptoms was yet to be identified.

To allow continued access by healthcare practitioners, it should not be included inAppendix C of the Standard for the Uniform Scheduling of Drugs and Poisons.

The OCM minutes stated that �Members expressed concern for the potential prohibitionof supply of this herb to practitioners if NDPSC decided to include M. azedarach intoAppendix C of SUSDP. Although CMEC recommended that the herb was unsuitable foruse in Listed medicines for safety reasons, the Committee considered that there was notenough evidence to warrant the inclusion of it into Appendix C of SUSDP. TheCommittee asked OCM to communicate to NDPSC that:

• CMEC recognised a significant history of use for M. azedarach by practitioners oftraditional herbal medicine; and,

• due to the history of use by these practitioners, access to the herb should not belimited by inclusion into Appendix C.�

The Committee interpreted the CMEC recommendation to mean that M. azedarach wasnot suitable for inclusion in manufactured preparations for sale in healthfood shops andsupermarkets but was suitable for use in medicines dispensed by healthcare practitioners.The Committee noted that there was no national system for accrediting healthcarepractitioners, e.g. osteopaths, naturopaths and homeopaths, to ensure consistency inprofessional standards and competencies in dispensing extemporaneously preparedmedicines. With this in mind, members supported the approach of specifying a limit onthe amount of M. azedarach to be allowed in medicines extemporaneously prepared byhealthcare practitioners which took into account the overall acute toxicity of the plant andsafety of such preparations in long term use.

The Committee noted pre-meeting comment from the XXXXXXXXXXXX opposed anychange to the status of M. azedarach which was not consistent with the CMEC findings.

OUTCOME

The Committee agreed not to proceed with the foreshadowed inclusion of M. azedarachin Appendix C of the SUSDP but to foreshadow the inclusion of M. azedarach inSchedule 7, based on its overall toxicity profile and potential for adverse effects onreproductive parameters. Whilst it was recognised that there may be grounds forexempting medicines extemporaneously prepared by healthcare practitioners, theCommittee was unable to extrapolate from the data available to determine a safe level onwhich to base a cut-off for exemption to accommodate CMEC�s recommendations. Toassist the NDPSC in its consideration at the October 2004 meeting, the Committee agreedto ask CMEC and CHC to propose an appropriate cut-off for exemption for dilute


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medicines, including those extemporaneously prepared by healthcare practitioners, andprovide a justification to support any proposal.

FORESHADOWED DECISION(for consideration at the NDPSC 42 Meeting of October 2004)


MELIA AZEDARACH.

13.2 PANCREATIC ENZYMES

PURPOSE

The Committee considered the scheduling of products containing porcine pancreaticenzyme extract.

BACKGROUND

The NDPSC 39th Meeting (October 2003) noted ADEC�s recommendation that the useof porcine pancreatic enzyme extract products be restricted to indications for conditionscharacterised by pancreatic exocrine enzyme insufficiency and foreshadowed theinclusion of all pancreatic enzyme preparations in Schedule 4 based on the followingreasons:

• that contamination of Australian marketed pancreatic enzyme products with porcineparvovirus (PPV) and potential risk of human infection could not be ruled out;

• the available data suggested that the benefits associated with treatment of pancreaticexocrine insufficiency with porcine pancreatic enzymes outweighed the potential riskof PPV contamination of these products; and.

• the risk-benefit ratio for the use of porcine pancreatic enzymes for conditionsunrelated to pancreatic insufficiency, as OTC products or complementary medicineswas too high, and those products should be withdrawn.

The NDPSC 40th Meeting (February 2004) noted the advice from ComplementaryMedicines Evaluation Committee (CMEC) to the TGA that products containingpancreatic enzyme extracts of porcine origin were suitable for use as an ingredient inlistable or registrable complementary medicines, for indications other than pancreaticexocrine enzyme insufficiency subject to certain manufacturing conditions to recude thepotential for PPV infectivity. Following the February 2004 meeting, the Secretariatwrote to OCM suggesting that advice should be sought from TGA Laboratories todetermine whether the potential for PPV infectivity of porcine products could beaddressed in the manufacturing process or via a suitable inactivation processes forproducts containing porcine pancreatic enzyme extracts.


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DISCUSSION

The Committee noted advice that OCM was proceeding to consult with the industryadvising them of CMEC's recommendation and requesting the sponsor to provide thefollowing information:

• the timeframe and the method proposed for reducing the potential of PPV infectivityin the finished product; or

• an assurance that following the agreed timeframe, companies either ensure that themanufacturing process is validated for PPV inactivation/clearance and if necessary,will introduce additional steps or obtain TGA pre-clearance as indicated above.

• OCM stated that it would accordingly notify the NDPSC once the above responsesfrom the sponsors had been evaluated by the Viral and Prion Safety Section of theTGA Laboratories and CMEC.

The Committee discussed the following issues;• Pre-meeting submissions received from the sponsor, XXXXXXXXXXXX and from

some practicing clinicians (XXXXXXXXXXXX and XXXXXXXXXXXX) opposedthe inclusion of all preparations containing pancreatic enzymes in Schedule 4 of theSUSDP as it would limit the availability and access to such products. In addition,some stakeholders and a sponsor (XXXXXXXXXXXX) had claimed thatrescheduling the products to S4 would adversely impact on the communication andeducational support network currently made available to cystic fibrosis clinics,patients and their families by the sponsor.

• The XXXXXXXXXXXX representative advised the Committee that mostXXXXXXXXXXXX supported the proposed rescheduling of all pancreatic enzymepreparations to S4. It was notified that patients preferred to purchase the PrescriptionOnly products as not all pharmacies stock the OTC products and that retaining suchproducts in S4 would ensure that patients would continue to access their medicationunder the Pharmaceutical Benefit Scheme (PBS).

• Members noted that stakeholders (CF State organisations vs. those who providedpublic submissions) were divided in their views as to whether all pancreatic enzymeproducts should be rescheduled to S4. Members, however, considered that themajority of patients would access these products on the prescription by a medicalpractitioner and the proposed change would maintain the same level of access bypatients.

DECISION 2004/41 - 17

The Committee agreed that the scheduling of pancreatic enzymes other than porcinepancreatic enzymes (PPE) remained appropriate, on the basis that the risk of PPVinfectivity in humans was only associated with those pancreatic extracts of porcine origin.Members agreed with ADEC in that the inclusion in S4 should ensure that all PPEpreparations would be used only for the treatment of pancreatic exocrine insufficiency


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given that the benefits of such a use outweighed the potential risk of PPV contaminationin these products.


PORCINE PANCREATIC ENZYMES.

13.3 PSEUDOEPHEDRINE

PURPOSE

The Committee continued its consideration of the scheduling of the remainingpseudoephedrine preparations in Schedule 2, i.e. undivided, combination and slowrelease.

BACKGROUND

The NDPSC 35th Meeting (June 2002) agreed to reschedule all OTC single-activeimmediate release pseudoephedrine preparations from Schedule 2 to Schedule 3 of theSUSDP on the rationale that pharmacist intervention would help reduce the problem ofdiversion to the illicit drug trade while maintaining access for legitimate users. TheCommittee however, deferred the consideration of the remaining S2 products, as the dataavailable at the meeting was considered inadequate to allow an assessment of theappropriateness of rescheduling these formulations to S3. Consequently, the Committeeforeshadowed a review of the scheduling of the remaining pseudoephedrine-containingproducts in S2 at the NDPSC 36th Meeting (October 2002) meeting and sought additionaldata from the jurisdictions and industry on formulation details, extractability of thepseudoephedrine from the formulation, and annual sales volume (no. of units) for eachformulation for the last five years.

The NDPSC June 2002 meeting also noted that XXXXXXXXXXXX, a �bilayer�formulation (where the pseudoephedrine could be readily separated or extracted fromother components in the formulation by simple dissolution or other physical means), wasbeing targeted for diversion and that this formulation was not covered by the term�compounded� used in some pseudoephedrine entries in the SUSDP. To address thisdiscrepancy, the Committee agreed to replace the term �compounded� used in thepseudoephedrine entries with �combination� to cover products such asXXXXXXXXXXXX.

The NDPSC had since kept a watching brief of the remaining pseudoephedrinepreparations in S2 over several meetings to allow for the final report of analyticalinvestigations being undertaken on the extractability of pseudoephedrine from variouspseudoephedrine formulations to become available. In addition, the Committee took theopportunity to ask sponsors to indicate their plans for existing and future product lines,particularly in relation to �bilayer� preparations. XXXXXXXXXXXX, sponsor ofXXXXXXXXXXXX, advised the NDPSC 38th Meeting (June 2003) meeting that there


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was a new compounded formulation of XXXXXXXXXXXX under development and thatit was anticipated that a submission for this would be made to the TGA within the next 12months. XXXXXXXXXXXX, another sponsor of a �bilayer� product, also advised that ithad no plans of modifying XXXXXXXXXXXX formulation based on economicgrounds, and that it did not consider the product a 'bilayer' formulation. In addition,XXXXXXXXXXXX indicated that the sales data XXXXXXXXXXXX did not suggestthat it was being targeted for diversion.

The NDPSC October 2002 Meeting noted the Australian Self-Medication Industry�s(ASMI) Code of Conduct, which was formally approved for implementation for a periodof five years by the Australian Competition and Consumer Commission (ACCC) startingfrom 13 November 2003. The Code was designed to help prevent diversion ofpseudoephedrine-containing medicines. Furthermore, the Pharmaceutical Society ofAustralia (PSA) disseminated a Code of Practice for pseudoephedrine in late 2002. ThisCode provided a substance-specific guidance to pharmacists to ensure that pharmacistscontinue to provide the most appropriate medicines and therapeutic advice to patientswithout inadvertently contributing to the problem of diversion of pseudoephedrine-containing products.

The National Working Group on the Diversion of Chemical Precursors (NWG) at itsNovember 2003 meeting noted the recent report by the House of RepresentativesStanding Committee on Family and Community Affairs (CFC), Road to Recovery, inparticular Recommendations 82 and 83. The NDPSC February 2004 meeting noted thatRecommendation 83 stated that: �the Commonwealth government amend its Standard foruniform scheduling of drugs and poisons to make all substances containingpseudoephedrine a Schedule 4 Prescription Only Medicine.� Members discussed thisrecommendation and noted that the Commonwealth Government�s response to this reportwas yet to be made available. The NDPSC noted that the NWG resolved that the TGAand Customs would address the next working group meeting in relation to the Reportrecommendations.

The NDPSC 40th Meeting (February 2004) noted a copy of the Draft Resolutions from theNWG November 2003 meeting. Members were advised that the researchers hadexamined the ease of extraction of pseudoephedrine from a range of products and hadreported the preliminary results to NWG. It was understood that extraction from singleand/or multiple component products via different approaches was effective and that therecovery/yield may be significant. No deliberations or conclusions on this issue weremade at the NWG meeting, and the NWG expected a second presentation of the finalresearch results on extraction and conversion of pseudoephedrine at the next meeting(March 2004).

Following the NDPSC February 2004 meeting, the Secretariat wrote to the NWGSecretariat expressing concern about the delay in making available the final report on theresearch into pseudoephedrine extraction and conversion and advised that the NDPSChad planned to consider the scheduling of pseudoephedrine at the NDPSC 41st Meeting(June 2004) meeting. Furthermore, the Commonwealth�s Drug Strategy Branch was


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asked by the Secretariat to provide the NDPSC with the Commonwealth Government�sresponse to Recommendation 83 when available.

