National Drugs and Poisons Schedule Committee
Record of Reasons
41st Meeting 22-23 June 2004
Section 52D(2) of the Therapeutic Goods Act 1989 (the Act) provides the power for the NDPSC to amend the Poisons Standard or prepare a new Standard. The NDPSC takes into account relevant matters mentioned in Section 52E of the Act when making a scheduling decision. The Record of the Reasons contains the basis of scheduling decisions and other outcomes arising from the meeting. Please note that the Record of the Reasons includes extracts from the NDPSC minutes which have been edited to remove confidential information. National Drugs and Poisons Schedule Committee Record of Reasons 41 – June 2004 i
TABLE OF CONTENTS
GLOSSARY...... IV
1.5 ADMINISTRATION ...... 9 1.5.1 Correction to the Minutes of the NDPSC 38th Meeting – Melaleuca Oil ...... 9 1.5.2 Correction to the Minutes of the NDPSC 39th (October 2003) & 40th (February 2004) Meetings – Hyoscyamus niger ...... 10 1.8 TRANS-TASMAN HARMONISATION WORKING PARTY...... 11 1.8.1 Minutes from the 10th (October 2003) TTHWP Meeting...... 11 1.8.1.1 Phenylephrine ...... 11 1.8.1.4 Propantheline...... 12 1.8.2 Matters arising from previous consideration of TTHWP items...... 13 1.8.2.1 Meclozine...... 13 1.8.2.2 Amphotericin...... 15 1.8.2.3 Definition for “Day-Night” Preparations...... 17 1.8.2.4 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) ...... 18 3.2 CHILD-RESISTANT PACKAGING DEFINITION...... 22 4. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS...... 26
4.1 EYELASH AND EYEBROWN TINTING PRODUCTS ...... 26 4.2 METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL...... 28 4.3 CREOSOTE...... 30 4.4 ALKALINE SALTS...... 34 4.5 VINCLOZO LIN...... 37 5. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FOR THE UNIFORM SCHEDULING OF DRUGS AND POISONS...... 39 5.1 SUSDP, PART 4...... 39 5.2 SUSDP, PART 5...... 40 5.2.1 Bifluorides...... 40 6. MATTERS REFERRED BY THE AUSTRALIAN PESTICIDES AND VETERINARY MEDICINES AUTHORITY...... 41
6.1 MOLINATE...... 41 6.2 GONADOTROPHIN RELEASING HORMONE ...... 44 6.3 POTASSIUM BICARBONATE...... 44 6.4 OCTENOL ...... 46 6.5 FIROCOXIB...... 48 6.6 QUINCLORAC...... 50 6.7 FLUMICLO RAC PENTYL ESTER ...... 51 6.8 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 Committee Record of Reasons 41 – June 2004 ii
8. ANTIBIOTICS FOR CONSIDERATION FOLLOWING RECOMMENDATIONS OF THE JOINT EXPERT TECHNICAL ADVISORY COMMITTEE ON ANTIBIOTIC RESISTANCE (JETACAR) ...... 57
8.1-8.7 SULFONAMIDES...... 58 8.8 TIAMULIN ...... 61 9. OTHER MATTERS FOR CONSIDERATION...... 61
9.1 SODIUM HYPOCHLORITE ...... 61 9.2 SODIUM FLUOROACETATE...... 64 10. INITIAL REVIEW AND/OR FORMAL OPINIONS (AG/VET, INDUSTRIAL & DOMESTIC CHEMICALS)...... 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 ...... 67 12.2 SODIUM FLUORIDE ...... 68 12.3 MITRAGYNA SPECIOSA...... 72 13. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS...... 76
13.1 MELIA AZEDARACH...... 76 13.2 PANCREATIC ENZYMES...... 79 13.3 PSEUDOEPHEDRINE...... 81 13.4 MEDIC AL DEVICES ...... 86 13.5 KAVA AND KAVALACTONES...... 88 13.6 ARIPIPRAZOLE...... 90 13. 7-13.9 [ITEMS DELETED ]...... 91 13.10 IBUPROFEN ...... 91 14. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FOR THE UNIFORM SCHEDULING OF DRUGS AND POISONS...... 100
14.1 SUSDP, PART 4...... 100 14.1.1 Diclofenac...... 100 14.1.2 Nicotine...... 104 14.2 SUSDP, PART 5...... 108 15. MATTERS REFERRED BY THE AUSTRALIAN DRUG EVALUATION COMMITTEE (ADEC)...... 108
15.1 NEW SUBSTANCES...... 108 15.1.1 Atomoxetine...... 108 15.1.2 Atazanavir...... 109 15.1.3 Treprostinil ...... 110 15.1.4 Amotosalen...... 111 15.1.5 Ciclesonide...... 112 15.1.6 Rosuvastatin...... 113 15.1.7 Alefacept ...... 114 15.1.8 Aprepitant ...... 115 16. OTHER MATTERS FOR CONSIDERATION...... 116 National Drugs and Poisons Schedule Committee Record 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 Committee Record 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 Committee Record 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 of Chemicals.
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 Committee Record 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 a population of experimental organisms. Usually expressed as mg per litre (mg/L) as a concentration in air.
LD50 The concentration of a substance that produces death in 50% of a population of experimental organisms. Usually expressed as milligrams 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 Committee Record 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 Committee Record of Reasons 41 – June 2004 viii
WHO World Health Organization
WP Working Party
WS Warning statement National Drugs and Poisons Schedule Committee 9 Record of Reasons 41 – June 2004
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 from XXXXXXXXXXXX which sought clarification over references and quotations included in the Minutes of the NDPSC 38th Meeting (June 2003) relating to Item 2.4.1 eucalyptus oil and melaleuca oil.
BACKGROUND
The NDPSC 38th Meeting (June 2003) considered a proposal to amend the Standard Statements in Appendix E, Part 2 required for eucalyptus oil and melaleuca oil.
DISCUSSION
The Committee noted the correspondence from XXXXXXXXXXXX and the NDPSC Secretariat’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 which reads:
… However, lower literature LD50 values for eucalyptus oil such as 1560 mg/kg (oral/rat and 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 of 0.05 mL/lg to 0.5 mL/kg (human, adult) (Hindle RC, 1994, Eucalyptus oil ingestion. NZ Med. J, May: 185-186) were not referred to.
The Committee noted the transcription errors in relation to the words symptomatic and asymptomatic as contained in the fifth dot point under melaleuca oil of Item 2.4.1, which currently reads:
The submission quoted Webb and Pitt (1993) "Seventy seven per cent of children were symptomatic despite several large ingestions….The authors consider that prudent management of cases where estimated volume ingested is large…..should include gastrointestinal decontamination using charcoal and sorbitol…". This suggested that 23% were asymptomatic and that a number of these would require medical assessment/management. National Drugs and Poisons Schedule Committee 10 Record of Reasons 41 – June 2004 should be amended to read:
The submission quoted Webb and Pitt (1993) "Seventy seven per cent of children were asymptomatic despite several large ingestions….The authors consider that prudent management of cases where estimated volume ingested is large…..should include gastrointestinal decontamination using charcoal and sorbitol…". This suggested that 23% were symptomatic and that a number of these would require medical assessment/management.
OUTCOME
The Secretariat was asked to amend the Record of Reasons and Ratified Minutes of the NDPSC 38th Meeting (June 2003) by including a footnote highlighting the error and that this 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 – HYOSCYAMUS NIGER
PURPOSE
The Committee considered correspondence dated 3 May 2003 from XXXXXXXXXXXX seeking 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 Hyoscyamus niger to exempt preparations containing 30 micrograms or less of total solanaceous alkaloids from the requirements of scheduling. The amendment was agreed to by the NDPCS 40th Meeting (February 2004).
DISCUSSION
The Committee noted the XXXXXXXXXXXX correspondence and that there had been a transcription error whereby 30 micrograms had been incorrectly recorded as 300 micrograms 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 Reasons Agenda Item 13.9, third paragraph National Drugs and Poisons Schedule Committee 11 Record of Reasons 41 – June 2004
“The 29th (May 2003) MCC meeting considered a submission from XXXXXXXXXX seeking reclassification of Hyoscyamus niger from pharmacy only medicine to general sale medicine when in packs containing 300µg or less of total solanaceous alkaloids …”
NDPSC 40th Meeting (February 2004) Record of Reasons Agenda 13.3, third paragraph
“The 29th (May 2003) MCC meeting considered a submission from XXXXXXXXXXXX seeking reclassification of Hyoscyamus niger from a pharmacy only medicine to a general sale medicine when in packs containing 300µg or less of total solanaceous alkaloids ...”
OUTCOME
The Committee agreed to amend the Record of Reasons and Ratified Minutes of the NDPSC 39th (October 2003) and 40th (February 2004) Meetings by including a footnote highlighting 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) and considered 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 the 2-year list.
BACKGROUND
The Committee noted that phenylephrine was considered for harmonisation at the NDPSC 20th Meeting (February 1999) where the entries in the Schedules for phenylephrine in the SUSDP were amended to harmonise with New Zealand. Whilst the scheduling of phenylephrine became harmonised, the supply of nasal preparations remained unharmonised as such products in New Zealand could be sold at airports.
The TTHWP 10th Meeting (October 2003) meeting discussed this matter and agreed that there was no further action required as the regulatory outcomes in terms of scheduling were already harmonised. To this end, the TTHWP 10th Meeting made a National Drugs and Poisons Schedule Committee 12 Record of Reasons 41 – June 2004 recommendation (Decision 10/4) that the NDPSC remove phenylephrine from the 2-year list.
DISCUSSION
The Committee noted that harmonisation efforts were focused on the scheduling provisions and that differences in supply arrangements within both countries could occasionally lead to an unharmonised approach in respect to supply. This was the case with phenylephrine where, despite consistency in the scheduling provisions, nasal preparations would continue to remain unharmonised in that such products would continue 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 the scheduling was harmonised but the provisions on supply between the countries varied to be ‘essentially harmonised’ with New Zealand. The Committee noted that harmonisation of supply mechanisms were yet to be addressed in the overall trans-Tasman harmonisation 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 in order to achieve harmonisation of scheduling with New Zealand.
BACKGROUND
The NDPSC 21st Meeting (May 1999) considered harmonisation of the S2 entry for propantheline but agreed that the existing S4 entry in Australia remained appropriate at the time. This decision was made on the grounds that there was one existing product in Australia containing propantheline which was indicated for adjunctive therapy in the treatment of peptic ulcer, neurogenic bladder, urinary incontinence in patients with detrusor 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 in Schedule 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 provision for a less restrictive classification. The TTHWP 10th Meeting had also noted that the oral preparation containing propantheline bromide for use as an adjunctive therapy in the treatment of peptic ulcer (gastric and duodenal), neurogenic bladder, urinary incontinence National Drugs and Poisons Schedule Committee 13 Record of Reasons 41 – June 2004 in patients with detrusor hyperactivity and hyperhidrosis was still registered in Australia. There were no other registered products for human topical use or veterinary use containing propantheline.
DISCUSSION
The Committee agreed that, as there were no topical human or veterinary preparations containing propantheline registered in Australia, harmonisation of scheduling could be achieved by deletion of the Schedule 2 entry.
OUTCOME
On the grounds of harmonisation, the Committee agreed to foreshadow for the NDPSC 42nd 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 OF TTHWP ITEMS
The Committee considered the following matters which had arisen from previous meetings of the TTHWP.
1.8.2.1 MECLOZINE
PURPOSE
The Committee considered the scheduling of meclozine for the purpose of harmonisation with New Zealand.
BACKGROUND
The TTHWP 8th Meeting (October 2002) recommended that the NDPSC consider exempting from scheduling, small packs of meclozine for the prevention or treatment of National Drugs and Poisons Schedule Committee 14 Record of Reasons 41 – June 2004 motion sickness. The TTHWP had advised that small packs of travel sickness preparations containing meclozine were allowed to be sold in New Zealand as general sales medicines (unscheduled) through specified outlets such as transport terminals or aboard a ship or plane. NDPSC members noted that there was one such product on the market in New Zealand but none in Australia.
The NDPSC 40th Meeting (February 2004) noted that meclozine was included in Schedule 4 of the SUSDP and that this classification was possibly due to meclozine’s potential teratogenicity. NDPSC Members recalled that the last time the teratogenicity of meclozine was discussed was in December 1969 when the Australian Drug Evaluation Committee (ADEC) had noted that there was no evidence of teratogenicity in humans at the recommended dosage. A number of submissions were received at the NDPSC 40th Meeting including submissions from XXXXXXXXXXXX expressing concern that the proposal to include small packs of meclozine in Schedule 2 would increase the level of abuse of meclozine products.
The NDPSC 40th Meeting foreshadowed agreement to the TTHWP’s proposal to reschedule meclozine from Schedule 4 to Schedule 2 for the treatment or prevention of motion sickness and requested that advice from the ADEC be sought about the teratogenicity of meclozine for consideration at the NDPSC 41st Meeting (June 2004).
DISCUSSION
The Committee was informed that advice from the ADEC had raised the following points:
• meclozine was last considered in 1971 and since that time, the ADEC has not had cause to review meclozine or to conduct a systematic literature review. • the Adverse Drugs Reactions Advisory Committee (ADRAC) had advised ADEC that four adverse reaction reports of congenital abnormalities associated with meclozine had been identified but these had occurred over a long time. ADRAC had not received any recent adverse reports. • in the 2nd edition of the publication “Medicines in Pregnancy”, for which ADEC was responsible, meclozine had been included in Category A – “Drugs which had been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful 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 supply and its omission from the PP Guide and MIMS. • any future application to register meclozine as a Schedule 4 product to be referred to the ADEC for comment. A pre-meeting submission was received from XXXXXXXXXXXX advising XXXXXXXXXXXX was now in agreement with the scheduling proposal. National Drugs and Poisons Schedule Committee 15 Record of Reasons 41 – June 2004
The Committee noted that to fully harmonise with New Zealand would require a Schedule 2 entry for meclozine exempting small packs containing 12 or less tablets or capsules as well as the deletion of the Schedule 4 entry. Members recalled that the NDPSC 40th Meeting noted that there was no Schedule 4 product containing meclozine in Australia and that any proposed new product would be fully evaluated by the TGA for registration prior to sale to the public. On this basis, the Committee agreed that it could achieve a common regulatory outcome between Australia and New Zealand by including small pack sizes of meclozine in Schedule 2. Retaining the Schedule 4 entry in the SUSDP 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 for registration in the future, then they would be subjected to an appropriate level of evaluation.
DECISION 2004/41 - 1
On the grounds of harmonisation, the Committee confirmed the foreshadowed amendments to include meclozine in primary packs containing 12 or less tablets or capsules 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 for the prevention or treatment of motion sickness, except in preparations for the treatment 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 topical preparations containing amphotericin for the treatment of oral candidiasis following advice from the Expert Advisory Group on Antimicrobial Resistance (EAGAR) on the potential for the development of resistance.
BACKGROUND
The Committee recalled that the TTHWP 8th Meeting (October 2002) recommended that topical preparations containing amphotericin for the treatment of oral candidiasis be National Drugs and Poisons Schedule Committee 16 Record of Reasons 41 – June 2004 included in Schedule 3 of the SUSDP (Recommendation 8.11). This change would harmonise the scheduling with New Zealand.
The item was considered at the NDPSC 39th Meeting (October 2003). A pre-meeting submission from XXXXXXXXXXXX submitted that amphotericin should not be rescheduled to Schedule 3. XXXXXXXXXXXX noted that amphotericin was the treatment of choice for the most serious systemic fungal infections and was therefore concerned that more widespread use could lead to the development of resistance and therefore reduced effectiveness. Further discussion was deferred to allow advice to be sought from the ADEC on the potential for resistance to develop with topical use of amphotericin. The ADEC subsequently advised that the matter should be referred to EAGAR.
The NDPSC 40th Meeting (February 2004) agreed to refer the matter to EAGAR, noting that, should EAGAR consider that the issue was outside its terms of reference, EAGAR be asked to convene a special advisory panel to provide advice to NDPSC on the potential for resistance development with amphotericin. A decision on the harmonisation proposals was deferred pending advice from EAGAR. The Chair of EAGAR undertook to 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 to amphotericin as being of critical importance and therefore requested that a detailed risk assessment should be compiled before further advice could be given. EAGAR recommended that there be no change in the scheduling of amphotericin pending a broad ranging review of antifungals.
The Committee noted that EAGAR had been more concerned with antibiotic resistance rather than fungal resistance. The Committee also noted that the NHMRC had recently advised that in future, EAGAR would not undertake primary reviews but would review the outcome of reviews of the potential for antibiotic resistance undertaken by regulatory authorities. As a result, an assessment of the potential for resistance development associated with more widespread use of products containing amphotericin would need to be arranged by the NDPSC and the outcome submitted to the EAGAR for review.
The Committee also noted pre-meeting advice from the XXXXXXXXXXXX agreeing to the 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 Secretariat arrange for a review of amphotericin for possible resistance development arising from more widespread use should there be a relaxation of the scheduling. National Drugs and Poisons Schedule Committee 17 Record of Reasons 41 – June 2004
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 relating to the possible abuse, misuse and regulatory controls over injectable preparations with a view to harmonising the regulation of injectable preparations between Australia and New Zealand.
The NDPSC 38th Meeting was advised that, on the basis of an extensive literature review that there was no evidence of any problem associated with the legitimate use of injectable preparations in developed countries including Australia and New Zealand. On this basis the Committee agreed that there was no need to control such preparations through scheduling and that should future evidence to the contrary come to light, the matter would be considered on a case-by-case basis. The working party was asked to reconsider the scheduling of “injectable medicines” with a view to recommending harmonisation on the least restrictive schedule, that is ‘unscheduled’ and removal of the Part III entry for injectables in the New Zealand medicines classification category.
The issue was again raised at the NDPSC 39th Meeting (October 2003) when Members were advised that removal of the class entry for injectable medicines from Part III was not likely to have a negative impact on public health outcomes in New Zealand as controls on injectable medicines would still be covered by the scheduling of the active ingredient (s) as was the case in Australia. The NDPSC 39th Meeting agreed to recommend to the NZ Ministry of Health (MOH) that, in the absence of evidence associated with abuse or misuse of injectable dose forms in either country, harmonisation with Australia should be achieved by deleting the Part III class entry (Schedule 2) for injectable 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 for injectable medicines, but recognising their safety record in both countries and in order to achieve a common regulatory outcome, injectable medicines containing vitamins (e.g folic acid and vitamin K), multivitamins, potassium chloride and other salts, dextrose and other sugars, and homeopathic injections be exempt from scheduling. Advice was National Drugs and Poisons Schedule Committee 18 Record of Reasons 41 – June 2004 received from NZ Medsafe that as from 29 April 2004, injectable preparations became exempt from scheduling unless specified elsewhere in the Schedules.
The Committee noted that the scheduling status of injectable preparations was now harmonised between Australia and New Zealand, ie injectable preparations are unscheduled except when separately specified in the Schedules.
The Committee agreed to consider further, the proposal to exempt from scheduling injectable preparations containing vitamins, multivitamins, potassium chloride and other salts, dextrose and other sugars, and homeopathic injections. The Committee also noted the need to first examine the regulatory impact of the decision on individual products and to seek public comment on the proposal. The regulatory impact assessment would be presented to the TTHWP 12th Meeting (October 2004).
OUTCOME
The committee endorsed decision 10/3 of the TTHWP noting that this decision had since been accepted by NZMOH.
The NDPSC agreed to consider exempting injectable preparations containing vitamins, multivitamins, potassium chloride and other salts, dextrose and other sugars, and homeopathic injections from scheduling.
AGRICULTURAL/VETERINARY, INDUSTRIAL AND DOMESTIC CHEMICALS
3. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUS MEETING (CONSIDERATION OF POST-MEETING SUBMISSIONS UNDER 42ZCZ)
3.1 10,10’-OXYDIPHENOXARSINE (OBPA)
PURPOSE
The Committee considered post-meeting comment regarding the initial scheduling decision for 10,10′-oxydiphenoxarsine (OBPA).
BACKGROUND
The NDPSC 40th Meeting (February 2004) considered an application to down-schedule preparations containing 5.25% w/w or less of OBPA from Schedule 7 to Schedule 6 on the basis that they would not be supplied to the public and would only be used by trained industrial polymer/plastic processors. The applicant also sought to have OBPA exempt from the requirements of scheduling when contained in polymer/plastic articles National Drugs and Poisons Schedule Committee 19 Record of Reasons 41 – June 2004 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 be included in Schedule 6 limiting its supply to industrial users through the inclusion of the following 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 to limit the availability OBPA to industrial users and did not support the inclusion of OBPA preparations in Schedule 6. The Committee did, however, agree that OBPA polyvinyl chloride and polyurethane extruded and moulded articles did not pose an unreasonable risk to human health where OBPA particles from these articles did not come into contact with food, drinking water, peoples’ skin or animal feeds. The Schedule 7 entry for arsenic was amended accordingly. This decision was made after consideration of a NICNAS assessment of a submission received from XXXXXXXXXXXX.
DISCUSSION
The Committee was informed that post-meeting comment had been received from XXXXXXXXXXXX in regard to the scheduling decisions made at the NDPSC 40th Meeting. The Members were advised that the applicant’s submission was forwarded to NICNAS for evaluation. The sponsor raised the following two issues for the consideration of Members:
The Committee’s decision not to reschedule preparations containing 5.25% or less of OBPA is not based on the toxicity profile of OBPA. The applicant was of the view that the Committee’s decision not to down-schedule preparations containing 5.25% w/w or less of OBPA on the grounds that limiting the availability of OBPA to industrial users would be difficult when classified as a Schedule 6 poison. The applicant sought a reconsideration of the decision on the grounds that the toxicity profile of OBPA preparations with a concentration of 5.25% or less fits with in the definition of a Schedule 6 poison. The NICNAS assessment reported that no significant new data had been presented by the applicant. Data summarising the results of an acute oral LD50 study in rats, acute dermal LD50 study in rabbits, and a skin irritation test in rabbits for XXXXXXXXXXXX had been provided. The acute toxicology of XXXXXXXXXXXX is consistent with low acute oral and dermal toxicity, however, there was insufficient data to evaluate the potential dermal irritancy of XXXXXXXXXXXX. The acute toxicology of XXXXXXXXXXXX is consistent with moderate acute oral and dermal toxicity, and high dermal and eye irritancy. No chronic toxicity data was available for the 5% OBPA preparations XXXXXXXXXXXX or XXXXXXXXXXXX. No toxicity data was provided for other XXXXXXXXXXXX preparations. However, the assessment considered it unlikely that there would be significant differences in toxicity given the carriers specified by the applicant. The potential for preparations containing 5.25% OBPA to be source of elemental arsenic cannot be discounted. The lowest NOEL in studies submitted on OBPA National Drugs and Poisons Schedule Committee 20 Record of Reasons 41 – June 2004 pertains to foetal toxicity following dermal application: NOEL = 0.3 mg/kg bw. An equivalent oral dose study was not available. The assessment highlighted that the XXXXXXXXXXXX range of preparations are intended solely for industrial use and would be subject to relevant State and Territory occupational, health and safety legislation.
The Committee’s decision to exempt only polyvinyl chloride and polyurethane extruded and moulded articles is too restrictive. The applicant proposed two alternatives for the Committee’s consideration. Firstly, that the Schedule 7 entry for arsenic be amended to include an exemption for “plastic” extruded and moulded articles containing 160 mg/kg or less of arsenic citing alkyl-tin compounds in Schedule 7 as a precedent. Alternatively, the Schedule 7 entry for arsenic could be amended to include an exemption for “water-insoluble polymers”. The applicant proposed that alternative because “water-soluble polymers” may release OBPA more readily thus increasing the bioavailability 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 and synthetic rubber. In response, the NICNAS assessment reported that the main risks associated with the use of 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 PVC and PU articles containing not more than 525 ppm OBPA from the SUSDP. However, additional information about potential leach and dislodgment rates should be sought from the applicant to support an extension of the exclusion to other specific polymers requested. The assessment also drew to the Committee’s attention that it was unknown whether plastic toys were an intended application for OBPA. The present Schedule entry states OBPA-treated plastics will not be used for contact with food stuffs, animal feeds or potable water; clothing and footwear in contact with the skin; in infant wear; or packaging materials. Due to concerns over potential for arsenic accumulation, the exemption from the schedule for such articles should not be applied to OBPA treated toys.
