National Drugs and Poisons Schedule Committee

Record of Reasons

56th Meeting 16-17 June 2009

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 i

TABLE OF CONTENTS

GLOSSARY...... IV

1. PRELIMINARY MATTERS...... 1 1.5 ADMINISTRATION...... 1 1.5.1 Schedule for Future NDPSC Meetings ...... 1 1.5.2 Meeting Date for the October 2009 Meeting...... 1 1.6 XXXXX ...... 1 1.7 PROCEDURAL MATTERS...... 1 1.8 NDPSC WORKING PARTIES ...... 1 1.9 PROPOSED ROUTINE CHANGES TO THE SUSDP ...... 1 2. PROPOSED CHANGES/ADDITIONS TO PARTS 1 TO 3 AND PART 5 OF THE STANDARD FOR THE UNIFORM SCHEDULING OF DRUGS AND POISONS...... 1 2.1 SUSDP, PART 1...... 1 2.2 SUSDP, PART 2...... 1 2.3 SUSDP, PART 3...... 1 2.4 SUSDP, PART 5...... 2 AGRICULTURAL/VETERINARY, INDUSTRIAL AND DOMESTIC CHEMICALS...... 3

3. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUS MEETING (CONSIDERATION OF POST-MEETING SUBMISSIONS UNDER 42ZCY(1)(c)) ...... 3

4. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS...... 3 4.1 GUANIDINE ...... 3 5. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FOR THE UNIFORM SCHEDULING OF DRUGS AND POISONS...... 9 5.2 SUSDP, PART 5...... 10 6. MATTERS REFERRED BY THE AUSTRALIAN PESTICIDES AND VETERINARY MEDICINES AUTHORITY (APVMA)...... 10 6.1 MONEPANTEL...... 10 6.2 SAFLUFENACIL...... 15 7. MATTERS REFERRED BY OFFICE OF CHEMICAL SAFETY AND ENVIRONMENTAL HEALTH (OCS&EH) OR THE NATIONAL INDUSTRIAL CHEMICALS NOTIFICATION AND ASSESSMENT SCHEME (NICNAS)...... 20

8. OTHER MATTERS FOR CONSIDERATION ...... 20

9. INFORMATION ITEMS (AG/VET, INDUSTRIAL & DOMESTIC CHEMICALS)...... 20

PHARMACEUTICALS...... 21

10. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUS MEETING (CONSIDERATION OF POST-MEETING SUBMISSIONS UNDER 42ZCY(1)(c)...... 21 10.1 GUAIPHENESIN ...... 21

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 ii

11. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS ...... 23 11.1 ARBUTIN ...... 23 11.2 XXXXX ...... 31 11.3 SCHEDULING OF OTC PRODUCTS CONTAINING CODEINE ...... 32 11.4 MAGNESIUM SULFATE ...... 63 11.5 PIPER METHYSTICUM (KAVA)...... 67 11.6 SOMATROPIN...... 75 11.7 HYDROQUINONE ...... 75 11.8 CLARIFICATION OF THE SCHEDULING OF CODEINE IN COMBINATION WITH MENTHOL & AMMONIUM CHLORIDE ...... 81 12. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FOR THE UNIFORM SCHEDULING OF DRUGS AND POISONS...... 84 12.1 SUSDP, PART 4...... 84 12.1.1 Fexofenadine...... 84 12.1.2 HMG-CoA Reductase Inhibitors (Statins) ...... 87 12.1.3 Loperamide ...... 93 12.1.4 Rabeprazole ...... 101 12.1.5 Succimer (DMSA) ...... 119 12.2 SUSDP, PART 5...... 125 12.2.1 Di-Iodohydroxyquinoline (Iodoquinol)...... 125 13. MATTHERS REFERRED BY THE REGISTRATION PROCESS FOR PRESCRIPTION MEDICINES...... 128 13.1 NEW SUBSTANCES (NOT SEEN BEFORE BY NDPSC)...... 128 13.1.1 Doripenem ...... 128 13.1.2 Japanese Encephalitis Vaccine...... 130 13.1.3 Human Papillomavirus Vaccine ...... 132 13.2 FOR INFORMATION (SUBSTANCES ALREADY SCHEDULED)...... 135 14. OTHER MATTERS FOR CONSIDERATION ...... 135

15. MATTERS REFERRED BY THE MEDICINES EVALUATION COMMITTEE (MEC).135

16. MATTERS REFERRED BY THE MEDICINES CLASSIFICATION COMMITTEE (MCC) OF NEW ZEALAND ...... 135 16.1.1 Golimumab...... 135 16.1.2 Lacosamide ...... 136 16.1.3 Liraglutide ...... 138 16.1.4 Prasugrel ...... 139 16.2 MEDICINES HARMONISED – FOR INFORMATION...... 140 16.2.1 Anidulafungin...... 140 16.2.2 Blood and Blood Products ...... 140 16.2.3 Desvenlafaxine...... 141 16.2.4 Fluorides...... 141 16.2.5 Glyceryl Trinitrate for Rectal Use ...... 141 16.2.6 Ketotifen Fumarate 0.025 Per Cent for Ophthalmic Use ...... 142 16.2.7 Nitric Oxide...... 142 16.2.8 Romiplostim ...... 142 16.2.9 Rotigotine...... 143 16.2.10 Temsirolimus...... 143 17. MINUTES OF THE ADVERSE DRUG REACTIONS ADVISORY COMMITTEE (ADRAC)...... 143

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 iii

18. MINUTES OF THE MEDICAL DEVICE EVALUATION COMMITTEE (MDEC) ...... 143

19. INFORMATION ITEMS (PHARMACEUTICALS)...... 143 XXXXX...... 143 20. GAZETTAL NOTICES...... 143

21. AMENDMENTS TO THE SUSDP...... 144 21.1 EDITORIAL CHANGES AND ERRATA ...... 144 21.2 SUSDP 24 AMENDMENT 1 – EDITORIALS ...... 144 22. CLOSURE AND NEXT MEETING...... 147

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 iv

GLOSSARY

ABBREVIATION NAME

AAN Australian Approved Name

AC Active Constituent

ACCC Australian Competition and Consumer Commission

ADEC Australian Drug Evaluation Committee

ADI Acceptable Daily Intake

ADR Adverse Drug Reaction

ADRAC Adverse Drug Reactions Advisory Committee

AHMAC Australian Health Ministers' Advisory Council

APVMA Australian Pesticides and Veterinary Medicines Authority

AQIS Australian Quarantine and Inspection Service

ARfD Acute Reference Dose

ASCC Australian Safety and Compensation Council

ASMI Australian Self-Medication Industry

ARTG Australian Register of Therapeutic Goods

CACC Combination analgesic containing codeine

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 of Meeting 56 – June 2009 v

CRC Child-Resistant Closure

CTFAA Cosmetic, Toiletry & Fragrance Association of Australia

CWP Codeine Working Party

DAP Drafting Advisory Panel

ECRP Existing Chemicals Review Program

EPA Environment Protection Authority

ERMA Environmental Risk Management Authority

FAISD First Aid Instructions and Safety Directions

FOI Freedom of Information Act 1982

FSANZ Food Standards Australia New Zealand

GHS Globally Harmonised System for Classification and Labelling of Chemicals.