DISCUSSION

The Committee noted the draft Executive Summary of the report on the research ofpseudoephedrine products which was funded by the National Drug Law EnforcementResearch Fund (NDLERF) at the request of the NWG. It was advised that the final reportwas yet to be approved by the NDLERF Board of Management but it agreed that theNDPSC be provided with the Executive Summary to assist in its considerations. TheCommittee noted the following points:

• The aim of the research project was to determine whether pseudoephedrine could beextracted from the range of products available and establish the ability to convertthese products into methylamphetamine via commonly used illicit drugmanufacturing processes. Eight pharmaceutical products were selected, representingthe different pseudoephedrine product formulations available within Australia.

• The overall extraction results demonstrated that pseudoephedrine could be extractedfrom all products, with an efficiency ranging from 24%-90%. No significantrelationship was established between the product formulation, the extraction processand the efficiency of extraction.

• The greatest variation observed in the process was the need to differ the amounts ofsolvent used in the various extraction procedures. The quantity of solvent wasimpacted by the starting quantity of the pharmaceutical product, which wasinfluenced by the total tablet or capsule mass and the quantity of pseudoephedrinecontained in each formulation.

• Despite these issues the research showed no significant chemistry skills orsophisticated equipment was required to facilitate extraction of pseudoephedrine fromany of the nominated product formulations.

• Overall, the results of the study demonstrated that pseudoephedrine could beextracted from a variety of pharmaceutical products currently available on theAustralian market. The type of formulation, i.e. whether single or multiple entity, didnot prohibit the extraction of pseudoephedrine although some product formulationsmay be better suited to a particular extraction process.

• To reduce the risk of the diversion of pseudoephedrine containing products into theillicit drug production market, it was important to consider the full variety ofavailable products and ensure that whatever restrictions may be applied would bedone so evenly across all pharmaceutical product lines.

The Committee discussed the following issues:

• Most pre-meeting submissions received from various professional pharmacy groupsand pharmaceutical companies, including the sponsors of pseudoephedrine products,


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supported the retention of existing products in S2 (except XXXXXXXXXXXXwhich supported the inclusion of all pseudoephedrine products in S3). TheCommittee was advised that the initiatives implemented in pharmacies to address theproblem of diversion included stock minimisation, recording of consumer personaldetails, storage of all pseudoephedrine products behind the counter, communitypharmacy vigilance and collaboration with State/Territory Police and HealthDepartments.

• The Committee noted that no new issues were highlighted in the pre-meetingsubmissions received although some stakeholders indicated that should products berescheduled to S3, the preferred approach was for all formulations to be rescheduledconcurrently, irrespective of the type of formulation. Some stakeholders again raisedthe issue that scheduling was not the appropriate mechanism for addressing thediversion problem and that such a problem could be managed more appropriatelythrough implementation of a coordinated national approach, which should maintainaccess by legitimate consumers since there was no other effective alternative topseudoephedrine.

• Members advised that thefts of multiple packs of S2 pseudoephedrine products storedat the front of the shop continued to be a problem in the jurisdictions, and that whilstsome jurisdictions had moved all pseudoephedrine behind the counter to address thisproblem, this approach failed to deter serial pseudoephedrine shoppers. A memberalso reported that the strategy of recording the purchaser�s personal details for S3products had proven to be ineffective as serial shoppers were capable of producingseveral fake identification papers within a very short timeframe. The Committeenoted that the formulation type no longer appeared to be a significant factor in thechoice of pseudoephedrine product selected for diversion, based on the productsfound in clandestine laboratories seized by the State/Territory Police.

• Members also noted that there was no data available, e.g. �before and after� sales data,listing of products found in clandestine laboratories, etc., to allow an assessment ofthe effectiveness and impact of the strategies implemented by industry and pharmacygroups on the overall pseudoephedrine diversion problem. Members recalled that theAustralian Competition and Consumer Commission (ACCC) granted an interimauthorisation for the implementation of the ASMI Code of Conduct on 13 February2003, and an undertaking was made that the ASMI would provide regular updates tothe Committee regarding the implementation of the Code and its impact on theproblem of diversion of pseudoephedrine products.

The Committee was advised that a proposal in New Zealand to re-classifypseudoephedrine and ephedrine under the Misuse of Drugs Act 1975 (MODA) andinclude pseudoephedrine in Regulation 28(4)(b) of the Misuse of Drugs Regulations 1977was being progressed. This move was in response to the dramatic increase in theimportation of pseudoephedrine and ephedrine as a result of the tightening of controls inNZ on domestic supply of pseudoephedrine. Pseudoephedrine and ephedrine werecurrently controlled under the Medicines Act 1981 and that the reclassification of thesesubstances in NZ would provide stronger Customs powers. However, members noted


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that such a move would also have a major impact on harmonisation in that it would thenrequire Pharmacy-only pseudoephedrine products in NZ to be labelled with �ControlledDrug C3�, and all prescription doses of pseudoephedrine and ephedrine to be labelledwith �Controlled Drug C5�.

OUTCOME

The Committee agreed to foreshadow the inclusion of the remaining S2 pseudoephedrinepreparations in S3, i.e. undivided, combination and slow release preparations, based onthe findings of the research on pseudoephedrine products and reports from thejurisdictions that such products were being diverted to the illicit drug market.



PSEUDOEPHEDRINE � delete entry.


PSEUDOEPHEDRINE in preparations (other than preparations for stimulant, appetitesuppression or weight-control purposes), with a recommended daily dose of 240 mg orless of pseudoephedrine:

(a) in undivided preparations containing 60 mg or less ofpseudoephedrine per recommended dose;

(b) when the only therapeutically active substances in dividedpreparations containing 60 mg or less of pseudoephedrineper recommended dose in a pack containing 30 or lessdosage units;

(c) when combined with other therapeutically activesubstances; or

(d) in slow release preparations.


PSEUDOEPHEDRINE except when included in Schedule 3.


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13.4 MEDICAL DEVICES

PURPOSE

The Committee considered the inclusion of an entry for medical devices in Appendix Aof the SUSDP.

BACKGROUND

The NDPSC 31st Meeting (May 2001) agreed that a strategy for medical devicescontaining scheduled poisons needed to be developed to achieve meaningful public healthoutcomes in terms of labelling and controls over access and availability. The Committeerecognised the need for a clear and positive statement in the SUSDP to resolve thegeneral confusion in terms of when a device containing a medicine required scheduling.This matter was considered over several meetings of the NDPSC and was subsequentlydeferred to a future meeting to allow sufficient time to examine the new deviceclassification listings.

The Therapeutic Goods Amendment (Medical Devices) Act 2002 came into effect inOctober 2002 and representatives from the Medical Devices Assessment (MDA) areaprovided the NDPSC 37th (February 2003) NDPSC meeting with a brief overview of thenew legislation. The new regulatory regime for medical devices adopts a classificationsystem that has currently 5 classes of medical devices under this system. From these,MDA developed a list of Class III ECRI medical devices which may require schedulingon the basis that they could likely contain scheduled substance(s) and likely to be usedoutside hospital and medical settings.

The NDPSC 40th Meeting (February 2004) agreed that as the first step, an Appendix Aentry should be developed to clearly identify those devices not requiring controls viascheduling and asked the XXXXXXXXXXXX and XXXXXXXXXXXX member to re-examine the list provided by MDA and suggest an appropriate entry.

DISCUSSION

The Committee was advised that a teleconference on 18 May 2004, which was attendedby the XXXXXXXXXXXX and XXXXXXXXXXXX member, XXXXXXXXXXXXand XXXXXXXXXXXX and XXXXXXXXXXXX, discussed the draft Appendix Aentry developed by the XXXXXXXXXXXX and XXXXXXXXXXXX member. Themeeting endorsed an Appendix A entry which exempted Class III medical devicescontaining scheduled substances considered to be of low abuse or misuse potential on thebasis of their exclusive use within the hospital or medical setting. In addition, it was alsoagreed that the Appendix A entry should specify the group of medical devices which maynot be appropriate for exemption, e.g. disinfectants, injectable collagen or tissuereconstructive materials, rather than just provide a �blanket� exemption. It was noted thatfurther amendments to the Appendix A entry could be made on a case-by-case basis viathe usual NDPSC procedures, where appropriate. The meeting also agreed that the


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NDPSC be provided with future MDEC minutes to allow identification of medicaldevices, which may be of interest to the NDPSC.

Comment was sought from ODBT on the draft Appendix A entry prior to the NDPSC 41st

Meeting (June 2004) and it was advised that whilst there was some concern with regardto the consistency of NDPSC and ODBT�s understanding of the scope of devices withinClass III, the draft Appendix A entry nonetheless covered critical areas. On this basis,ODBT supported the proposal going forward and proposed that a review be undertakenafter 12-18 months.

The XXXXXXXXXXXX member had received further advice regarding intrauterinedevices and considered that the Appendix A entry could also cover these products giventhat such devices are generally supplied through medical practitioners due to potentialadverse effects.

The Committee recalled that the XXXXXXXXXXXX representative agreed at theNDPSC February 2004 meeting to seek feedback from sponsors on the proposedAppendix A entry for medical devices and report to the October 2004 meeting.

OUTCOME

The Committee agreed to foreshadow consideration of the proposed Appendix A entry atthe NDPSC 42nd Meeting (October 2004).


Appendix A – New entries

MEDICAL DEVICES classified as Class III by the classification rules set out inSchedule 2 to the Therapeutic Goods (Medical Devices) Regulation 2002, as specified oramended from time to time, except:

(a) injectable collagen;

(b) tissue reconstructive materials;

(c) anticoagulants;

(d) artificial tears; or

(e) urinary catheters.


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13.5 KAVA AND KAVALACTONES

PURPOSE

The Committee considered the scheduling of kava (Piper methysticum) and its activeconstituents kavalactones.

BACKGROUND

Piper methysticum (kava), a member of the pepper family (Piperaceae), has a widedistribution throughout the Pacific. Kava has been used in traditional medicine to treatvenereal disease, gout, rheumatism, diarrhoea, asthma, and to calm nervous children andinduce women�s breast milk flow. Pharmacologically, kava is described as having ananxiolytic effect, is a muscle relaxant and has anticonvulsant and spasmolytic activity. Itis a sedative and can depress the limbic system. Its effects appear to be mainly due to theactivity of the compounds in the lipid soluble resin � the kavalactones. Thepharmacological properties of kava are comparable to those of benzodiazepines, althoughkavalactones bind very weakly to GABA-A and benzodiazepine receptors. Morerecently, kavalactones had been extracted for therapeutic products using volatile organicsolvents.

The NDPSC 39th Meeting (October 2003) noted a safety evaluation report prepared bythe Kava Evaluation Group (KEG)/Office of Complementary Medicines (OCM) on kavacontaining medicines, which made recommendations on the regulation of kava as aningredient in Listed Medicines. Due to the potential risk of liver toxicity from use ofnon-aqueous extracts of kava plants at high doses, the Committee considered the need torestrict the use of alcohol/acetone extracts of kava including those for bulk supply tohealth care practitioners for use in extemporaneously compounded preparations. Inaddition, it was agreed that a schedule entry to minimise the risk without affecting thecurrent usage of listed complementary products should be considered by the Committeefollowing the review of products on the ARTG.