On the basis of these considerations, the NICNAS assessment made the following recommendations:
• That the Committee re-confirm Decision 2004/40 – 8. That is reject the applicant’s request for the rescheduling of preparations containing 5.25% or less of OBPA from Schedule 7 to Schedule 6. • Amend Schedule 7 such that PVC and PU extruded and moulded articles containing no more than 160 mg/kg of arsenic as OBPA be exempt from the Schedule except when included in articles intended as children’s toys. • Request that the applicant provide information regarding potential leach and dislodgment rates of OBPA from plastics other than PVC and PU in order to determine whether an exemption beyond PVC and PU is appropriate. National Drugs and Poisons Schedule Committee 21 Record of Reasons 41 – June 2004
The Committee noted that no significant new data had been presented by the applicant that warranted a change to Decision 2004/40 – 8. Furthermore, Members were still of the opinion that an amendment to the Schedule 6 entry form arsenic to include OBPA did not limit its availability exclusively to industrial users.
Similarly, the Committee did not favour expanding the exemption for extruded and moulded articles to include plastics other than PVC and PU in the absence of information on dislodgment rates from these other plastics. Accordingly, Members asked that further data be sought from the applicant regarding the potential leach and dislodgment rates of OBPA from plastics other than PVC and PU.
Members also expressed concern that OBPA may be incorporated into children’s toys and asked that further information be sought from the applicant regarding the likelihood of 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 the amendment (Decision 2004/40 – 8) to the Schedule 7 entry for arsenic exempting from the requirements of scheduling polyvinyl chloride and polyurethane extruded and moulded articles containing a maximum of 525 mg/kg OBPA (equivalent to 160 mg/kg arsenic).
Schedule 7 - Amendment
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 mastic containing 120 mg/kg or less of arsenic;
(e) as 10,10′-oxydiphenoxarsine contained in polyvinyl chloride and polyurethane extruded and moulded articles containing 160 mg/kg or less of arsenic other than when included in articles: National Drugs and Poisons Schedule Committee 22 Record of Reasons 41 – June 2004
(i) in contact with food stuffs, animal feeds or potable water;
(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 calculated on the non-volatile content of the paint.
3.2 CHILD-RESISTANT PACKAGING DEFINITION
PURPOSE
The Committee considered post-meeting comment regarding the proposed definitions for child-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 of child-resistant closure/packaging in the SUSDP was too narrow for the purposes of poisons regulation. Specifically, the current definitions did not account for packaging and closures which were sufficient to render their contents inaccessible to children but would fail to meet the strict definition of CRP or CRC according to AS1928-2001. The Committee agreed to adopt the definition for child-resistant packaging from the Draft Therapeutic Good Order (TGO) 65 and considered the foreshadowed amendment at the NDPSC 40th Meeting (February 2004).
DISCUSSION
The Committee was informed that a post-meeting comment had been received from XXXXXXXXXXXX. XXXXXXXXXXXX highlighted the following four issues he wished the Committee to consider in regard to the definitions for CRP and CRC.
Currency of Compliance: XXXXXXXXXXXX considered that the Committee did not fully discuss his recommendation that CRC and CRP be compliant with the current version of a Standard, or in the absence of a version change then the product itself be field-tested every three to five years. Members noted that in response to XXXXXXXXXXXX’s earlier submission, the Committee did amend the SUSDP to include the phrase “as specified or amended from time to time” in relation to the Standards specified. The Committee was of the opinion that any change to a standard should incorporate an adequate lead time to ensure that after National Drugs and Poisons Schedule Committee 23 Record of Reasons 41 – June 2004 the implementation date all product at all points of the supply chain should comply with the incoming standard. Consequently, mandatory field testing of products after a change to a standard would not be necessary. Furthermore, spot inspections by State and Territory health authorities would ensure that non-compliant products would be removed from 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. He highlighted that those products which only comply with AS4710-2001 cannot claim to be “child-resistant” despite AS4710 & AS1928 being essentially similar Standards with similar aims. In his opinion the three options proposed by the XXXXXXXXXXXX at the February meeting all have merit, however, he would support amending AS1928-2001 to include child-testing for non-reclosable packaging or modifying AS4710-2001. In order to facilitate this recommendation, XXXXXXXXXXXX suggested that the Committee seek the assistance of Standards Australia. XXXXXXXXXXXX also considered that the deliberations of Committee seem to be strongly influenced by medical and veterinary considerations over those of industry. XXXXXXXXXXXX suggested that perhaps the Minister could nominate a representative from the packaging or plastics industries to join the Committee thus allowing their points of view in relation to child-resistant packaging to be expressed. The Committee noted that Section 42ZCD of the Therapeutic Goods Regulations 1990 allows for only one representative from industry on the NDPSC and consequently XXXXXXXXXXXX proposal to include a representative from the packaging or plastics industries would require legislative change. Members also noted that at the NDPSC 40th Meeting (February 2004), the Committee considered the inclusion of AS4710-2001 in the definition of CRP but agreed that it was inappropriate on the grounds that the Standard tests for packaging that is designed not to be opened.
The XXXXXXXXXXXX suggested that perhaps this issue should be referred to the soon to be formed Therapeutic Good Committee’s (TGC) expert committee on child-resistant containers. The Committee was of the view that it was inappropriate to refer an issue regarding an Australian standard to a subcommittee concerned only with the packaging of medicines. However, the Committee agreed to refer the matter to Standards Australia and to brief the TGC of its consideration of this issue and course of action.
Different Requirements in Different Australian Jurisdictions: XXXXXXXXXXXX highlighted that there are significant differences between the States & Territories in their legislation in regard to CRC and CRP resulting in a burden to industry. He urged the Committee to work towards national criteria so that acceptance of a CRC or CRP in one jurisdiction 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 the Jurisdictions in the requirements for retail storage of Schedule 5 (and Schedule 6) National Drugs and Poisons Schedule Committee 24 Record of Reasons 41 – June 2004 poisons. The Committee agreed that this matter should be referred to XXXXXXXXXXXX with a view to the development of uniform approach to the storage of these substances.
Organisations Seeking to Go Beyond the Minimum Requirements: XXXXXXXXXXXX expressed concern that there did not appear to be a clear policy position on whether industry should be encouraged to voluntarily package more products in child resistant packaging or whether this practice diluted the effectiveness of child resistant packages. XXXXXXXXXXXX supported improvements to policies and procedures and recommended that a full public discussion be undertaken with consumer groups, parent groups, child care representatives as well as industry groups and government representatives being invited to participate. The Committee was advised that there was no evidence that the use of CRCs or CRPs on products which did not require these measures diluted their effectiveness. Furthermore, the Member believed that there were not a large number of products unnecessarily fitted with CRCs or packaged in CRPs and that the storage of these products did not differ from those not packaged in this manner. The Committee agreed that it should not discourage the 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, British Standards Institution Standard BS EN 28317:1993, Canadian Standards Association Standard 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-resistant Closure”, none actually define CRCs and reference to them was subsequently removed from the definition.
DECISION 2004/41 – 3 (Variation of Decision 2004/40-4)
The Committee agreed to delete the current definitions for child-resistant closure and child-resistant packaging and replace these with the following definitions and to include a definition for non-reclosable packaging in the SUSDP. The Committee also agreed to vary the 40th Meeting (February 2004) Decision 2004/40-4 by deleting reference to the four international standards from the CRC definition. It was noted that these changes would be included in the SUSDP 19 Amendment 1, which is planned to come into effect through 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: National Drugs and Poisons Schedule Committee 25 Record of Reasons 41 – June 2004
(a) a closure that complies with the requirements for a child- resistant closure in the Australian Standard AS1928-2001 entitled Child-resistant packages as specified or amended from 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 the design 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 specified or amended from time to time;
(b) is reclosable and complies with the requirements of at least one of the following standards as specified or amended from time to time.
(i) the International Organization for Standardization Standard ISO 8317:1989 entitled Child-resistant packaging - Requirements and testing procedures for reclosable packages;
(ii) the British Standards Institution Standard BS EN 28317:1993 entitled Child-resistant packaging - Requirements and testing procedures for reclosable packages;
(iii) the Canadian Standards Association Standard CSA Z76.1-99 entitled Reclosable Child-Resistant Packages;
(iv) the United States Code of Federal Regulations, Title 16, Section 1700.15, entitled Poison prevention packaging standards and Section 1700.20, entitled Testing procedure for special packaging;
(c) is approved as child-resistant by any order made under section 10(3) of the Commonwealth Therapeutic Goods Act 1989; or National Drugs and Poisons Schedule Committee 26 Record of Reasons 41 – June 2004
(d) is in the form of blister or strip packaging in which a unit of use is individually protected until the time of release and that complies with Section 3 (Requirements for non- Reclosable Packages) of Australian Standard AS 1928-2001 Child-resistant packages.
Part 1 – Interpretation – New Entry
Sub-paragraph 1.(1)
“Non-access packaging” is packaging that complies with the requirements of Australian Standard AS4710-2001 entitled Packages for chemicals not intended for access or contact with their contents by humans, in relation to products that are not intended for human therapeutic use.
4. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS
4.1 EYELASH AND EYEBROWN TINTING PRODUCTS
PURPOSE
The Committee noted updates from the XXXXXXXXXXXX regarding the NICNAS review on hair dyes and the progress of a compliance and education program with industry on the regulatory requirements under NICNAS facilitated by XXXXXXXXXXXX.
BACKGROUND
At the NDPSC 40th Meeting (February 2004) the Committee was updated on the progress of investigations being separately conducted by XXXXXXXXXXXX and XXXXXXXXXXXX on incorrectly packed and labelled eyelash and eyebrow tinting and hair care products. The XXXXXXXXXXXX Member advised the Committee that all lash/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 the XXXXXXXXXXXX. Given this evidence of incorrectly packed and labelled products, the XXXXXXXXXXXX Member agreed to facilitate a compliance and education program with industry on the regulatory requirements under NICNAS. The Committee also considered a public submission from the XXXXXXXXXXXX seeking an exemption from scheduling for eyelash/eyebrow tinting products containing paraphenylenediamine and toluenediamine on the grounds that application by professional beauty therapists would minimises the risk associated with their use. The Committee was of the view that it did not have enough data to determine the potential danger posed to the eye by paraphenylenediamine and toluenediamine should the use of eyelash and eyebrow tinting products be permitted by a change to the label requirements. Given that NICNAS was at National Drugs and Poisons Schedule Committee 27 Record of Reasons 41 – June 2004 that time in the process of conducting a major review of all hair dye ingredients currently used in Australia, the Committee agreed to defer this matter to a future meeting to allow consideration of the final NICNAS review.
DISCUSSION
The Committee noted updates on the progress of investigations being separately conducted by XXXXXXXXXXXX and XXXXXXXXXXXX on incorrectly packed and labelled eyelash and eyebrow tinting and hair care products.
The XXXXXXXXXXXX Member advised the Committee that XXXXXXXXXXXX had investigated recent claims of the inappropriate retail sale of several hair dye products. The distributors (one in XXXXXXXXXXXX and three in XXXXXXXXXXXX) were contacted and asked to remove the products from retail sale. The XXXXXXXXXXXX Member advised the Committee that the XXXXXXXXXXXX has informed companies that, until the labelling of eyelash and eyebrow tinting products issue is resolved, XXXXXXXXXXXX will only allow salon use of these products. Companies have also been warned that, if such a product were to be found on retail sale, action may be taken against a company. The XXXXXXXXXXXX Member indicated that for there to be a successful resolution to this issue the Committee would need to assess the potential for eye damage resulting from exposure to eyelash and eyebrow tinting products containing paraphenylenediamine and toluenediamine. The XXXXXXXXXXXX advised the Committee that paraphenylenediamine and toluenediamine are included in the list of chemicals being reviewed in Europe and agreed to seek the toxicity profiles and classifications on skin/eye irritancy and report to the next meeting.
The XXXXXXXXXXXX submitted the following comments regarding the NICNAS hair dye review for the information of the Committee:
• [Paragraphs deleted].
The XXXXXXXXXXXX Member submitted the following update for the information of the Committee:
• XXXXXXXXXXXX from the XXXXXXXXXXXX has confirmed that generally it would not be his member companies that are importing or supplying products for eyelash/eyebrow tinting either for retail or salon use. • During a recent meeting with the beauty therapists representatives in Brisbane, they indicated that their interest is apparently in the sale of salon only eyelash and eyebrow tinting products. They contend that the formulations of these products are different to that of other hair dyes, and hence demonstrate a different safety profile. Confirmation of this has been requested, together with other relevant information for the Committee to subsequently consider (at the October 2004 meeting) the appropriate labelling of these products eg. safety experience locally (and possibly internationally). National Drugs and Poisons Schedule Committee 28 Record of Reasons 41 – June 2004
• A consultant to a company has expressed interested in retail sale of eyelash and eyebrow tinting products (NB: these have been currently withdrawn from the market) and discussed with the XXXXXXXXXXXX Member the nature of the information that would be necessary to compile a submission to the NDPSC. Presumably a submission will be provided to the Secretariat in due course. OUTCOME
The Committee noted the updates given by Members and agreed to include this matter on the agenda for the next meeting.
4.2 METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL
PURPOSE
The Committee considered comment regarding the proposed scheduling of methylcyclopentadienyl manganese tricarbonyl (MMT).
BACKGROUND
The NDPSC 39th Meeting (October 2003) considered the scheduling of MMT where it was proposed that this substance be included in Schedule 7 with a cut-off to Schedule 6 for 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 of MMT and that the use pattern of consumer products fitted with a child-resistant closure would limit the exposure direct to the public. The scheduling of MMT was considered following the completion of a Priority Existing Chemical (PEC) Assessment Report by NICNAS. The Committee noted that the companies producing MMT products who had provided information to NICNAS for assessment had not taken the opportunity to make a submission to the NDPSC with regard to the scheduling of MMT. The Committee agreed to foreshadow the proposed scheduling of MMT to allow interested parties to comment prior to a decision being made.
At the NDPSC 40th Meeting (February 2004) the Committee noted that a number of public submissions were received from companies and industry groups involved in the importation, reformulation and manufacture of MMT or products containing the substance. However, the consensus of opinion regarding the foreshadowed scheduling proposal was that industry had not had sufficient time to fully assess the regulatory and commercial impact of the Committee’s decision. Consequently, the Committee deferred the matter to allow for industry to complete an adequate assessment of the implications resulting 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 to unleaded petrol by the vehicle owner and acts as a lubricating agent to prevent excessive valve seat wear and recession of the valve seat into the automotive cylinder head. National Drugs and Poisons Schedule Committee 29 Record of Reasons 41 – June 2004
DISCUSSION
The Committee was advised that public submissions had been received from XXXXXXXXXXXX, XXXXXXXXXXXX XXXXXXXXXXXX, XXXXXXXXXXXX, XXXXXXXXXXXX, XXXXXXXXXXXX, XXXXXXXXXXXX and XXXXXXXXXXXX.
The Committee noted that the consensus of opinion from industry was that the scheduling of MMT for industrial use was unnecessary and would result in limited public health benefits. Furthermore, the inclusion of MMT in Schedule 7 would subject industrial users to additional regulatory burden. Given that the scheduling was targeted at the regulation of consumer sized containers, industry was of the view that an exemption from the requirements of scheduling was appropriate for industrial use and may be achieved through a pack size limit. It was proposed by XXXXXXXXXXXX and others that MMT and all preparations containing MMT be exempt from the requirements of scheduling when in pack sizes greater than 20 litres or when used in laboratory analysis. For pack sizes less than 20 litres, MMT be included in Schedule 7 with a cut-off to Schedule 6 for preparations containing 10% or less and a cut-off to Schedule 5 for preparations containing 5% or less when fitted with a child-resistant closure.
Members noted that the concerns raised by the public submissions relate to the varying controls flowing from the inclusion of MMT in Schedule 7 and posed questions regarding the 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 covered fully by the requirements of the various National and State Dangerous Goods and Occupational 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 lead replacement petrol at refineries. A relatively small quantity of MMT is imported in 205 L steel drums for formulation into after market fuel additives containing less than 10% w/w MMT 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 stations and retail outlets. MMT (as Mn) is currently listed in the NOHSC List of Designated Hazardous Substances with no classification. Therefore, preparations intended solely for industrial use would be subject to State and Territory occupational, health and safety legislation.
The Committee was advised that several jurisdictions had the capacity to allow exemptions for the industrial use of Schedule 7 substances through their respective legislation. The Committee did not consider it appropriate to exempt a Schedule 7 poison from 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 State and Territory legislation. Furthermore, the Committee did not agree that a further cut-off to Schedule 5 for preparations containing 5% or less of MMT was warranted in the absence of specific toxicological data. National Drugs and Poisons Schedule Committee 30 Record of Reasons 41 – June 2004
The Committee asked that the Jurisdictions advise the Secretariat of the requirements for industrial use exemptions in each State and Territory with a view to providing this information to the companies that import MMT or manufacture products containing the substance.
Whilst the Committee appreciated the concerns raised by industry, Members were of the view that the inclusion of MMT in Schedule 7 with a cut-off to Schedule 6 for fuel additive preparations containing 10% or less was justified on the basis of its toxicological profile.
OUTCOME
The Committee agreed to foreshadow the proposal to include MMT in Schedule 7 with a cut-off to Schedule 6 for fuel additive preparations containing 10% or less of MMT when fitted with a child-resistant closure.
FORESHADOWED DECISION (for consideration at the NDPSC 42nd Meeting of October 2004)
Schedule 7 – New Entry
METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL except when included in Schedule 6.
Schedule 6 – New Entry
METHYLCYCLOPENTADIENYL MANGANESE TRICARBONYL in fuel additive preparations containing 10 per cent or less of methylcyclopentadienyl manganese tricarbonyl when fitted with a child-resistant closure.
4.3 CREOSOTE
PURPOSE
The Committee considered the scheduling of creosotes and related compounds or fractions.
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 being raised about the carcinogenic potential of creosote and safety for use as a wood preservative. At the June 2003 meeting, the Committee considered an overview of the draft CICAD on coal tar creosote prepared by the OCS. The Committee was asked to consider: National Drugs and Poisons Schedule Committee 31 Record of Reasons 41 – June 2004
• The creation of a specific SUSDP entry for coal tar creosote, with entries if and as necessary for other coal tar derived mixtures, and wood creosote. • Whether the marketing of coal-tar creosote as a wood preservative should be limited to industrial use and to licensed applicators. • Whether all marketed coal tar creosote preparations should be required to contain limits on specific toxic and carcinogenic contaminants of concern (eg. less than 0.005% 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 of psoriasis (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 sought from the APVMA, MEC and OCM regarding the potential impact on existing products should creosote and related substances be scheduled. This advice was provided to the NDPSC 40th Meeting (February 2004) for consideration by the Committee.
The APVMA advised that at the time there were 10 products containing creosote registered by the APVMA. The majority (7) were for the treatment of timber and timber products, 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/L to 1044 g/L. In addition to these products, there are another 11 products containing coal tar or tar acids. These products were registered for use as dog and cat washes, equine grooming aids, ointments, disinfectants and blowfly strike treatments with concentrations ranging between 3 g/L to 419 g/L.
The Medicines Evaluation Committee (MEC) highlighted the following for consideration:
• The ARTG includes products containing ‘creosote’, coal tar, ‘tar’ (pine tar) and cade oil (juniper tar). • None of the products containing ‘creosote’ have been evaluated by the TGA; most are listed and most appear to be indicated for use as expectorants/decongestants for coughs; • 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 the evaluated products indicated for itchy skin and/or scalp conditions (eg. psoriasis, seborrhoeic dermatitis, seborrhoea, dandruff, eczema, dermatitis) – ie. conditions consistent with those accepted by the ARGOM policy guideline on ‘Coal tar preparations’; National Drugs and Poisons Schedule Committee 32 Record of Reasons 41 – June 2004
• At least two of the “grandfathered” products containing coal tar are indicated for nappy rash – ie. these products do not comply with the ARGOM guideline; • Most of the evaluated registered products containing pine tar are indicated for use on itchy and/or inflamed skin (eg. dermatitis, eczema, dry skin, nappy rash, psoriasis); • Most of the products containing cade oil are “grandfathered” – all the registered products 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 as an over-the-counter registrable, they are unable to provide comment.
The Committee expressed concern that there appeared to be no uniformity in the use of the 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 the MEC 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 the registered and listed medicines and agricultural and veterinary products be determined in consultation with the TGA and the APVMA and that “coal tar creosote” be clearly defined. The Committee deferred its consideration of creosote to the 41st Meeting (June 2004) to allow further information and advice to be obtained.
DISCUSSION
The Committee noted that advice had been received from the APVMA and the OTC Medicines Section of the TGA.
The APVMA provided the information it had available on the specifications and chemical composition of the coal derivative/s in certain agricultural and veterinary products and advised that:
• Approximately half of the products containing creosote, coal tar and tar acids (and synonyms) were registered under previous State-based registration systems and that the 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 is available (eg. complies with a particular Australian Standard or pharmacopeial monograph). However in some cases, the cited pharmacopeial monographs are out of date. • Information regarding composition and general specifications were found for some coal derived active constituents. However, detailed chemical specifications and CAS numbers were generally not available. The OTC Medicines Section of the TGA advised that the AAN 'creosote' refers to creosote as defined by Martindale - ie. wood creosote. Therefore, all products stated as containing creosote should contain wood creosote. The five registered products National Drugs and Poisons Schedule Committee 33 Record of Reasons 41 – June 2004 containing creosote identified in their previous advice were “grandfathered” and have not been evaluated by the TGA. As such, no information is available on these products, and the type of creosote present has never been required to be characterised. Four of these products would be regulated by the OTC Medicines Section if marketed and the fifth registered product (also “grandfathered”) would to be regulated by the Office of Complementary Medicines (OCM). The listed products containing creosote for supply in Australia are the responsibility of the OCM and, as such, further information would need to be obtained on those products from them.
The OTC Medicines Section further advised that the TGA requires coal tar (any relevant AAN) or tar (ie. pine tar) in registered products to meet the requirements of the BP monographs for 'Coal tar' or 'Tar', respectively. No further information is currently available on products containing tars, as the OTC Medicines Section has not evaluated any of these products.
The Committee expressed disappointment that more information could not be gathered on the 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 on coal tar and that this involved extensive consultation with industry. The Member suggested that perhaps the Committee could seek advice from MEC on this matter. The Committee 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’s intention to include entries for creosote derived from coal and creosote derived from beechwood in Schedule 7 of the SUSDP on the basis of their toxicity and carcinogenic characteristics. The Committee would also redefine the current creosote entries in Schedules 2 and 6 to specify creosote derived from wood other than beechwood. It was hoped that in doing so sponsors of human therapeutic and veterinary products, particularly those “grandfathered” into their respective regulatory schemes, would be encouraged to provide data on the nature of the creosote present thus allowing the Committee to draft schedule entries for these creosotes and to set cut-offs where appropriate.
OUTCOME
The Committee agreed to defer this agenda item to the 42nd Meeting (October 2004) to allow further information and advice to be obtained.
FORESHADOWED DECISION (for consideration at the NDPSC 42nd Meeting of October 2004)
Schedule 7 – New entry
CREOSOTE derived from coal. National Drugs and Poisons Schedule Committee 34 Record of Reasons 41 – June 2004
CREOSOTE derived from beechwood.
Schedule 6 – Amendment
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 per cent or less of creosote (derived from wood other than beechwood); or
(c) in other preparations containing 3 per cent or less of phenols and homologues of phenol boiling below 220°C.
Schedule 2 – Amendment
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 from wood 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 of alkaline salts prepared by the Hazardous Substances Section of XXXXXXXXXXXX. The alkaline salts review addressed issues relating to the cut-off pH for scheduling, total alkalinity, the concentration at which the pH of a product should be measured, and the greater accessibility of automatic dishwasher detergents compared with laundry detergents 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 a product is scheduled; National Drugs and Poisons Schedule Committee 35 Record of Reasons 41 – June 2004
• Specify performance criteria when considering the scheduling of products containing alkaline 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 to 50% 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 amending the Schedule 5 entry for alkaline salts in accordance with the options presented by the XXXXXXXXXXXX. Accordingly, the Committee asked that more information be obtained by NICNAS on the control of similar substances in the US, Canada, NZ and Europe and in particular the way the issue of irritancy is addressed.
At its 40th Meeting (February 2004), the Committee also considered a public submission from XXXXXXXXXXXX in which the company expressed concerned that the first aid statements required for product containing alkaline salts was unnecessary stronger than those 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 revised to mirror that of sodium hydroxide. Specifically, that the entry for alkaline salts in Appendix 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 a change to the first aid instructions and agreed to consider this proposal as part of the consideration of alkaline salts at a future meeting.