GIT Gastro-intestinal Tract

GORD Gastro-oesophageal Reflux Disorder

GP General Practitioner

H2A H2 receptor antagonist

HCN Health Communication Network

INCB International Narcotics Control Board

INN International Non-proprietary Name

ISO International Standards Organization

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.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 vi

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

LOAEL Lowest Observed Adverse Effect Level

LOEL Lowest Observed Effect Level

MCC Medicines Classification Committee (NZ)

MEC Medicines Evaluation Committee

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

NOAEL No Observed Adverse Effect Level

NOEL No Observed Effect Level

NOHSC National Occupational Health & Safety Commission

OCM Office of Complementary Medicines

OCSEH Office of Chemical Safety and Environmental Health

ODBT Office of Devices, Blood and Tissues

OLSS Office of Laboratories and Scientific Services

OOS Out of Session

OPM Office of Prescription Medicine

OTC Over-the-Counter

PACIA Plastics And Chemicals Industries Association

PAR Prescription Animal Remedy

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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

PSC Poisons Schedule (Standing) Committee (now NDPSC)

PSSC Poisons Schedule Sub-Committee (now NDPSC)

QCPP Quality Care Pharmacy Program

QUM Quality Use of Medicines

RFI Restricted Flow Insert

SCCNFP Scientific Committee on Cosmetic and Non-Food Products

SCCP Scientific Committee on Consumer Products

STANZHA States and Territories and New Zealand Health Authorities

SUSDP Standard for the Uniform Scheduling of Drugs and Poisons

SUSMP Standard for the Uniform Scheduling of Medicines 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

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 viii

TTHWP Trans-Tasman Harmonisation Working Party

TTMRA Trans-Tasman Mutual Recognition Agreement

USFDA United States Food and Drug Administration

WHO World Health Organization

WP Working Party

WS Warning statement

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 1

1. PRELIMINARY MATTERS

1.5 ADMINISTRATION

1.5.1 SCHEDULE FOR FUTURE NDPSC MEETINGS

The Committee agreed to a proposal to routinely plan two day meetings for the expected remainder of the NDPSC meeting schedule. Members noted that it was always open for a three day meeting to be planned where this was warranted by the expected workload. Members also agreed that meetings would continue to commence on the Tuesday of a meeting week.

1.5.2 MEETING DATE FOR THE OCTOBER 2009 MEETING

The Committee agreed to a request from a Member to move the October 2009 meeting from 13-15 October 2009 to the following week i.e. 20-21 October 2009 (two days as per the decision in item 1.5.1). Members agreed that none of the pre- or post-meeting deadlines were to be affected by the change to the sitting date.

1.6 XXXXX

1.7 PROCEDURAL MATTERS

No items.

1.8 NDPSC WORKING PARTIES

No items.

1.9 PROPOSED ROUTINE CHANGES TO THE SUSDP

No items.

2. PROPOSED CHANGES/ADDITIONS TO PARTS 1 TO 3 AND PART 5 OF THE STANDARD FOR THE UNIFORM SCHEDULING OF DRUGS AND POISONS.

2.1 SUSDP, PART 1

No items.

2.2 SUSDP, PART 2

No items.

2.3 SUSDP, PART 3

No items.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 2

2.4 SUSDP, PART 5

No items.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 3

AGRICULTURAL/VETERINARY, INDUSTRIAL AND DOMESTIC CHEMICALS

3. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUS MEETING (CONSIDERATION OF POST-MEETING SUBMISSIONS UNDER 42ZCY(1)(c))

No items.

4. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS

4.1 GUANIDINE

PURPOSE

The Committee considered the scheduling of guanidine.

BACKGROUND

Guanidine carbonate is a precursor for preparing guanidine hydroxide, the active ingredient in some chemical hair relaxing treatments. Guanidine carbonate has a solubility of up to 45 g/100 g water, with a saturated aqueous pH of 11-11.5.

Chemical hair relaxing is a method for permanently straightening curly hair. It is a non- reversible one-step chemical process involving the application of strong alkali. In the late 1950s hair relaxing used 1.5-2.5 per cent sodium hydroxide (or ‘lye’). In 1978 a ‘no-lye’ treatment based on guanidine hydroxide was introduced which claimed to be less irritating to the scalp. A guanidine hydroxide hair relaxer has a pH in the same range as that of sodium or potassium hydroxide based relaxers (pH 12-14). Guanidine hydroxide is unstable and hydrolyses to form urea and ammonia and must therefore be generated in situ immediately prior to use by reaction of guanidine carbonate and calcium hydroxide.

The August 1999 meeting first included guanidine in Schedule 4 following a recommendation from the Trans-Tasman Harmonisation Working Party based on guanidine’s toxicity. This was also in line with the generally applied policy that substances for human therapeutic use be placed in Schedule 4 if there was no marketed product in either Australia or New Zealand (NZ).

The February 2009 meeting considered a request to exempt guanidine carbonate for hair relaxing from scheduling. The Committee generally considered a Schedule 6 entry to be appropriate for non-therapeutic use of guanidine but, noting the possible broad impact of such an entry and the lack of data supporting possible exemption cut-offs, decided to foreshadow the following in order to allow time for further public consultation:

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 4

• Restricting the Schedule 4 entry for guanidine to therapeutic use only; • Including a new parent entry in Schedule 6 for guanidine; and • Including a new entry in Appendix E, Part 2 with the following standard statements: − A “For advice, contact a Poisons Information Centre (Phone eg Australia 13 1126; New Zealand 0800 764 766) or a doctor (at once)”. − G3 “If swallowed, do NOT induce vomiting”. − E2 “If in eyes, hold eyelids apart and flush the eye continuously with running water. Continue flushing until advised to stop by the Poisons Information Centre or a doctor, or for at least 15 minutes.” − S1 “If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water”.

DISCUSSION - SUBMISSIONS

Pre-meeting Submission

Members noted the following from XXXXX pre-meeting submission: • The foreshadowed proposal was welcomed. However, the proposed Appendix E entry’s inclusion of statement S1 may be confusing to industry if there were no exemption cut-offs from the Schedule 6 entry. • The February 2009 meeting indicated that it would be reasonable for a sponsor to reword S1, given that some guanidine products are for use on hair, and in keeping with the Appendix E introduction that ‘standard statements specified in this appendix may be varied provided that the intent is not changed’. • Guanidine salts, such as guanidine carbonate and guanidine phosphate, are used in the EU as skin conditioning products. As these are intended to be in contact with the skin, addition of warning statement S1 on the label would not be appropriate. • While warning statement S1 for corrosive products containing guanidine was supported, XXXXX believed it was impractical and unhelpful to impose the statement on cosmetic products containing guanidine. • Hair products containing guanidine generally contained ≤ 5 per cent guanidine, while skin care products contained ≤ 1 per cent guanidine. • Such products have been in safe use for some time in the EU market. The EU does not impose a limit on concentration of guanidine in such cosmetic products. • Consideration of a scheduling exemption for guanidine at ≤ 1 per cent and a Schedule 5 entry for guanidine at ≤ 5 per cent was supported. This cut-off was in line with highly corrosive substances such as sodium hydroxide, and given the absence of specified cut-offs in countries with similar regulatory systems, might be considered conservative.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 5

No other pre-meeting submissions were received.

February 2009 Discussion

The key factors in considering separate scheduling controls for non-therapeutic use of guanidine were the caustic nature of some guanidine salts/derivatives and the inherent toxicity of guanidine. Guanidine hydroxide preparations (often generated in situ from guanidine carbonate and calcium hydroxide) could be very caustic and highly irritant to eyes, lungs and skin, and could therefore pose a serious risk, especially for children.