The NDPSC 40th Meeting (February 2004) was advised that CMEC�s Recommendation41.3 had been included in Schedule 4 of the Therapeutic Goods Regulations 1990 (TGRegulations) to only allow specified concentrations of aqueous kava extracts in Listedmedicines and that all other kava products had been cancelled from the ARTG. TheCommittee noted that the available information suggested that whole or peeled kavarhizomes and their aqueous preparations containing 250mg or less of kavalactones wereacceptable for use in exempt medicines while medical advice was necessary for safe useof other kava preparations due to toxicity. On this basis, the Committee agreed toforeshadow the inclusion of kava (Piper methysticum) in Schedule 4 of the SUSDP withexemptions consistent with those specified in the TG Regulations. In addition, theCommittee also asked the Drafting Advisory Panel (DAP) to draft an entry forconsideration at the NDPSC 41st Meeting (June 2004).


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DISCUSSION

The Committee noted the Food Standards Australia New Zealand�s (FSANZ) FinalAssessment Report of the Review of Kava. It was advised that Standard 2.6.3 of theFood Product Standards was to be retained to operate in conjunction with the NationalCode of Kava Management, including its prohibition in relation to mixing of kava withother foods (other than in those foods regulated under the New Zealand DietarySupplement Regulations 1985). In addition, members noted that Standard 2.6.3 wasamended to allow kava for use as traditional beverage but the use in food of extractsprepared by organic solvent extraction would be prohibited and the labellingrequirements were to be retained to ensure the safe use of kava by consumers. FSANZalso advised that the foreshadowed decision to include non-aqueous extracts of kava inSchedule 4 of the SUSDP was consistent with the amendments made to Standard 2.6.3,and was not expected to have any impact on the sale or supply of kava as a food.

The Committee noted the advice from OCM stating that the amendments to Schedule 4 ofthe TG Regulations, as recommended by CMEC, was intended to allow only aqueousextracts of kava in Listed goods. In addition, OCM indicated that all extracts of kavawere approved by CMEC for use in homoeopathic medicines and preparations for topicalapplication to the skin under the stipulated conditions in the TG Regulations.

Members noted that the pre-meeting submissions received from XXXXXXXXXXXXXXXXXXXXXXXX supported the CMEC recommendations. In addition,XXXXXXXXXXXX suggested that for clarity the Schedule entry in the SUSDP for kavashould specify that the maximum recommended daily dose was 250 mg kavalactones forexempt preparations containing 250 mg or less of kavalactones.

The Committee considered the draft Schedule 4 entry for kava and kavalactonesdeveloped by the NDPSC�s DAP which took into account the provisions of the TGRegulations for consistency. The DAP informed the Committee that the proposedSUSDP S4 entry for kava did not specify a daily dose cut-off for dermal preparationsbased on the advice received from OCM that the cut-off of 250 mg kavalactones per dayfor dermal preparations specified in the TG Regulations was included in error. Inaddition, the DAP also advised that a cut-off for homeopathic preparations as stated in theTG Regulations (>1000-fold dilution of a mother tincture) was not reflected in the entryas it was below the general exemption specified under Part 1 of the SUSDP, i.e. 10 mg/kgor 10 mg /L.

The Committee agreed to adopt the S4 entry for kava proposed by the DAP with minoramendment to the warning statement required for exempt products. Members did notagree to reflect on the label of exempt products the statement �If symptoms persist, seekadvice from a health care practitioner�. The Committee noted that this was inconsistentwith the existing warning statements contained in the SUSDP which directed consumersto consult a medical doctor when symptoms persisted.


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DECISION 2004/41 - 18

On the grounds of public health and safety, the Committee agreed to include Pipermethysticum (Kava) in Schedule 4 of the SUSDP, as well as adopt the exemptionsspecified in the Therapeutic Goods Regulations 1990. In addition, it was agreed to cross-reference kava to Piper Methysticum in the index of the SUSDP for clarity.

Schedule 4 – New entry:

PIPER METHYSTICUM (Kava) in preparations for human use except:

(a) in preparations for oral use containing dried whole or peeledrhizome or containing aqueous dispersions or aqueousextracts of whole or peeled rhizome when labelled with arecommended daily dose of 250 mg or less of kavalactones:

(i) containing more than 25 mg of kavalactones perdose, labelled with the statement:

WARNING: Not for prolonged use. Notrecommended for use by pregnant or lactatingwomen. May harm the liver;

(ii) in tablet or capsule form containing 125 mg or lessof kavalactones per tablet or capsule; or

(iii) in the form of a teabag when the amount of driedwhole or peeled rhizome does not exceed 3g;

(b) in topical preparations for use on the rectum, vagina orthroat containing dried whole or peeled rhizome orcontaining aqueous dispersions or aqueous extracts ofwhole or peeled rhizome; or

(c) in dermal preparations.

13.6 ARIPIPRAZOLE

PURPOSE

The Committee considered the inclusion of aripiprazole in Appendix K of the SUSDP.

BACKGROUND

Aripiprazole is an atypical antipsychotic agent indicated for the treatment ofschizophrenia. It is believed that the mechanism of its action is mediated through a


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combination of partial agonist activity at dopamine D2 receptors and serotonin 5-HT1Areceptors and antagonist activity at 5-HT2A receptors.

The NDPSC 39th Meeting (October 2003) agreed to include aripiprazole in Schedule 4 ofthe SUSDP. However, the NDPSC 40th Meeting (February 2004) was advised ofinformation drawn from open literature that aripiprazole has a high potential for causingsedation (Keck et al, Am J Psychiatry 2003; Potkin et al, Arch Gen Psychiatry 2003;Goodnick et al, Expert Opin Pharmacother 2002) and that there was a need to investigatethis issue further. Members noted that this conflicted with the findings of a placebo-controlled 26-week study on schizophrenia patients (Pigott et al, J Clin Psychiatry 2003),where aripiprazole was well tolerated and no evidence of marked sedation was observed.Subsequently, the Committee agreed to seek expert advice in relation to the potential foraripiprazole to cause sedation and consider the matter again at the June 2004.

DISCUSSION

The Committee was informed that advice had been sought from the XXXXXXXXXXX,however, a response was yet to be received.

OUTCOME

The Committee agreed to defer further consideration of the matter until the expert advicewas received.

13. 7-13.9 [ITEMS DELETED ]

These items were deleted as they were not likely to result in amendments to the SUSDP.

13.10 IBUPROFEN

PURPOSE

The Committee considered a minor amendment to the Schedule 2 (S2) entry foribuprofen.

BACKGROUND

The NDPSC 38th Meeting (June 2003) agreed to exempt from scheduling dividedpreparations containing 200 mg or less of ibuprofen per dosage unit in packs containing25 or less dosage units, when labelled with prescribed warning statements with arecommended maximum daily dose of 1200 mg of ibuprofen. The decision was based onthe safety profile of low dose ibuprofen, its comparison with similar unscheduledanalgesic products, the proposed indications are suitable for self-identification and self-treatment without professional advice, its low potential for abuse and OTC marketingexperience in Australia.


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Following consideration of post-meeting comments in relation to the NDPSC June 2003decision to exempt small packs of low dose ibuprofen, the NDPSC 39th Meeting (October2003) agreed to vary its decision and amended the warning statements required onexempt ibuprofen his, the Committee simplified certain warning statements and amendedthose relating to GI complications, pregnancy, asthma and use in certain age groups, toenhance specificity and clarity.

DISCUSSION

The Committee noted an email received from XXXXXXXXXXXX, suggesting that theword �or� be inserted following the warning statement (WS) �WARNING - Thismedication may be dangerous when used in large amounts or for a long time (period)�under part (b)(iv) of the Schedule 2 (S2) entry. It was pointed out that this shouldmaintain consistency with the reverse scheduling provisions for paracetamol and aspirin.

The Committee was advised that OTC Medicines Section wrote to the Secretariatadvising that the warning statements in relation to long term or excessive use ofibuprofen without medical supervision required under (b)(iv) of the Schedule 2 entry wasalso duplicated under (b)(v). In addition, OTC pointed out an error in that aspirin, insteadof ibuprofen, was used in the WS �Unless a doctor has told you to, don�t use [thisproduct/name of product]: ..�.With other medicines containing aspirin or anti-inflammatory medicines�� under (b)(v) of the S2 entry.

The Committee was advised of correspondence received by the XXXXXXXXXXXX,XXXXXXXXXXXX, from XXXXXXXXXXXX in relation to its concerns about therigour of the process that was used by the NDPSC in determining that small packs ofibuprofen should be exempt from scheduling. The XXXXXXXXXXXX brought to theattention of XXXXXXXXXXXX what it considered to be �new materials� with respect toibuprofen and asked that they be reviewed as new evidence. The XXXXXXXXXXXXalso urged that the labelling of unscheduled ibuprofen be reconsidered on the groundsthat the variation and inconsistency in approach to the warning statements compoundedthe complexity consumers face in safely self-selecting these medicine. On this basis, theXXXXXXXXXXXX asked that the regulation of ibuprofen be reviewed in the light ofthis new evidence and concerns regarding the medicine labels.

In response to XXXXXXXXXXXX�s request, parallel and independent evaluations ofthe following materials cited by XXXXXXXXXXXX were undertaken by the clinicalpharmacologist expert member on the NDPSC, XXXXXXXXXXXX andXXXXXXXXXXXX:

i) Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin inducedasthma and its implications for clinical practice. BMJ. 2004 Feb 21;328(7437):434;

ii) Rodriguez L, Hernandez-Diaz S. Risk of uncomplicated peptic ulcer among usersof aspirin and nonaspirin anti-inflammatory drugs. Am J Epidemiol 2004;159:23-31;


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iii) Suitability and choice of simple analgesics � balancing benefits and risks. Presentedby Dr. Alison Jones at the 25th Annual Scientific Meeting of the Australian Pain SocietyMeeting, Canberra 10th March 2004.

iv) ADRAC Bulletin Volume 22, Number 4The Committee noted the comments below made by the evaluators after reviewing thepapers referred to by the PGA:

i) Jenkins paper The paper assessed the prevalence of aspirin�induced asthma througha systematic review of published studies and selected randomised controlled trials.Concerning cross-sensitivity, the authors selected for review double blind or single blindrandomised studies.

The discussion section of the paper opens with the sentence �The prevalence of aspirin-induced asthma is 21% for adults and 5% for children according to our systematicreview�. One of the evaluators noted that this statement was not precise and lent itself tomisquoting. Correctly stated, it should be that �The prevalence of aspirin-inducedasthma in patients with asthma is 21% for adults and 5% for children according to thesystematic review�. The paper defined a positive aspirin-induced asthma response as a20 % or more reduction in FEV1 within 3-4 hours of an oral aspirin challenge. Using thiscriterion, it was found that the pooled incidence of aspirin-induced asthma was 21%,regardless of whether the patients had or had not a history of aspirin-induced asthma. Incontrast, the prevalence of aspirin-induced asthma determined using history alone was2.7%. Around half (57/113) of those who had positive reactions to oral challenge did soat low doses of aspirin (>80 mg), indicating that they were highly sensitive. Thesefigures were within the authors� own quoted range of published data for aspirin-inducedasthma (4-44%). Aspirin-induced asthma in this analysis was less common in children,the prevalence being around 5% (0-14%) by oral provocation testing and 2% (1-3%) onhistory alone.

An evaluator noted that the figure for children related to a population that may includeadolescents up to 16 or more years of age and that this may have biased the incidencefigure upwards.

Ten (10) studies reported the incidence of cross-sensitivity to 3 commonly used NSAIDs,ibuprofen, naproxen and diclofenac. Only 3 of these studies were eligible for inclusionand based on these, the incidence of cross-sensitivity was ~90-100%. Cross-sensitivity toparacetamol was 7% (0-16%) in ten level 1 studies. The paper suggested that patientswho were highly sensitive to aspirin were more likely sensitive to paracetamol, e.g. withsensitivity to an aspirin dose of 30 mg, 83% (5/6) of such patients reacted to paracetamol,but when the dose was 150 mg aspirin, none (0/4) of the patients reacted to paracetamol.