DISCUSSION
The Committee was advised that NICNAS had provided a review of the international regulation of alkaline salts. In summary, NICNAS submitted the following points for the Committee’s consideration:
• The regulation of hazardous substances and preparations (products) for consumers was examined for each of the countries surveyed. No entries were found in the poisons or hazardous substances regulations in the USA, Canada, New Zealand and Europe pertaining to alkaline salts as a group in consumer products. No controls including first aid instructions were found for this group of substances. • In hazardous substances regulations for consumer products, performance criteria for classification of corrosivity and irritancy differed in each country. In the USA, consumer products are regulated by the Consumer Product Safety Commission with the Federal Hazardous Substances Act. Regulations provide for separate Corrosive and Irritant categories and labelling requirements based on the results of animal tests specified in the regulations. There are no criteria for corrosivity or irritation based on physicochemical properties such as pH alone. National Drugs and Poisons Schedule Committee 36 Record of Reasons 41 – June 2004
• In Canada, consumer chemical products are regulated by the Consumer Chemicals and Containers Regulations, 2001. Separate categories of Very Corrosive, Corrosive and Irritant exist. The category of Very Corrosive is reserved for ethyl bromoacetate and fluoride. The categories of both Corrosive and Irritant are based on strictly prescribed pH and alkali reserve criteria or the results from animal testing or human experience. These categories have separate labelling requirements. • In New Zealand, hazardous substances including household products are regulated by the Hazardous Substances and New Organisms (HSNO) Act 1996. The thresholds and classification scheme are based on the OECD Global Harmonisation System (GHS). Separate Corrosive and Irritant categories exist based on the results from animal testing or on limited pH and acidic/alkaline reserve criteria. A substance is deemed a skin 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 have separate specified labelling requirements. • Several regulatory instruments are used in the European Union for hazardous substances and preparations (products). Separate Corrosive and Irritant categories exist 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) and alkaline or acidic reserves alone. The criteria for acidic or alkaline reserve are not stated. For irritation, classification is based on animal data or human experience only. There are no pH and acidic/alkaline reserve criteria for irritation. These categories have separate labelling requirements. The Committee noted that XXXXXXXXXXXX had advised that they have an interest in the Committee’s consideration of alkaline salts and sought the right to make post-meeting comment.
Members were of the view that to reduce the current pH cut-off for alkaline salts in Schedule 5 to pH 11 the Committee would need to know the number of products currently marketed with a pH between 11 and 11.5 and the number of harmful exposures attributed to the use of these product. Accordingly, the Committee asked that the XXXXXXXXXXXX Member determine the number of products currently on the Australian market with a pH between 11 and 11.5 and that the XXXXXXXXXXXX and XXXXXXXXXXXX Members seek from their respective Poisons Information Centres information regarding the number of poisonings attributed to these products and the identity 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 from XXXXXXXXXXXX in which they highlighted their concerns over inconsistencies in the first aid statements required for alkaline salts and sodium hydroxide. The Committee agreed that it was appropriate to amend the Appendix E, Part 2 entry for alkaline salts to mirror that of sodium hydroxide. National Drugs and Poisons Schedule Committee 37 Record of Reasons 41 – June 2004
DECISION 2004/41 - 4
The Committee agreed to further review the current scheduling of alkaline salts at the NDPSC 42nd Meeting (October 2004). The Committee also agreed to amend the Appendix E, Part 2 entry for alkaline salts to mirror that of sodium hydroxide in accordance with XXXXXXXXXXXX submission to the NDPSC 40th Meeting (February 2004).
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 of a procymidone, a dichlorophenyl dicarboximide fungicide closely related to vinclozolin. The Committee agreed that there was sufficient information regarding the teratogenic potential of procymidone to warrant inclusion in Schedule 7.
The Committee noted that vinclozolin and procymidone are closely related chemically and toxicologically and have similar hazard profiles. Consequently, Members thought it appropriate to foreshadow a reconsideration of the scheduling of vinclozolin.
The Committee asked that the Secretariat review the previous considerations of vinclozolin relating to the teratogenicity and endocrine disrupting potential of this substance and report to the 41st Meeting (June 2004).
DISCUSSION
The Committee noted the following advice from the Secretariat regarding the previous considerations of the scheduling of Vinclozolin:
• Vinclozolin was first considered by the Committee in February 1979. The Committee noted that the acute toxicity of vinclozolin was very low. However, some concern was expressed over the formation of 3,5-dichloroaniline in strawberries and grapes treated with the compound. The Committee deferred its consideration of vinclozolin to allow more information regarding the carcinogenic/mutagenic potential of 3,5- dichloroaniline to be obtained. At the August 1979 meeting the Committee was National Drugs and Poisons Schedule Committee 38 Record of Reasons 41 – June 2004
advised that several literature searches had failed to yield any evidence of carcinogenic or mutagenic activity associated with 3,5-dichloroaniline. The matter was referred to the Carcinogenic Substances Committee. Vinclozolin was exempted from the requirements of scheduling and included in Appendix B. • At the August 1988 meeting the Committee considered a review of toxicological data submitted in support a TGAC clearance of vinclozolin. The data reviewed suggested that vinclozolin exhibited low acute oral, dermal and inhalational toxicity in rats and guinea pigs. It was considered to be a mild skin and eye irritant in rabbits, a moderate skin sensitiser in guinea pigs and did not exhibit systemic toxicity in a 21-day rabbit dermal study. Chronic studies in mice and rats showed no carcinogenic potential. A 3- generation rat reproduction study showed no dose related effects and the teratology package, containing a mouse and rabbit study, indicated that vinclozolin was not considered to be teratogenic. Based on this data, the Committee considered that the entry for vinclozolin in Appendix B remained appropriate. • At the NDPSC 7th Meeting (November 1995) the Committee considered additional toxicological data relating to a review undertaken by the then Chemicals Policy and Review Section of Environmental Health and Safety Unit. The mechanistic studies indicated that in the rat vinclozolin acted as an anti-androgen through several of its metabolites binding preferentially on androgen receptors, thus preventing testosterone from activating the receptor. This produces serious reproductive and teratogenic adverse effects in both adult and developing animals. The Committee assumed that, in the absence of pharmacokinetic data in humans, the human is as sensitive as the rat to this effect. Serious reproductive effects across a range of doses (gross alteration of male reproduction organs rendering F1 males incapable of reproduction and accompanied 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 potential risk 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 animal species (rat, mouse, dog) and at various dose levels, including low doses. ! Vinclozolin exerts chronic effects at relatively low doses and has a very steep dose-response. ! In-vitro evidence that vinclozolin preferentially binds to human androgen receptors, and exposure studies showing that humans could be exposed to toxic levels in the course of daily activities involving contact with vinclozolin. ! The potential of ingestion of minimally processed food containing of significant amounts 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 National Drugs and Poisons Schedule Committee 39 Record of Reasons 41 – June 2004 as an option. However, the Committee, noting that there was a threshold for the effects and that its uses were to be restricted in order to minimise human exposure as well as applying more stringent safety directions, were of the view that Schedule 6 was appropriate. Consequently, the Committee also recommended Warning Statement 46 of Appendix F, because of the potential of vinclozolin for teratogenicity and adverse reproductive effects. The then National Registration Authority for Agricultural and Veterinary Chemicals (NRA) undertook a special review of vinclozolin due to toxicological and worker exposure concerns and cancelled all vinclozolin registrations effective 31 December 1996. Members noted that that the Organisation for Economic Co-operation and Development (OECD) had recently validated the Hershberger Assay, a Test Guideline designed to screen potential endocrine disruptors in which procymidone and vinclozolin are used as positive controls.
The Committee noted that as a consequence of the NRA review, there are currently no products containing vinclozolin registered with the APVMA. Therefore, any change in the 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 teratogenic potential and in order to maintain consistency with its previous decision regarding the scheduling of procymidone.
Schedule 6 – Amendment
VINCLOZOLIN - delete entry
Schedule 7 – New entry
VINCLOZOLIN.
5. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FOR THE UNIFORM SCHEDULING OF DRUGS AND POISONS.
5.1 SUSDP, PART 4
There were no items considered. National Drugs and Poisons Schedule Committee 40 Record of Reasons 41 – June 2004
5.2 SUSDP, PART 5
5.2.1 BIFLUORIDES
PURPOSE
The Committee considered the inclusion of entries for Schedule 7 bifluorides in Appendices E and F.
BACKGROUND
At the NDPSC 31st Meeting (May 2001) the Committee considered the scheduling of corrosive fluorides following the release of the NICNAS Priority Existing Chemical (PEC) Report for hydrofluoric acid. After further consideration of corrosive fluorides at the 32nd (August 2001), the 33rd (November 2001) and the 34th (February 2002) Meetings, the Committee agreed that the corrosive fluorides including the bifluorides should be more restrictively scheduled in a like fashion to hydrofluoric acid on a chemically equivalent basis. And that appropriate amendments should also be made to Appendices 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 in Schedule 7 intended to mirror those for hydrofluoric acid had been omitted from the SUSDP.
DISCUSSION
The Committee considered it appropriate to include:
• A, G3, E2 and S5 to the Appendix E, Part 2 entry for bifluorides when included in Schedule 7; and • Warning Statements 1, 17, and 93 and Safety Directions 1, 3, 4, 5, 8, 29 and 35 to the Appendix F, Part 3 entry for bifluorides when included in Schedule 7.
DECISION 2004/41 - 6
Members agreed to amend Appendix E, Part 2 and Appendix F, Part 3 entries for bifluorides 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) National Drugs and Poisons Schedule Committee 41 Record of Reasons 41 – June 2004
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...... 2 Safety directions...... 1,4
(b) when included in Schedule 6 or 7
Warning statements...... 1,17,93 Safety directions…………………… 1,3,4,5,8,29,35
6. MATTERS REFERRED BY THE AUSTRALIAN PESTICIDES AND 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 irreversible damage to nerves (neuropathy) and interfere with the development of the foetus and the young (developmental toxicity).
Molinate was last reviewed in 1986. The Acceptable Daily Intake (ADI) of 0.002 mg/kg bw established at that time was based on the No Observed Effect Level (NOEL) of 0.2 mg/kg bw for adverse effects on fertility in male rats. The database reviewed in 1986 did not contain any studies which indicated that molinate could cause neuropathy and developmental toxicity. National Drugs and Poisons Schedule Committee 42 Record of Reasons 41 – June 2004
Molinate is a thiocarbamate herbicide which has been used to control barnyard grass and silver top or brown beetle grass in rice crops in Australia for over 30 years. Currently there are four products containing molinate registered by the APVMA.
DISCUSSION
The Committee noted the following points raised in the OCS evaluation report for consideration:
• In rats, molinate has low to moderate oral toxicity (LD50 = 549 mg/kg bw) and low dermal toxicity (LD50 ~ 4350 mg/kg bw). Data evaluated in 1986 indicated that molinate 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 skin sensitiser in the guinea pig maximisation test. • Molinate is formulated as an emulsifiable concentrate at 960 g/L, and is used solely as a herbicide in rice cultivation. It is applied as a spray, either on-ground or aerially, to dry rice bays, rice in permanent water or to inflowing water. Molinate can be used undiluted 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 in 5-10 L for permanent water. For aerial application, the use rate per hectare is 3.75 L in 10-100 L. • Certain aspects of the reproductive toxicity of molinate were recognised when the chemical underwent a public health assessment in Australia in 1980 and 1986. The ADI established at the time (0.002 mg/kg bw/d) was based on the NOEL of 0.2 mg/kg bw/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, indicated that molinate caused neuropathy and developmental toxicity in experimental animals at low doses. The potential relevance of the neuropathy findings to humans is considered high because the lesions developed in four species and there was no evidence that they were reversible. The major issues raised by the EPA assessment were: ! 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 25 mg/kg bw (decreased motor activity, increased time to tail flick). The LOAEL in the 90-day study was 4 mg/kg bw/d (decreased brain cholinesterase activity and neuropathy target esterase activity), while nerve fibre degeneration in the sciatic and 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 in morphometric measurements of certain areas of the cerebellum also occurred in pups at the maternal NOAEL (6.9 mg/kg bw/d). National Drugs and Poisons Schedule Committee 43 Record of Reasons 41 – June 2004
! The NOAEL for developmental toxicity (2.2 mg/kg bw/d; increased runting) was below the NOAEL for maternotoxicity in rats (35 mg/kg bw/d). ! In a 2-generation reproduction study, a NOAEL was not determined for decreased brain 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 low doses (0.8 mg/kg bw/d). ! The absence of NOAELs for neuropathy in chronic rat and dog studies. The LOAEL in rats was 0.4 mg/kg bw/d based on the increased incidence of degeneration 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 in the lumbar, sacral and thoracic regions of the spinal cord. • The OCS evaluator indicated that none of the data underpinning the EPA’s assessment were submitted for evaluation as part of the current Australian review on molinate. Furthermore, other studies submitted to the OCS for evaluation did not address concerns relating to the potential neuropathy and developmental toxicity of molinate. In the absence of data to address these serious toxicological concerns the OCS recommended that approval of molinate active constituent and the registration of molinate products no longer be supported. Additionally, the Committee was asked to consider the inclusion of entries for molinate in Schedule 7 and Appendix J of the SUSDP.
The Committee was advised that Nufarm Australia Limited, Farmoz Pty Ltd, Crop Care Australasia Pty Ltd and Sipcam Pacific Australia Pty Ltd market Nufarm Molinate 960 Herbicide, Farmoz Molinate 960 Herbicide, Ordram Herbicide and Sirion Herbicide, respectively. According to the PUBCRIS database, all 4 products (containing molinate at a concentration of 960 g/L) are currently labelled as Schedule 6 substances and used exclusively in rice crops.
The Committee was informed that the scheduling consideration of molinate was included in the pre-June 2004 meeting gazette notice and no public submissions were received.
A Member informed the Committee that the neurotoxicity and developmental effects exhibited by molinate warranted a reconsideration of its Schedule 6 entry.
The Committee was informed that the sponsor of molinate in the USA no longer supported its continued registration and that its use would be phased out over a five year period. The evaluator further advised that the sponsor no longer supported the registration of molinate in Australia and that this was the justification for the non-submission of the data referred to above.
The XXXXXXXXXXXX Member reminded the Committee that molinate was currently under review by the XXXXXXXXXXXX and sought support amongst Members for a delayed implementation date in order to allow the review to be completed. The Member National Drugs and Poisons Schedule Committee 44 Record of Reasons 41 – June 2004 advised that, in the absence of further data, the XXXXXXXXXXXX could be in a position to make a decision by early 2005. Should further data be provided by the sponsor, time would be needed to assess this information, thus delaying the decision by several months.
A Member reminded the Committee that molinate had clearly been implicated in neurotoxicity in humans and that such a delay may not be justified as the Committee must be seen to take appropriate regulatory action. Members also noted that any decision made at the NDPSC 41st Meeting (June 2004) meeting would not come into effect until 1 January 2005.
DECISION 2004/41 - 7
The Committee agreed to include molinate in Schedule 7 and Appendix J.
Schedule 6 – Amendment
MOLINATE – delete entry
Schedule 7 – New 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, potassium bicarbonate (950 g/kg). XXXXXXXXXXXX will be used for the control of powdery mildew on grapes, cucurbits, strawberries, tomatoes, ornamentals and black spot in roses. National Drugs and Poisons Schedule Committee 45 Record of Reasons 41 – June 2004
A similar product, XXXXXXXXXXXX for control of powdery mildew is currently registered in USA.
Potassium bicarbonate is found throughout nature in living systems and in non-living environments. It is also found in human food. According to the US EPA, no adverse health effects are expected when potassium bicarbonate is used as pesticides. The US Food and Drug Administration (FDA) also considers that potassium bicarbonate is generally recognised as safe.
Currently there are no products containing potassium bicarbonate registered by the APVMA. However, there are 24 products containing sodium bicarbonate currently registered with the APVMA for such uses as anti-scour treatments, electrolyte replacements, digestive and mineral supplements and tick fever vaccines.
DISCUSSION
The Committee noted the following points raised in the OCS evaluation report for consideration:
• Potassium bicarbonate has low acute oral, dermal and inhalation toxicity, is a slight eye irritant, but not a skin sensitiser or skin irritant. The acute oral LD50 for potassium bicarbonate of 2825 mg/kg bw, is consistent with the NDPSC guidelines for inclusion in Schedule 5 of the SUSDP. • Sodium bicarbonate also exhibits low acute oral toxicity (LD50 4220 mg/kg bw in the rat) 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, a normal constituent of human tissues and generally recognised as safe by the FDA, the OCS recommended the inclusion of potassium bicarbonate in Appendix B of SUSDP. Furthermore, given its similar toxicological profile and uses, the OCS recommended that the Committee also consider exempting sodium bicarbonate from the requirements of scheduling. Members were advised that according to the PUBCRIS database, all 24 products containing sodium bicarbonate are currently labelled as unscheduled substances. The Committee noted that if it were to decide that the inclusion of an entry in Schedule 5 for potassium bicarbonate was warranted, there would be no regulatory impact for agricultural and veterinary chemicals as there are no products containing potassium bicarbonate currently registered with the APVMA. However, the inclusion of potassium bicarbonate in Schedule 5 was likely to have a significant regulatory impact on human therapeutics as there are currently 66 products listed on the ARTG containing potassium bicarbonate, most of which would be either unscheduled or in a lower schedule than that proposed. There would also be a significant regulatory impact on certain food products if potassium bicarbonate were to be included in Schedule 5. National Drugs and Poisons Schedule Committee 46 Record of Reasons 41 – June 2004
The Committee was informed that a public submission had been received from XXXXXXXXXXXX. The company advised that it has an interest in potassium bicarbonate and sought to reserve the right to make post-meeting comment.
A Member expressed the opinion that in light of their low toxicities, exempting potassium bicarbonate and sodium bicarbonate from the requirements of scheduling was not unreasonable.
DECISION 2004/41 - 8
The Committee agreed to exempt potassium bicarbonate and sodium bicarbonate for the requirements of scheduling on the basis of its low toxicity.
Appendix B – New entries
SUBSTANCE DATE OF REASON AREA ENTRY FOR OF LISTING USE
POTASSIUM BICARBONATE June 2004 a 1 SODIUM 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 an attractant, luring mosquitoes and biting midges into a trap where they are dehydrated and die 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 and vegetables. Furthermore, it is widely used as a flavouring ingredient in foods and is approved by the US FDA as a direct food additive and the Council of Europe as an artificial flavouring agent. The US FDA considers that octenol is generally recognised as safe (GRAS). National Drugs and Poisons Schedule Committee 47 Record of Reasons 41 – June 2004
DISCUSSION
The Committee noted the following points raised in the OCS evaluation report for consideration:
• 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. Each cartridge is contained within a PET tray with a plastic cover over the top. The operator does not need to touch the cartridge in use of the product as the tray is placed, intact, into the trapping device. • Octenol has moderate acute oral toxicity (LD50) of 340 mg/kg bw, low dermal toxicity (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 octenol be included in Schedule 6 of the SUSDP with a cut off to Schedule 5 when packed in bite and crush resistant cartridges containing 2 g or less of octenol.
The Committee was informed that the scheduling consideration of octenol was included in the pre-June 2004 meeting gazette notice and no public submissions were received.
A Member expressed the opinion that based on the toxicological information submitted an entry for octenol in Schedule 6 was appropriate. However, the Member was concerned that there did not appear to be a recognised standard to test whether the packaging is “bite and crush resistant” as the sponsor had claimed. Members agreed that it was difficult to consider 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 the Committee 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 for consideration by the Committee at the 42nd Meeting (October 2004).
The Committee further agreed that, in order to assist Members in making future scheduling decisions regarding domestic, agricultural and veterinary chemicals, examples of product packaging should be provided with the evaluation report in situations where the packaging proposed did not conform to a recognised standard. Furthermore, the evaulator should also provide specific comment in the evaluation report on the packaging and presentation of the product, particularly in regard to public safety.
The XXXXXXXXXXXX advised the Committee that octanol is used in perfumes and soaps 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 additives would also need to be obtained for consideration at the 42nd Meeting (October 2004). National Drugs and Poisons Schedule Committee 48 Record of Reasons 41 – June 2004
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 the registration of the sponsor’s product. As an alternative the Committee agree to consider an 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’s packaging. This would also allow time to determine the regulatory impact on cosmetics and food additives resulting from the proposed scheduling of octenol.
DECISION 2004/41 - 9
The Committee agreed to include an entry for 1-octen-3-ol in Schedule 6 on the basis of its acute oral toxicity.
Schedule 6 – New entry
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 and 227 mg of the active ingredient firocoxib. The company advises that the product is likely to be used in older dogs to relieve inflammation and pain from ailments such as osteoarthritis and other age-related conditions. The product may also be used to treat other 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 immediate early response gene product in inflammatory and immune cells. COX-2 also plays a physiological role in a number of tissues including the female reproductive tract, the kidney and vascular endothelium.
DISCUSSION
The Committee noted the following points raised in the OCS evaluation report for consideration:
• [Paragraphs deleted] National Drugs and Poisons Schedule Committee 49 Record of Reasons 41 – June 2004
Based on firocoxib’s low acute toxicity, its intended use as a therapeutic agent, which requires professional veterinary advice and management prior to use, the OCS recommended inclusion in Schedule 4.
[sentences deleted] The OCS thus recommended that the committee consider restricting the product pack size to blister packs containing 10-30 tablets to ensure that the product was dispensed in its original packaging displaying the appropriate safety directions to the consumer. The Committee was advised that Part 2 – Labels and Containers stipulates that a person must not sell or supply a poison unless it is labelled in accordance with paragraphs 3 to 19 of this Standard. Furthermore, paragraphs 7(n) and 7(o) specifically require that, if a poison may be harmful to the user, the label must carry appropriate safety directions and warning statements.
The Committee noted that XXXXXXXXXXXX had subsequently advised that XXXXXXXXXXXX XXXXXXXXXXXX. XXXXXXXXXXXX contended that the availability of the 60 tablet bottle to veterinarians was important for use in veterinary hospitals and that there would be little motivation to dispense from the 60 tablet bottle given the ready availability of a 10 tablet blister pack.
The Committee was advised that the draft label provided in the submission stated under Precautions that “Safe use in breeding, pregnant or lactating dogs has not been established” and thus did not highlight the teratogenic potential of firocoxib. It was recommended that the Committee consider drawing this issue to the attention of the APVMA.
The Committee was informed that the scheduling consideration of firocoxib was included in 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 were discouraged from dispensing small numbers of tablets to clients without appropriate labels. Furthermore, advising the APVMA that warning statements be included in the product statement regarding the effect of the substance on breeding animals would also be appropriate.
Accordingly, the Committee agreed to recommend that the APVMA consider that the product only be available to the consumer in blister packs with the 60 tablet bottle restricted to veterinary hospitals and that appropriate warnings regarding the potential for teratogenic effects in female dogs intended from breeding purposes be included in the product information and on product packaging.
DECISION 2004/41 - 10
The Committee agreed to include an entry for firocoxib in Schedule 4 on the grounds that the condition being treated necessitates appropriate veterinary diagnosis and the safe use of this medicine requires management and monitoring of the treated dog by a veterinary professional. National Drugs and Poisons Schedule Committee 50 Record of Reasons 41 – June 2004
Schedule 4 – New entry
FIROCOXIB.
6.6 QUINCLORAC
PURPOSE
The Committee considered the scheduling of quinclorac.
BACKGROUND
XXXXXXXXXXXX submitted an application for new active constituent, quinclorac, and the registration of a new product XXXXXXXXXXXX containing 750 g/kg quinclorac. XXXXXXXXXXXX is intended for the post-emergence control of summer grass and white clover and the suppression of kikuyu in turf. XXXXXXXXXXXX XXXXXXXXXXXX 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 wall disruptor.
DISCUSSION
The Committee noted the following points raised in the OCS evaluation report for consideration:
• [Paragraphs deleted] The Committee was informed that the scheduling consideration of quinclorac was included in the pre-June 2004 meeting gazette notice and no public submissions were received.
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, an entry in Schedule 5 was appropriate.
A Member expressed concern that the product containing quinclorac would be marketed to home gardeners in pack sizes greater than 1 kg. Members agreed that pack size was not an 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 its acute oral toxicity and skin sensitisation potential. National Drugs and Poisons Schedule Committee 51 Record of Reasons 41 – June 2004
Schedule 5 – New entry
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. The product will contain 100 g/L flumiclorac pentyl as the active ingredient in a formulation containing hydrocarbon solvent.