Members noted US reports of harm in children from ingestion of guanidine hair straighteners. Similar risks, although probably less severe, were likely to exist for some other salts/derivatives of guanidine. Additionally, there appeared to be little in the way of human toxicity data available, beyond oral toxicity for some guanidine salts (significant effects on the gastrointestinal and nervous system and on the neuromuscular systems). Several Members asserted that this data alone was compelling.

Members considered a proposal to limit the current Schedule 4 entry to internal therapeutic use. It was noted that there may in the future be non-oral therapeutic uses developed and these should not be exempted from scheduling without proper supportive data justifying such an exemption being presented to the Committee.

The Committee considered limiting the current Schedule 4 guanidine parent entry to therapeutic use, and capturing all other uses of guanidine in Schedule 6 (together with appropriate Appendix E first aid instructions). Members generally felt this was appropriate, given the information at hand.

The Committee also considered an exemption cut-off from the Schedule 6 parent entry for non-therapeutic use of guanidine. Members noted that while an exemption was proposed for ≤ 25 per cent guanidine carbonate, no evidence was provided to demonstrate that this concentration diminished the risk enough to warrant a scheduling exemption. Indeed, a Member noted that a high pH had to be reached at some point for the hair straightening chemical reaction to work, and that the guanidine hair straightener involved in a reported incident in Victoria causing skin burns had < 25 per cent guanidine carbonate. Members generally agreed that an exemption for ≤ 25 per cent was not appropriate.

An exemption based on a pH limit, in line with the current sodium hydroxide scheduling, was considered but not supported, given a lack of data. The Committee therefore agreed that an exemption from the Schedule 6 parent entry could not be justified with the data that was before it.

A Member advised that in the EU, guanidine salts/derivatives were allowed for cosmetic use beyond hair straightening and other possible cosmetic use patterns must be taken into consideration. A Member noted that cosmetics mostly require prolonged dermal contact on a daily basis, which differed significantly from the exposure pattern for hair

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 6

straighteners. Another Member noted, however, that guanidine was not dermally absorbed and this may mitigate risk.

Noting the possible broad impact of a Schedule 6 parent entry for non-therapeutic guanidine and the lack of data supporting possible exemption cut-offs, the Committee agreed that it would be appropriate to foreshadow consideration at the June 2009 meeting, in order to allow time for further public consultation.

Members also wished to confirm, in relation to the applicant’s assertion that imported guanidine based hair straightening products were available in Australia, that such products would currently be captured by the Schedule 4 entry for guanidine. A Member advised that importers of such products were unlikely to be large scale companies (who might be more likely to be conversant with scheduling requirements) but, rather, smaller scale businesses such as hair salons, or those selling products from overseas via the internet.

February 2009 Application

Members recalled the following from the XXXXX application and from the various articles in the supplementary data: • Guanidine carbonate has been used in hair relaxing kits for many years worldwide and in Australia. It was well accepted by consumers using these products that irritation may occur due to the caustic nature of the ingredients. − The February 2009 meeting concluded that consumers’ awareness of the risk associated with the use of these products in no way justified exempting them from scheduling restrictions. • The accidental ingestion of the guanidine carbonate solution was the most likely incidence of misuse. The ingestion of caustic hair relaxers had been examined by a number of articles. The conclusions reached by these articles included that the ingestion of caustic hair relaxers made up a major proportion of all children admitted to hospital in the US for caustic ingestion. However, no significant oesophageal injuries had been associated with hair relaxer ingestion. The problem of hair relaxer ingestion was more pronounced in the US where these products are marketed for young children and are often in packaging intended to be attractive to children, without adequate child-resistance closures. • Members additionally noted the following from the supplementary data: − Hair relaxer ingestion can cause moderate to severe chemical burns on the lips, face, oral cavity and occasionally on the pharynx. − Guanidine carbonate is an irritant to skin, eyes, and mucous membranes and also has an irritating effect on lungs upon inhalation. There are no known allergic or sensitization effects. In solution the pH of guanidine may approach corrosivity, depending on the concentration.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 7

− The acute and chronic toxicity of guanidine carbonate was not fully known. It was known to be very hazardous if ingested, with a reported mouse oral LD50 of 350 mg/kg. − No data on the carcinogenic properties of guanidine carbonate was available. − More research is needed on the long term health effects and toxicology associated with the use of caustic agents in hair relaxers. − Guanidine HCl does not appear to be absorbed through the skin, and the only information on human exposure comes from the US pharmaceutical industry, where it is used as an orally administered drug. It is known to have significant effects on the gastrointestinal, nervous and neuromuscular systems. − There are no published studies of the effect of guanidine on humans, however the Buehler and Draize test have been performed on rabbits and guinea pigs and both concluded that guanidine applied topically was a mild skin irritant. − A study exploring hair care practices and alopecia among black women indicated that there was no significant correlation between development of central centrifugal cicatricial alopecia and the use of relaxers nor a history of burns or raw spots after use of relaxers but that some doctors were informing patients that relaxers were implicated.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (a) toxicity and safety, (b) risks and benefits, (d) extent and patterns of use, (e) dosage and formulation and (f) the need for access.

It was agreed that the major concern for the Committee remained the caustic nature of some guanidine salts, noting that there were also other toxicity issues as discussed at the February 2009 meeting. A Member noted that sodium hydroxide had cut-offs from Schedule 6 at ≤ 5 per cent (Schedule 5 with a pH > 11.5 and exempt with a pH ≤ 11.5) and suggested that this may be a reasonable proposal for guanidine salts. Other Members noted that the use pattern of guanidine was quite different i.e. on the scalp. Members recalled that high pH levels were a fundamental part of the hair straightening products mode of action and therefore would always be associated with an irritancy risk (particularly to eyes and skin).

A Member felt that some of the guanidine salts had a corrosive potential more in keeping with Schedule 7 than Schedule 6, at least at high concentrations. The Member conceded that such high concentrations were unlikely with the current cosmetic use pattern but asserted that a ≤ 5 per cent cut-off to Schedule 5 was not acceptable.

A Member advised that XXXX claim that guanidine hair and skin care products have been in safe use for some time in the EU market and that the EU does not impose a limit on concentration of guanidine in such products was not an accurate description of the EU

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 8

circumstances. Hair straighteners containing calcium hydroxide and a guanidine salt are in fact controlled, through the calcium hydroxide entry in directive 2002/34/EC (Annex III, part 1, reference 15c). This entry also mandates label warnings including ‘avoid contact with eyes’ and ‘can cause blindness’.

A Member advised that there were many consumer websites which provided information that guanidine hair straightening products will irritate or burn the scalp. The Member reiterated the point from the February 2009 meeting that just because there is a consumer awareness of a risk does not mean that such risk is acceptable. Another Member advised of an incident involving a first time user of a guanidine hair straightening product which resulted in severe scalp irritation requiring treatment from a dermatologist, demonstrating that not all consumers are aware of the risks.

Members also noted that XXXXX suggested cut-offs (exemption at ≤ 1 per cent, Schedule 5 at ≤ 5 per cent) appeared to be based on XXXXX understanding of levels in cosmetics available in Europe and were not directly linked to the toxicity data to hand. Additionally, XXXXX asserted that the cut-offs would capture hair straighteners in Schedule 5. Members recalled their February 2009 intent was to capture these in Schedule 6 i.e. that a possible exemption from Schedule 6 classification would only be considered with regards to other uses such as cosmetic dermal uses.