The authors of the paper also acknowledged that a prospective study of asthmatic andnon-asthmatic patients given aspirin, non-aspirin NSAIDs and paracetamol was needed toresolve the issue of cross-sensitivity.


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In conclusion, the authors indicated that a significant proportion of asthmatic patientsbeing sensitive to aspirin justified the need to include simple standardised warnings onpacks of aspirin and NSAIDs alerting patients to the potential risks. The evaluators notedthat such package warnings had already been included in the proposed unscheduledpackaging for ibuprofen.

ii) Rodriguez paper The authors studied the association between prescription NSAIDsand the risk of symptomatic ulcer in a population-based cohort studies in the UK between1995 and 1999. Rodriguez and Hernandez-Diaz used data from the UK General PracticeResearch Database (GPRD) to estimate the incidence of uncomplicated but symptomaticpeptic ulcer and used a case control method to estimate risk and its association to use ofaspirin and non-aspirin NSAIDs. The study population was 40-79 years of age whichincluded an upper age limit well above the ibuprofen general sale warning statementrelating to patients of 65 years and older. Also, usage of NSAIDs was measured byprescriptions and defined a current user as one who had obtained a most recentprescription within 30 days before the date of detection of the symptomatic ulcer by aspecialist or when in hospital, usually by endoscopy.

Of relevance to the scheduling of ibuprofen, there were no data specifically available onshort duration (few days) use.

The authors made an estimate of background incidence for the population studied of 1.03cases per 1000 person years. The incidence of symptomatic peptic ulcer essentiallydoubled between the 50-59 and 60-69 year age group exposed to NSAIDs. Current useof an NSAID increased the risk of symptomatic peptic ulcer by 4 times. For low tomedium dose of NSAIDs (including ibuprofen of 1200 mg a day or less dose) the riskwas 2.6. These estimates were adjusted for age, sex, year of diagnosis and some otherfactors. Current intake of paracetamol had a relative risk of 1.9 and there was no doseresponse detected with paracetamol.

Ibuprofen has a relative risk compared with non use of 2.7, which is the lowest ofnaproxen, ketoprofen, flurbiprofen, diclofenac, indomethacin and piroxicam. This studygave useful estimates of the incidence in the general population and estimates of riskincreases of uncomplicated symptomatic peptic ulcer associated with aspirin and NSAIDsincluding low to medium dose ibuprofen and paracetamol. However, the spread of agesand the duration based on prescriptions limit the relevance to short term general sale.The paper also reinforced the relatively low risk associated with the use of low doseibuprofen. In contrast, a higher risk of symptomatic peptic ulcer with paracetamol thanhad previously been reported was suggested.

iii) Presentation by Dr. Alison Jones Dr. Jones made a presentation at the AnnualScientific Meeting of the Australia Pain Society in Canberra on 10 March 2004, whichwas sponsored by XXXXXXXXXXXX. Dr. Jones is Director, National PoisonsInformation Service, London. XXXXXXXXXXXX requested and was provided with the


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Powerpoint slides of the presentation by Dr. Jones. The comments below from theevaluators relate to each topic as discussed by Dr. Jones.


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Suitability and tolerability of OTC analgesicsContraindications, Precautions and Interactions of NSAIDs and paracetamol weresummarised from the Australian product information for XXXXXXXXXXXX,XXXXXXXXXXXX and a recent National Prescribing Service (NPS) newsletter.

Quantifying the size of the ‘at risk’ populationsDr. Jones cited data available from an abstract of a presentation to the European LeagueAgainst Rheumatism (EULAR) 2002 Congress. In this study, the exclusion criteria forthe PAIN STUDY were applied to a UK GP database of 6,169 patients aged 18-75 years.Of these, 3.1% had contraindications to the use of ibuprofen and a further 23.3% �shouldhave consulted a doctor before using the drug�. For paracetamol, the figures were0.015% and 1.68%.

Australian data were also cited from an unpublished report submitted toXXXXXXXXXXXX by XXXXXXXXXXXX on �Determining Screening Failure Ratefor an OTC analgesic study using a general practice research network�. This was inrelation to a random sample of GP users of the �Medical Director� software who wereinvited to participate in the GPRN (General Practice Research Network) via email. Thesame exclusion criteria were applied and the result was very similar to the UK figure.

Consequences of inappropriate analgesic useDr. Jones cited the Jenkins systematic review with regard to aspirin-induced asthma. Inparticular, she stated the prevalence of aspirin induced asthma was 21%; in childrenprevalence was much higher than expected at 5%; the cross reactivity with ibuprofen was98%; cross reactivity to paracetamol was uncommon � 7% of aspirin sensitive asthmaticsor less than 2% of all asthmatics. Dr. Jones then proceeded to draw public healthimplications including that at least 1 in 5 asthmatics are sensitive to widely availableaspirin and other NSAIDs. At least in the Powerpoint slides, there was no mention of:

The actual age groups analysed for children;The acknowledgement, by Jenkins, that her results are not congruent to other recentreviews.

NSAIDs use in pregnancyDr. Jones cited the study by Li DK et al, BMJ 2003, 327;368. This study was reviewedand reported on by Professor Frauman at the October 2003 NDPSC meeting. This was aprospective cohort study in patients of the Kaiser Permanente Medical Care Program inNorthern California. The study was initially conducted on pre-natal exposure to magneticfields and was published in Epidemiology 2002. The work on associations with NSAIDsseemed to be a post-hoc analysis. The paper reported increased risks of miscarriageassociated with NSAID use that was started in the first week of gestational age (describedalso as �at conception�), and separately with use for more than one week. Hazard ratioswere 5.6 and 8.1 respectively � both with very wide confidence intervals reflecting smallnumbers of cases and controls. Importantly, the increased risks if the NSAIDs weretaken after the first gestational week (1.2) or for less than one week (1.3) were small and


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not statistically significant. For paracetamol the risk was not significant. The resultswere consistent with NSAIDs interfering with the conception process but it was unclearwhy exposure of more than 1 week was necessary.

Dr. Jones supported the use of paracetamol in pregnancy.

Gastrointestinal effectsDr. Jones cited a systematic review of the literature which showed that OTC doses ofNSAIDs were associated with a two-fold increase in gastro-intestinal (GI) bleeding(Tarone RE et al. Am J Therapy 2004, 11:17-25). The review reported increased risksand increased rates of GI events among takers of NSAIDs. Importantly, the authors ofthe review noted that in multiple studies ibuprofen tended to show the lowest risk ratios.It was also noted by Tarone et al that across 9 studies looking at the effect with dose thecut-off for low dose ibuprofen in some studies was 1500 mg (and not 1200 mg). Taronealso referenced a study by Wang (2002) stated as having reported a relatively risk of lowdose ibuprofen of 1.2.

Drug interactionsDr. Jones� Powerpoint states that NSAIDs have multiple drug interactions. They wereaccurately listed. She also referred to the studies of Catella Lawson et al NEMJ 2001;345:1809-1817 which described a possible mechanism for ibuprofen to interfere with theantiplatelet effects of aspirin. Also cited by Dr. Jones was the paper by MacDonald andWei, Lancet 2004, claiming to show the clinical impact of the effect of ibuprofen on thecardioprotective effect of aspirin.

Both these papers were reviewed by XXXXXXXXXXXX for the October 2003 NDPSCmeeting. The clinical paper was based on the prescription use of ibuprofen and did notreport about short term use of OTC ibuprofen. Furthermore, at least one epidemiologicalpaper published more recently (Kurth T et al. Circulation 2003; 108:1191-1195) did notsupport a clinically measurable effect of this interaction at least for low dose shortduration ibuprofen (in contrast, an increase in risk of first myocardial infarction in malepatients was reported where the NSAID was taken for more than 60 days in a year).

Triple WhammyDr Jones cited 2 papers about this well-established interaction between ACE inhibitordrugs, diuretics and NSAIDs. She cited 2 references which were to papers in 1986(Kleinknecht D et al) and 1998 (Heerdink E R et al). The evaluators did not findanything controversial or new in Dr. Jones� presentation of the two papers.

iv) ADRAC Bulletin Volume 22, Number 4, August 2003 XXXXXXXXXXXX citedthis publication in its list of new evidence. It was noted by XXXXXXXXXXXX that thispublication was not available at the time of the initial consideration of the schedulingchange of ibuprofen. The evaluators noted that the Bulletin had been distributed beforethe October 2003 meeting and that, further, the Record of Reasons (RoR) for that meetingdisclosed publicly that NDPSC was provided with ADRAC data at that October 2003


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meeting. On this basis, it was unclear why XXXXXXXXXXXX had cited this as newevidence.

Conclusion Both the evaluators were not convinced, after review of the materials cited,that new or concerning data had been provided regarding the lack of safety ofunscheduled low-dose ibuprofen vs. any other commonly used unscheduled analgesics(e.g. aspirin and paracetamol) for short-term use in patients with minor ailments.

DECISION 2004/41 - 19

The Committee agreed to editorially amend the S2 entry for ibuprofen to include an �or�after the warning statement �WARNING - This medication may be dangerous when usedin large amounts or for a long time (period)� under part (b)(iv). The Committee alsoagreed to replace �aspirin� with �ibuprofen� in the WS �Unless a doctor has told you to,don�t use [this product/name of product]: ..�.With other medicines containing aspirin oranti-inflammatory medicines�� under (b)(v).

The Committee agreed with the evaluators that the materials cited by XXXXXXXXXXXas �new evidence� did not raise new issues or concerns which had not been previouslyconsidered by the NDPSC.

EDITORIAL AMENDMENT


IBUPROFEN - amend entry to read:

IBUPROFEN in preparations for oral use when labelled with a recommended daily doseof 1200 mg or less of ibuprofen:

(a) in liquid preparations when sold in the manufacturer�soriginal pack containing 4 grams or less of ibuprofen; or

(b) in divided preparations, each containing 200 mg or less ofibuprofen, in packs of 100 or less dosage units exceptwhen:

(i) as the only therapeutically active constituent otherthan an effervescent agent;

(ii) packed in blister or strip packaging or in acontainer with a child-resistant closure;

(iii) in a primary pack of 25 or less dosage units;


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(iv) the primary pack is labelled with a warningstatement to the following effect:

WARNING - This medication may be dangerouswhen used in large amounts or for a long time(period); or

CAUTION - This preparation is for the relief ofminor and temporary ailments and should be usedstrictly as directed. Prolonged use without medicalsupervision could be harmful; or

CAUTION - This preparation is for the relief ofminor and temporary ailments and should be usedstrictly as directed. Prolonged or excessive usewithout medical supervision could be harmful; and

(v) the primary pack is labelled with warningstatements to the following effect:

Don�t use [this product / name of the product]:If you have astomach ulcerIn the last 3 months of pregnancy [This statement may be omittedin preparations used exclusively for the treatment ofdysmenorrhoea]If you are allergic to ibuprofen or other anti-inflammatorymedicines; and

Unless a doctor has told you to, don�t use [this product / name ofthe product]:For more than a few days at a timeWith other medicines containing ibuprofen or other anti-inflammatory medicines or other medicines that you are takingregularlyIf you have asthmaIn children 6 years of age or lessIf you are aged 65 years or overIf you are pregnant [This statement may be omitted in npreparations used exclusively for the treatment ofdysmenorrhoea].