Flumiclorac pentyl is a N-phenylimide herbicide and a porphyrin biosynthesis pathway inhibitor, 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 cotton plants.
DISCUSSION
The Committee noted the following points raised in the OCS evaluation report for consideration:
• [Paragraphs deleted] Based on the above data, the OCS recommended that flumiclorac pentyl be exempt from the requirements of scheduling.
The Committee was informed that the scheduling consideration of flumiclorac pentyl was included in the pre-June 2004 meeting gazette notice and no public submissions were received.
A Member expressed the opinion that the data presented was deficient in information regarding flumiclorac pentyl’s primary mode of action in biosynthesis. The Member advised that in previous considerations of similar substances these had been included in Schedule 7. In particular, concern was expressed that protoporphyrinogen oxidase is the penultimate enzyme in both chlorophyll and heme biosynthesis and should a susceptible person to porphyria come in contact with flumiclorac pentyl, it may trigger an attack. The evaluator informed Members that the assessment did not identify any significant haematological concerns in the mammalian studies evaluated and that this may result from flumiclorac pentyl exhibiting a greater plant specificity than other analogues previously considered by the Committee. The Member acknowledged that flumiclorac pentyl did exhibit a lower toxicity profile and produced less porphyrin when compared National Drugs and Poisons Schedule Committee 52 Record of Reasons 41 – June 2004 with other compounds in its class, however, in his view the sponsor failed to supply data on this matter for the Committee’s consideration.
A Member noted that flumiclorac pentyl had been identified as a potential skin sensitiser on the basis of tests conducted in the late 1980’s and early 1990’s. The Member was concerned that perhaps there may be more recent experiences since 1992 with the substance’s skin sensitiser potential that have not been made available to the Committee for consideration. The evaluator advised the Committee that, given the time lag between product registration and product sale, there was unlikely to be any significant exposure and epidemiological monitoring to produce such information. Furthermore, the evaluator reminded the Committee that the sponsor is obliged to provide all known data to the OCS for evaluation including any monitoring data, however, in this case the sponsor had indicated that there were no findings to report. The XXXXXXXXXXXX advised the Committee that flumiclorac pentyl would be considered to be a skin sensitiser in the workplace on the basis of the tests submitted.
OUTCOME
The Committee agreed to defer consideration of the scheduling of flumiclorac pentyl in order to seek more information regarding porphyrin metabolism and its potential to trigger an attack of porphyria. Furthermore, the Committee asked that the sponsor confirm that there is no evidence of skin sensitisation or the onset of acute porphyric attacks 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 product XXXXXXXXXXXX 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) and imidacloprid (100 g/L). The applicant proposed a change to the scheduling for permethrin to allow inclusion in Schedule 5 when packed in single use containers having a capacity of 4 mL or less. Currently, the product would be labelled as a Schedule 6 poison on the basis 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) or monthly 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 ectoparasiticide belonging to the chloronicotinyl group of compounds. National Drugs and Poisons Schedule Committee 53 Record of Reasons 41 – June 2004
Permethrin was first considered at the May 1977 meeting where it was exempted from the requirements of scheduling on the grounds of low toxicity. At the NDPSC 2nd Meeting (August 1994) the Committee considered new data suggesting that permethrin exhibited moderate acute oral toxicity but delayed making a decision until a list of registered products containing permethrin was obtained from the NRA. A decision to delete permethrin from Appendix B and include an entry in Schedule 6 with a cut-off to Schedule 5 for preparations containing 25% or less was made at the NDPSC 3rd Meeting (November 1994). Preparations containing 2% or less of permethrin remained exempt from the requirements of scheduling.
DISCUSSION
The Committee noted the following points raised in the OCS evaluation report for consideration:
• [Paragraphs deleted] • The ADI for permethrin is 0.05 mg/kg/day based on a NOEL of 5 mg/kg/day in chronic studies in rats and dogs. Imidacloprid has an ADI of 0.06 mg/kg bw/day based on a NOEL of 6 mg/kg bw/day in a 2 year rat study. Target organs for toxicity were liver (permethrin) and thyroid (imidacloprid). There is no ARfD established for either permethrin or imidacloprid. • In animal studies, permethrin was not carcinogenic, and it did not show any reproductive or developmental toxicity. Imidacloprid was not carcinogenic and did not show reproductive toxicity, but showed embryofetal effects (wavy ribs in rats; increased post-implantation loss, and decreased fetal weights and development in rabbits) but the changes were associated with maternal toxicity (NOEL: 10 and 30 mg/kg bw/d for maternal and fetal toxicity in rats, respectively; 8 and 24 mg/kg bw/d for maternal and fetal toxicity in rabbits, respectively). Based on the acute toxicity profile of XXXXXXXXXXXX, the OCS recommended a Schedule 5 entry for preparations containing 26-50% permethrin when packed in single use containers having a capacity of 4 mL or less.
The Committee was advised that, according to the PUBCRIS database, there are 269 products containing permethrin of which 63 are veterinary pesticides and 5 are veterinary medicines. The Committee noted that an amendment to the Schedule 5 entry for permethrin to include preparations containing 50% or less when packed in single use containers having a capacity of 4 mL or less would result in 9 products currently registered with the APVMA being down-scheduled from Schedule 6 to Schedule 5. These products, containing 40% permethrin, are all used to control fleas and ticks on dogs and are available in single dosage units of 2 and 4 mL.
The Committee was informed that public submissions were received XXXXXXXXXXXX, XXXXXXXXXXXX, and XXXXXXXXXXXX. National Drugs and Poisons Schedule Committee 54 Record of Reasons 41 – June 2004
XXXXXXXXXXXX advised that it holds the registration for XXXXXXXXXXXX containing permethrin currently labelled as Schedule 5. The company also provided a copy of their product’s registered label and sought the right to make post-meeting comment.
XXXXXXXXXXXX advised that it has an interest in permethrin and sought the right to make post-meeting comment.
XXXXXXXXXXXX advised that, in its opinion, permethrin poses a significant toxicological risk to cats. Specifically, the company expressed concern that this non- target species would be exposed to the substance through contact with dogs and product misuse. Therefore, XXXXXXXXXXXX recommended that permethrin remain in Schedule 6 and that the Committee consider lowering the 25% cut-off to Schedule 5. The Committee was advised that the submission was forwarded to the OCS for assessment. In response, the OCS advised the Committee that while there are genuine concerns, the issues identified primarily relates to off label use or inappropriate use and as such were an issue for the APVMA to consider during deliberations on label directions. In the OCS’s view, scheduling is not an appropriate mechanism for controlling the use of products in contravention of the label directions. The OCS considered that the possible use on or exposure to cats was an issue of off-label use and as such a matter for the APVMA and recommended that Committee refer these issues to the APVMA.
A Member expressed concern over the possibility of exposure to non-target animals such as cats, not only through off label use but also through exposure to treated dogs in the same household. The Member advised the Committee that while permethrin is non-toxic to dogs at the dosage rates recommended by the sponsor, it is extremely toxic to cats at the same levels. The Member considered it inappropriate to remove the “Poisons” label requirement by down-scheduling the sponsor’s product because the consumer should be made aware of the risks to non-target animals such as cats.
A Member also expressed the opinion that a product that exhibited severe eye irritation which was not reversible within 7 days should remain in Schedule 6.
A Member highlighted the issue of accidental ingestion by children. Specifically, the statement in the OCS report referring to a child safety study in which up to 19% of children successfully opened the product packaging and thereby could ingest the contents. The Member expressed the opinion that ingestion of the product by a child may result in exposure to permethrin approaching a possibly toxic level and that moving a product such as this into Schedule 5 was inappropriate.
The Committee was concerned that down-scheduling of permethrin may increase the possibility 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 Members that there were products currently labelled as Schedule 5 containing 25% or less of National Drugs and Poisons Schedule Committee 55 Record of Reasons 41 – June 2004 permethrin in pack sizes with a volume of much greater than 4 mL that would pose a greater risk of exposure if accessed by children. The Committee acknowledged that there appeared to be an inconsistency in the approach to the scheduling of these products given their decision regarding the sponsor’s product and asked the Secretariat to review the existing 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 which indicated that a significant proportion of children could gain access to the sponsor’s product packaging and thus potentially ingest the contents. The Committee was concerned that agreeing to the company’s request to increase the Schedule 5 cut-off for permethrin to 50% would result in the product being more readily available in homes and thus increasing the potential for permethrin exposure to children. Similarly, Members were concerned that a change to the Schedule 5 entry for permethrin in accordance with the company’s proposal may also result in an increase in the poisoning of non-target species such as cats. Accordingly, the Committee agreed that the current scheduling of permethrin remained appropriate.
7. MATTERS REFERRED BY THE OFFICE OF CHEMICAL SAFETY (OCS)
7.1 ANDROSTENEDIONE ALBUMEN CONJUGATE WITH DEA DEXTRAN ADJUVANT
PURPOSE
The Committee considered the scheduling of androstenedione albumen conjugate with DEA dextran adjunct.
BACKGROUND
Androstenedione albumin conjugate with DEA Dextran adjuvant (AAC), also known as polyandroalbumin, is a vaccine intended for use in sheep to increase the frequency of twins born to breeding ewes. The active has previously been marketed in Australia as XXXXXXXXXXXX but was removed from the market for commercial reasons.
Androstenedione albumen conjugate with DEA dextran adjunct was first considered at the 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 Committee supported the view that due to the nature of the product, AAC should be exempt from the requirements of scheduling. Accordingly, an entry for AAC was included in Appendix B of the SUSDP. National Drugs and Poisons Schedule Committee 56 Record of Reasons 41 – June 2004
Appendix B was removed from SUSDP 11 and subsequent editions because of concerns that it may be misinterpreted, particularly as reasons for the inclusion of many substances on the list were unclear.
Appendix B was reinstated at the NDPSC 37th Meeting (February 2003). AAC was not included in the list at this time due to there being no or limited toxicological information and the understanding that there were no AAC products registered with the NRA (APVMA) at the time. In 2000, the OCS reviewed a registration application for XXXXXXXXXXXX containing AAC at a concentration of 600 mg/L. The OCS recommended that the product be labelled as an exempt product on the basis of the earlier Appendix B entry. The application was not referred to the NDPSC as no new toxicological data was submitted.
In response to a question raised by Industry regarding the scheduling of AAC, the Secretariat sought advice for OCS on whether there was sufficient toxicological data available to allow the reinstatement of ACC in Appendix B.
DISCUSSION
In response to the Secretariat’s request, the Committee noted that the OCS provided its XXXXXXXXXXXX evaluation report and a summary of their principle conclusions. Members noted that the OCS report identified the following two issues for the Committee’s consideration:
• The primary hazards associated with the occupational use of XXXXXXXXXXXX are the potential for allergic reaction following acute exposure and a potential for temporary disturbance of reproduction in women that may result in multiple births or temporary infertility. The limited evidence available suggests that these effects would be of limited duration and dependent on the attainment of substantial antibody titres. Under most circumstances of accidental self-injection the exposure is likely to be insufficient for the necessary antibody levels to result. However, these conclusions are drawn from minimal information, and whilst the hazards associated with accidental self-administration appear likely to be low, some, slight, potential exists for reproductive disturbance to result. • The key conclusion from the toxicological assessment was that AAC was found to be inactive both anabolically and androgenically in castrated male rats. On the basis of their evaluation, the OCS expressed the view that there are no toxicological hazards inconsistent with the inclusion of AAC in Appendix B of the SUSDP.
A Member expressed concern that the products steroidal content may encourage misuse should the product remain unscheduled. The evaluator advised the Committee that the steroidal component of the product was present at a very low concentration such that it was unlikely that enough could be injected into the body to aid muscle growth. National Drugs and Poisons Schedule Committee 57 Record of Reasons 41 – June 2004
Furthermore, the Committee was reminded that studies in rats had shown that ACC did not exhibit any anabolic or androgenic effects.
DECISION 2004/41 - 12 The Committee agreed to exempt androstenedione albumen conjugate with DEA dextran adjunct from the requirements of scheduling on the basis of its low toxicity.
Appendix B – New entry
SUBSTANCE DATE OF REASON AREA ENTRY FOR OF LISTING USE
ANDROSTENEDIONE ALBUMEN June 2004 a 2.1 CONJUGATE WITH DEA DEXTRAN ADJUNCT
8. ANTIBIOTICS FOR CONSIDERATION FOLLOWING RECOMMENDATIONS OF THE JOINT EXPERT TECHNICAL ADVISORY 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 “the concept that all antibiotics for use in humans and animals (including fish) be classified as S4 (prescription only)”. However, the Government’s acceptance was qualified by highlighting that “… certain antibiotic products might be exempted from this scheduling class where the Australian Pesticides and Veterinary Medicines Authority (APVMA), the Therapeutic Goods Administration (TGA) and the NDPSC assess the antibiotic products as having a low and acceptable risk of promoting antibiotic resistance”.
The Committee agreed at the 35th Meeting (June 2002) that the scheduling of antibiotics currently registered with the APVMA and listed outside of Schedule 4 in the SUSDP would be reviewed. This intention was included in the post - October 2002 meeting notice published in the Commonwealth of Australia Gazette No GN 49, 11 December 2002. National Drugs and Poisons Schedule Committee 58 Record of Reasons 41 – June 2004
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 initially considered 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 folic acid, essential for the production of amino acids and nucleotides. Within the folic acid pathway, dihydropteroate synthase (DHPS) catalyses the synthesis of 7,8-dihydropteroate from pterin pyrophosphate and para-aminobenzoate (PABA); sulfonamides compete with PABA for this enzyme and inhibit its activity.
A search of the PUBCRIS database revealed that there are approximately 90 products registered with the APVMA containing sulfacetamide, sulfadiazine, sulfadimidine, sulfamerazine, sulfaquinoxaline, sulfadoxine, sulfathiazole, sulfatroxazole and trimethoprim. Of these products containing these sulfonamides, 13 are labelled as either Schedule 5 or Schedule 6 products and their uses include the treatment of aquarium fish or caged ornamental birds or for the for treatment of coccidiosis in poultry. With the exception of one product that is available in a 25 kg pack, all other products are available in 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 and trimethoprim. Of these the following have entries outside Schedule 4: mafenide (S6 for treatment of aquarium fish), sulfamerazine (S5 for ornamental fish), sulfaquinoxaline (S5 as a coccidiostat in poultry, exempt in animal feeds and vermin baits), sulfacetamide (S3 for ophthalmic use, S5 for ornamental fish and birds), sulfadiazine (S5 for ornamental fish and birds), sulfadimidine (S5 for ornamental fish and birds) and sulfathiazole (S5 for ornamental 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 National Drugs and Poisons Schedule Committee 59 Record of Reasons 41 – June 2004 company further stated that the product is a topical preparation indicated for the treatment of minor ocular infections such as mild to moderate conjunctivitis. The Committee was advised that the covering letter and submission were forwarded to EAGAR for their consideration.
The Committee noted advice from EAGAR which recommended that, as the potential for and realisation of resistance to agents in the same class as sulfonamides and to the development of cross resistance to other antibiotics, all sulfonamides currently registered for 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 in aquariums, for ornamental fish and for caged ornamental birds need not be included in Schedule 4 on the basis that the exposure of bacteria to the sulfonamides resulting from these uses would be insignificant and, consequently, there would be minimal potential for the development of resistance transferable to humans. The scheduling of these products outside Schedule 4 was recommended by EAGAR on the condition that:
• Pack sizes are such that would preclude the use of these products for commercial poultry or aquaculture; and • The products contain a restraint on the label that the product is not to be used on food animals. The Committee noted advice from the APVMA that supported the recommendations made by EAGAR. The APVMA advised that all sulfonamides used in food producing animals, except sulfaquinoxaline when packed and labelled for use as a coccidiostat in poultry, are currently only available under veterinary prescription. Furthermore, of the 5 products containing sulfaquinoxaline, 3 products also contain diveridine and are consequently labelled as Schedule 4 products. The APVMA further advised that the poultry industry has access to two other coccidostats currently labelled outside Schedule 4 and as such the regulatory impact resulting from the inclusion of the sulfaquinoxaline in Schedule 4 would be minimal.
The Committee noted that the Schedule 4 sulfonamide entry currently included an exemption for sulfaquinoxaline when incorporated into baits for the destruction of vermin and for sulfonamides when packed and labelled solely for use as a herbicide. The Committee was advised that, according to PUBCRIS, no such products were currently registered with the APVMA.
Members noted that the majority of products containing sulfonamides for the treatment of food animals were available in packs sizes of less that 1 kg/L, and expressed concern that it would be difficult to limit their availability to domestic use through scheduling. A Member suggested that appropriate pack size limits for products for aquariums, ornamental fish and caged ornamental birds were a matter for the APVMA and could be controlled during the product registration process.
Members also noted that a decision to reschedule sulfacetamide from Schedule 3 to Schedule 4 in accordance with the EAGAR recommendation would lead to an National Drugs and Poisons Schedule Committee 60 Record of Reasons 41 – June 2004 unharmonised scheduling position with New Zealand. The Committee noted that confirmation had been sought from EAGAR that it considered the public submission from XXXXXXXXXXXX before recommending that all sulfonamides used in human and non-food producing animals be included in Schedule 4. EAGAR advised that the XXXXXXXXXXXX submission had been taken into consideration and that the Committee should note its initial recommendation regarding the scheduling of the sulfonamides. A Member expressed concerned that there appeared to be no evidence of a detailed review of the XXXXXXXXXXXX submission concerning the 10% sulfacetamide product currently labelled as a Schedule 3. The Committee thought it appropriate that the XXXXXXXXXXXX submission be independently reviewed and advice obtained on whether maintaining an entry for a 10% sulfacetamide preparation in Schedule 3 presented an unacceptable risk of promoting antibiotic resistance. The scheduling of sulfacetamide would be further considered at the October 2004 meeting.
DECISION 2004/41 - 13 The Committee agreed to include the sulfonamides (except sulfacetamide pending advice) 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 4 to ornamental fish and for caged ornamental birds. The Committee also agreed to make an editorial amendment to the mafenide Schedule 6 entry for consistency with other sulfonamide entries in Schedule 5.
Schedule 4 – New entry
SULFAQUINOXALINE.
Schedule 4 – Amendment
SULFONAMIDES – Amend to read:
SULFONAMIDES except:
(a) when separately specified in this Schedule; or
(b) when included in Schedule 3, 5 or 6.
Schedule 5 - Amendment
SULFAQUINOXALINE – delete entry. National Drugs and Poisons Schedule Committee 61 Record of Reasons 41 – June 2004
EDITORIAL AMENDMENT
Schedule 6 – 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 JETACAR recommendation 6 at the NDPSC 40th Meeting (February 2004). At that time EAGAR was unable to provide a completed assessment report for tiamulin but it provided an interim recommendation that the substance be included in Schedule 4 for all uses as it is a valuable therapeutic agent in pigs and poultry. The Committee endorsed EAGAR’s recommendation and agreed to include tiamulin for all uses in Schedule 4 of the SUSDP which was consistent with the Government response to JETACAR Recommendation 6.
DISCUSSION
The Committee was provided with the EAGAR final assessment for tiamulin that confirmed 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. National Drugs and Poisons Schedule Committee 62 Record of Reasons 41 – June 2004
BACKGROUND
The scheduling of sodium hypochlorite was considered by the Committee as part of a class 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 entry for chlorinating compounds in Schedule 6 with a cut-off to Schedule 5 at 20% available chlorine. During these considerations the Committee noted that sodium hypochlorite exhibited a low acute oral toxicity (LD50 of 8910 mg/kg bw) and agreed to exempt it from the requirements of scheduling. These amendments were included in SUSDP 18 Amendment 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 sodium hypochlorite solutions containing sodium hydroxide. The company highlighted that sodium hypochlorite is manufactured via a reaction between sodium hydroxide and chlorine gas in water. In order to ensure that the equilibrium reaction is maintained in favour of hypochlorite formation and to prevent the liberation of chlorine gas, a small excess of sodium hydroxide is added to maintain the pH between 11 and 13. Consequently, commercially available preparations of sodium hypochlorite contain small quantities of sodium hydroxide (≤ 1% w/v).
The Committee noted that currently sodium hypochlorite is exempt from the requirements of scheduling. However, the presence of sodium hydroxide would require these preparations to be labelled as either Schedule 5 or Schedule 6 poisons depending of the percentage of available chlorine and the pH of the particular solution.
Members were informed that the company had sought clarification of this issue from XXXXXXXXXXXX and was advised that “If a solution of sodium hypochlorite contains sodium hydroxide and the pH is above 11.5, it would still be scheduled based on its alkalinity”. XXXXXXXXXXXX proposed that sodium hypochlorite solutions with a pH of less than 11.5 be exempt from the requirements of scheduling while those with a pH above 11.5 should remain scheduled. Furthermore, the Committee should ensure that the entry in the SUSDP preclude the intentional adjustment of strong chlorine solutions to below pH 11.5 by the addition of sodium hydroxide. The Committee noted that by setting a sodium hydroxide cut-off a 1% w/v, the possibility of the intentional adjustment of strong chlorine solutions to below pH 11.5 by the addition of sodium hydroxide would be avoided. Furthermore, allowing for the presence of sodium hydroxide at this level would mirror the levels currently available in commercial preparations.
The Committee was of the view that as the presence of sodium hydroxide in sodium hypochlorite solutions is unavoidable, an exemption from the requirements of scheduling for preparations containing 1% or less is a reasonable proposition. National Drugs and Poisons Schedule Committee 63 Record of Reasons 41 – June 2004
OUTCOME
The Committee agreed to exempt from the requirements of scheduling all sodium hypochlorite solutions containing not more than 1% sodium hydroxide and with a pH of less than 11.5.
FORESHADOWED DECISION (for consideration at NDPSC 42nd Meeting of October 2004)
Schedule 5 - Amendment
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 than 1 per cent sodium hydroxide and with a pH of less than 11.5;
(c) liquid preparations containing not less than 2 per cent but not more than 4 per cent of available chlorine when labelled with the statements:
WARNING – Ensure adequate ventilation when using. Vapour may be harmful. May give off dangerous gas if mixed with other products;
(d) liquid preparations containing less than 2 per cent of available chlorine; or
(e) other preparations containing 4 per cent or less of available chlorine.
Schedule 6 - Amendment
CHLORINATING COMPOUNDS – Amend to read:
CHLORINATING COMPOUNDS except:
(a) when included in Schedule 5;
(b) when separately specified in these Schedules; National Drugs and Poisons Schedule Committee 64 Record of Reasons 41 – June 2004
(c) sodium hypochlorite preparations containing not more than 1 per cent sodium hydroxide and with a pH of less than 11.5;
(d) in liquid preparations containing not less than 2 per cent but not more than 4 per cent of available chlorine when labelled with the statements:
WARNING – Ensure adequate ventilation when using. Vapour may be harmful. May give off dangerous gas if mixed with other products;
(e) in liquid preparations containing less than 2 per cent of available chlorine; or
(f) in other preparations containing 4 per cent or less of available 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 was included in Schedule 7 of the Uniform Poisons Schedules in 1955. At the August 1977 meeting the Committee also included the amide of fluoroacetic acid in Schedule 7.
DISCUSSION
The Committee noted that the XXXXXXXXXXXX Member raised the following issues for the discussion:
• The regulation of sodium fluoroacetate baits (1080 baits) has been raised in XXXXXXXXXXXX following a decision by XXXXXXXXXXXX to require Chemcert training of all purchasers of Schedule 7 pesticides and a proposal by XXXXXXXXXXXX to follow this lead and require Chemcert training for all users of Schedule 7 poisons. The impact of such requirements on volunteers involved in biodiversity programs has been raised. • Sodium fluoroacetate is currently Schedule 7 with no cut off. 1080 baits are therefore not permitted to be sold for domestic use. It is also included in the list of pesticides under XXXXXXXXXXXX legislation which is subject to more stringent controls including licensing requirements. National Drugs and Poisons Schedule Committee 65 Record of Reasons 41 – June 2004
• Sodium fluoroacetate has also been listed in the AgVet Code as a Restricted Chemical Product 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 some Schedule 6) and Schedule 7 poisons. The Committee discussed the various controls on the manufacture and use of vermin baits containing sodium fluoroacetate in each of the jurisdictions. The Committee was advised that currently each of the States and Territories only allows authorised persons who have undergone prescribed chemical user training to manufacture and use such baits.