A Member noted that concerns had again been raised about the suitability of the Appendix E statements. A Member noted that any risk of an alkaline type burn to the eyes was a serious concern and maintained the need for a strong warning regarding eye exposure (i.e. supported statement E2). There was some discussion about the appropriateness of statement S1 due to the unavoidable hair contact of hair straightening products, but Members generally reiterated the February 2009 conclusion that that it would be reasonable for sponsors to reword S1, given that some guanidine products are for use on hair, and in keeping with the Appendix E introduction that ‘standard statements specified in this appendix may be varied provided that the intent is not changed’.

A Member suggested that the S1 statement, and indeed any scheduling controls, was probably not warranted for low level non-therapeutic guanidine use and supported the proposed exemption cut-off at ≤ 1 per cent. Other Members agreed, noting that this was likely to avoid scheduling of the low level use in dermal cosmetics (≤ 1 per cent) for which there appears to have been no reported concerns.

RESOLUTION 2009/56 - 1

The Committee decided: • To restrict the Schedule 4 entry for guanidine to therapeutic use only. • To include a new parent entry in Schedule 6 for non-therapeutic use of guanidine.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 9

• To exempt non-therapeutic preparations containing 1 per cent or less of guanidine from the requirements of scheduling. • To include a new entry in Appendix E, Part 2 with the following standard statements to apply: − A “For advice, contact a Poisons Information Centre (Phone eg Australia 13 1126; New Zealand 0800 764 766) or a doctor (at once)”. − G3 “If swallowed, do NOT induce vomiting”. − E2 “If in eyes, hold eyelids apart and flush the eye continuously with running water. Continue flushing until advised to stop by the Poisons Information Centre or a doctor, or for at least 15 minutes.” − S1 “If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water”.

Schedule 4 – Amendment

GUANIDINE – Amend entry to read:

GUANIDINE for therapeutic use.

Schedule 6 – New Entry

GUANIDINE except:

(a) when included in Schedule 4; or

(b) in preparations containing 1 per cent or less of guanidine.

Appendix E, Part 2 – New Entry

POISON ...... STANDARD STATEMENT

Guanidine...... A,G3,E2,S1

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

5.1 SUSDP, PART 4

No items.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 10

5.2 SUSDP, PART 5

No items.

6. MATTERS REFERRED BY THE AUSTRALIAN PESTICIDES AND VETERINARY MEDICINES AUTHORITY (APVMA)

6.1 MONEPANTEL

PURPOSE

The Committee considered the scheduling of monepantel.

BACKGROUND

Monepantel is the first member of the novel class of anthelmintics, the amino-acetonitrile derivatives (AADs). It is a broad spectrum oral anthelmintic drench for the control of gastro-intestinal nematode parasites (roundworms) in sheep. Monepantel works differently from all other anthelmintics using a unique mode of action that paralyses worms by attacking a previously undiscovered receptor – Hco-MPTL-1 – only present in nematodes.

Monepantel is the approved common name. The chemical name (IUPAC) is N-[(1S)-1- Cyano-2-(5-cyano-2-trifluoromethyl-phenoxy)-1-methylethyl]-4-trifluoromethylsulfanyl- benzamide (CAS number 887148-69-8). The chemical structure is given below:

DISCUSSION - SUBMISSIONS

XXXXX prepared an evaluation report on an XXXXX application by XXXXX to register a new technical grade active constituent (TGAC), monepantel and a new XXXXX product, XXXXX.

XXXXX.

Members noted the following recommendations from the evaluation report: Public Health Standards • The ADI for monepantel had been established at 0.02 mg/kg bw/day based on a LOEL of 100 ppm (2.96 mg/kg bw/day) in a XXXXX dietary study in XXXXX and applying a safety factor of 200 for a dose related decrease in activated partial

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 11

thromboplastin time, an increase in alkaline phosphatase activity and an increased absolute and relative thyroid weight in both sexes at the lowest dose level. − Members noted subsequent advice from the evaluator that the LOEL assumption for the pivotal ADI study had been reconsidered in light of the arguments put forward in the applicant’s response to the evaluation report (see below). The LOEL has therefore been revised down to a NOEL. • The ARfD for monepantel had not been established and there were not sufficient data to allow an ARfD to be set at this point in time. • Based on its toxicity profile, monepantel met the criteria for inclusion in Schedule 5.

Members particularly noted the following from the evaluation report: • For the purposes of the risk assessment, there was no information relating to this particular class of chemicals for comparison purposes with the TGAC. Members noted the evaluator’s advice that it was a normal practice to check other substances in the same chemical class as the TGAC under consideration as this could help identify possible concerns, including adverse reactions. When the evaluator attempted such a comparison in this instance, however, it was determined that there were no other registered chemicals found relating to this particular class of chemicals. However, a comprehensive data submission was assessed which enabled the toxicology to be determined. • There were no products containing monepantel available in Australia or internationally. Therefore, there was no post-marketing adverse reaction or epidemiological data available on which to inform the scheduling recommendation.

The following toxicological information on the TGAC was noted by the Members: XXXXX

• Based on the findings of the acute toxicological studies evaluated, monepantel TGAC has low acute oral and dermal toxicity in XXXXX, it is not a skin irritant but a slight eye irritant in XXXXX and is not a skin sensitiser in XXXXX. • In repeat-dose toxicity studies by the oral route, the liver, the haematological system, and the adrenals and thyroid were identified as target organs in XXXXX. The liver is the primary target organ of toxicity in XXXXX. Effects included statistically significant increases in lipid biochemical parameters, such as cholesterol, triglycerides, phospholipids and globulin. Changes in biochemical parameters such as bilirubin, alkaline phosphatase and aspartate aminotransferase were common to most repeat dose studies. Further effects common to most studies included increases in the incidence and severity of fatty liver changes, in conjunction with increased absolute and relative liver weight changes at doses of XXXXX in XXXXX, and from the lowest dose tested of XXXXX in XXXXX.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 12

• In XXXXX, other less common observations at higher doses included increased absolute and relative kidney and heart weights, and increased levels of diffuse follicular hypertrophy in the thyroid gland. • Monepantel did not cause reproductive effects in a 2-generation reproduction study in XXXXX, although both the parents and offspring consistently exhibited liver toxicity at all doses tested. No treatment related maternal or developmental toxicity was observed in XXXXX at dose up to XXXXX. However, the chemical caused limited developmental effects in XXXXX foetuses at the top dose of XXXXX in a developmental toxicity study. • In a development study, the assumed pregnant XXXXX received XXXXX of monepantel. There were no treatment-related deaths and no clinical signs. Food consumption and body weight were not affected. • In a XXXXX chronic oral toxicity study, XXXXX were dosed with monepantel in the diet at XXXXX. There were no test item-related mortalities, clinical signs or nodules and masses, ophthalmoscopic findings, and no changes in the food consumptions. Mean body weights were consistently lower in XXXXX. Monepantel related changes were observed in the clinical chemistry, including increasing cholesterol, phospholipids and triglycerides levels. Other effects observed include increased protein, albumin, globulin and decreased glucose levels. There were no observed macroscopic findings relating to monepantel dosing. All microscopic findings recorded were within the range of normal background lesions which may be recorded in animals of this strain and age. • In a series of in vitro tests, XXXXX were treated with different concentrations of monepantel ranging from XXXXX. In all XXXXX used and at all concentrations tested, monepantel treatment did not lead to increase in the number of revertant above negative control values. Therefore, monepantel did not elicit mutagenic potential in this in vitro study. • No acute inhalational toxicity study for the TGAC was submitted. • The available data indicated that monepantel would pose a relatively low hazard from repeated use and that it was unlikely to produce irreversible toxicity. The evaluator also concluded that there were no grounds for cut-offs or exemptions. • XXXXX.