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14. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FORTHE UNIFORM SCHEDULING OF DRUGS AND POISONS.

14.1 SUSDP, PART 4

14.1.1 DICLOFENAC

PURPOSE

The Committee considered a proposal by XXXXXXXXXXXX to reschedule fromSchedule 3 to Schedule 2 diclofenac in divided preparations for oral use containing 12.5mg or less per dosage unit in a pack containing 30 or less dosage.

BACKGROUND

Diclofenac is a NSAID with potent anti-inflammatory, analgesic, and antipyreticproperties. It is a reversible, competitive inhibitor of cyclooxygenase. In 1986 aformulation containing immediate release diclofenac potassium 25 and 50mg tablets waslaunched as XXXXXXXXXXXX and XXXXXXXXXXXX designed for short-termtreatment of acute painful and inflammatory conditions. XXXXXXXXXXXX productsare available in over 80 countries including Australia, New Zealand, the EU and USA.Generally, the fast acting diclofenac potassium form is intended for acute pain reliefand/or short-term (up to one week treatment) while diclofenac sodium is claimed to bemore appropriate for chronic pain states including rheumatoid arthritis and osteoarthritis.

Diclofenac was included in S4 in March 1981. The Committee then agreed to reschedulediclofenac 25 mg or less in packs of 30 or less for oral use to S3 in August 1999, asrecommended by the TTHWP, and listed it in Appendix H of the SUSDP in August 2001.At the NDPSC 12th Meeting (February 1997), diclofenac 1% or less for dermal use wasrescheduled to S2. Subsequently, all dermal preparations were subsequently madeexempt from scheduling requirements at the NDPSC 26th Meeting (February 2000).

At the time of the meeting, tablets containing 25mg diclofenac potassium (4,5,6,10, 20 or30 tablets per pack) and tablets containing 25mg diclofenac sodium (20 or 50 tablets perpack) were registered on the ARTG and included in S3 of the SUSDP. Only one S3product formulated as a suppository was currently listed on the ARTG containing 12.5mg diclofenac sodium.

DISCUSSION

The Committee noted that an application to register �XXXXXXXXXXXX� (diclofenacpotassium 12.5mg) tablets in packs of 10 and 20 tablets was also lodged with the OTCMedicines Section of the TGA in December 2003 [XXXXXXXXXXXX] for:

• temporary relief of headache, dental pain, period pain, rheumatic and muscular pain,back ache;


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• temporary relief of symptoms of cold and flu including aches and pains, sore throatpain; and

• reduction of fever.The recommended duration of treatment was not to exceed 5 days for pain relief and 3days for treatment of fever, while the recommended daily dose was not to exceed 6tablets per day. The outcomes of the evaluation of this application were not available toNDPSC at this meeting.

Members noted that pre-meeting submissions were received from XXXXXXXXXXXX,XXXXXXXXXXXX, XXXXXXXXXXXX, XXXXXXXXXXXX, andXXXXXXXXXXXX.

The Committee discussed the points cited by the sponsor in support of their application(in bold):

Safety and Efficacy of XXXXXXXXXXXX for indications sought.

The Committee noted the overall estimated GI complications from 18 large post-marketing treatment studies in general practice was around 2.2 per 10,000 patients,although these studies had no comparator groups (XXXXXXXXXXXX Update 1994).The same post-marketing studies found that in patients using prescribed diclofenac at 75-200 mg/day for up to 2 weeks (115,000 subjects), the overall estimated incidence ofadverse events (AEs) was <20% and the vast majority of AEs were not serious. Theevaluator reported that a published review of open studies (Catalana. Am. J. Med. 1986)suggested that in 162 open studies conducted from 1972 to 1982 in 85, 361 patients, theoverall AE frequency was reported as 11.8%, with 7.6% as GI AEs. The evaluatorsupported the overall safety of diclofenac and concurred with the sponsor�s claim that anacceptable safety profile could be reasonably extrapolated to the low-dose regimenproposed for non-prescription use at up to 75mg per day.

A member suggested that listing of the salt, i.e. diclofenac potassium, in the Schedule 2entry, if supported, should be considered by the Committee to retain other preparations(i.e. diclofenac sodium) for the treatment of chronic conditions in S3.

Some stakeholders claimed in pre-meeting submissions that over-the-counter (OTC)NSAIDS should be made available to consumers only in conjunction with pharmacistadvice to reduce the potential for adverse effects. Whilst it was recognised that NSAIDsas a therapeutic class were well-understood, the rates of adverse effects, drug interactions,side effects and contraindications associated with these drugs could not be consideredinsignificant from a public health perspective.

The Committee noted that some stakeholders questioned the efficacy of 12.5 mgdiclofenac tablets at 75 mg per daily dose for treating all pain states covered in theproposed indications. In addition, it was also noted that the practicality and volume of12.5 mg diclofenac tablets required for treating painful conditions, e.g. 16 x 12.5 mg


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tablets for the treatment of one or more migraines in a 24-hr period and up to 36 tabletsfor a thee-day treatment, was a common concern highlighted in pre-meeting submissions.

The safety of diclofenac products in wide-spread usage around the world for almost30 years, including Schedule 3 usage in Australia.

The Committee was advised that the 12.5 mg diclofenac oral formulation had not everbeen marketed in Australia, even as a prescription medicine, hence there was no localclinical experience with this formulation. A pre-meeting respondent also advised that12.5 mg diclofenac oral formulation was not on the market in New Zealand. OnlyGermany and Switzerland appeared to have post-marketing OTC experience withdiclofenac 12.5 mg tablets and that it was unlikely for many �comparable� overseascountries (as specified in NDPSC Guidelines) to have OTC post-marketing data for thisformulation.

The Committee agreed with the view that the absence of public experience with OTC useof the 12.5 mg diclofenac oral formulation in Australia could potentially lead toinappropriate use of the product. Without consumer familiarity with the product, theOTC availability of diclofenac in more than one dosage strength for similar indicationscould confuse consumers particularly given that pharmacists may not have theopportunity to provide counselling or give guidance to those who would self-select an S2product.

The availability of comparable NSAIDs as S2 or exempted substances in Australia(eg. aspirin or ibuprofen).

The Committee noted that NSAID products available as unscheduled or S2 included 11products containing ibuprofen, 1 with ibuprofen and codeine, 3 with naproxen sodiumand 1 with mefenamic acid and aspirin. More recently, low-dose ibuprofen also becameexempt from scheduling in Australia on 1 January 2004 when in divided preparationslabelled with up to 1200 mg ibuprofen daily dose containing 200 mg or less ibuprofen perdose and compliant with labelling, packaging and pack size restrictions.

The November 2002 Medicine Classification Committee (New Zealand) agreed toclassify diclofenac as a Pharmacy Only medicine (equivalent to S2) when in soliddose forms containing 12.5mg or less per dose form in packs of not more than 20tablets or capsules.

The Committee noted the NZ Medicines Classification Committee�s (MCC) decision inNovember 2002 to classify 12.5 mg diclofenac tablets or capsules to Pharmacy-Onlymedicine. The MCC minutes stated that ��members agreed that the potential for misusewas small and there was a need for consistency in that 250 milligram naproxen tabletswere already available as a pharmacy-only medicine. Nor was there any limit to theamount of aspirin available despite its side effects. It was agreed that 12.5 milligramdiclofenac tablets should be available as pharmacy-only medicine when sold in packs ofnot more than 20 tablets�.


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Members noted that the sponsor�s submission was for packs in Australia to contain 30 orless 12.5 mg diclofenac dosage units, ie., maximum of 6/day, for 5 days, to allow for theproposed indications. Members preferred the 5-day pack size of 30 tablets for OTCavailability for consistency with pack sizes of other medicines for short-term treatment ofpain.

Members also noted that there was no entry in Appendix F, Part 3 of the SUSDP fordiclofenac and that the sponsor did not propose any warning statement (WS) for theproposed S2 product. The NSAIDs listed in Appendix F, Part 3 including ibuprofen,mefenamic acid and naproxen are required to have Appendix F WS 101 and 104(mandatory from 1 May 2005). These warning statements warned against the following:use in patients with stomach ulcer, use during last 3 months of pregnancy, use whenallergic to anti-inflammatory medicines, use for more than a few days at a time,concomitant use with aspirin or other anti-inflammatory medicines, use in patients withasthma, use in children under 12 years of age and use during pregnancy. The Committeediscussed the current warning statements required for NSAIDs and came to theconclusion that the following deficiencies in the current WSs needed to be referred toMEC for consideration:

• WS 101 � did not warn against use in patients with a past history of stomach ulcer.

• WS 102 & 104 � did not warn against use in elderly patients most at risk of GIcomplications from use of NSAIDs, i.e. > 60 years old, and did not list medicinescommonly taken by consumers on a regular basis which could interact with NSAIDs,e.g. antihypertensives and diuretics.

OUTCOME

The Committee noted the available information suggested that the overall GI safety ofdiclofenac potassium 12.5mg across its range of doses was comparable to low doseibuprofen. An important caveat was that the information submitted was mainly in theform of reviews. The NDPSC evaluator had not been provided with any of the individualstudies which had been reviewed. Having regard to this and the absence of an evaluationfor OTC registration and local post-marketing experience with the 12.5 mg oral doseformulation in Australia to establish safety, efficacy and use pattern for the indicationssought, members were not convinced that a change in scheduling status for 12.5 mgdiclofenac was appropriate at this time. The Committee was mindful that the datarequirements for scheduling considerations are limited and are not comparable to thatrequired for registration. On this basis, members agreed that it would be appropriate forproduct formulations, not previously registered in Australia, to be assessed and approvedfor registration first prior to scheduling. The Committee agreed to consider this matter asa policy issue at the NDPSC 42nd Meeting (October 2004).

Further, the Committee considered the current warning statements required for NSAIDsin Appendix F, Part 3 of the SUSDP needed to be strengthened in order to warnconusmers against the important adverse effects associated with diclofenac potassium as


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well as other NSAIDs. The Committee decided not to approve the requested change atthis time.

14.1.2 NICOTINE

PURPOSE

The Committee considered the proposal to reschedule nicotine in sublingual tablets forNicotine Replacement Therapy (NRT) from Schedule 3 (S3) to S2 of the SUSDP.

BACKGROUND

The NDPSC 20th Meeting (February 1999) agreed to a number of scheduling changesrelating to nicotine for the purpose of obtaining consistency between Australian and NZSchedule entries. One such change to the SUSDP was the inclusion of sublingual tabletsin Schedule 3.

The August 2000 Meeting of the Medicines Evaluation Committee consideredXXXXXXXXXXXX 2 mg and 4 mg sublingual tablets. They were registered inAustralia in November 2001 and the 2 mg tablets and was launched as a Pharmacist OnlyMedicine in 2004.

The November 2003 MCC meeting agreed to reclassify nicotine in lozenges andsublingual tablets from Restricted medicine to Pharmacy-Only medicine.

XXXXXXXXXXXX submitted an application seeking rescheduling from S3 to S2 ofnicotine sublingual tablets in the interest of ensuring trans-Tasman schedulingharmonisation.

DISCUSSION

The Committee noted that submissions were received from the XXXXXXXXXXXXXXXXXXXXXXXX and XXXXXXXXXXXX advocating the retention of nicotinesublingual tablets in Schedule 3 in view of the limited experience of use in Australia. Incontrast, only one submission from XXXXXXXXXXXX supported the rescheduling ofnicotine sublingual tablets from S3 to S2.