The APVMA Member confirmed that both commercially and non-commercially produced vermin baits containing sodium fluoroacetate are registered by the APVMA. Sodium fluoroacetate is a Restricted Chemical Product, however, the AgVet code provisions do not allow the APVMA to prescribe the level of competency or the training required to use this substance.
A Member expressed the opinion that it was not the role of the poisons legislation to prescribe the training necessary for chemicals use but rather its role was as a “broad brush approach” to the control the availability of substances. Another Member agreed that the issue was beyond the scope of the main focus of the Committee.
The XXXXXXXXXXXX Member sought clarification from the Committee of the issues that would be considered when determining the scheduling status of a prepared product. The Committee confirmed that the matters taken into account when making a scheduling decision would be in accordance with those set out in section 52E of the Therapeutic Good 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 sodium fluoroacetate by untrained or unauthorised persons. In the Committee’s view the controls currently 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. National Drugs and Poisons Schedule Committee 66 Record of Reasons 41 – June 2004
11. INFORMATION ITEMS (AG/VET, INDUSTRIAL & DOMESTIC CHEMICALS)
No items were considered. National Drugs and Poisons Schedule Committee 67 Record of Reasons 41 – June 2004
PHARMACEUTICALS
12. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUS MEETING (CONSIDERATION OF POST-MEETING SUBMISSIONS UNDER 42ZCZ)
12.1 TRIAMCINOLONE
PURPOSE
The Committee considered post-meeting comments in relation to the February 2004 decision to include intranasal preparations for short term use containing triamcinolone acetonide in Schedule 2.
BACKGROUND
Triamcinolone is a synthetic fluorinated corticosteroid with mainly glucocorticoid activity. Intranasal triamcinolone is registered in 64 countries including the UK and USA. 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 preparations containing triamcinolone acetonide from S3 to S2 for use up to 6 months for the treatment of allergic rhinitis. In addition, the Committee also agreed to amend the nomenclature used in the S2 entry to reflect the moiety, i.e. triamcinolone, for consistency with other triamcinolone entries in the SUSDP and the daily dose limit was also adjusted accordingly to 200 mcg.
DISCUSSION
Post-meeting comment was received from XXXXXXXXXXXX highlighting that the maximum recommended daily dose in the S2 entry for triamcinolone published in the post-meeting gazette notice was 200 microgram instead of 220 microgram. XXXXXXXXXXXX also drew attention to the errors in the February 2004 Record of Reasons (RoR) for triamcinolone stating that under “BACKGROUND”, the dosage per actuation of 55 micrograms was erroneously written as 55 g and the maximum recommended daily dose read “220 g” instead of 220 micrograms. Furthermore, an email from OTC Medicines Section (OTC) was also received seeking clarification on the recommended daily dose specified in the S2 entry published in the February 2004 RoR for triamcinolone.
Members noted that whilst the recommended daily dose published in the February 2004 post-meeting gazette notice and RoR was adjusted to 200 mcg to reflect the equivalent amount of triamcinolone, the amount per actuation in the Schedule 2 entry was not adjusted accordingly for consistency. National Drugs and Poisons Schedule Committee 68 Record of Reasons 41 – June 2004
DECISION 2004/41 – 14 (Variation of Decision 2004/40-33)
The Committee agreed to vary Decision 2004/40-33 the Schedule 2 triamcinolone entry published in the February 2004 post-meeting gazette notice to amend the amount per actuation to 50 micrograms triamcinolone (equivalent to 55 micrograms triamcinolone acetonide) 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 of triamcinolone acetonide.
Members also agreed that the Record of Reasons and ratified minutes for the February 2004 meeting published on the NDPSC website should be amended by including a footnote under item 14.1.2 and highlighting that under ‘BACKGROUND’ the dose per actuation had been corrected to read “55 micrograms” instead of 55 g and the maximum recommended daily dose would read “220 micrograms” instead of 220 g. Furthermore, the amount per actuation to 55 microgram triamcinolone would be corrected to read 50 microgram in the S2 entry.
Schedule 2 – New entry
TRIAMCINOLONE in aqueous nasal sprays delivering 50 micrograms or less of triamcinolone per actuation when the maximum recommended daily dose is no greater than 200 micrograms and when packed in a primary pack containing 120 actuations or less, for prophylaxis or treatment of allergic rhinitis for up to 6 months in adults and children 12 years of age and over.
Schedule 3 – Amendment
TRIAMCINOLONE ACETONIDE – amend entry to read:
TRIAMCINOLONE for the treatment of mouth ulcers, in preparations containing 0.1 per cent or less of triamcinolone in a pack of 5 g or less.
Schedule 4 – Amendment
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 exempt from scheduling requirements 0.022% fluoride (220 mg/kg or 220 mg/L) in mouth rinse preparations complying with certain conditions. National Drugs and Poisons Schedule Committee 69 Record of Reasons 41 – June 2004
BACKGROUND
The NDPSC 40th Meeting (February 2004) agreed to the proposal by XXXXXXXXXXXX to exempt from scheduling oral mouth rinse preparations containing 0.022% fluoride (0.05% sodium fluoride). This exemption was conditional upon the product complying with the pack size restriction of 120 mg, the requirement for a child-resistant closure (CRC) and label warnings against swallowing the product and using in children under six years of age. Such preparations were then included in Schedule 2.
DISCUSSION
Post meeting comments were received from XXXXXXXXXXXX, XXXXXXXXXXXX, XXXXXXXXXXXX and XXXXXXXXXXXX. The Committee noted that whilst the decision to limit the pack size and require certain label warnings on products was supported in post-meeting submissions received, the main concern raised was the requirement for CRC to be fitted on exempt dental hygiene products, e.g. mouthwashes and rinses. The following reasons were cited:
• Exempt products containing up to 100 mg/L fluoride were not required to be fitted with CRC and the higher strength S2 products containing 220 mg/L were already available on the market without CRCs. The 220 mg/L fluoride product was already available on the market without CRC as S2 medicine, and currently being used in the home setting with no evidence of harm. An exempt status for this product was unlikely 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 ingestion and subsequent development of fluorosis in children. Literature showed that fluorosis could occur after continual use of high fluoride preparations, including ingestion of fluorides from dietary sources, however there was no evidence of fluorosis occurring following accidental ingestion. Using the most conservative fluoride dose advice of 5 mg F/kg, a 10-kg child would need to consume 215 mL of 220 mg fluoride mouthwash to achieve a Probably Toxic Dose. Given that fluorides are powerful emetics, it is unlikely that a child would absorb all ingested fluoride. • Many oral hygiene products are packed in unique non-standard packaging which is sponsor-specific and part of a particular product feature. To require sponsors to develop specific closures for their products which are already sold in general sale outlets without CRCs without evidence-based justification, would create a unique Australian requirement. The Committee also received a submission from XXXXXXXXXXXX, a private consultant working for the TGA, advising that many dental hygiene products were Excluded Goods under the Therapeutic Goods Act 1989 and therefore were not subject to regulation by the TGA when for human therapeutic use. To resolve this discrepancy, it was suggested that the lead-in words in the SUSDP fluoride entries be amended where appropriate to “Fluorides for human use, except…”. National Drugs and Poisons Schedule Committee 70 Record of Reasons 41 – June 2004
Further, one post-meeting submission suggested that if the amendments proposed were to revise the harmonised meaning and replace it with ‘pastes, powders or gels for the cleaning of teeth’ then NZ should amend their legislation to harmonise with the Australian fluoride entries given the differing definition for ‘dentrifice’ in the Medicines Act 1981. Members recalled that the NDPSC 40th Meeting agreed in principle to replace the 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 the fluoride entries from this consideration should address this matter.
The Committee noted that the acute toxicity level given for accidental ingestion of sodium fluoride in children was 5 mg/kg fluoride (Poisindex). For a 10-kg child, this equated to ingestion of ~227 mL of mouthwash containing 220 mg/L flouride. Members remained concerned at the risk of toxicity from ingestion of more concentrated fluoride products and agreed that CRC on these products should alert consumers to the potential toxicity as well as reinforce the message that such products were not appropriate for use in young children.
DECISION 2004/41 – 15 (Variation of Decision 2004/40-32)
The Committee agreed to the retention of the CRC requirement on exempt products containing up to 220 mg/L or 220 mg/kg fluoride, on the grounds of public health and safety. In addition, the Committee agreed to vary the NDPSC 40th Meeting (February 2004) decision by replacing any reference to ‘for human therapeutic use’ in the Schedule 2 and Schedule 4 entries with “for human use”.
Schedule 2 - Amendment
FLUORIDES - amend entry to read:
FLUORIDES for human use (except in preparations containing 15 mg/kg or 15 mg/L or less of fluoride ion):
(a) as sodium fluoride, in preparations for ingestion containing 2.2 mg or less of sodium fluoride per dosage unit; or
(b) in preparations for topical use containing 2.5 per cent or less of 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 220 mg/kg or 220 mg/L or less of fluoride ion, in packs National Drugs and Poisons Schedule Committee 71 Record of Reasons 41 – June 2004
containing not more than 120 mg total fluoride, fitted with a child-resistant closure and labelled with 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.
Schedule 3 – Amendment
FLUORIDES – amend entry to read:
FLUORIDES in pastes, powders and gels containing more than 1000 mg/kg of fluoride ion.
Schedule 4 – Amendment
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, containing 1000 mg/kg or less of fluoride ion;
(c) other dental hygiene products containing 220 mg/kg or 220 mg/L or less of fluoride ion, in packs containing not more than 120 mg total fluoride, fitted with a child-resistant closure and labelled with warnings to the following effect:
(i) Do not swallow; and
(ii) Do not use [this product/name of product] in children six years of age or less; or
(d) in other preparations containing 15 mg/kg or 15 mg/L or less of fluoride ion.
Schedule 5 – Amendment
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; National Drugs and Poisons Schedule Committee 72 Record of Reasons 41 – June 2004
(b) pastes, powders or gels for the cleaning of teeth, containing 1000 mg/kg or less of fluoride ion;
(c) other dental hygiene products containing 220 mg/kg or 220 mg/L or less of fluoride ion, in packs containing not more than 120 mg total fluoride, fitted with a child-resistant closure and labelled with warnings to the following effect:
(i) Do not swallow; and
(ii) Do not use [this product/name of product] in children six years of age or less; or
(d) in other preparations containing 15 mg/kg or 15 mg/L or less of fluoride ion.
Schedule 6 – Amendment
FLUORIDE – amend entry to read:
FLUORIDES except:
(a) when included in Schedule 2,3,4 or 5;
(b) pastes, powders or gels for the cleaning of teeth, containing 1000 mg/kg or less of fluoride ion;
(c) other dental hygiene products containing 220 mg/kg or 220 mg/L or less of fluoride ion, in packs containing not more than 120 mg total fluoride, fitted with a child-resistant closure and labelled with warnings to the following effect:
(i) Do not swallow; and
(ii) Do not use [this product/name of product] in children six years of age or less; or
(d) in other preparations containing 15 mg/kg or 15 mg/L or less of fluoride ion.
12.3 MITRAGYNA SPECIOSA
PURPOSE
The Committee considered post-meeting comments in relation to the February 2004 decision to include Mitragyna speciosa (M.speciosa) in Schedule 9 of the SUSDP based on abuse potential. National Drugs and Poisons Schedule Committee 73 Record of Reasons 41 – June 2004
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 is used as an opium or heroin substitute by Malayans (Burkill 1935). M.speciosa leaves are used extensively in Thailand (also in Malaysia) to increase work output and tolerance to direct sunlight, and are usually chewed, smoked or drunk as tea to achieve the desired affect. The leaves are chewed 3 to 10 times a day, with stimulant effects occurring after 5 to 10 minutes. M.speciosa was regulated as a narcotic drug in Thailand and carried the same restrictions and penalties as cocaine.
The NDPSC considered the inclusion of mitragynine and M.speciosa (the plant) in Schedule 9 of the SUSDP over several meetings (February 2003 to February 2004) based on abuse potential. Subsequently, the NDPSC 39th Meeting (October 2003) agreed to include the alkaloid, mitragynine, in Schedule 9 of the SUSDP and foreshadowed to consider at the February 2004 meeting the inclusion in S9 of the plant, M.speciosa. The 40th Meeting (February 2004) then agreed to include M.speciosa in S9 following consideration of several public submissions.
DISCUSSION
The Committee noted post-meeting comments from XXXXXXXXXXXX and XXXXXXXXXXXX. The Committee discussed the issues raised in post-meeting submissions in relation to matters mentioned in s.52E of the Therapeutic Goods Act 1989:
The potential hazards associated with the use of a substance
XXXXXXXXXXXX advised the Committee of the findings of the pre-clinical trial conducted in the 1960s by the then XXXXXXXXXXXX to investigate the possible therapeutic properties of mitragynine from M. speciosa. The company confirmed the report that the pre-clinical trial apparently revealed unacceptable acute effects (Raffauf 1986) and was discontinued.
People taking Kratom in the ‘traditional method’ (i.e. drinking like tea) could unwittingly become addicted based on the evidence showing that habitual chewing of Kratom leaves could lead to gradual addiction and that during early stages of addiction the user may take only 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 through consumption of the lower-dose tea type preparations and therefore the risk of opiate effects was correspondingly low. A member raised the issue that given the amount of information available on the Internet about use of this substance and the fact that plants National Drugs and Poisons Schedule Committee 74 Record of Reasons 41 – June 2004 were being sold for propagation in Australia, there was no guarantee that this type of consumption and pattern of use would remain unchanged.
The Committee was advised that a large number of websites were found on the Internet promoting the use of M. speciosa as an illicit drug with detailed instructions on how to prepare and use the plant to achieve the ‘desired’ effects. The most common methods of use suggested were smoking the leaves, drinking infused water like tea and smoking the residue (as concentrated resin) from boiling leaf extracts until dry. Members also noted several websites on the Internet dedicated to ‘exposing bogus Kratom Market’ suggesting a 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 S9 based on the claim that there was no evidence to demonstrate harm or abuse and that the plant was beneficial for use as an analgesic, mood-elevating agent or relaxant, and substitute 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 should not be restricted.
Members noted that the United Nations Bulletin on Narcotics (1975 Issue 3) stated in relation to a study conducted on 30 Kratom eaters in Thailand that “In the early stages of addiction the user may take only few leaves to obtain satisfactory results. The dosage is then 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 to an indefinite number of leaves. The addicts chew about 3-10 times a day, depending on their sensation of weariness to overcome”.
The psychological effects occurring after 5-10 minutes of consuming Kratom were described as feeling happy, strong and active. The UN Bulletin reported that long term Kratom addicts became thin, their skin darkened, particularly on the face (on both cheeks) which gave the appearance similar to that of a hepatic face. Five cases of Kratom addiction mentioned in the Bulletin revealed psychotic symptoms including convulsions, mental confusion, clouding of consciousness, episodes of delusions and persecutory ideation, hallucinations, dizziness and headaches. Typical withdrawal symptoms noted in Kratom 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 the same time possessing the chemical structure one might expect of a psychedelic.
The Committee noted that almost all the human data published in recognised scientific journals about the use of M. speciosa related to traditional use in Thailand. A member indicated that whilst mitragynine is structurally unrelated to other opiates, it appeared to National Drugs and Poisons Schedule Committee 75 Record of Reasons 41 – June 2004 act on mu- and delta-opioid receptor subtypes. Since mu-opioid receptors were thought to be involved in both the analgesic action, as well as the euphoric and addictive properties of opiates, there appeared to be a pharmacological basis for mitragynine to have similar effects. The action of mitragynine on opiate receptors may also explain the use of M. speciosa as a substitute for opium and heroin. It was noted that a number of post-meeting submissions mentioned the use of M. speciosa for treating opium and heroin withdrawal symptoms. A member stated that a possible reason for the attenuation of withdrawal from opiates by M. speciosa may be compared to the concept of using methadone to treat addicts in that, pharmacologically, one opiate was used to replace another.
The need for access to a substance, taking into account its toxicity compared with other substances available for a similar purpose
A Member noted that based on the available data there was little evidence to show that M.speciosa was widely used for therapeutic purposes other than as a substitute for other addictive opiates and one other traditional use as an antidiarrhoeal. Although the pharmacology of M. speciosa suggested that analgesic effects were likely given the findings of studies quoted in several papers [e.g. Journal of Psychoactive Drugs (Vol 20[4], Oct-Dec 1988], there was little data to suggest that Kratom was used traditionally as a pain reliever. On this basis, the Committee noted that despite post-meeting comments about the usefulness of M.speciosa for treating migraines, there was little evidence available to support a legitimate therapeutic need for the plant and members also noted that a number of other alternatives including complementary medicines were already available. A Member observed that information on Internet websites referred mainly to the use of Kratom for producing psychoactive effects and in contrast, there was paucity 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 injury resulting from its use
It was pointed out in post-meeting comment received that emergency scheduling is an option available to the Committee. However, members contended that in view of the evidence before the Committee on habituation to M.speciosa, as traditionally consumed in Thailand, and anecdotal evidence of abuse from numerous websites, a pro-active approach to curb the potential for abuse of M.speciosa was considered necessary to protect public health and safety.
A jurisdictional Member advised the Committee that M.speciosa had been included in a State’s Prohibited Substances List, on the request of the police force due to ‘undesirable’ activities. National Drugs and Poisons Schedule Committee 76 Record of Reasons 41 – June 2004
DECISION 2004/41 – 16 (Confirmation of Decision 2004/40 – 27)
The Committee confirmed the decision made at the NDPSC 40th Meeting (February 2004) to include of Mitragyna speciosa in Schedule 9 of the SUSDP based on its abuse potential.
Schedule 9 - New entry
MITRAGYNA SPECIOSA.
13. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS
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 were considered poisonous and there was great variability in the symptoms seen due to genetic variation of the plant. The ingestion of as few as 6-8 berries had been fatal in some geographic locations but in other areas the fruits may be eaten without harm. Ingestion of 0.3-0.4 g of the fruit by children was reported to cause toxic reactions and 2-4 g caused death (The Complementary and Alternative Healing University website, 2003). Parts of the plant that are used for medicinal purposes are the bark, fruits, root bark, leaves and flowers.
The NDPSC 35th Meeting (June 2002) agreed to foreshadow the inclusion of Melia azedarach or its extracts or its derivatives in Appendix C of the SUSDP, on public health and safety grounds. Whilst the Committee recognised the need to restrict the use of Melia azedarach, it agreed to seek additional data from stakeholders on issues such as the appropriate cut-off for exemption, long term safety of Melia azedarach and the nature of plant extracts in products. The matter had since been considered over several meetings but due to the lack of data from the public the NDPSC 38th Meeting (June 2003) agreed to again defer consideration to the June 2004 meeting to allow completion of a safety review on Melia azedarach being undertaken by the OCM.
Melia azedarach is the TGA-approved terminology. National Drugs and Poisons Schedule Committee 77 Record of Reasons 41 – June 2004
DISCUSSION
There were 19 entries containing Melia azedarach listed on the ARTG. Three of these contained M. azedarach as a dried powder of the fruit or seed, ranging from 8.5-129.2 mg. 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 extracts of the fruit (dry equivalents 105-340mg/tablets), and two entries contained ethanol; water extracts (~50:50) of the leaf (dry equivalents 135mg/mL and 1.96 g/tablet). Three entries did not specify the preparation method, part used or indications. None of the entries specified a recommended daily dosage. All products except one were intended for oral use and the majority of indications related to claims for assisting digestion or as a ‘liver tonic’; six were for cystitis or menstrual symptoms, one was for dry or inflamed skin, and one topical product claimed to be a head lice remedy. There were no reports of adverse reactions associated with products containing M. azedarach recorded in the ADRAC database or on the WHO database.
The Committee noted the OCM safety review report on Melia azedarach and discussed the 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 isolated from M. azedarach, was toxic after five doses of 8-10 mg/kg in dogs and rabbits. Rats fed a diet with 25 % leaf content for more than 14 days showed degeneration of the skeletal muscle and lead to death of most of the animals. However, rabbits fed Melia fruit up to 10 g/kg/day for 35 days showed no apparent toxicity. Relatively minimal toxicity was seen in male rats given ethanolic extracts of the leaves at 100 mg/kg/day for 21 days. Female rats given 500 mg/kg/day of leaf or root extracts for 10 days showed marked impairment of the reproductive function. At 250 mg/kg/day of ethanolic root bark extract but not leaf extract, female rats showed adverse effects on reproductive parameters. This result suggested that root barks are more toxic than leaves for female reproductive function.”
“An apparent lack of cytotoxicity of leaf extracts at concentrations that have been shown to produce antiviral and immunomodulatory effects in vitro suggests that there appears to be 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 accurate establishment 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 complicated by the fact that the sensitivity to M. azedarach toxins is species-dependent, apparently increasing 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 with the acute toxicity of substances included in Schedule 7 of the SUSDP. In addition, a National Drugs and Poisons Schedule Committee 78 Record of Reasons 41 – June 2004 study by Chang and But (1986) mentioned in the OCM safety review report on the bark and root bark of M. azedarach also found that at doses of 0.8 mg/kg in adults, severe reactions such as peripheral neuritis, arrhythmia, hypotension, and dypsnoea were observed. The report also noted that the enteric toxin responsible for the gastrointestinal tract symptoms was yet to be identified.
To allow continued access by healthcare practitioners, it should not be included in Appendix C of the Standard for the Uniform Scheduling of Drugs and Poisons.
The OCM minutes stated that “Members expressed concern for the potential prohibition of supply of this herb to practitioners if NDPSC decided to include M. azedarach into Appendix C of SUSDP. Although CMEC recommended that the herb was unsuitable for use in Listed medicines for safety reasons, the Committee considered that there was not enough evidence to warrant the inclusion of it into Appendix C of SUSDP. The Committee asked OCM to communicate to NDPSC that:
• CMEC recognised a significant history of use for M. azedarach by practitioners of traditional herbal medicine; and, • due to the history of use by these practitioners, access to the herb should not be limited by inclusion into Appendix C.” The Committee interpreted the CMEC recommendation to mean that M. azedarach was not suitable for inclusion in manufactured preparations for sale in healthfood shops and supermarkets but was suitable for use in medicines dispensed by healthcare practitioners. The Committee noted that there was no national system for accrediting healthcare practitioners, e.g. osteopaths, naturopaths and homeopaths, to ensure consistency in professional standards and competencies in dispensing extemporaneously prepared medicines. With this in mind, members supported the approach of specifying a limit on the amount of M. azedarach to be allowed in medicines extemporaneously prepared by healthcare practitioners which took into account the overall acute toxicity of the plant and safety of such preparations in long term use.
The Committee noted pre-meeting comment from the XXXXXXXXXXXX opposed any change 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. azedarach in Appendix C of the SUSDP but to foreshadow the inclusion of M. azedarach in Schedule 7, based on its overall toxicity profile and potential for adverse effects on reproductive parameters. Whilst it was recognised that there may be grounds for exempting medicines extemporaneously prepared by healthcare practitioners, the Committee was unable to extrapolate from the data available to determine a safe level on which to base a cut-off for exemption to accommodate CMEC’s recommendations. To assist the NDPSC in its consideration at the October 2004 meeting, the Committee agreed to ask CMEC and CHC to propose an appropriate cut-off for exemption for dilute National Drugs and Poisons Schedule Committee 79 Record of Reasons 41 – June 2004 medicines, including those extemporaneously prepared by healthcare practitioners, and provide a justification to support any proposal.
FORESHADOWED DECISION (for consideration at the NDPSC 42 Meeting of October 2004)
Schedule 7 – New entry
MELIA AZEDARACH.
13.2 PANCREATIC ENZYMES
PURPOSE
The Committee considered the scheduling of products containing porcine pancreatic enzyme extract.