Members noted the following regarding the formulated product: XXXXX

• The formulated product containing XXXXX monepantel has low acute oral and dermal toxicity in XXXXX. It was a slight skin and eye irritant in XXXXX and a skin sensitiser in XXXXX. • XXXXX

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• Members additionally noted that monepantel TGAC was not a skin sensitiser, however, the formulated product was at concentrations XXXXX. Neither the evaluator’s report nor the applicant’s submitted studies provided reason for this effect. This was instead addressed by the applicant’s response to the evaluation report.

The applicant’s response to the evaluation report asserted that, overall, the evaluation was very thorough and scientifically valid. Members particularly noted the following from the applicant’s response: Skin sensitisation • The applicant argued that since the active ingredient was not skin sensitising, the monepantel formulated product was also not skin sensitising. The applicant asserted that there was a known propensity for the test used to produce false positive results in the presence of irritation. Therefore the applicant considered that the formulation was devoid of a contact allergenic potential. The report also asserted that during the XXXXX of development, no cases of sensitisation had been observed in XXXXX. Members noted that this statement had not been substantiated. Activated partial thromboplastin time (APTT) • The applicant asserted that the decreasing APTT levels observed at high dose levels in a XXXXX study was not associated with any other changes in coagulation parameters and was without any clinical or pathological sequels. The response observed also was fully reversible. Further, decreasing APTT was not known to be associated with any clinically relevant disorders. Alkaline phosphatase (ALP) • With regard to the increase in the mean ALP observed in a XXXXX study, the applicant asserted that the XXXXX ALP, as a consequence of its sensitivity to drug induction, was a poor indicator for hepatobiliary disease. The applicant concluded that elevation of ALP alone due to monepantel in the absence of other indicators of liver toxicity was not considered to represent a relevant toxicological endpoint. Thyroid weight • The applicant indicated that they observed increased thyroid weights in their XXXXX and XXXXX week study at concentrations of XXXXX. However, the applicant asserted that in the absence of changes in clinical pathology, histopathological findings, clinical signs that could support an increased thyroid activity, the relationship to treatment of this change remained doubtful and could not be considered of toxicological importance. The applicant concluded that the thyroid values in their XXXXX week study with monepantel were within the normal physiological range.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 14

NOEL determination • The applicant asserted that based on the biological and statistical evaluations of the data in the pivotal XXXXX study, 3 mg/kg body weight was considered to be a valid NOEL for the risk assessment. The applicant also indicated that an assessment factor of 100 was considered sufficient as the XXXXX was the most sensitive species and the findings at the NOEL/NOAEL were minor and not considered adverse.

The Committee also considered the international status of monepantel: • EU: On 14 November 2009 the European Medicines Agency accepted monepantel for veterinary use on the basis of an ADI of 0.03 mg/kg. • New Zealand: In January 2009, the product was granted registration in New Zealand with a withdrawal period of 7 days for meat, based on the ADI of 0.03 mg/kg bw/day.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (a) toxicity and safety, (b) risks and benefits, (c) potential hazards, (d) extent and patterns of use and (f) the need for access to a substance, taking into account its toxicity compared with other substances available for a similar purpose.

A Member asserted that the positive skin sensitisation results for the product were likely due to the solvents or excipients in the product given that there was no skin sensitisation found for the TGAC. As such, this was a matter for the regulator and was not relevant to the scheduling consideration of monepantel. XXXXX.

A Member noted that the submission did not include any inhalational toxicity studies, however, since the product would be used as an oral drench for sheep, inhalation exposure would be unlikely.

A Member asserted that there was a real need for this substance as monepantel is one of the few substances that is highly efficient against various drug resistant worms in sheep. The Member noted that monepantel had already been registered in New Zealand. A Member advised that the regulator had already received public enquires about the registration status of monepantel.

The Committee generally agreed that the low acute oral and dermal toxicity, with only slight eye and dermal irritant potential, constituted a risk that could be adequately addressed through a Schedule 5 listing.

RESOLUTION 2009/56 - 2

The Committee decided to include a new entry in Schedule 5 for monepantel.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 15

Schedule 5 – New entry

MONEPANTEL.

6.2 SAFLUFENACIL

PURPOSE

The Committee considered the scheduling of saflufenacil.

BACKGROUND

Saflufenacil is a member of the pyrimidindiones group of herbicides. Its mode of action is through a process of membrane disruption which is initiated by the inhibition of the enzyme protoporphyrinogen oxidase (PPO). This inhibition interferes with the chlorophyll biosynthetic pathway. The chemical can be rapidly absorbed by roots and foliage of the plant, and results in membrane damage and eventually plant death by inhibiting the PPO enzyme in the presence of light.

Saflufenacil provides rapid burn-down of emerged broadleaf weeds. Saflufenacil has been shown to effectively control many key broadleaf species, including glyphosate or ALS resistant biotypes, such as horseweed, prickly lettuce, common lambsquarters, ragweed species, and pigweed species.

Other pyrimidindione herbicides include benzfendizone and butafenacil. Benzfendizone is not registered in Australia. Butafenacil is in Appendix B.

Saflufenacil is the provisionally approved common name. The chemical name (IUPAC) is N'-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydro-1(2H)- pyrimidinyl)benzoyl]-N-isopropyl-N-methylsulfamide. The CAS number is 372137-35- 4. The chemical structure is given below:

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 16

DISCUSSION - SUBMISSIONS

XXXXX prepared an evaluation report on an XXXXX application by XXXXX to register a new technical grade active constituent (TGAC) saflufenacil and XXXXX products, XXXXX.

Members noted the following from the evaluation report: XXXXX. • Public Health Standards − The ADI for saflufenacil was established at 0.017 mg/kg bw/d based on a NOAEL of 5 mg/kg bw/d in a developmental XXXXX study and using a 300-fold safety factor. − The ARfD for saflufenacil was established at 0.017 mg/kg bw/d based on a NOAEL of 5 mg/kg bw/d (which is also the NOEL) in a developmental XXXXX study and using a 300-fold safety factor. − Based on the developmental toxicity observed in XXXXX at a relatively low dose in the absence of maternal toxicity, and the potential human relevance of these effects, the evaluator asserted that it was appropriate to include saflufenacil in Schedule 6, with Appendix F Warning Statement 27, i.e. “This product contains saflufenacil which causes birth defects in certain laboratory animals. Women of child bearing age are advised not to mix, load or spray this product. They should keep out of crops being sprayed”. Members recalled, however, that Appendix F warning statements were not applicable to APVMA registered products. − Members subsequently noted advice from the evaluator that Schedule 7 listing may also be appropriate for saflufenacil given the developmental toxicity concerns.

Members also noted that the evaluation recommended the following warning statement should appear on product labels: • This product contains saflufenacil which causes birth defects in certain laboratory animals. Women of child bearing age are advised not to mix, load or spray this product. They should keep out of crops being sprayed.