The Committee discussed the application and the evaluation report of theXXXXXXXXXXXX �s submission:

Safety and efficacy of sublingual tablets containing 4 mg nicotine

The application stated that nicotine sublingual tablet has the same site of absorption(buccal) as nicotine inhaler (S2), gum and lozenge (both exempt), and shows similarsafety profile to these nicotine preparations for NRT. The sponsor claimed that nicotine


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sublingual tablets provide relief from the symptoms of nicotine withdrawal and are aneffective aid for helping smokers quit.

The evaluator noted that the adverse effect profile of NRT in various forms is wellestablished. The most common adverse effects included headache, nausea,gastrointestinal discomfort, hiccups, coughing, sore mouth or throat, dry mouth andburning sensation in the mouth. The evaluator considered that there is no reason toexpect that the use of the sublingual tablet would be more hazardous than the use of thegum.

Low potential for abuse or harm from inappropriate use

The evaluator noted that whilst the sponsor acknowledged that inappropriate long-termuse may occur, it claimed that any risks were likely to be far less than the risks ofcontinued smoking. The Periodic Safety Update Report indicated 7 reports of addictionto the sublingual tablets during the period August 2002 � July 2003, two of which hadserious effects (pernicious anaemia following long term use for 3 years and panic attackand increased sweating reported after August 2002, with use having commenced inNovember 2001.

The evaluator indicated that the abuse potential of nicotine-containing products is relatedto the rapidity with which nicotine is absorbed from the product and that cigarettes whichprovide a bolus of nicotine to the brain within 10 seconds of each inhalation, have muchgreater abuse potential than products such as gums and lozenges, which produce a peakplasma concentration after about 30 minutes. The abuse potential for sublingual tablets,which produce a slow rise in plasma concentrations similar to that of other NRT productsincluding nicotine gum is likely to be very similar to other preparations included in S2 orto those available for unrestricted sale.

The evaluator also pointed out that although nicotine itself could have severe toxicity inacute poisoning (acute fatal dose 30-60 mg in an adult), there had been no cases ofoverdose or reports of deliberate or accidental poisoning with the sublingual productsince it was first marketed overseas in October 1998.

Low or well characterised incidence of adverse effects or side effects and contra-indications for which advice or counselling is available

The sponsor claimed that nicotine in sublingual tablets has low or well characterisedincidence of severe adverse effects or side effects and contra-indications for which adviceor counselling is available at S2 setting. In addition, the product has a low risk ofmasking a serious disease. It was indicated that the 4 mg sublingual tablet is not marketedin Australia and that the majority of the data is based on the 2 mg product (which wasrecently marketed in Australia). However, since the 2 mg sublingual tablet isbioequivalent to the 2 mg nicotine chewing gum, there was no expectation that the


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adverse event profile for 4 mg sublingual tablets would be any different from that for 4mg chewing gum

The evaluator noted that the contra-indications for the formulation were the same as forother forms of NRT and that these were disclosed in the CMI and on the productpackaging. The evaluator also noted that based on available data the risk of masking aserious disease for nicotine sublingual tablets used as nicotine replacement therapy isvery low.

Pattern of use and the need for access to the formulation

The application stated that nicotine for NRT had been available in different dosage formsfor many years, and was widely recognised and used by both consumers and healthcareprofessionals. The nicotine sublingual tablets are suitable for those smokers who forsocial reasons or personal preference do not like to use or cannot use nicotine chewinggum. For example, this group may include people with dentures or jaw conditions whereconstant chewing is not desirable and increasing the availability of the product wouldprovide an additional choice to these consumers.

Local clinical experience with the sublingual formulation

The sponsor stated that while the nicotine sublingual tablets (2 mg) had just beenlaunched in Australia, they had been marketed in the UK since March 1999 and in 12other European/Scandinavian countries from October 1998. Whilst the sponsorconsidered the safety profile of the sublingual formulation comparable to exempt NRTformulations, i.e. gums, patches and lozenges, it recognised the need to gain local post-marketing experience at the S2 level.

The majority of post-meeting submissions argued against rescheduling nicotine insublingual tablets to S2 on the basis of limited local experience with this formulation andthat the 4 mg sublingual formulation had not ever been marketed in Australia. Membersnoted that XXXXXXXXXXXX 2 mg (sublingual tablet) had been assessed forregistration by the Medicines Evaluation Committee (MEC) and was currently being soldon the Australian market. The PI for XXXXXXXXXXXX, which has been approved bythe TGA, also allows a 2 x 2 mg dose for highly dependent smokers, which isbioequivalent to a single 4 mg sublingual tablet.

DECISION 2004/41 - 20

The Committee agreed to include sublingual tablets containing 4 mg or less of nicotinefor use as an aid in withdrawal from tobacco smoking in S2 of the SUSDP. TheCommittee took into account the relevant matters set out in s.52E of the TherapeuticGoods Act 1989 and based its decision on these reasons:


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• the safety and adverse effect profile of the formulation for its intended use fulfills thecriteria for an S2 medicine, where pharmacist advice is available to consumers whenrequired;

• low potential for masking a serious disease;

• low potential for abuse or misuse;

• making the formulation more readily available to consumers would provide anadditional choice to consumers and encourage more people to quit smoking;

• there is significant overseas post marketing experience with the sublingualformulation and no new or emerging safety issues were identified; and


NICOTINE � amend entry to read:

NICOTINE for use as an aid in withdrawal from tobacco smoking in preparations forinhalation or sublingual use.


NICOTINE � delete entry.



NICOTINE for use as an aid in withdrawal from tobacco smoking (includingpreparations for nasal administration) except:


(b) in chewing gum;

(c) in lozenges; or

(d) in preparations for transdermal use.



NICOTINE except:

(a) when included in Schedule 2,4 or 6;


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(b) in chewing gum;

(c) in lozenges;

(d) in preparations for transdermal use; or

(e) in tobacco prepared and packed for smoking.

14.2 SUSDP, PART 5

No items considered.

15. MATTERS REFERRED BY THE AUSTRALIAN DRUGEVALUATION COMMITTEE (ADEC)

15.1 NEW SUBSTANCES

15.1.1 ATOMOXETINE

PURPOSE

The Committee considered the scheduling of atomoxetine.

BACKGROUND

Atomoxetine hydrochloride is a selective noradrenaline reuptake inhibitor used for thetreatment of attention deficit hyperactivity disorder (ADHD) in adults and children.

The December 2003 ADEC meeting recommended the approval of an application byXXXXXXXXXXXX to register XXXXXXXXXXXX containing the new medicineatomoxetine hydrochloride XXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXX:

The treatment of attention deficit hyperactivity disorder (ADHD) as defined byDSM-IV criteria in children 6 years of age and older, adolescents and adults.

ADEC also recommended that approval be subject to the finalisation of the ProductInformation to the satisfaction of the TGA.

DISCUSSION

The Committee noted the December 2003 ADEC minutes which reported that a smallstudy (n=16) concluded that abuse potential was low. [Sentence deleted]. ADECrequested that the small number of patients in the study be explicitly stated in the ProductInformation description.

[Sentence deleted].


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The Committee noted that atomoxetine is classified as a prescription medicine in NewZealand.

DECISION 2004/41 - 21

The Committee agreed to include atomoxetine in Schedule 4 of the SUSDP on thegrounds that the condition being treated necessitated appropriate medical diagnosis andthe safe use of this medicine required patient management and monitoring by a medicalprofessional and to harmonise with New Zealand.


ATOMOXETINE.

15.1.2 ATAZANAVIR

PURPOSE

The Committee considered the scheduling of the new medicine atazanavir.

BACKGROUND

Atazanavir is an HIV-1 protease inhibitor.

The December 2003 ADEC meeting recommended the approval of an application byXXXXXXXXXXXX to register XXXXXXXXXXXX containing the new medicineatazanavir sulfate XXXXXXXXXXXX XXXXXXXXXXXX:

Atazanavir sulfate is indicated for the treatment of HIV-1 infection, incombination with other antiretroviral agents.

ADEC also recommended that:


DISCUSSION

[Paragraph deleted]

The Committee noted that atazanavir was classified as a prescription medicine in NewZealand.


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DECISION 2004/41 - 22

The Committee agreed to include atazanavir in Schedule 4 of the SUSDP on the groundsthat the condition being treated necessitated appropriate medical diagnosis and the safeuse of this medicine required patient management and monitoring by a medicalprofessional and to harmonise with New Zealand.


ATAZANAVIR.

15.1.3 TREPROSTINIL

PURPOSE

The Committee considered the scheduling of the new medicine treprostinil.

BACKGROUND

Treprostinil sodium is a prostacyclin (PGI2)/epoprostenol (Flolan) analogue with potentpulmonary and systemic vasodilator activity and inhibition of platelet aggregation.

The December 2003 ADEC meeting recommended the approval of an application byXXXXXXXXXXXX to register XXXXXXXXXXXX solution for injection, containingthe new medicine treprostinil sodium XXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXX:

XXXXXXXXXXXX is indicated as a continuous subcutaneous infusion for thetreatment of pulmonary arterial hypertension in patients with NYHA class III-IVto diminish symptoms associated with exercise.


DISCUSSION

The Committee noted that there were not a lot of agents to treat pulmonary arterialhypertension, a rare disease which may be primary or secondary to systemic diseasessuch as scleroderma.

[Paragraph deleted]

The Committee noted that treprostinil was not a classified medicine in New Zealand.


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DECISION 2004/41 - 23

The Committee agreed to include treprostinil in Schedule 4 of the SUSDP on the groundsthat the condition being treated necessitated appropriate medical diagnosis and the safeuse of this medicine required administration, ongoing patient management andmonitoring by a medical professional.


TREPROSTINIL.

15.1.4 AMOTOSALEN

PURPOSE

The Committee considered the scheduling of the new medicine amotosalen.

BACKGROUND

Amotosalen is a synthetic psoralen which, under UV-A, irreversibly intercalates withRNA and DNA, preventing replication of bacteria and viruses.

The TGA Office of Devices, Blood and Tissues (ODBT) requested ADEC to consider anapplication by XXXXXXXXXXXX for the device XXXXXXXXXXXX containing thenew medicine amotosalen hydrochloride. ODBT requested that ADEC review datarelating to the quality and safety of the amotosalen hydrochloride component ofXXXXXXXXXXXX.

The December 2003 ADEC meeting recommended to ODBT that the data presented forthe evaluation of the medicinal component of the XXXXXXXXXXXX, containing thenew medicine amotosalen present as hydrochloride XXXXXXXXXXXXXXXXXXXXXXXX XXXXXXXXXXXX had satisfactorily established adequateevidence of quality and safety for the proposed indication:

XXXXXXXXXXXX platelets are indicated for transfusion support of patientsrequiring platelet transfusions according to clinical practice guidelines. Anythrombocytopenia resulting from disease, therapy or injury can be treated withXXXXXXXXXXXX platelets. XXXXXXXXXXXX platelets are not clinicallydifferent from untreated platelets and are infused according to standard plateletinfusion methods.

ADEC recommended that registration should be conditional upon regulatoryrequirements of the XXXXXXXXXXXX being fully met to the satisfaction of the TGA.

[Paragraphs deleted]


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DISCUSSION

[Paragraphs deleted]

OUTCOME

The Committee agreed not to schedule amotosalen at this time and to await theassessment of additional data on the medical device.

15.1.5 CICLESONIDE

PURPOSE

The Committee considered the scheduling of the new medicine ciclesonide.

BACKGROUND

Ciclesonide is a glucocorticoid for inhalation or intranasal administration.