BACKGROUND
The NDPSC 39th Meeting (October 2003) noted ADEC’s recommendation that the use of porcine pancreatic enzyme extract products be restricted to indications for conditions characterised by pancreatic exocrine enzyme insufficiency and foreshadowed the inclusion of all pancreatic enzyme preparations in Schedule 4 based on the following reasons:
• that contamination of Australian marketed pancreatic enzyme products with porcine parvovirus (PPV) and potential risk of human infection could not be ruled out; • the available data suggested that the benefits associated with treatment of pancreatic exocrine insufficiency with porcine pancreatic enzymes outweighed the potential risk of PPV contamination of these products; and. • the risk-benefit ratio for the use of porcine pancreatic enzymes for conditions unrelated to pancreatic insufficiency, as OTC products or complementary medicines was too high, and those products should be withdrawn. The NDPSC 40th Meeting (February 2004) noted the advice from Complementary Medicines Evaluation Committee (CMEC) to the TGA that products containing pancreatic enzyme extracts of porcine origin were suitable for use as an ingredient in listable or registrable complementary medicines, for indications other than pancreatic exocrine enzyme insufficiency subject to certain manufacturing conditions to recude the potential for PPV infectivity. Following the February 2004 meeting, the Secretariat wrote to OCM suggesting that advice should be sought from TGA Laboratories to determine whether the potential for PPV infectivity of porcine products could be addressed in the manufacturing process or via a suitable inactivation processes for products containing porcine pancreatic enzyme extracts. National Drugs and Poisons Schedule Committee 80 Record of Reasons 41 – June 2004
DISCUSSION
The Committee noted advice that OCM was proceeding to consult with the industry advising them of CMEC's recommendation and requesting the sponsor to provide the following information:
• the timeframe and the method proposed for reducing the potential of PPV infectivity in the finished product; or • an assurance that following the agreed timeframe, companies either ensure that the manufacturing 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 responses from the sponsors had been evaluated by the Viral and Prion Safety Section of the TGA 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) opposed the inclusion of all preparations containing pancreatic enzymes in Schedule 4 of the SUSDP as it would limit the availability and access to such products. In addition, some stakeholders and a sponsor (XXXXXXXXXXXX) had claimed that rescheduling the products to S4 would adversely impact on the communication and educational support network currently made available to cystic fibrosis clinics, patients and their families by the sponsor. • The XXXXXXXXXXXX representative advised the Committee that most XXXXXXXXXXXX supported the proposed rescheduling of all pancreatic enzyme preparations to S4. It was notified that patients preferred to purchase the Prescription Only products as not all pharmacies stock the OTC products and that retaining such products in S4 would ensure that patients would continue to access their medication under the Pharmaceutical Benefit Scheme (PBS). • Members noted that stakeholders (CF State organisations vs. those who provided public submissions) were divided in their views as to whether all pancreatic enzyme products should be rescheduled to S4. Members, however, considered that the majority of patients would access these products on the prescription by a medical practitioner and the proposed change would maintain the same level of access by patients. DECISION 2004/41 - 17
The Committee agreed that the scheduling of pancreatic enzymes other than porcine pancreatic enzymes (PPE) remained appropriate, on the basis that the risk of PPV infectivity 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 PPE preparations would be used only for the treatment of pancreatic exocrine insufficiency National Drugs and Poisons Schedule Committee 81 Record of Reasons 41 – June 2004 given that the benefits of such a use outweighed the potential risk of PPV contamination in these products.
Schedule 4 – New entry
PORCINE PANCREATIC ENZYMES.
13.3 PSEUDOEPHEDRINE
PURPOSE
The Committee continued its consideration of the scheduling of the remaining pseudoephedrine preparations in Schedule 2, i.e. undivided, combination and slow release.
BACKGROUND
The NDPSC 35th Meeting (June 2002) agreed to reschedule all OTC single-active immediate release pseudoephedrine preparations from Schedule 2 to Schedule 3 of the SUSDP on the rationale that pharmacist intervention would help reduce the problem of diversion to the illicit drug trade while maintaining access for legitimate users. The Committee however, deferred the consideration of the remaining S2 products, as the data available at the meeting was considered inadequate to allow an assessment of the appropriateness of rescheduling these formulations to S3. Consequently, the Committee foreshadowed a review of the scheduling of the remaining pseudoephedrine-containing products in S2 at the NDPSC 36th Meeting (October 2002) meeting and sought additional data from the jurisdictions and industry on formulation details, extractability of the pseudoephedrine from the formulation, and annual sales volume (no. of units) for each formulation 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 from other components in the formulation by simple dissolution or other physical means), was being targeted for diversion and that this formulation was not covered by the term ‘compounded’ used in some pseudoephedrine entries in the SUSDP. To address this discrepancy, the Committee agreed to replace the term ‘compounded’ used in the pseudoephedrine entries with ‘combination’ to cover products such as XXXXXXXXXXXX.
The NDPSC had since kept a watching brief of the remaining pseudoephedrine preparations in S2 over several meetings to allow for the final report of analytical investigations being undertaken on the extractability of pseudoephedrine from various pseudoephedrine formulations to become available. In addition, the Committee took the opportunity to ask sponsors to indicate their plans for existing and future product lines, particularly in relation to ‘bilayer’ preparations. XXXXXXXXXXXX, sponsor of XXXXXXXXXXXX, advised the NDPSC 38th Meeting (June 2003) meeting that there National Drugs and Poisons Schedule Committee 82 Record of Reasons 41 – June 2004 was a new compounded formulation of XXXXXXXXXXXX under development and that it was anticipated that a submission for this would be made to the TGA within the next 12 months. XXXXXXXXXXXX, another sponsor of a ‘bilayer’ product, also advised that it had no plans of modifying XXXXXXXXXXXX formulation based on economic grounds, and that it did not consider the product a 'bilayer' formulation. In addition, XXXXXXXXXXXX indicated that the sales data XXXXXXXXXXXX did not suggest that 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 period of five years by the Australian Competition and Consumer Commission (ACCC) starting from 13 November 2003. The Code was designed to help prevent diversion of pseudoephedrine-containing medicines. Furthermore, the Pharmaceutical Society of Australia (PSA) disseminated a Code of Practice for pseudoephedrine in late 2002. This Code provided a substance-specific guidance to pharmacists to ensure that pharmacists continue to provide the most appropriate medicines and therapeutic advice to patients without inadvertently contributing to the problem of diversion of pseudoephedrine- containing products.
The National Working Group on the Diversion of Chemical Precursors (NWG) at its November 2003 meeting noted the recent report by the House of Representatives Standing Committee on Family and Community Affairs (CFC), Road to Recovery, in particular Recommendations 82 and 83. The NDPSC February 2004 meeting noted that Recommendation 83 stated that: “the Commonwealth government amend its Standard for uniform scheduling of drugs and poisons to make all substances containing pseudoephedrine a Schedule 4 Prescription Only Medicine.” Members discussed this recommendation and noted that the Commonwealth Government’s response to this report was yet to be made available. The NDPSC noted that the NWG resolved that the TGA and Customs would address the next working group meeting in relation to the Report recommendations.
The NDPSC 40th Meeting (February 2004) noted a copy of the Draft Resolutions from the NWG November 2003 meeting. Members were advised that the researchers had examined the ease of extraction of pseudoephedrine from a range of products and had reported the preliminary results to NWG. It was understood that extraction from single and/or multiple component products via different approaches was effective and that the recovery/yield may be significant. No deliberations or conclusions on this issue were made at the NWG meeting, and the NWG expected a second presentation of the final research results on extraction and conversion of pseudoephedrine at the next meeting (March 2004).
Following the NDPSC February 2004 meeting, the Secretariat wrote to the NWG Secretariat expressing concern about the delay in making available the final report on the research into pseudoephedrine extraction and conversion and advised that the NDPSC had planned to consider the scheduling of pseudoephedrine at the NDPSC 41st Meeting (June 2004) meeting. Furthermore, the Commonwealth’s Drug Strategy Branch was National Drugs and Poisons Schedule Committee 83 Record of Reasons 41 – June 2004 asked by the Secretariat to provide the NDPSC with the Commonwealth Government’s response to Recommendation 83 when available.
DISCUSSION
The Committee noted the draft Executive Summary of the report on the research of pseudoephedrine products which was funded by the National Drug Law Enforcement Research Fund (NDLERF) at the request of the NWG. It was advised that the final report was yet to be approved by the NDLERF Board of Management but it agreed that the NDPSC be provided with the Executive Summary to assist in its considerations. The Committee noted the following points:
• The aim of the research project was to determine whether pseudoephedrine could be extracted from the range of products available and establish the ability to convert these products into methylamphetamine via commonly used illicit drug manufacturing processes. Eight pharmaceutical products were selected, representing the different pseudoephedrine product formulations available within Australia. • The overall extraction results demonstrated that pseudoephedrine could be extracted from all products, with an efficiency ranging from 24%-90%. No significant relationship was established between the product formulation, the extraction process and the efficiency of extraction. • The greatest variation observed in the process was the need to differ the amounts of solvent used in the various extraction procedures. The quantity of solvent was impacted by the starting quantity of the pharmaceutical product, which was influenced by the total tablet or capsule mass and the quantity of pseudoephedrine contained in each formulation. • Despite these issues the research showed no significant chemistry skills or sophisticated equipment was required to facilitate extraction of pseudoephedrine from any of the nominated product formulations. • Overall, the results of the study demonstrated that pseudoephedrine could be extracted from a variety of pharmaceutical products currently available on the Australian market. The type of formulation, i.e. whether single or multiple entity, did not prohibit the extraction of pseudoephedrine although some product formulations may be better suited to a particular extraction process. • To reduce the risk of the diversion of pseudoephedrine containing products into the illicit drug production market, it was important to consider the full variety of available products and ensure that whatever restrictions may be applied would be done so evenly across all pharmaceutical product lines. The Committee discussed the following issues:
• Most pre-meeting submissions received from various professional pharmacy groups and pharmaceutical companies, including the sponsors of pseudoephedrine products, National Drugs and Poisons Schedule Committee 84 Record of Reasons 41 – June 2004
supported the retention of existing products in S2 (except XXXXXXXXXXXX which supported the inclusion of all pseudoephedrine products in S3). The Committee was advised that the initiatives implemented in pharmacies to address the problem of diversion included stock minimisation, recording of consumer personal details, storage of all pseudoephedrine products behind the counter, community pharmacy vigilance and collaboration with State/Territory Police and Health Departments. • The Committee noted that no new issues were highlighted in the pre-meeting submissions received although some stakeholders indicated that should products be rescheduled to S3, the preferred approach was for all formulations to be rescheduled concurrently, irrespective of the type of formulation. Some stakeholders again raised the issue that scheduling was not the appropriate mechanism for addressing the diversion problem and that such a problem could be managed more appropriately through implementation of a coordinated national approach, which should maintain access by legitimate consumers since there was no other effective alternative to pseudoephedrine. • Members advised that thefts of multiple packs of S2 pseudoephedrine products stored at the front of the shop continued to be a problem in the jurisdictions, and that whilst some jurisdictions had moved all pseudoephedrine behind the counter to address this problem, this approach failed to deter serial pseudoephedrine shoppers. A member also reported that the strategy of recording the purchaser’s personal details for S3 products had proven to be ineffective as serial shoppers were capable of producing several fake identification papers within a very short timeframe. The Committee noted that the formulation type no longer appeared to be a significant factor in the choice of pseudoephedrine product selected for diversion, based on the products found 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 of the effectiveness and impact of the strategies implemented by industry and pharmacy groups on the overall pseudoephedrine diversion problem. Members recalled that the Australian Competition and Consumer Commission (ACCC) granted an interim authorisation for the implementation of the ASMI Code of Conduct on 13 February 2003, and an undertaking was made that the ASMI would provide regular updates to the Committee regarding the implementation of the Code and its impact on the problem of diversion of pseudoephedrine products. The Committee was advised that a proposal in New Zealand to re-classify pseudoephedrine and ephedrine under the Misuse of Drugs Act 1975 (MODA) and include pseudoephedrine in Regulation 28(4)(b) of the Misuse of Drugs Regulations 1977 was being progressed. This move was in response to the dramatic increase in the importation of pseudoephedrine and ephedrine as a result of the tightening of controls in NZ on domestic supply of pseudoephedrine. Pseudoephedrine and ephedrine were currently controlled under the Medicines Act 1981 and that the reclassification of these substances in NZ would provide stronger Customs powers. However, members noted National Drugs and Poisons Schedule Committee 85 Record of Reasons 41 – June 2004 that such a move would also have a major impact on harmonisation in that it would then require Pharmacy-only pseudoephedrine products in NZ to be labelled with “Controlled Drug C3”, and all prescription doses of pseudoephedrine and ephedrine to be labelled with “Controlled Drug C5”.
OUTCOME
The Committee agreed to foreshadow the inclusion of the remaining S2 pseudoephedrine preparations in S3, i.e. undivided, combination and slow release preparations, based on the findings of the research on pseudoephedrine products and reports from the jurisdictions that such products were being diverted to the illicit drug market.
FORESHADOWED DECISION (for consideration at the NDPSC 42nd Meeting of October 2004)
Schedule 2 – Amendment
PSEUDOEPHEDRINE – delete entry.
Schedule 3 – Amendment
PSEUDOEPHEDRINE in preparations (other than preparations for stimulant, appetite suppression or weight-control purposes), with a recommended daily dose of 240 mg or less of pseudoephedrine:
(a) in undivided preparations containing 60 mg or less of pseudoephedrine per recommended dose;
(b) when the only therapeutically active substances in divided preparations containing 60 mg or less of pseudoephedrine per recommended dose in a pack containing 30 or less dosage units;
(c) when combined with other therapeutically active substances; or
(d) in slow release preparations.
Schedule 4 – Amendment
PSEUDOEPHEDRINE except when included in Schedule 3. National Drugs and Poisons Schedule Committee 86 Record of Reasons 41 – June 2004
13.4 MEDICAL DEVICES
PURPOSE
The Committee considered the inclusion of an entry for medical devices in Appendix A of the SUSDP.
BACKGROUND
The NDPSC 31st Meeting (May 2001) agreed that a strategy for medical devices containing scheduled poisons needed to be developed to achieve meaningful public health outcomes in terms of labelling and controls over access and availability. The Committee recognised the need for a clear and positive statement in the SUSDP to resolve the general confusion in terms of when a device containing a medicine required scheduling. This matter was considered over several meetings of the NDPSC and was subsequently deferred to a future meeting to allow sufficient time to examine the new device classification listings.
The Therapeutic Goods Amendment (Medical Devices) Act 2002 came into effect in October 2002 and representatives from the Medical Devices Assessment (MDA) area provided the NDPSC 37th (February 2003) NDPSC meeting with a brief overview of the new legislation. The new regulatory regime for medical devices adopts a classification system 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 scheduling on the basis that they could likely contain scheduled substance(s) and likely to be used outside hospital and medical settings.
The NDPSC 40th Meeting (February 2004) agreed that as the first step, an Appendix A entry should be developed to clearly identify those devices not requiring controls via scheduling 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 attended by the XXXXXXXXXXXX and XXXXXXXXXXXX member, XXXXXXXXXXXX and XXXXXXXXXXXX and XXXXXXXXXXXX, discussed the draft Appendix A entry developed by the XXXXXXXXXXXX and XXXXXXXXXXXX member. The meeting endorsed an Appendix A entry which exempted Class III medical devices containing scheduled substances considered to be of low abuse or misuse potential on the basis of their exclusive use within the hospital or medical setting. In addition, it was also agreed that the Appendix A entry should specify the group of medical devices which may not be appropriate for exemption, e.g. disinfectants, injectable collagen or tissue reconstructive materials, rather than just provide a ‘blanket’ exemption. It was noted that further amendments to the Appendix A entry could be made on a case-by-case basis via the usual NDPSC procedures, where appropriate. The meeting also agreed that the National Drugs and Poisons Schedule Committee 87 Record of Reasons 41 – June 2004
NDPSC be provided with future MDEC minutes to allow identification of medical devices, 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 regard to the consistency of NDPSC and ODBT’s understanding of the scope of devices within Class 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 undertaken after 12-18 months.
The XXXXXXXXXXXX member had received further advice regarding intrauterine devices and considered that the Appendix A entry could also cover these products given that such devices are generally supplied through medical practitioners due to potential adverse effects.
The Committee recalled that the XXXXXXXXXXXX representative agreed at the NDPSC February 2004 meeting to seek feedback from sponsors on the proposed Appendix 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 at the NDPSC 42nd Meeting (October 2004).
FORESHADOWED DECISION (for consideration at the NDPSC 42nd Meeting of October 2004)
Appendix A – New entries
MEDICAL DEVICES classified as Class III by the classification rules set out in Schedule 2 to the Therapeutic Goods (Medical Devices) Regulation 2002, as specified or amended from time to time, except:
(a) injectable collagen;
(b) tissue reconstructive materials;
(c) anticoagulants;
(d) artificial tears; or
(e) urinary catheters. National Drugs and Poisons Schedule Committee 88 Record of Reasons 41 – June 2004
13.5 KAVA AND KAVALACTONES
PURPOSE
The Committee considered the scheduling of kava (Piper methysticum) and its active constituents kavalactones.
BACKGROUND
Piper methysticum (kava), a member of the pepper family (Piperaceae), has a wide distribution throughout the Pacific. Kava has been used in traditional medicine to treat venereal disease, gout, rheumatism, diarrhoea, asthma, and to calm nervous children and induce women’s breast milk flow. Pharmacologically, kava is described as having an anxiolytic effect, is a muscle relaxant and has anticonvulsant and spasmolytic activity. It is a sedative and can depress the limbic system. Its effects appear to be mainly due to the activity of the compounds in the lipid soluble resin – the kavalactones. The pharmacological properties of kava are comparable to those of benzodiazepines, although kavalactones bind very weakly to GABA-A and benzodiazepine receptors. More recently, kavalactones had been extracted for therapeutic products using volatile organic solvents.
The NDPSC 39th Meeting (October 2003) noted a safety evaluation report prepared by the Kava Evaluation Group (KEG)/Office of Complementary Medicines (OCM) on kava containing medicines, which made recommendations on the regulation of kava as an ingredient in Listed Medicines. Due to the potential risk of liver toxicity from use of non-aqueous extracts of kava plants at high doses, the Committee considered the need to restrict the use of alcohol/acetone extracts of kava including those for bulk supply to health care practitioners for use in extemporaneously compounded preparations. In addition, it was agreed that a schedule entry to minimise the risk without affecting the current usage of listed complementary products should be considered by the Committee following the review of products on the ARTG.
The NDPSC 40th Meeting (February 2004) was advised that CMEC’s Recommendation 41.3 had been included in Schedule 4 of the Therapeutic Goods Regulations 1990 (TG Regulations) to only allow specified concentrations of aqueous kava extracts in Listed medicines and that all other kava products had been cancelled from the ARTG. The Committee noted that the available information suggested that whole or peeled kava rhizomes and their aqueous preparations containing 250mg or less of kavalactones were acceptable for use in exempt medicines while medical advice was necessary for safe use of other kava preparations due to toxicity. On this basis, the Committee agreed to foreshadow the inclusion of kava (Piper methysticum) in Schedule 4 of the SUSDP with exemptions consistent with those specified in the TG Regulations. In addition, the Committee also asked the Drafting Advisory Panel (DAP) to draft an entry for consideration at the NDPSC 41st Meeting (June 2004). National Drugs and Poisons Schedule Committee 89 Record of Reasons 41 – June 2004
DISCUSSION
The Committee noted the Food Standards Australia New Zealand’s (FSANZ) Final Assessment Report of the Review of Kava. It was advised that Standard 2.6.3 of the Food Product Standards was to be retained to operate in conjunction with the National Code of Kava Management, including its prohibition in relation to mixing of kava with other foods (other than in those foods regulated under the New Zealand Dietary Supplement Regulations 1985). In addition, members noted that Standard 2.6.3 was amended to allow kava for use as traditional beverage but the use in food of extracts prepared by organic solvent extraction would be prohibited and the labelling requirements were to be retained to ensure the safe use of kava by consumers. FSANZ also advised that the foreshadowed decision to include non-aqueous extracts of kava in Schedule 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 of the TG Regulations, as recommended by CMEC, was intended to allow only aqueous extracts of kava in Listed goods. In addition, OCM indicated that all extracts of kava were approved by CMEC for use in homoeopathic medicines and preparations for topical application to the skin under the stipulated conditions in the TG Regulations.
Members noted that the pre-meeting submissions received from XXXXXXXXXXXX XXXXXXXXXXXX supported the CMEC recommendations. In addition, XXXXXXXXXXXX suggested that for clarity the Schedule entry in the SUSDP for kava should specify that the maximum recommended daily dose was 250 mg kavalactones for exempt preparations containing 250 mg or less of kavalactones.
The Committee considered the draft Schedule 4 entry for kava and kavalactones developed by the NDPSC’s DAP which took into account the provisions of the TG Regulations for consistency. The DAP informed the Committee that the proposed SUSDP S4 entry for kava did not specify a daily dose cut-off for dermal preparations based on the advice received from OCM that the cut-off of 250 mg kavalactones per day for dermal preparations specified in the TG Regulations was included in error. In addition, the DAP also advised that a cut-off for homeopathic preparations as stated in the TG Regulations (>1000-fold dilution of a mother tincture) was not reflected in the entry as it was below the general exemption specified under Part 1 of the SUSDP, i.e. 10 mg/kg or 10 mg /L.
The Committee agreed to adopt the S4 entry for kava proposed by the DAP with minor amendment to the warning statement required for exempt products. Members did not agree to reflect on the label of exempt products the statement ‘If symptoms persist, seek advice from a health care practitioner’. The Committee noted that this was inconsistent with the existing warning statements contained in the SUSDP which directed consumers to consult a medical doctor when symptoms persisted. National Drugs and Poisons Schedule Committee 90 Record of Reasons 41 – June 2004
DECISION 2004/41 - 18
On the grounds of public health and safety, the Committee agreed to include Piper methysticum (Kava) in Schedule 4 of the SUSDP, as well as adopt the exemptions specified 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 peeled rhizome or containing aqueous dispersions or aqueous extracts of whole or peeled rhizome when labelled with a recommended daily dose of 250 mg or less of kavalactones:
(i) containing more than 25 mg of kavalactones per dose, labelled with the statement:
WARNING: Not for prolonged use. Not recommended for use by pregnant or lactating women. May harm the liver;
(ii) in tablet or capsule form containing 125 mg or less of kavalactones per tablet or capsule; or
(iii) in the form of a teabag when the amount of dried whole or peeled rhizome does not exceed 3g;
(b) in topical preparations for use on the rectum, vagina or throat containing dried whole or peeled rhizome or containing aqueous dispersions or aqueous extracts of whole 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 of schizophrenia. It is believed that the mechanism of its action is mediated through a National Drugs and Poisons Schedule Committee 91 Record of Reasons 41 – June 2004 combination of partial agonist activity at dopamine D2 receptors and serotonin 5-HT1A receptors and antagonist activity at 5-HT2A receptors.
The NDPSC 39th Meeting (October 2003) agreed to include aripiprazole in Schedule 4 of the SUSDP. However, the NDPSC 40th Meeting (February 2004) was advised of information drawn from open literature that aripiprazole has a high potential for causing sedation (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 investigate this 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 for aripiprazole 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 advice was 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 for ibuprofen.
BACKGROUND
The NDPSC 38th Meeting (June 2003) agreed to exempt from scheduling divided preparations containing 200 mg or less of ibuprofen per dosage unit in packs containing 25 or less dosage units, when labelled with prescribed warning statements with a recommended maximum daily dose of 1200 mg of ibuprofen. The decision was based on the safety profile of low dose ibuprofen, its comparison with similar unscheduled analgesic products, the proposed indications are suitable for self-identification and self- treatment without professional advice, its low potential for abuse and OTC marketing experience in Australia. National Drugs and Poisons Schedule Committee 92 Record of Reasons 41 – June 2004
Following consideration of post-meeting comments in relation to the NDPSC June 2003 decision to exempt small packs of low dose ibuprofen, the NDPSC 39th Meeting (October 2003) agreed to vary its decision and amended the warning statements required on exempt ibuprofen his, the Committee simplified certain warning statements and amended those relating to GI complications, pregnancy, asthma and use in certain age groups, to enhance specificity and clarity.
DISCUSSION
The Committee noted an email received from XXXXXXXXXXXX, suggesting that the word “or” be inserted following the warning statement (WS) ‘WARNING - This medication 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 should maintain consistency with the reverse scheduling provisions for paracetamol and aspirin.
The Committee was advised that OTC Medicines Section wrote to the Secretariat advising that the warning statements in relation to long term or excessive use of ibuprofen without medical supervision required under (b)(iv) of the Schedule 2 entry was also duplicated under (b)(v). In addition, OTC pointed out an error in that aspirin, instead of ibuprofen, was used in the WS ‘Unless a doctor has told you to, don’t use [this product/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 the rigour of the process that was used by the NDPSC in determining that small packs of ibuprofen should be exempt from scheduling. The XXXXXXXXXXXX brought to the attention of XXXXXXXXXXXX what it considered to be ‘new materials’ with respect to ibuprofen and asked that they be reviewed as new evidence. The XXXXXXXXXXXX also urged that the labelling of unscheduled ibuprofen be reconsidered on the grounds that the variation and inconsistency in approach to the warning statements compounded the complexity consumers face in safely self-selecting these medicine. On this basis, the XXXXXXXXXXXX asked that the regulation of ibuprofen be reviewed in the light of this new evidence and concerns regarding the medicine labels.