Members particularly noted the following from the evaluation report: • The toxicology assessment of saflufenacil was conducted jointly by scientist from XXXXX. The database supplied by the applicant was considered to be adequate for the purposes of risk assessment. • The evaluator advised that given the difficulties in determining whether some observed effects were necessarily adverse, Australian toxicological assessments usually used the terms NOEL and LOEL instead of NOAEL and LOAEL (the

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 17

XXXXX approach). However, as the report relied heavily on the international work- share assessment, the evaluator had adopted NOAEL and LOAEL approach using scientific justification for their adoption. The Committee noted that for developmental toxicity the NOAEL value was also a NOEL.

The following toxicological information on the TGAC was noted by the Members: XXXXX Based on the findings of the acute toxicological studies evaluated, TGAC saflufenacil was of low acute toxicity by the oral, dermal, and inhalation routes XXXXX. It was minimally irritant to eyes and slightly irritating to skin in XXXXX. Skin sensitization testing in XXXXX did not demonstrate a potential for skin sensitization.

Repeat dosing of saflufenacil in XXXXX caused microcytic hypochromic anaemia and porphyria, and clinical chemistry and histopathological changes in the liver, spleen and/or bone marrow.

Saflufenacil was not genotoxic in in vitro and in vivo tests. There were no carcinogenicity potential found in long-term studies in XXXXX.

It was not a neurotoxin or reproduction toxin in XXXXX.

The estimation of ADI was based on the lowest NOAEL observed in subchronic and chronic toxicity, carcinogenicity, reproduction and neurotoxicity studies with saflufenacil. Results from the relevant toxicity studies identified the lowest NOAEL was 4.6 mg/kg bw/d in the XXXXX carcinogenicity study in XXXXX. This translated into an ADI of 0.046 mg/kg bw/d after applying a safety factor of 100. This was considered to be appropriate for the general public excluding women of child bearing age. However, saflufenacil exhibited foetal toxicity in the absence of maternal toxicity in a XXXXX development study. Decreased foetal body weights and increased skeletal malformations were observed at XXXXX. Moreover, due to limited foetal findings at XXXXX and their toxicological significance and incidence, the evaluator considered that the mid-dose of XXXXX is likely to be close to the foetal NOAEL/LOAEL threshold. To protect women of child bearing age, the evaluator determined ADI based on the developmental NOAEL of 5 mg/kg bw/d, by applying the standard uncertainly safety of 100 and an extra safety factor of 3 accounts for the developmental concerns. This resulted in an ADI of 0.017 mg/kg bw/d.

Members noted the following regarding the formulated product – XXXXX

• It was of low acute oral, dermal and inhalational toxicity in XXXXX. It was a slight skin and eye irritant in XXXXX, but was not a skin sensitiser in XXXXX.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 18

Members also noted the following points regarding the formulated product – XXXXX

• It was low to moderate acute oral toxicity, and low dermal and inhalational toxicity in XXXXX. It was a moderate skin and severe eye irritant in XXXXX. It showed skin sensitisation potential in a modified Buehler test. • Members noted that the toxicity profile of the TGAC saflufenacil was different to that of XXXXX, and that the evaluator did not elaborate on possible reasons for this. XXXXX.

Members noted that with the available toxicology information, the evaluator had classified saflufenacil as a hazardous substance according to NOHSC Approved Criteria for Classifying Hazardous Substances (NOHSC, 2004), with the risk phrase: ‘Possible risk of harm to unborn child for concentrations ≥ 5%’.

Members also noted that the applicant response to the evaluation report argued that the results of toxicity studies showed end points which suggest that saflufenacil falls into the parameters for consideration as a Schedule 5 substance. Members particularly noted that the applicant did not provide any specific argument to address the developmental toxicity concern.

Members additionally noted that a pre-meeting comment from XXXXX asserted that the results of the acute toxicology studies fall within the parameters of a Schedule 5 substance.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (a) toxicity and safety, (b) risks and benefits, (c) potential hazards, (d) extent and patterns of use and (h) purpose for which the substance is to be used.

A Member noted that the issue of most concern with regards to the scheduling of saflufenacil was the developmental toxicity results, which occurred in the absence of any significant signs of maternal toxicity. However, the Member observed that this was only the case for the studies in XXXXX. The toxicity studies in XXXXX showed effects on the foetus only at levels associated with maternal toxicity and there was no evidence of teratogenicity. The Member therefore recommended a Schedule 6 entry for saflufenacil.

A Member noted, however, that the bent scapula effect was particularly concerning as it was a highly unusual developmental toxicity marker and this may be grounds for considering a Schedule 7 rather than Schedule 6 entry. Another Member agreed, noting that this alone may be a sufficient driver for considering Schedule 7. Such an irreversible effect, it was agreed, would fit well with the Schedule 7 criteria.

A Member noted that, while the TGAC was not intended for home garden use, it was difficult to enforce this intent with only a Schedule 6 listing, although there were avenues

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 19

available to the regulator. Another Member noted the intended pack size of the products (1 and 5 kg for XXXXX and 1, 2, 5 and 10L for XXXXX) may suggest intent from the applicant for domestic market supply.

A Member aired concerns about public exposure to this substance given the developmental toxicity data. The Member noted that the intended use of this product could see it sprayed in various public areas, including nature strips and commercial areas. The Member was particularly concerned about the lack of information on the environmental fate and possible withholding period for the formulated product. The Member therefore suggested that appropriate label warning statements were crucial. Several Members generally agreed that this would have to be addressed by APVMA through registration.

Another Member was concerned about the evidence of an anaemia effect at low exposures and felt that this was relevant to occupational exposure.

On the basis of the product’s intended use and toxicity profile, the Committee generally agreed to include saflufenacil in Schedule 7. The Committee recalled that Schedule 7 restricted access to licensed users.

Other matters

A Member expressed concern over the significantly higher oral toxicity of the XXXXX, compared with the TGAC, while not an issue for scheduling, the Member felt that there were some issues which should be brought to the attention of the regulator: • the toxicity studies conducted on the product were, in the Member’s opinion, inadequate and the data presented was incomplete; • the studies were done on a small number of animals (n=3) and no post mortem was conducted on the two animals that died; and • there were concerns as to whether the methodology of these studies was satisfactory.

A Member also expressed concern over the proposed product names. The proposed words, XXXXX and XXXXX, seemed to trivialise the fact that the active substance was a herbicide chemical. A Member indicated that the proposed trade names should have appropriate meaning, should not be offensive or misleading. A Member particularly noted, however, the potential for confusion from the name XXXXX given that there is a dermal product of that name in the market for XXXXX.

RESOLUTION 2009/56 - 3

The Committee decided to include a new entry in Schedule 7 for saflufenacil.

Schedule 7 – New entry

SAFLUFENACIL.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 20

7. MATTERS REFERRED BY OFFICE OF CHEMICAL SAFETY AND ENVIRONMENTAL HEALTH (OCS&EH) OR THE NATIONAL INDUSTRIAL CHEMICALS NOTIFICATION AND ASSESSMENT SCHEME (NICNAS)

No items.

8. OTHER MATTERS FOR CONSIDERATION

XXXXX

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

No items.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 21

PHARMACEUTICALS

10. MATTERS ARISING FROM THE MINUTES OF THE PREVIOUS MEETING (CONSIDERATION OF POST-MEETING SUBMISSIONS UNDER 42ZCY(1)(c)

10.1 GUAIPHENESIN

PURPOSE

The Committee considered a post-meeting submission concerning the decision to include modified release guaiphenesin in Schedule 2 and amend the Schedule 4 entry.