The December 2003 ADEC meeting recommended the approval of the application byXXXXXXXXXXXX to register XXXXXXXXXXXX XXXXXXXXXXXX, containingthe new chemical entity ciclesonide XXXXXXXXXXXX XXXXXXXXXXXX, for theprophylactic treatment of asthma. This recommendation was made after theconsideration of new information, XXXXXXXXXXXX XXXXXXXXXXXXXXXXXXXXXXXX.


DISCUSSION

The Committee noted the minutes of the December 2003 ADEC meeting, the approvedProduct Information for XXXXXXXXXXXX and that ciclesonide was not a classifiedmedicine in New Zealand.

DECISION 2004/41 - 24

The Committee agreed to include ciclesonide in Schedule 4 of the SUSDP on the groundsthat the condition being treated necessitated appropriate medical diagnosis and the safeuse of this medicine required patient management and monitoring by a medicalprofessional.


CICLESONIDE.


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15.1.6 ROSUVASTATIN

PURPOSE

The Committee considered the scheduling of the new medicine rosuvastatin.

BACKGROUND

Rosuvastatin is a potent HMG-CoA reductase inhibitor (statin).

The February 2004 ADEC meeting recommended the approval of an application by toregister XXXXXXXXXXXX containing the new medicine rosuvastatin (calcium)XXXXXXXXXXXX and XXXXXXXXXXXX for the indications:

XXXXXXXXXXXX is indicated, at a starting dose of XXXXXXXXXXXX, asan adjunct to diet when the response to diet and exercise is inadequate for thetreatment of:

1. Hypercholesterolaemia2. Heterozygous and homozygous familial hypercholesterolaemia

Prior to initiating therapy with rosuvastatin, secondary causes ofhypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism,nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drugtherapy, alcoholism) should be identified and treated.


Further, ADEC recommended the rejection of the application to registerXXXXXXXXXXXX on the grounds of inadequate safety.

DISCUSSION

The XXXXXXXXXXXX Member, XXXXXXXXXXXX, declared a potential conflict ofinterest for this item. The Member had worked XXXXXXXXXXXX until August 2002.The Member left the room whilst the Committee discussed this declaration. TheCommittee considered that this activity was not a conflict of interest and agreed that theMember could continue to participate with voting rights.

The Committee noted that the Drugdex Drug Evaluation includes:

• a USFDA pregnancy Category X for rosuvastatin; and

• pregnancy warnings in the Patient Instructions for XXXXXXXXXXXX.However, the Committee noted that other statins in this class carry a Pregnancy CategoryC in Australia.


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The Committee noted that rosuvastatin was classified as a prescription medicine in NewZealand.

DECISION 2004/41 -25


ROSUVASTATIN.

15.1.7 ALEFACEPT

PURPOSE

The Committee considered the scheduling of the new medicine alefacept.

BACKGROUND

Alefacept is a recombinant leukocyte function-associated antigen-3 (LFA-3)-immunoglobulin G1 (IgG1) fusion protein.

The February 2004 ADEC meeting recommended the approval of an application byXXXXXXXXXXXX to register XXXXXXXXXXXX for Injection containing the newmedicine alefacept XXXXXXXXXXXX and XXXXXXXXXXXX for the indication:

Treatment of adult patients with moderate to severe chronic plaque psoriasiswho are candidates for phototherapy or systemic therapy. Safety and efficacybeyond two courses have not been demonstrated.


DISCUSSION

The Committee noted the minutes of the February 2004 ADEC meeting which reportedthat:

• [Paragraphs deleted]The Committee noted the approved Product Information which cautions thatXXXXXXXXXXXX may increase the risk of malignancies; some patients in clinicalstudies developed malignancies; in preclinical studies, animals developed B cellhyperplasia and one animal developed a lymphoma.

With the possible increased risk of malignancies, and as safety and efficacy beyond twocourses of treatment had not been demonstrated, the Committee agreed that alefaceptshould be available only on the prescription or order of a dermatologist. Therefore, the


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Committee agreed that alefacept be included in Appendix D of the SUSDP to placeadditional controls on supply and availability for public health and safety reasons.

DECISION 2004/41 - 26

The Committee agreed to include alefacept in Schedule 4 of the SUSDP on the groundsthat the condition being treated necessitated appropriate medical diagnosis and the safeuse of this medicine requires patient management and monitoring by a specialist medicalprofessional.

The Committee also agreed to include alefacept in Appendix D of the SUSDP for publichealth and safety reasons, to be available only on the prescription or order of adermatologist.


ALEFACEPT.

Appendix D – New entry

7. Poisons available only from or on the prescription or order of a dermatologist.

ALEFACEPT for human use.

15.1.8 APREPITANT

PURPOSE

The Committee considered the scheduling of the new medicine aprepitant.

BACKGROUND

Aprepitant is a neurokinin-1 (NK-1)-receptor antagonist.

The February 2004 ADEC meeting recommended the approval of an application byXXXXXXXXXXXX to register XXXXXXXXXXXX containing the new medicineaprepitant XXXXXXXXXXXX and XXXXXXXXXXXX for the indication:

Use in combination with other antiemetic agents for the prevention of acute anddelayed nausea and vomiting associated with initial and repeat courses of highlyemetogenic cancer chemotherapy, including high-dose cisplatin.

ADEC also recommended that approval be subject to finalisation of the ProductInformation to the satisfaction of the TGA.


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DISCUSSION

The Committee noted the minutes of the February 2004 ADEC meeting, which reportedthat:

• [Paragraphs deleted]The Committee also noted that aprepitant was classified as a prescription medicine inNew Zealand.

DECISION 2004/41 - 27

The Committee agreed to include aprepitant in Schedule 4 of the SUSDP on the groundsthat the condition being treated necessitated appropriate medical diagnosis and the safeuse of this medicine required patient management and monitoring by a medicalprofessional and to harmonise with New Zealand.


APREPITANT.

16. OTHER MATTERS FOR CONSIDERATION

16.1 KETAMINE

PURPOSE

The Committee noted the paper prepared by the XXXXXXXXXXXX member onketamine.

DISCUSSION

The Committee was advised that the National Working Group on the Diversion ofChemical Precursors (NWG) would be seeking to reschedule ketamine to Schedule 8 (S8)of the SUSDP (currently in S4) at the NDPSC 42nd Meeting (October 2004) due to theproblem of diversion of the substance to the illicit drug trade.

The Committee noted that the NWG was established by the Australian Government withbroad membership including health and law enforcement representatives from thejurisdictions and representatives from the pharmaceutical industry and the pharmacyprofession. The Terms of Reference for the Working Group are as follows:

• To provide a peak forum for all stakeholders in the management of precursorchemicals and equipment used in the production of illicit drugs to work together.

• To ensure a consistent national approach and promote better coordination andcollaboration across all sectors.


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• To discuss and identify best practice, with a view to national implementation.

• To focus on identification of:! Current strategies;! Issues not being addressed elsewhere, including research requirements and

knowledge gaps;! Potential new strategies, including education initiatives;

! Required industry and law enforcement partnerships and networks; and

! Consistent legislative frameworks.! To make recommendations for action to key decision-making bodies.

Members were informed that the March 2004 NWG meeting considered the issue ofmisuse and diversion of ketamine. At this meeting, NWG noted that the therapeutic useof ketamine had been increasing from that as a human and veterinary anaesthetic toanalgesic in palliative care and emergency medicine for use by medical practitioners anddentists. However, NWG was advised that there was growing evidence of illicit use ofketamine due to its psychotropic effects and that the substance had been found in eitherits pure form or in combination with other substances such as MDMA [N,(-dimethyl-3,4-(methylenedioxy)phenylethylamine]. NWG noted that ketamine is not easily synthesisedtherefore the supply to the illicit drug market was most likely through diversion ofpharmaceutical products from various points and through importation. It was advisedthat some jurisdictions had increased the storage and reporting requirements for ketaminein health services but these may not necessarily cover all diversion points.

XXXXXXXXXXXX members reported increasing problems with ketamine in theirXXXXXXXXXXXX including loss of ketamine shipments and procurement ofunreasonably large quantities of ketamine by certain individuals.

OUTCOME

The Committee agreed to consider the matter at the NDPSC 42nd Meeting (October 2004)meeting and asked XXXXXXXXXXXX to investigate the issue in theirXXXXXXXXXXXX and advise the October meeting of their findings.

17. MATTERS REFERRED BY THE MEDICINES EVALUATIONCOMMITTEE (MEC)

17.1 ASPIRIN

PURPOSE

The Committee considered comment from the Medicines Evaluation Committee (MEC)in relation to the Schedule 2 (S2) entry for aspirin.


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BACKGROUND

Reye�s Syndrome was first described in 1963. Reye reported on a series of 21 childrenadmitted to XXXXXXXXXXXX in NSW over the period 1951-1962, with acuteencephalopathy and fatty changes in the liver. Similar cases were reported in the USAand the UK, mostly in association with use of aspirin. Reye�s Syndrome generallypresents as pernicious vomiting following a viral illness. Encephalopathy subsequentlyoccurs, often as hyperexcitability which may progress to coma and death.

Regulatory action concerning warning statements on aspirin products had been takenrecently in both the UK and the USA. The Committee on Safety of Medicines (CSM) inthe UK reviewed the need to amend the aspirin warning statements in 2002 and agreedthat all aspirin-containing products be labelled with �Do not give to children under 16years of age, unless on the advice of a doctor� as from October 1, 2003. In the USA, theFDA on 17 April 2003 amended the warning statement required of all oral and rectalOTC drug products containing aspirin including those containing non-aspirin salicylatesto read �Children and teenagers who have or are recovering from chicken pox, flusymptoms or flu should NOT use this product. If nausea, vomiting, or fever occur,consult a doctor because these symptoms could be an early sign of Reye�s Syndrome, arare but serious illness�.

At the NDPSC 40th Meeting (February 2004), the NDPSC confirmed its decision toinclude MEC�s proposed label warning statements for aspirin in the Schedule 2 (Decision2003/39-27). However, members agreed to vary the amendment by including the words�to the following effect� where there was a requirement for certain warning statements onunscheduled products. The Committee also decided at this meeting that the words �to thefollowing effect� should not be added to paragraphs (b) (iii) or (c) (iv) of the S2 entry, onthe advice of MEC that the warning statement �Consult a doctor before giving thismedication to children or teenagers with chicken pox, influenza or fever� should beretained pending the outcome of the review of the aspirin warning statement in relation toReye�s syndrome.

DISCUSSION

The Committee noted a minute from OTC Medicines Section containing therecommendations of the MEC February 2004 meeting which included a copy of theReview of Aspirin/Reye�s Syndrome Warning Statement investigating the link betweenaspirin use in children and teenagers to Reye�s syndrome. The Review found that:

• The available evidence suggested that while a proportion of cases meeting thedefinition of Reye�s Syndrome were in fact other condition (including in born errorsof metabolism, drug toxicity and others), there had still been a number of cases of�idiopathic� or �classic� North American-type Reye�s syndrome. Althoughindividually many of the studies investigating a possible link between aspirin andReye�s syndrome were flawed, the overall weight of evidence suggested that there


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was a real association between aspirin administration during prodromal illness, andthis �idiopathic� Reye�s Syndrome. Whether this link is causal had not been proven.