In response to XXXXXXXXXXXX’s request, parallel and independent evaluations of the following materials cited by XXXXXXXXXXXX were undertaken by the clinical pharmacologist expert member on the NDPSC, XXXXXXXXXXXX and XXXXXXXXXXXX: i) Jenkins C, Costello J, Hodge L. Systematic review of prevalence of aspirin induced asthma 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 users of aspirin and nonaspirin anti-inflammatory drugs. Am J Epidemiol 2004;159:23-31; National Drugs and Poisons Schedule Committee 93 Record of Reasons 41 – June 2004 iii) Suitability and choice of simple analgesics – balancing benefits and risks. Presented by Dr. Alison Jones at the 25th Annual Scientific Meeting of the Australian Pain Society Meeting, Canberra 10th March 2004. iv) ADRAC Bulletin Volume 22, Number 4 The Committee noted the comments below made by the evaluators after reviewing the papers referred to by the PGA: i) Jenkins paper The paper assessed the prevalence of aspirin–induced asthma through a systematic review of published studies and selected randomised controlled trials. Concerning cross-sensitivity, the authors selected for review double blind or single blind randomised 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 systematic review”. One of the evaluators noted that this statement was not precise and lent itself to misquoting. Correctly stated, it should be that ‘The prevalence of aspirin-induced asthma in patients with asthma is 21% for adults and 5% for children according to the systematic review’. The paper defined a positive aspirin-induced asthma response as a 20 % or more reduction in FEV1 within 3-4 hours of an oral aspirin challenge. Using this criterion, 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. In contrast, the prevalence of aspirin-induced asthma determined using history alone was 2.7%. Around half (57/113) of those who had positive reactions to oral challenge did so at low doses of aspirin (>80 mg), indicating that they were highly sensitive. These figures were within the authors’ own quoted range of published data for aspirin-induced asthma (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%) on history alone.
An evaluator noted that the figure for children related to a population that may include adolescents up to 16 or more years of age and that this may have biased the incidence figure 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 inclusion and based on these, the incidence of cross-sensitivity was ~90-100%. Cross-sensitivity to paracetamol was 7% (0-16%) in ten level 1 studies. The paper suggested that patients who were highly sensitive to aspirin were more likely sensitive to paracetamol, e.g. with sensitivity 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 and non-asthmatic patients given aspirin, non-aspirin NSAIDs and paracetamol was needed to resolve the issue of cross-sensitivity. National Drugs and Poisons Schedule Committee 94 Record of Reasons 41 – June 2004
In conclusion, the authors indicated that a significant proportion of asthmatic patients being sensitive to aspirin justified the need to include simple standardised warnings on packs of aspirin and NSAIDs alerting patients to the potential risks. The evaluators noted that such package warnings had already been included in the proposed unscheduled packaging for ibuprofen. ii) Rodriguez paper The authors studied the association between prescription NSAIDs and the risk of symptomatic ulcer in a population-based cohort studies in the UK between 1995 and 1999. Rodriguez and Hernandez-Diaz used data from the UK General Practice Research Database (GPRD) to estimate the incidence of uncomplicated but symptomatic peptic ulcer and used a case control method to estimate risk and its association to use of aspirin and non-aspirin NSAIDs. The study population was 40-79 years of age which included an upper age limit well above the ibuprofen general sale warning statement relating to patients of 65 years and older. Also, usage of NSAIDs was measured by prescriptions and defined a current user as one who had obtained a most recent prescription within 30 days before the date of detection of the symptomatic ulcer by a specialist or when in hospital, usually by endoscopy.
Of relevance to the scheduling of ibuprofen, there were no data specifically available on short duration (few days) use.
The authors made an estimate of background incidence for the population studied of 1.03 cases per 1000 person years. The incidence of symptomatic peptic ulcer essentially doubled between the 50-59 and 60-69 year age group exposed to NSAIDs. Current use of an NSAID increased the risk of symptomatic peptic ulcer by 4 times. For low to medium dose of NSAIDs (including ibuprofen of 1200 mg a day or less dose) the risk was 2.6. These estimates were adjusted for age, sex, year of diagnosis and some other factors. Current intake of paracetamol had a relative risk of 1.9 and there was no dose response detected with paracetamol.
Ibuprofen has a relative risk compared with non use of 2.7, which is the lowest of naproxen, ketoprofen, flurbiprofen, diclofenac, indomethacin and piroxicam. This study gave useful estimates of the incidence in the general population and estimates of risk increases of uncomplicated symptomatic peptic ulcer associated with aspirin and NSAIDs including low to medium dose ibuprofen and paracetamol. However, the spread of ages and 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 dose ibuprofen. In contrast, a higher risk of symptomatic peptic ulcer with paracetamol than had previously been reported was suggested. iii) Presentation by Dr. Alison Jones Dr. Jones made a presentation at the Annual Scientific Meeting of the Australia Pain Society in Canberra on 10 March 2004, which was sponsored by XXXXXXXXXXXX. Dr. Jones is Director, National Poisons Information Service, London. XXXXXXXXXXXX requested and was provided with the National Drugs and Poisons Schedule Committee 95 Record of Reasons 41 – June 2004
Powerpoint slides of the presentation by Dr. Jones. The comments below from the evaluators relate to each topic as discussed by Dr. Jones. National Drugs and Poisons Schedule Committee 96 Record of Reasons 41 – June 2004
Suitability and tolerability of OTC analgesics Contraindications, Precautions and Interactions of NSAIDs and paracetamol were summarised from the Australian product information for XXXXXXXXXXXX, XXXXXXXXXXXX and a recent National Prescribing Service (NPS) newsletter.
Quantifying the size of the ‘at risk’ populations Dr. Jones cited data available from an abstract of a presentation to the European League Against Rheumatism (EULAR) 2002 Congress. In this study, the exclusion criteria for the 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% ‘should have consulted a doctor before using the drug’. For paracetamol, the figures were 0.015% and 1.68%.
Australian data were also cited from an unpublished report submitted to XXXXXXXXXXXX by XXXXXXXXXXXX on “Determining Screening Failure Rate for an OTC analgesic study using a general practice research network”. This was in relation to a random sample of GP users of the “Medical Director” software who were invited to participate in the GPRN (General Practice Research Network) via email. The same exclusion criteria were applied and the result was very similar to the UK figure.
Consequences of inappropriate analgesic use Dr. Jones cited the Jenkins systematic review with regard to aspirin-induced asthma. In particular, she stated the prevalence of aspirin induced asthma was 21%; in children prevalence was much higher than expected at 5%; the cross reactivity with ibuprofen was 98%; cross reactivity to paracetamol was uncommon – 7% of aspirin sensitive asthmatics or less than 2% of all asthmatics. Dr. Jones then proceeded to draw public health implications including that at least 1 in 5 asthmatics are sensitive to widely available aspirin 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 recent reviews.
NSAIDs use in pregnancy Dr. Jones cited the study by Li DK et al, BMJ 2003, 327;368. This study was reviewed and reported on by Professor Frauman at the October 2003 NDPSC meeting. This was a prospective cohort study in patients of the Kaiser Permanente Medical Care Program in Northern California. The study was initially conducted on pre-natal exposure to magnetic fields and was published in Epidemiology 2002. The work on associations with NSAIDs seemed to be a post-hoc analysis. The paper reported increased risks of miscarriage associated with NSAID use that was started in the first week of gestational age (described also as ‘at conception’), and separately with use for more than one week. Hazard ratios were 5.6 and 8.1 respectively – both with very wide confidence intervals reflecting small numbers of cases and controls. Importantly, the increased risks if the NSAIDs were taken after the first gestational week (1.2) or for less than one week (1.3) were small and National Drugs and Poisons Schedule Committee 97 Record of Reasons 41 – June 2004 not statistically significant. For paracetamol the risk was not significant. The results were consistent with NSAIDs interfering with the conception process but it was unclear why exposure of more than 1 week was necessary.
Dr. Jones supported the use of paracetamol in pregnancy.
Gastrointestinal effects Dr. Jones cited a systematic review of the literature which showed that OTC doses of NSAIDs 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 risks and increased rates of GI events among takers of NSAIDs. Importantly, the authors of the 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 the cut-off for low dose ibuprofen in some studies was 1500 mg (and not 1200 mg). Tarone also referenced a study by Wang (2002) stated as having reported a relatively risk of low dose ibuprofen of 1.2.
Drug interactions Dr. Jones’ Powerpoint states that NSAIDs have multiple drug interactions. They were accurately 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 the antiplatelet effects of aspirin. Also cited by Dr. Jones was the paper by MacDonald and Wei, Lancet 2004, claiming to show the clinical impact of the effect of ibuprofen on the cardioprotective effect of aspirin.
Both these papers were reviewed by XXXXXXXXXXXX for the October 2003 NDPSC meeting. The clinical paper was based on the prescription use of ibuprofen and did not report about short term use of OTC ibuprofen. Furthermore, at least one epidemiological paper published more recently (Kurth T et al. Circulation 2003; 108:1191-1195) did not support a clinically measurable effect of this interaction at least for low dose short duration ibuprofen (in contrast, an increase in risk of first myocardial infarction in male patients was reported where the NSAID was taken for more than 60 days in a year).
Triple Whammy Dr Jones cited 2 papers about this well-established interaction between ACE inhibitor drugs, 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 find anything controversial or new in Dr. Jones’ presentation of the two papers. iv) ADRAC Bulletin Volume 22, Number 4, August 2003 XXXXXXXXXXXX cited this publication in its list of new evidence. It was noted by XXXXXXXXXXXX that this publication was not available at the time of the initial consideration of the scheduling change of ibuprofen. The evaluators noted that the Bulletin had been distributed before the October 2003 meeting and that, further, the Record of Reasons (RoR) for that meeting disclosed publicly that NDPSC was provided with ADRAC data at that October 2003 National Drugs and Poisons Schedule Committee 98 Record of Reasons 41 – June 2004 meeting. On this basis, it was unclear why XXXXXXXXXXXX had cited this as new evidence.
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 of unscheduled 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 used in large amounts or for a long time (period)’ under part (b)(iv). The Committee also agreed 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 or anti-inflammatory medicines…’ under (b)(v).
The Committee agreed with the evaluators that the materials cited by XXXXXXXXXXX as ‘new evidence’ did not raise new issues or concerns which had not been previously considered by the NDPSC.
EDITORIAL AMENDMENT
Schedule 2 - Amendment
IBUPROFEN - amend entry to read:
IBUPROFEN in preparations for oral use when labelled with a recommended daily dose of 1200 mg or less of ibuprofen:
(a) in liquid preparations when sold in the manufacturer’s original pack containing 4 grams or less of ibuprofen; or
(b) in divided preparations, each containing 200 mg or less of ibuprofen, in packs of 100 or less dosage units except when:
(i) as the only therapeutically active constituent other than an effervescent agent;
(ii) packed in blister or strip packaging or in a container with a child-resistant closure;
(iii) in a primary pack of 25 or less dosage units; National Drugs and Poisons Schedule Committee 99 Record of Reasons 41 – June 2004
(iv) the primary pack is labelled with a warning statement to the following effect:
WARNING - This medication may be dangerous when used in large amounts or for a long time (period); or
CAUTION - This preparation is for the relief of minor and temporary ailments and should be used strictly as directed. Prolonged use without medical supervision could be harmful; or
CAUTION - This preparation is for the relief of minor and temporary ailments and should be used strictly as directed. Prolonged or excessive use without medical supervision could be harmful; and
(v) the primary pack is labelled with warning statements to the following effect:
Don’t use [this product / name of the product]:If you have a stomach ulcer In the last 3 months of pregnancy [This statement may be omitted in preparations used exclusively for the treatment of dysmenorrhoea] If you are allergic to ibuprofen or other anti-inflammatory medicines; and
Unless a doctor has told you to, don’t use [this product / name of the product]: For more than a few days at a time With other medicines containing ibuprofen or other anti- inflammatory medicines or other medicines that you are taking regularly If you have asthma In children 6 years of age or less If you are aged 65 years or over If you are pregnant [This statement may be omitted in n preparations used exclusively for the treatment of dysmenorrhoea]. National Drugs and Poisons Schedule Committee 100 Record of Reasons 41 – June 2004
14. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FOR THE 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 from Schedule 3 to Schedule 2 diclofenac in divided preparations for oral use containing 12.5 mg or less per dosage unit in a pack containing 30 or less dosage.
BACKGROUND
Diclofenac is a NSAID with potent anti-inflammatory, analgesic, and antipyretic properties. It is a reversible, competitive inhibitor of cyclooxygenase. In 1986 a formulation containing immediate release diclofenac potassium 25 and 50mg tablets was launched as XXXXXXXXXXXX and XXXXXXXXXXXX designed for short-term treatment of acute painful and inflammatory conditions. XXXXXXXXXXXX products are 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 relief and/or short-term (up to one week treatment) while diclofenac sodium is claimed to be more appropriate for chronic pain states including rheumatoid arthritis and osteoarthritis.
Diclofenac was included in S4 in March 1981. The Committee then agreed to reschedule diclofenac 25 mg or less in packs of 30 or less for oral use to S3 in August 1999, as recommended 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 was rescheduled to S2. Subsequently, all dermal preparations were subsequently made exempt 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 or 30 tablets per pack) and tablets containing 25mg diclofenac sodium (20 or 50 tablets per pack) were registered on the ARTG and included in S3 of the SUSDP. Only one S3 product formulated as a suppository was currently listed on the ARTG containing 12.5 mg diclofenac sodium.
DISCUSSION
The Committee noted that an application to register “XXXXXXXXXXXX” (diclofenac potassium 12.5mg) tablets in packs of 10 and 20 tablets was also lodged with the OTC Medicines Section of the TGA in December 2003 [XXXXXXXXXXXX] for:
• temporary relief of headache, dental pain, period pain, rheumatic and muscular pain, back ache; National Drugs and Poisons Schedule Committee 101 Record of Reasons 41 – June 2004
• temporary relief of symptoms of cold and flu including aches and pains, sore throat pain; and • reduction of fever. The recommended duration of treatment was not to exceed 5 days for pain relief and 3 days for treatment of fever, while the recommended daily dose was not to exceed 6 tablets per day. The outcomes of the evaluation of this application were not available to NDPSC at this meeting.
Members noted that pre-meeting submissions were received from XXXXXXXXXXXX, XXXXXXXXXXXX, XXXXXXXXXXXX, XXXXXXXXXXXX, and XXXXXXXXXXXX.
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 of adverse events (AEs) was <20% and the vast majority of AEs were not serious. The evaluator 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, the overall AE frequency was reported as 11.8%, with 7.6% as GI AEs. The evaluator supported the overall safety of diclofenac and concurred with the sponsor’s claim that an acceptable safety profile could be reasonably extrapolated to the low-dose regimen proposed 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 2 entry, 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 pharmacist advice to reduce the potential for adverse effects. Whilst it was recognised that NSAIDs as a therapeutic class were well-understood, the rates of adverse effects, drug interactions, side effects and contraindications associated with these drugs could not be considered insignificant from a public health perspective.
The Committee noted that some stakeholders questioned the efficacy of 12.5 mg diclofenac tablets at 75 mg per daily dose for treating all pain states covered in the proposed indications. In addition, it was also noted that the practicality and volume of 12.5 mg diclofenac tablets required for treating painful conditions, e.g. 16 x 12.5 mg National Drugs and Poisons Schedule Committee 102 Record of Reasons 41 – June 2004 tablets for the treatment of one or more migraines in a 24-hr period and up to 36 tablets for 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 almost 30 years, including Schedule 3 usage in Australia.
The Committee was advised that the 12.5 mg diclofenac oral formulation had not ever been marketed in Australia, even as a prescription medicine, hence there was no local clinical experience with this formulation. A pre-meeting respondent also advised that 12.5 mg diclofenac oral formulation was not on the market in New Zealand. Only Germany and Switzerland appeared to have post-marketing OTC experience with diclofenac 12.5 mg tablets and that it was unlikely for many ‘comparable’ overseas countries (as specified in NDPSC Guidelines) to have OTC post-marketing data for this formulation.
The Committee agreed with the view that the absence of public experience with OTC use of the 12.5 mg diclofenac oral formulation in Australia could potentially lead to inappropriate use of the product. Without consumer familiarity with the product, the OTC availability of diclofenac in more than one dosage strength for similar indications could confuse consumers particularly given that pharmacists may not have the opportunity to provide counselling or give guidance to those who would self-select an S2 product.
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 11 products containing ibuprofen, 1 with ibuprofen and codeine, 3 with naproxen sodium and 1 with mefenamic acid and aspirin. More recently, low-dose ibuprofen also became exempt from scheduling in Australia on 1 January 2004 when in divided preparations labelled with up to 1200 mg ibuprofen daily dose containing 200 mg or less ibuprofen per dose and compliant with labelling, packaging and pack size restrictions.
The November 2002 Medicine Classification Committee (New Zealand) agreed to classify diclofenac as a Pharmacy Only medicine (equivalent to S2) when in solid dose forms containing 12.5mg or less per dose form in packs of not more than 20 tablets or capsules.
The Committee noted the NZ Medicines Classification Committee’s (MCC) decision in November 2002 to classify 12.5 mg diclofenac tablets or capsules to Pharmacy-Only medicine. The MCC minutes stated that “…members agreed that the potential for misuse was small and there was a need for consistency in that 250 milligram naproxen tablets were already available as a pharmacy-only medicine. Nor was there any limit to the amount of aspirin available despite its side effects. It was agreed that 12.5 milligram diclofenac tablets should be available as pharmacy-only medicine when sold in packs of not more than 20 tablets”. National Drugs and Poisons Schedule Committee 103 Record of Reasons 41 – June 2004
Members noted that the sponsor’s submission was for packs in Australia to contain 30 or less 12.5 mg diclofenac dosage units, ie., maximum of 6/day, for 5 days, to allow for the proposed indications. Members preferred the 5-day pack size of 30 tablets for OTC availability for consistency with pack sizes of other medicines for short-term treatment of pain.
Members also noted that there was no entry in Appendix F, Part 3 of the SUSDP for diclofenac and that the sponsor did not propose any warning statement (WS) for the proposed 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 when allergic 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 with asthma, use in children under 12 years of age and use during pregnancy. The Committee discussed the current warning statements required for NSAIDs and came to the conclusion that the following deficiencies in the current WSs needed to be referred to MEC 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 GI complications from use of NSAIDs, i.e. > 60 years old, and did not list medicines commonly 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 of diclofenac potassium 12.5mg across its range of doses was comparable to low dose ibuprofen. An important caveat was that the information submitted was mainly in the form of reviews. The NDPSC evaluator had not been provided with any of the individual studies which had been reviewed. Having regard to this and the absence of an evaluation for OTC registration and local post-marketing experience with the 12.5 mg oral dose formulation in Australia to establish safety, efficacy and use pattern for the indications sought, members were not convinced that a change in scheduling status for 12.5 mg diclofenac was appropriate at this time. The Committee was mindful that the data requirements for scheduling considerations are limited and are not comparable to that required for registration. On this basis, members agreed that it would be appropriate for product formulations, not previously registered in Australia, to be assessed and approved for registration first prior to scheduling. The Committee agreed to consider this matter as a policy issue at the NDPSC 42nd Meeting (October 2004).
Further, the Committee considered the current warning statements required for NSAIDs in Appendix F, Part 3 of the SUSDP needed to be strengthened in order to warn conusmers against the important adverse effects associated with diclofenac potassium as National Drugs and Poisons Schedule Committee 104 Record of Reasons 41 – June 2004 well as other NSAIDs. The Committee decided not to approve the requested change at this time.
14.1.2 NICOTINE
PURPOSE
The Committee considered the proposal to reschedule nicotine in sublingual tablets for Nicotine 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 changes relating to nicotine for the purpose of obtaining consistency between Australian and NZ Schedule entries. One such change to the SUSDP was the inclusion of sublingual tablets in Schedule 3.
The August 2000 Meeting of the Medicines Evaluation Committee considered XXXXXXXXXXXX 2 mg and 4 mg sublingual tablets. They were registered in Australia in November 2001 and the 2 mg tablets and was launched as a Pharmacist Only Medicine in 2004.
The November 2003 MCC meeting agreed to reclassify nicotine in lozenges and sublingual tablets from Restricted medicine to Pharmacy-Only medicine.
XXXXXXXXXXXX submitted an application seeking rescheduling from S3 to S2 of nicotine sublingual tablets in the interest of ensuring trans-Tasman scheduling harmonisation.
DISCUSSION
The Committee noted that submissions were received from the XXXXXXXXXXXX XXXXXXXXXXXX and XXXXXXXXXXXX advocating the retention of nicotine sublingual tablets in Schedule 3 in view of the limited experience of use in Australia. In contrast, only one submission from XXXXXXXXXXXX supported the rescheduling of nicotine sublingual tablets from S3 to S2.
The Committee discussed the application and the evaluation report of the XXXXXXXXXXXX ‘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 similar safety profile to these nicotine preparations for NRT. The sponsor claimed that nicotine National Drugs and Poisons Schedule Committee 105 Record of Reasons 41 – June 2004 sublingual tablets provide relief from the symptoms of nicotine withdrawal and are an effective aid for helping smokers quit.
The evaluator noted that the adverse effect profile of NRT in various forms is well established. The most common adverse effects included headache, nausea, gastrointestinal discomfort, hiccups, coughing, sore mouth or throat, dry mouth and burning sensation in the mouth. The evaluator considered that there is no reason to expect that the use of the sublingual tablet would be more hazardous than the use of the gum.
Low potential for abuse or harm from inappropriate use
The evaluator noted that whilst the sponsor acknowledged that inappropriate long-term use may occur, it claimed that any risks were likely to be far less than the risks of continued smoking. The Periodic Safety Update Report indicated 7 reports of addiction to the sublingual tablets during the period August 2002 – July 2003, two of which had serious effects (pernicious anaemia following long term use for 3 years and panic attack and increased sweating reported after August 2002, with use having commenced in November 2001.
The evaluator indicated that the abuse potential of nicotine-containing products is related to the rapidity with which nicotine is absorbed from the product and that cigarettes which provide a bolus of nicotine to the brain within 10 seconds of each inhalation, have much greater abuse potential than products such as gums and lozenges, which produce a peak plasma 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 products including nicotine gum is likely to be very similar to other preparations included in S2 or to those available for unrestricted sale.
The evaluator also pointed out that although nicotine itself could have severe toxicity in acute poisoning (acute fatal dose 30-60 mg in an adult), there had been no cases of overdose or reports of deliberate or accidental poisoning with the sublingual product since 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 characterised incidence of severe adverse effects or side effects and contra-indications for which advice or counselling is available at S2 setting. In addition, the product has a low risk of masking a serious disease. It was indicated that the 4 mg sublingual tablet is not marketed in Australia and that the majority of the data is based on the 2 mg product (which was recently marketed in Australia). However, since the 2 mg sublingual tablet is bioequivalent to the 2 mg nicotine chewing gum, there was no expectation that the National Drugs and Poisons Schedule Committee 106 Record of Reasons 41 – June 2004 adverse event profile for 4 mg sublingual tablets would be any different from that for 4 mg chewing gum
The evaluator noted that the contra-indications for the formulation were the same as for other forms of NRT and that these were disclosed in the CMI and on the product packaging. The evaluator also noted that based on available data the risk of masking a serious disease for nicotine sublingual tablets used as nicotine replacement therapy is very 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 forms for many years, and was widely recognised and used by both consumers and healthcare professionals. The nicotine sublingual tablets are suitable for those smokers who for social reasons or personal preference do not like to use or cannot use nicotine chewing gum. For example, this group may include people with dentures or jaw conditions where constant chewing is not desirable and increasing the availability of the product would provide 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 been launched in Australia, they had been marketed in the UK since March 1999 and in 12 other European/Scandinavian countries from October 1998. Whilst the sponsor considered the safety profile of the sublingual formulation comparable to exempt NRT formulations, 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 in sublingual tablets to S2 on the basis of limited local experience with this formulation and that the 4 mg sublingual formulation had not ever been marketed in Australia. Members noted that XXXXXXXXXXXX 2 mg (sublingual tablet) had been assessed for registration by the Medicines Evaluation Committee (MEC) and was currently being sold on the Australian market. The PI for XXXXXXXXXXXX, which has been approved by the TGA, also allows a 2 x 2 mg dose for highly dependent smokers, which is bioequivalent to a single 4 mg sublingual tablet.