BACKGROUND

The February 2009 Meeting considered a rescheduling application from XXXXX proposing that modified release formulations of guaiphenesin be unscheduled or, alternatively, Schedule 2. The Committee decided that Schedule 2 would be the most appropriate.

The schedule wording agreed on by the Committee was as follows: Schedule 2 – New entry

GUAIPHENESIN in a modified release dosage form of 1200 mg or less of guaiphenesin with a recommended daily dose of 2400 mg or less when labelled not for the treatment of children under 12 years of age.

Schedule 4 – Amendment

GUAIPHENESIN – Amend entry to read:

GUAIPHENESIN for human therapeutic use except:

(a) in oral liquid preparations containing 2 per cent or less of guaiphenesin;

(b) in divided preparations containing 200 mg or less of guaiphenesin per dosage unit; or

(c) when included in Schedule 2.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 22

DISCUSSION - SUBMISSIONS

XXXXX has provided a post-meeting submission. The Committee noted that the following data provided was also presented in the original submission. The Committee further noted that, as the 20 week cut-off was met for this submission, a pre-meeting response on the evaluation report was received from the applicant for the February 2009 meeting. The following points were made in the post-meeting submission in relation to the evaluation report: • In regards to the potential for a release of high doses of guaiphenesin due to mastication, it was stated that guaiphenesin had a bitter taste and faint odour making it relatively unpalatable. Further, guaiphenesin had a wide margin of safety. The post- meeting submission referred to a study (Boyd EM, Sheppard EP & Boyd CE, 1967, The Pharmacological Basis of the Expectorant Action of Glyceryl Guaiacolate, Applied Therapeutics, pp55-59) which investigated the pharmacological activity of guaiphenesin when administered by stomach tube to anaesthetised rabbits. An LD50 of 2553 mg/kg was calculated. This indicated a large margin of safety over 600-1200 mg (8.5-17 mg/kg) provided by the recommended does of the modified release formulation. This study was provided in the original application. • The post-meeting submission referred to the evaluator’s comment on the possibility of an increase in the frequency of adverse events with modified release formulations compared to immediate release formulations of guaiphenesin and the subsequent need for post-marketing data to confirm or dispel this hypothesis. The post-meeting submission stated that post-marketing data relating to modified release formulations in the US was available from July 2002 to April 2008. • Out of 1.508 billion tablets sold, a total of 2010 cases reported 2838 adverse events. The most commonly reported events were: gastrointestinal disorders such as diarrhoea and nausea, nervous system disorders such as dizziness, headache and insomnia and general disorders and administration site conditions such as the product being ineffective. • The post-meeting submission concluded that there was little or no evidence available to suggest the frequency of adverse effects is increased with modified release formulations of guaiphenesin when compared to immediate release formulations. Further, that XXXXX remained diligent to post marketing surveillance as set out in the Pharmacolvigilance Guidelines by the International Conference on Harmonisation.

The Committee recalled the following from the February 2009 Meeting: • The Committee agreed that data presented in the application established bioequivalence between the standard formulation and the modified release formulation however; there was a lack of evidence in relation to the efficacy of either formulation. While efficacy was the remit of the regulator through the registration process, it is relevant to 52E(1)(b) the risks and benefits of a substance.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 23

• The use of guaiphenesin in the treatment of fibromyalgia and chronic fatigue syndrome was discussed. A Committee member spoke of several overseas based websites which promoted the use of modified release guaiphenesin formulations in the treatment of fibromyalgia (with the claim that the uricosuric effect of guaiphenesin leads to increased phosphate excretion). The doses recommended for the treatment of fibromyalgia appeared to align with the strength of the proposed modified release formulation but for a duration of months, potentially years. While this is not an approved indication, and indeed there appeared to be no published controlled trials supporting its use, the Committee was concerned that sufferers may choose to access modified release formulations for this purpose, in light of promotion via the internet. The Committee also noted that enquiries on this have been made to some jurisdictions’ drug information centres. • The Committee also discussed the lack of post-marketing data available on this particular formulation. Without such data, the Committee was unconvinced that a modified release formulation should be released on the Australian market exempt from scheduling (52E(1)(a) toxicity and safety). Therefore, it was felt more appropriate that modified release formulations be only available from pharmacies so that professional advice would be available if required. It was concluded that a Schedule 2 listing for modified release guaiphenesin would be the most appropriate.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the post-meeting submission provided no new information relevant to Section 52E (1) which might lead the Committee to vary its February 2009 decision.

RESOLUTION 2009/56 - 5

The Committee confirmed its February 2009 decision (2009/55-23).

11. OTHER OUTSTANDING MATTERS FROM PREVIOUS MEETINGS

11.1 ARBUTIN

PURPOSE

The Committee considered the scheduling of arbutin (glycosylated hydroquinone).

BACKGROUND

Arbutin is a glycosylated hydroquinone (CAS number 497-76-7, chemical name 4- hydroxyphenyl-beta -D-glucopyranoside) extracted from plants such as bearberry, blueberry, cranberry and mulberry. Arbutin is also found in most types of pears. Arbutin

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 24

has been used as a skin-lightening agent. Arbutin can be hydrolysed in the presence of weak acids to generate free hydroquinone.

At the February 2009 meeting, the Committee considered the scheduling of hydroquinone, including a proposal to amend the exemption for use in hair dyes. A pre- meeting submission to this consideration raised concerns about salts/derivatives (particularly arbutin) being captured under the hydroquinone schedule entries. The Committee decided: • To defer a decision on hydroquinone in skin bleaching products until the United States Food and Drug Administration’s (USFDA) final action was known. • To amend the exemption for hair preparations containing hydroquinone. • To confirm that the current scheduling of hydroquinone remains appropriate with respect to salts and derivatives. • To foreshadow specific scheduling entries for arbutin at the June 2009 meeting.

Previous consideration of hydroquinone derivatives

The May 1987 meeting noted that monobenzone was actually more potent than hydroquinone and agreed to foreshadow that it should be in Schedule 4, together with other derivatives of hydroquinone for human therapeutic or cosmetic use, with no exceptions (whereas hydroquinone had a Schedule 2 entry). The Members noted that the other ether derivatives of hydroquinone were more potent than hydroquinone and had a similar side effect profile to monobenzone.

The July 1987 meeting amended the monobenzone entry by specifying ‘other alkyl ethers of hydroquinone for human therapeutic use or cosmetic use’, rather than all derivatives. No reason was recorded. This remains the wording in the current monobenzone entry. Therefore, hydroquinone salts or derivatives which are not alkyl ethers of hydroquinone are likely to be captured by the current hydroquinone entries.