• Given the above information, the current Australian aspirin warning statement�Consult a doctor before giving this medicine to children or teenagers with chickenpox, influenza or fever� still seemed relevant. However, given the small number ofcases of Reye�s Syndrome in Australia in the last ten years, there is no evidence tosuggest that a stronger warning, such as the new UK warning �Do not give to childrenunder the age 16 years, unless on the advice of a doctor� was necessary on safetygrounds.

The Committee also noted the MEC February 2004 meeting consideration of the reportof the Review of Aspirin/Reye�s Syndrome Warning Statement. MEC noted arecommendation that the warning statement should refer to children recovering from, aswell as suffering from chicken pox, influenza or fever. On this basis, MECrecommended that the current warning statement �Consult a doctor before giving themedication to children or teenagers with chicken pox, influenza or fever� be deleted andwarning statement No. 102 in Appendix F, Part 1 of the SUSDP be amended as follows:

�102. Unless a doctor has told you to, don�t use [this product / name of theproduct]:For more than a few days at a timeWith other medicines containing aspirin or other anti-inflammatory medicinesIf you have asthmaIn children under 12 years of ageIn children 12-16 years of age with or recovering from chicken pox, influenzaor fever;If you are pregnant.�

Members noted the comment from OTC Medicines Section of the TGA highlighting aninconsistency in the existing Schedule 2 entry for aspirin published in the February 2004post-meeting gazette notice. The condition for exemption under (b) and (c) stated in theS2 aspirin entry was that aspirin may be exempt from scheduling when it was �the onlytherapeutically active constituent other than an effervescent agent� in the formulation.However, one of the labelling requirements under (b)(ii)(B) and (c)(iii)(B) (in each case),stated �See a doctor before taking [this product / name of the product] for thinning theblood or for your heart. [Can be omitted in products for inhibition of platelet aggregationor with additional active ingredients.]�. OTC Medicines Section felt that this warningstatement was inconsistent and confusing in that products containing aspirin incombination with other active ingredients would not meet the requirements forunscheduled medicines based on this S2 entry. To resolve this inconsistency, OTCMedicines Section suggested that the Committee consider deleting �or with additionalactive ingredients� from the Schedule 2 entry for Aspirin.

Furthermore, OTC Medicines Section pointed out that the wording of the S2 entry foraspirin agreed to at the NDPSC 40th Meeting (February 2004) meeting suggested that


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unscheduled aspirin products labelled with the new warning statements (mandatory from1 May 2005) would require the warnings "Unless a doctor has told you to, don't use ... inchildren under 12 years of age" [stated under parts (b)(ii)(B) and (c)(iii)(B)] and"CAUTION - Do not give to children under two years of age except on doctor's advice"[under parts (b)(iii) and (c)(iv)]. For clarity, OTC Medicines suggested that if the intentof the warning statement regarding children under 12 years was to replace the statementrelating to children under 2 years from 1 May 2005, it would be appropriate to include thestatement �permitted until 30 April 2005� in parts (b)(iii) and (c)(iv) of the S2 entry.

OUTCOME

For clarity, the Committee agreed to amend the S2 entry for aspirin to take into accountthe revised Reye�s Syndrome WS and the amendments suggested by OTC MedicinesSection and publish the proposal in the October 2004 pre-meeting gazette notice.

Noting this matter would be considered at the NDPSC 42nd Meeting (October 2004) andif agreed by the Committee, the new S2 entry for aspirin would take effect on 1 May2005 and thereby the existing (b)(ii)(A), (b)(iii), (c)(iii)(A) and (c)(iv) would no longer benecessary.



ASPIRIN - amend entry to read:

ASPIRIN except:

(a) when included in Schedule 4, 5 or 6;

(b) in individually wrapped powders or sachets of granuleseach containing 650 mg or less of aspirin as the onlytherapeutically active constituent other than an effervescentagent:

(i) when enclosed in a primary pack that contains 12or less such powders or sachets of granules;

(ii) when the primary pack is labelled with warningstatements to the following effect:

Don�t use [this product / name of the product]:If you have a stomach ulcerIn the last 3 months of pregnancy


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If you are allergic to aspirin or anti-inflammatorymedicines;

Unless a doctor has told you to, don�t use [thisproduct / name of the product]:For more than a few days at a timeWith other medicines containing aspirin or other anti-inflammatory medicinesIf you have asthmaIn children under 12 years of ageIn children 12-16 years of age with or recoveringfrom chicken pox, influenza or feverIf you are pregnant;

See a doctor before taking [this product / name ofthe product] for thinning the blood or for yourheart. [Can be omitted in products for inhibition ofplatelet aggregation.];

(c) in tablets or capsules each containing no other therapeuticallyactive constituent other than an effervescent agent when:

(i) packed in blister or strip packaging or in acontainer with a child-resistant closure;

(ii) in a primary pack of not more than 25 tablets orcapsules, each containing 325 mg or less of aspirin,or in a primary pack of not more than 16 tablets orcapsules, each containing 500 mg or less of aspirin;and

(iii) the primary pack is labelled with warningstatements to the following effect:

Don�t use [this product / name of the product]: Ifyou have a stomach ulcerIn the last 3 months of pregnancyIf you are allergic to aspirin or anti-inflammatorymedicines;

Unless a doctor has told you to, don�t use [thisproduct / name of the product]:For more than a few days at a timeWith other medicines containing aspirin or otheranti-inflammatory medicinesIf you have asthma


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In children under 12 years of ageIn children 12-16 years of age with or recoveringfrom chicken pox, influenza or feverIf you are pregnant;

See a doctor before taking [this product / name ofthe product] for thinning the blood or for yourheart. [Can be omitted in products for inhibition ofplatelet aggregation.]; or

(d) in tablets or capsules each containing no othertherapeutically active constituent other than aneffervescent agent when:

(i) packed in blister or strip packaging or in acontainer with a child-resistant closure;

(ii) in a primary pack containing 100 or less tablets orcapsules, each containing 100 mg or less of aspirinwhen packed and labelled for the prevention ofcardiovascular disease or for the inhibition ofplatelet aggregation; and

(iii) the primary pack is labelled with the warningstatement to the following effect:

For use under medical supervision only.

Appendix F, Part 1 – Amendment

Warning Statement 102 � Amend entry to read:

102. Unless a doctor has told you to, don�t use [this product / name of the product]:For more than a few days at a timeWith other medicines containing aspirin or other anti-inflammatory medicinesIf you have asthmaIn children under 12 years of ageIn children 12-16 years of age with or recovering from chicken pox, influenza orfever;If you are pregnant.


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Appendix F, Part 3 – Amendment

Aspirin � Amend entry to read: Warning statements

Aspirin(a) for inhibition of........................................36 platelet aggregation.

(b) in sustained release .................................36 preparations containing 650mg or more of aspirin.

(c) in other preparations................................101, 102 and 103

18. MATTERS REFERRED BY THE MEDICINES CLASSIFICATIONCOMMITTEE (MCC) OF NEW ZEALAND

18.1 ZINC IN DIETARY SUPPLEMENTS

PURPOSE

The Committee considered a summary of the study (AREDS) which suggests that intakeof high levels of antioxidants and zinc significantly reduced the risk of advanced age-related macular degeneration (AMD).

BACKGROUND

The XXXXXXXXXXXX Member requested that the AREDS Study be included on theagenda of the NDPSC 41st Meeting (June 2004) for preliminary discussions by theCommittee.

DISCUSSION

Members were advised that a GP in NZ, with interest in nutrition, drew the member�sattention of the XXXXXXXXXXXX Member to the AREDS study and sought advice onwhether there were any plans by regulatory authorities to accommodate productscontaining up to 80mg elemental zinc, in unscheduled dietary supplements. It was notedthat the current daily dose limit for unscheduled products was 25 mg or less of zinccompounds (or up to 50 mg zinc when products complied with certain labellingrequirements) in Australia and 20 mg elemental zinc in NZ.

OUTCOME

The Committee agreed to consider the scheduling of zinc at the NDPSC 42nd Meeting(October 2004). In addition, a member suggested that the issue of correlation betweenhigh-level zinc supplementation and copper intake should also be considered.


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19. INITIAL REVIEW/FORMAL OPINIONS (PHARMACEUTICALS)

No items considered.

22. AMENDMENTS TO THE SUSDP

22.1 EDITORIAL CHANGES AND ERRATA

PURPOSE

The Committee considered a number of editorial changes and errata to the SUSDP.

BACKGROUND

Nifursol and nimorazole were misspelt in the Ratified Minutes of the NDPSC�s 39th

Meeting (October 2003) and SUSDP No.18 Amendment No.3, appearing as nitrofursoland nimorazol.

The Office of Chemical Safety sought the Committee�s advice concerning thenomenclature used for dichlorobenzene entries in the SUSDP, with 1,2- and 1,4-dichlorobenzene listed in the SUSDP as o-dichlorobenzene or ortho-dichlorobenzene andPCB (paradichlorobenzene) respectively.

The Schedule 7 entry for nicotine had been overlooked during the NDPSC 40th Meeting(February 2004) consideration of nicotine in NRT.

DISCUSSION

The Committee agreed that the preferred nomenclature for 1,2- and 1,4-dichlorobenzeneentries should read lowercase ortho- and para-dichlorobenzene respectively.

The Committee agreed that the Schedule 7 entry for nicotine would be reviewed by theDrafting Advisory Panel under Item 14.1.2.

DECISION 2004/41 - 28

The Committee agreed to include the amended Schedule 7 nicotine entry in SUSDP 19/1when reviewed by DAP.

The Committee agreed to include an errata in SUSDP 19/1 for nifursol and nimorazole tocorrect the spelling errors. The Committee also agreed that the Record of Reasons andRatified Minutes for the NDPSC 39th Meeting (October 2003) be amended.

The Committee agreed to include an editorial in SUSDP 19/1 to amend thedichlorobenzene entries.


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NICOTINE except:

(a) when included in Schedule 2,3,4 or 6;

(b) in chewing gum;

(c) in lozenges;

(d) in preparations for transdermal use; or

(e) in tobacco prepared and packed for smoking.

Errata


NIFURSOL � delete entry

NIMORAZOLE � delete entry


PDB (paradichlorobenzene) � amend entry to read:

para-DICHLOROBENZENE.

Appendix E, Part 2 – Amendment

o-Dichlorobenzene � amend entry to read:

ortho-dichlorobenzene

New standard statement��.A,G3,E1,S1Old statements � old standard ��a,c,e,f,s


para-dichlorobenzene

New standard statement��.AOld statements � old standard��.a,b,dOld statements � T-value��.50


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Appendix F, Part 3 - Amendment


para-dichlorobenzene

Safety directions��.1,4

− Amendments to SUSDP No.20 Index, as follows:

SUSDP NO.19 index entry Action Proposed SUSDP No.20 index entry

DICHLOROBENZENE Delete

1,2-DICHLOROBENZENE seeORTHO-DICHLOROBENZENE

Amend to read 1,2-DICHLOROBENZENE seeortho-DICHLOROBENZENE

NB index under ‘D’

1,4-DICHLOROBENZENE seepara-DICHLOROBENZENE

New entry NB: index under ‘D’

ORTHO-DICHLOROBENZENE Amend to read ortho-DICHLOROBENZENE

NB: index under ‘D’ & include pagereference to Appendix E, Part 2entry

PARADICHLOROBENZENE Amend to read para-DICHLOROBENZENE

NB: index under ‘D’

PDB Amend to read PDB see para-DICHLOROBENZENE

NB: remove page references andindex under ‘D’

PDCB Remove

Documents

National Drugs and Poisons Schedule Committee...arising from the meeting. Please note that the Record of the Reasons includes extracts from the NDPSC minutes which have been edited