DECISION 2004/41 - 20
The Committee agreed to include sublingual tablets containing 4 mg or less of nicotine for use as an aid in withdrawal from tobacco smoking in S2 of the SUSDP. The Committee took into account the relevant matters set out in s.52E of the Therapeutic Goods Act 1989 and based its decision on these reasons: National Drugs and Poisons Schedule Committee 107 Record of Reasons 41 – June 2004
• the safety and adverse effect profile of the formulation for its intended use fulfills the criteria for an S2 medicine, where pharmacist advice is available to consumers when required; • low potential for masking a serious disease; • low potential for abuse or misuse; • making the formulation more readily available to consumers would provide an additional choice to consumers and encourage more people to quit smoking; • there is significant overseas post marketing experience with the sublingual formulation and no new or emerging safety issues were identified; and
Schedule 2 - Amendment
NICOTINE – amend entry to read:
NICOTINE for use as an aid in withdrawal from tobacco smoking in preparations for inhalation or sublingual use.
Schedule 3 – Amendment
NICOTINE – delete entry.
Schedule 4 – Amendment
NICOTINE – amend entry to read:
NICOTINE for use as an aid in withdrawal from tobacco smoking (including preparations for nasal administration) except:
(a) when included in Schedule 2;
(b) in chewing gum;
(c) in lozenges; or
(d) in preparations for transdermal use.
Schedule 7 – Amendment
NICOTINE – amend entry to read:
NICOTINE except:
(a) when included in Schedule 2,4 or 6; National Drugs and Poisons Schedule Committee 108 Record of Reasons 41 – June 2004
(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 DRUG EVALUATION 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 the treatment of attention deficit hyperactivity disorder (ADHD) in adults and children.
The December 2003 ADEC meeting recommended the approval of an application by XXXXXXXXXXXX to register XXXXXXXXXXXX containing the new medicine atomoxetine hydrochloride XXXXXXXXXXXX XXXXXXXXXXXX XXXXXXXXXXXX:
The treatment of attention deficit hyperactivity disorder (ADHD) as defined by DSM-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 Product Information to the satisfaction of the TGA.
DISCUSSION
The Committee noted the December 2003 ADEC minutes which reported that a small study (n=16) concluded that abuse potential was low. [Sentence deleted]. ADEC requested that the small number of patients in the study be explicitly stated in the Product Information description.
[Sentence deleted]. National Drugs and Poisons Schedule Committee 109 Record of Reasons 41 – June 2004
The Committee noted that atomoxetine is classified as a prescription medicine in New Zealand.
DECISION 2004/41 - 21
The Committee agreed to include atomoxetine in Schedule 4 of the SUSDP on the grounds that the condition being treated necessitated appropriate medical diagnosis and the safe use of this medicine required patient management and monitoring by a medical professional and to harmonise with New Zealand.
Schedule 4 – New Entry
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 by XXXXXXXXXXXX to register XXXXXXXXXXXX containing the new medicine atazanavir sulfate XXXXXXXXXXXX XXXXXXXXXXXX:
Atazanavir sulfate is indicated for the treatment of HIV-1 infection, in combination with other antiretroviral agents.
ADEC also recommended that:
• [Paragraphs deleted]
DISCUSSION
[Paragraph deleted]
The Committee noted that atazanavir was classified as a prescription medicine in New Zealand. National Drugs and Poisons Schedule Committee 110 Record of Reasons 41 – June 2004
DECISION 2004/41 - 22
The Committee agreed to include atazanavir in Schedule 4 of the SUSDP on the grounds that the condition being treated necessitated appropriate medical diagnosis and the safe use of this medicine required patient management and monitoring by a medical professional and to harmonise with New Zealand.
Schedule 4 – New Entry
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 potent pulmonary and systemic vasodilator activity and inhibition of platelet aggregation.
The December 2003 ADEC meeting recommended the approval of an application by XXXXXXXXXXXX to register XXXXXXXXXXXX solution for injection, containing the new medicine treprostinil sodium XXXXXXXXXXXX XXXXXXXXXXXX XXXXXXXXXXXX:
XXXXXXXXXXXX is indicated as a continuous subcutaneous infusion for the treatment of pulmonary arterial hypertension in patients with NYHA class III-IV to diminish symptoms associated with exercise.
ADEC also recommended that approval be subject to the finalisation of the Product Information to the satisfaction of the TGA.
DISCUSSION
The Committee noted that there were not a lot of agents to treat pulmonary arterial hypertension, a rare disease which may be primary or secondary to systemic diseases such as scleroderma.
[Paragraph deleted]
The Committee noted that treprostinil was not a classified medicine in New Zealand. National Drugs and Poisons Schedule Committee 111 Record of Reasons 41 – June 2004
DECISION 2004/41 - 23
The Committee agreed to include treprostinil in Schedule 4 of the SUSDP on the grounds that the condition being treated necessitated appropriate medical diagnosis and the safe use of this medicine required administration, ongoing patient management and monitoring by a medical professional.
Schedule 4 - New entry
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 with RNA and DNA, preventing replication of bacteria and viruses.
The TGA Office of Devices, Blood and Tissues (ODBT) requested ADEC to consider an application by XXXXXXXXXXXX for the device XXXXXXXXXXXX containing the new medicine amotosalen hydrochloride. ODBT requested that ADEC review data relating to the quality and safety of the amotosalen hydrochloride component of XXXXXXXXXXXX.
The December 2003 ADEC meeting recommended to ODBT that the data presented for the evaluation of the medicinal component of the XXXXXXXXXXXX, containing the new medicine amotosalen present as hydrochloride XXXXXXXXXXXX XXXXXXXXXXXX XXXXXXXXXXXX had satisfactorily established adequate evidence of quality and safety for the proposed indication:
XXXXXXXXXXXX platelets are indicated for transfusion support of patients requiring platelet transfusions according to clinical practice guidelines. Any thrombocytopenia resulting from disease, therapy or injury can be treated with XXXXXXXXXXXX platelets. XXXXXXXXXXXX platelets are not clinically different from untreated platelets and are infused according to standard platelet infusion methods.
ADEC recommended that registration should be conditional upon regulatory requirements of the XXXXXXXXXXXX being fully met to the satisfaction of the TGA.
[Paragraphs deleted] National Drugs and Poisons Schedule Committee 112 Record of Reasons 41 – June 2004
DISCUSSION
[Paragraphs deleted]
OUTCOME
The Committee agreed not to schedule amotosalen at this time and to await the assessment 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 by XXXXXXXXXXXX to register XXXXXXXXXXXX XXXXXXXXXXXX, containing the new chemical entity ciclesonide XXXXXXXXXXXX XXXXXXXXXXXX, for the prophylactic treatment of asthma. This recommendation was made after the consideration of new information, XXXXXXXXXXXX XXXXXXXXXXXX XXXXXXXXXXXX.
ADEC also recommended that approval be subject to the finalisation of the Product Information to the satisfaction of the TGA.
DISCUSSION
The Committee noted the minutes of the December 2003 ADEC meeting, the approved Product Information for XXXXXXXXXXXX and that ciclesonide was not a classified medicine in New Zealand.
DECISION 2004/41 - 24
The Committee agreed to include ciclesonide in Schedule 4 of the SUSDP on the grounds that the condition being treated necessitated appropriate medical diagnosis and the safe use of this medicine required patient management and monitoring by a medical professional.
Schedule 4 - New entry
CICLESONIDE. National Drugs and Poisons Schedule Committee 113 Record of Reasons 41 – June 2004
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 to register XXXXXXXXXXXX containing the new medicine rosuvastatin (calcium) XXXXXXXXXXXX and XXXXXXXXXXXX for the indications:
XXXXXXXXXXXX is indicated, at a starting dose of XXXXXXXXXXXX, as an adjunct to diet when the response to diet and exercise is inadequate for the treatment of: 1. Hypercholesterolaemia 2. Heterozygous and homozygous familial hypercholesterolaemia Prior to initiating therapy with rosuvastatin, secondary causes of hypercholesterolaemia (e.g. poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinaemias, obstructive liver disease, other drug therapy, alcoholism) should be identified and treated.
ADEC also recommended that approval be subject to the finalisation of the Product Information to the satisfaction of the TGA.
Further, ADEC recommended the rejection of the application to register XXXXXXXXXXXX on the grounds of inadequate safety.
DISCUSSION
The XXXXXXXXXXXX Member, XXXXXXXXXXXX, declared a potential conflict of interest for this item. The Member had worked XXXXXXXXXXXX until August 2002. The Member left the room whilst the Committee discussed this declaration. The Committee considered that this activity was not a conflict of interest and agreed that the Member 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 Category C in Australia. National Drugs and Poisons Schedule Committee 114 Record of Reasons 41 – June 2004
The Committee noted that rosuvastatin was classified as a prescription medicine in New Zealand.
DECISION 2004/41 -25
Schedule 4 - New entry
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 by XXXXXXXXXXXX to register XXXXXXXXXXXX for Injection containing the new medicine alefacept XXXXXXXXXXXX and XXXXXXXXXXXX for the indication:
Treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for phototherapy or systemic therapy. Safety and efficacy beyond two courses have not been demonstrated.
ADEC also recommended that approval be subject to the finalisation of the Product Information to the satisfaction of the TGA.
DISCUSSION
The Committee noted the minutes of the February 2004 ADEC meeting which reported that:
• [Paragraphs deleted] The Committee noted the approved Product Information which cautions that XXXXXXXXXXXX may increase the risk of malignancies; some patients in clinical studies developed malignancies; in preclinical studies, animals developed B cell hyperplasia and one animal developed a lymphoma.
With the possible increased risk of malignancies, and as safety and efficacy beyond two courses of treatment had not been demonstrated, the Committee agreed that alefacept should be available only on the prescription or order of a dermatologist. Therefore, the National Drugs and Poisons Schedule Committee 115 Record of Reasons 41 – June 2004
Committee agreed that alefacept be included in Appendix D of the SUSDP to place additional 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 grounds that the condition being treated necessitated appropriate medical diagnosis and the safe use of this medicine requires patient management and monitoring by a specialist medical professional.
The Committee also agreed to include alefacept in Appendix D of the SUSDP for public health and safety reasons, to be available only on the prescription or order of a dermatologist.
Schedule 4 - New entry
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 by XXXXXXXXXXXX to register XXXXXXXXXXXX containing the new medicine aprepitant XXXXXXXXXXXX and XXXXXXXXXXXX for the indication:
Use in combination with other antiemetic agents for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin.
ADEC also recommended that approval be subject to finalisation of the Product Information to the satisfaction of the TGA. National Drugs and Poisons Schedule Committee 116 Record of Reasons 41 – June 2004
DISCUSSION
The Committee noted the minutes of the February 2004 ADEC meeting, which reported that:
• [Paragraphs deleted] The Committee also noted that aprepitant was classified as a prescription medicine in New Zealand.
DECISION 2004/41 - 27
The Committee agreed to include aprepitant in Schedule 4 of the SUSDP on the grounds that the condition being treated necessitated appropriate medical diagnosis and the safe use of this medicine required patient management and monitoring by a medical professional and to harmonise with New Zealand.
Schedule 4 - New entry
APREPITANT.
16. OTHER MATTERS FOR CONSIDERATION
16.1 KETAMINE
PURPOSE
The Committee noted the paper prepared by the XXXXXXXXXXXX member on ketamine.
DISCUSSION
The Committee was advised that the National Working Group on the Diversion of Chemical 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 the problem of diversion of the substance to the illicit drug trade.
The Committee noted that the NWG was established by the Australian Government with broad membership including health and law enforcement representatives from the jurisdictions and representatives from the pharmaceutical industry and the pharmacy profession. The Terms of Reference for the Working Group are as follows:
• To provide a peak forum for all stakeholders in the management of precursor chemicals and equipment used in the production of illicit drugs to work together. • To ensure a consistent national approach and promote better coordination and collaboration across all sectors. National Drugs and Poisons Schedule Committee 117 Record of Reasons 41 – June 2004
• 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 of misuse and diversion of ketamine. At this meeting, NWG noted that the therapeutic use of ketamine had been increasing from that as a human and veterinary anaesthetic to analgesic in palliative care and emergency medicine for use by medical practitioners and dentists. However, NWG was advised that there was growing evidence of illicit use of ketamine due to its psychotropic effects and that the substance had been found in either its pure form or in combination with other substances such as MDMA [N,(-dimethyl-3,4- (methylenedioxy)phenylethylamine]. NWG noted that ketamine is not easily synthesised therefore the supply to the illicit drug market was most likely through diversion of pharmaceutical products from various points and through importation. It was advised that some jurisdictions had increased the storage and reporting requirements for ketamine in health services but these may not necessarily cover all diversion points.
XXXXXXXXXXXX members reported increasing problems with ketamine in their XXXXXXXXXXXX including loss of ketamine shipments and procurement of unreasonably 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 their XXXXXXXXXXXX and advise the October meeting of their findings.
17. MATTERS REFERRED BY THE MEDICINES EVALUATION COMMITTEE (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. National Drugs and Poisons Schedule Committee 118 Record of Reasons 41 – June 2004
BACKGROUND
Reye’s Syndrome was first described in 1963. Reye reported on a series of 21 children admitted to XXXXXXXXXXXX in NSW over the period 1951-1962, with acute encephalopathy and fatty changes in the liver. Similar cases were reported in the USA and the UK, mostly in association with use of aspirin. Reye’s Syndrome generally presents as pernicious vomiting following a viral illness. Encephalopathy subsequently occurs, often as hyperexcitability which may progress to coma and death.
Regulatory action concerning warning statements on aspirin products had been taken recently in both the UK and the USA. The Committee on Safety of Medicines (CSM) in the UK reviewed the need to amend the aspirin warning statements in 2002 and agreed that all aspirin-containing products be labelled with “Do not give to children under 16 years of age, unless on the advice of a doctor” as from October 1, 2003. In the USA, the FDA on 17 April 2003 amended the warning statement required of all oral and rectal OTC drug products containing aspirin including those containing non-aspirin salicylates to read “Children and teenagers who have or are recovering from chicken pox, flu symptoms 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, a rare but serious illness”.
At the NDPSC 40th Meeting (February 2004), the NDPSC confirmed its decision to include MEC’s proposed label warning statements for aspirin in the Schedule 2 (Decision 2003/39-27). However, members agreed to vary the amendment by including the words “to the following effect” where there was a requirement for certain warning statements on unscheduled products. The Committee also decided at this meeting that the words “to the following effect” should not be added to paragraphs (b) (iii) or (c) (iv) of the S2 entry, on the advice of MEC that the warning statement “Consult a doctor before giving this medication to children or teenagers with chicken pox, influenza or fever” should be retained pending the outcome of the review of the aspirin warning statement in relation to Reye’s syndrome.
DISCUSSION
The Committee noted a minute from OTC Medicines Section containing the recommendations of the MEC February 2004 meeting which included a copy of the Review of Aspirin/Reye’s Syndrome Warning Statement investigating the link between aspirin use in children and teenagers to Reye’s syndrome. The Review found that:
• The available evidence suggested that while a proportion of cases meeting the definition of Reye’s Syndrome were in fact other condition (including in born errors of metabolism, drug toxicity and others), there had still been a number of cases of ‘idiopathic’ or ’classic’ North American-type Reye’s syndrome. Although individually many of the studies investigating a possible link between aspirin and Reye’s syndrome were flawed, the overall weight of evidence suggested that there National Drugs and Poisons Schedule Committee 119 Record of Reasons 41 – June 2004
was a real association between aspirin administration during prodromal illness, and this ‘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 chicken pox, influenza or fever” still seemed relevant. However, given the small number of cases of Reye’s Syndrome in Australia in the last ten years, there is no evidence to suggest that a stronger warning, such as the new UK warning “Do not give to children under the age 16 years, unless on the advice of a doctor” was necessary on safety grounds. The Committee also noted the MEC February 2004 meeting consideration of the report of the Review of Aspirin/Reye’s Syndrome Warning Statement. MEC noted a recommendation that the warning statement should refer to children recovering from, as well as suffering from chicken pox, influenza or fever. On this basis, MEC recommended that the current warning statement “Consult a doctor before giving the medication to children or teenagers with chicken pox, influenza or fever” be deleted and warning 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 the product]: For more than a few days at a time With other medicines containing aspirin or other anti-inflammatory medicines If you have asthma In children under 12 years of age In children 12-16 years of age with or recovering from chicken pox, influenza or fever; If you are pregnant.”
Members noted the comment from OTC Medicines Section of the TGA highlighting an inconsistency in the existing Schedule 2 entry for aspirin published in the February 2004 post-meeting gazette notice. The condition for exemption under (b) and (c) stated in the S2 aspirin entry was that aspirin may be exempt from scheduling when it was “the only therapeutically 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 the blood or for your heart. [Can be omitted in products for inhibition of platelet aggregation or with additional active ingredients.]”. OTC Medicines Section felt that this warning statement was inconsistent and confusing in that products containing aspirin in combination with other active ingredients would not meet the requirements for unscheduled medicines based on this S2 entry. To resolve this inconsistency, OTC Medicines Section suggested that the Committee consider deleting “or with additional active ingredients” from the Schedule 2 entry for Aspirin.
Furthermore, OTC Medicines Section pointed out that the wording of the S2 entry for aspirin agreed to at the NDPSC 40th Meeting (February 2004) meeting suggested that National Drugs and Poisons Schedule Committee 120 Record of Reasons 41 – June 2004 unscheduled aspirin products labelled with the new warning statements (mandatory from 1 May 2005) would require the warnings "Unless a doctor has told you to, don't use ... in children 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 intent of the warning statement regarding children under 12 years was to replace the statement relating to children under 2 years from 1 May 2005, it would be appropriate to include the statement “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 account the revised Reye’s Syndrome WS and the amendments suggested by OTC Medicines Section 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) and if agreed by the Committee, the new S2 entry for aspirin would take effect on 1 May 2005 and thereby the existing (b)(ii)(A), (b)(iii), (c)(iii)(A) and (c)(iv) would no longer be necessary.
FORESHADOWED DECISION (for consideration at the NDPSC 42nd Meeting of October 2004)
Schedule 2 - Amendment
ASPIRIN - amend entry to read:
ASPIRIN except:
(a) when included in Schedule 4, 5 or 6;
(b) in individually wrapped powders or sachets of granules each containing 650 mg or less of aspirin as the only therapeutically active constituent other than an effervescent agent:
(i) when enclosed in a primary pack that contains 12 or less such powders or sachets of granules;
(ii) when the primary pack is labelled with warning statements to the following effect:
Don’t use [this product / name of the product]: If you have a stomach ulcer In the last 3 months of pregnancy National Drugs and Poisons Schedule Committee 121 Record of Reasons 41 – June 2004
If you are allergic to aspirin or anti-inflammatory medicines;
Unless a doctor has told you to, don’t use [this product / name of the product]: For more than a few days at a time With other medicines containing aspirin or other anti- inflammatory medicines If you have asthma In children under 12 years of age In children 12-16 years of age with or recovering from chicken pox, influenza or fever If you are pregnant;
See a doctor before taking [this product / name of the product] for thinning the blood or for your heart. [Can be omitted in products for inhibition of platelet aggregation.];
(c) in tablets or capsules each containing no other therapeutically active constituent other than an effervescent agent when:
(i) packed in blister or strip packaging or in a container with a child-resistant closure;
(ii) in a primary pack of not more than 25 tablets or capsules, each containing 325 mg or less of aspirin, or in a primary pack of not more than 16 tablets or capsules, each containing 500 mg or less of aspirin; and
(iii) the primary pack is labelled with warning statements to the following effect:
Don’t use [this product / name of the product]: If you have a stomach ulcer In the last 3 months of pregnancy If you are allergic to aspirin or anti-inflammatory medicines;
Unless a doctor has told you to, don’t use [this product / name of the product]: For more than a few days at a time With other medicines containing aspirin or other anti-inflammatory medicines If you have asthma National Drugs and Poisons Schedule Committee 122 Record of Reasons 41 – June 2004
In children under 12 years of age In children 12-16 years of age with or recovering from chicken pox, influenza or fever If you are pregnant;
See a doctor before taking [this product / name of the product] for thinning the blood or for your heart. [Can be omitted in products for inhibition of platelet aggregation.]; or
(d) in tablets or capsules each containing no other therapeutically active constituent other than an effervescent agent when:
(i) packed in blister or strip packaging or in a container with a child-resistant closure;
(ii) in a primary pack containing 100 or less tablets or capsules, each containing 100 mg or less of aspirin when packed and labelled for the prevention of cardiovascular disease or for the inhibition of platelet aggregation; and
(iii) the primary pack is labelled with the warning statement 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 time With other medicines containing aspirin or other anti-inflammatory medicines If you have asthma In children under 12 years of age In children 12-16 years of age with or recovering from chicken pox, influenza or fever; If you are pregnant. National Drugs and Poisons Schedule Committee 123 Record of Reasons 41 – June 2004
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 CLASSIFICATION COMMITTEE (MCC) OF NEW ZEALAND
18.1 ZINC IN DIETARY SUPPLEMENTS
PURPOSE
The Committee considered a summary of the study (AREDS) which suggests that intake of 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 the agenda of the NDPSC 41st Meeting (June 2004) for preliminary discussions by the Committee.
DISCUSSION
Members were advised that a GP in NZ, with interest in nutrition, drew the member’s attention of the XXXXXXXXXXXX Member to the AREDS study and sought advice on whether there were any plans by regulatory authorities to accommodate products containing up to 80mg elemental zinc, in unscheduled dietary supplements. It was noted that the current daily dose limit for unscheduled products was 25 mg or less of zinc compounds (or up to 50 mg zinc when products complied with certain labelling requirements) 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 between high-level zinc supplementation and copper intake should also be considered. National Drugs and Poisons Schedule Committee 124 Record of Reasons 41 – June 2004
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 nitrofursol and nimorazol.
The Office of Chemical Safety sought the Committee’s advice concerning the nomenclature used for dichlorobenzene entries in the SUSDP, with 1,2- and 1,4- dichlorobenzene listed in the SUSDP as o-dichlorobenzene or ortho-dichlorobenzene and PCB (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-dichlorobenzene entries should read lowercase ortho- and para-dichlorobenzene respectively.
The Committee agreed that the Schedule 7 entry for nicotine would be reviewed by the Drafting Advisory Panel under Item 14.1.2.
DECISION 2004/41 - 28
The Committee agreed to include the amended Schedule 7 nicotine entry in SUSDP 19/1 when reviewed by DAP.
The Committee agreed to include an errata in SUSDP 19/1 for nifursol and nimorazole to correct the spelling errors. The Committee also agreed that the Record of Reasons and Ratified Minutes for the NDPSC 39th Meeting (October 2003) be amended.
The Committee agreed to include an editorial in SUSDP 19/1 to amend the dichlorobenzene entries. National Drugs and Poisons Schedule Committee 125 Record of Reasons 41 – June 2004
Schedule 7 – Amendment
NICOTINE – amend entry to read:
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
Schedule 4 - Amendment
NIFURSOL – delete entry
NIMORAZOLE – delete entry
Schedule 5 – Amendment
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,S1 Old statements – old standard ………a,c,e,f,s
PDB (paradichlorobenzene) – amend entry to read: para-dichlorobenzene
New standard statement…………….A Old statements – old standard……….a,b,d Old statements – T-value…………….50 National Drugs and Poisons Schedule Committee 126 Record of Reasons 41 – June 2004
Appendix F, Part 3 - Amendment
PDB (paradichlorobenzene) – amend entry to read: 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 see Amend to read 1,2-DICHLOROBENZENE see ORTHO-DICHLOROBENZENE ortho-DICHLOROBENZENE
NB index under ‘D’
1,4-DICHLOROBENZENE see New entry NB: index under ‘D’ para-DICHLOROBENZENE
ORTHO-DICHLOROBENZENE Amend to read ortho-DICHLOROBENZENE
NB: index under ‘D’ & include page reference to Appendix E, Part 2 entry
PARADICHLOROBENZENE Amend to read para-DICHLOROBENZENE
NB: index under ‘D’
PDB Amend to read PDB see para- DICHLOROBENZENE
NB: remove page references and index under ‘D’
PDCB Remove