DISCUSSION - SUBMISSIONS

Pre-meeting Comments

A pre-meeting comment was received from XXXXX regarding hydroquinone and arbutin. Members particularly noted the following regarding arbutin: Conclusion • The scheduling of arbutin should remain equivalent to hydroquinone because arbutin hydrolyses on the skin to release hydroquinone. Discussion • The pharmacological effect of arbutin seemed to be due to the fact that it hydrolyses to hydroquinone under acidic conditions, such as on human skin.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 25

• Given the known side effects of hydroquinone, i.e. skin sensitivity, both hydroquinone and arbutin are appropriately controlled in Schedule 2 at a concentration of up to the equivalent of 2 per cent hydroquinone and Schedule 4 in higher concentrations. • The current Schedule 2 status of arbutin (under the current hydroquinone entry) means that products containing arbutin cannot be marketed in cosmetic products but can be registered as medicines for therapeutic use with the permission of the TGA. • Products containing hydroquinone are required by the TGA’s Required Advisory Statements for Medicines Labels (RASML) to include the following label statements: − WARNING - If a pigmented spot or mole has recently become darker, changed colour, become enlarged or itchy, or bleeds, do not use this product, see your doctor immediately . − Do not use on children. − Do not use near the eyes. − Mild irritation may occur; stop use if it becomes severe. − If fading is not evident in three months, seek doctor’s advice. − Long term and repeated use should be avoided because darkening of the skin could occur. • The submission contended that all products containing arbutin should be required to have these same label warning statements. • Although skin lightening products containing arbutin can currently be sold as cosmetics in Europe, this is under review following an opinion of the Scientific Committee on Consumer Products (SCCP) that ‘the SCCP considers the currently requested use of Beta-arbutin in cosmetic products unsafe’. Since there is currently a lack of data regarding arbutin and its properties the submission argued that arbutin should continue to be treated in the same manner as hydroquinone. • Asserted that there was no history of use of arbutin as a medicine or as a cosmetic in Australia so it was uncertain what adverse effects this substance may have if it were to become unscheduled and therefore freely available in cosmetics.

Members also noted the following from XXXXX pre-meeting submission: • Asserted that arbutin is an approved cosmetic ingredient in the EU, for use as an antioxidant and skin conditioner with no limitations imposed. • Noted that, although the recent opinion by the SCCP on arbutin raised some concerns over the bioavailability of hydroquinone under the conditions of intended use, the general toxicological assessment of arbutin suggested that the substance may be safe. • Noted that no decisions have yet been made by the Commission of European Communities based on the SCCP opinion.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 26

• Requested that an exemption cut-off from scheduling of 7% be considered.

February 2009 Pre-meeting Submission

Members recalled that a pre-meeting submission to the February 2009 meeting from XXXXX asserted that there was some potential for confusion with the schedule entry for hydroquinone and its application to hydroquinone derivatives, such as arbutin, and proposed that separate schedule entries for hydroquinone derivatives should be considered.

XXXXX noted that a number of plant extracts known to contain arbutin are currently used in cosmetic products in Australia at a low concentration. XXXXX also advised that on 15 April 2008, the SCCP published its opinion on arbutin. The general toxicological assessment of arbutin suggested that the substance may be safe. However, the SCCP raised some concerns over the bioavailability of hydroquinone under the conditions of intended use.

February 2009 Committee Discussion

The Committee additionally recalled the following from Members’ discussion at the February 2009 meeting: • The SCCP indicated, in relation to arbutin, that the bioavailability of hydroquinone under conditions of intended use of the substance was of concern. However, a Member noted that at this stage, the SCCP opinion had yet to be adopted in the EU. That said, this still provided a strong basis for not supporting the requested exemption from scheduling for salts and derivates of hydroquinone, especially arbutin. • A Member asserted that the SCCP report indicated that the risk from arbutin was less than that posed by hydroquinone, and that capture as a derivative of hydroquinone was therefore no longer appropriate. While one Member suggested deferring any decision on arbutin until the final EU decision, the Committee generally agreed that there appeared to be sufficient information to hand for considering a separate schedule entry for arbutin. A Member also noted that a specific entry would override capture as a derivative under the hydroquinone entry. Members therefore agreed to foreshadow consideration of a separate schedule entry for arbutin at the June 2009 NDPSC Meeting. • A Member asserted that there were a number of other ‘natural’ plant extracts that would possibly be considered derivatives of hydroquinone which industry may wish to incorporate into cosmetic products. Another Member noted, however, that a number of hydroquinone derivatives shared hydroquinone’s risk profile and, indeed, that some actually may be more of a risk than hydroquinone. The Member cautioned against a blanket approach to hydroquinone salts and derivatives and asserted that the June 2009 consideration should remain focused on arbutin alone. • The Committee therefore generally agreed that it was not appropriate to limit the current hydroquinone entry by excluding salts or derivatives. Members noted that, as

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 27

foreshadowed for arbutin, it remained open for specific hydroquinone salts/derivatives to be considered for separate schedule entries, should sufficient data be provided to the Committee.

SCCP Opinion on Arbutin

Members recalled the following from the SCCP opinion on arbutin: Conclusion • Although the general toxicological assessment of arbutin suggests that the substance may be safe, the bioavailability of hydroquinone under conditions of intended use was of concern. Whereas hydroquinone was initially permitted at a concentration of 2 per cent, a 1998 opinion of the Scientific Committee On Cosmetic and Non-Food Products (SCCNFP) recommended that the substance should not be used any more as a depigmentation agent in cosmetic products due to observed clinical side effects, among which was exogenous ochronosis. • Consequently, the SCCP considers the currently requested use of arbutin in cosmetic products unsafe. In addition, it was the opinion of the SCCP that the same concern can be expressed for other products that result in the release and/or formation of hydroquinone before or upon application on the skin. Background • Hydroquinone is listed in Annex III ‘List of Substances which cosmetic products must not contain except subject to restrictions and conditions laid down’ (entry 14) of the European Council’s Cosmetics Directive 76/768/EEC. Its permitted use is restricted to hair-dye products and artificial fingernails. Since the banning of hydroquinone as a skin whitener, other substances have been used for this purpose, including arbutin. • The effect of arbutin seemed to be due to the fact that it hydrolyses to hydroquinone. Arbutin is being used as an ingredient alone and in skin lightening products. • The SCCP was asked in July 2005 to review arbutin to address the following: − Does the SCCP consider the use of arbutin to be safe for consumers in cosmetic products in a concentration up to 7 per cent? − Does the SCCP recommend any restrictions with regard to the use of arbutin in cosmetic products?

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 28

Toxicity Summary Endpoint Conclusion Acute oral toxicity LD50 9804 mg/kg bw (mouse), 8715 mg/kg bw (rat). Acute dermal toxicity LD50 > 928 mg/kg bw (rats and mice) – maximum practically applicable dosage. Skin irritation 10 % aqueous solution was non-irritating to rabbit skin. Low irritation potential by human patch test. 0, 7 and 10 % in arbutin containing products displayed low irritation potential in human tests. Eye irritation 10% aqueous solution had little potential for irritation (rabbit). Skin sensitisation Not a sensitiser by Magnusson Kligman Guinea Pig Maximisation Test. Repeated dose No changes attributed to arbutin up to a dosage of 1000 mg/kg bw/day – can be considered the NOEL. Sub-chronic (90 days) No changes attributed to arbutin up to a dosage of 618 mg/kg dermal toxicity bw/day (the maximum technically applicable dosage) – can be considered the NOEL. Mutagenicity/Genotoxicity Nonmutagenic in reverse mutation tests in bacteria. Did not in vitro induce chromosomal aberrations at concentrations up to 0.34 mg/ml in Chinese hamster lung fibroblasts, irrespective of metabolic activation. Carcinogenicity Observed (non-)tumour lesions in mouse study are ones frequently observed in aging mice. The NOEL value for was therefore estimated to be 400 mg/kg bw/day in male and female mice. It was concluded that arbutin was not carcinogenic under the 18 month study conditions. Reproductive toxicity 400 mg/kg/day did not affect reproductive functions of parent and F1 rats but caused body weight decrease in female foetuses, decreased organ weights of the unilateral ovary of female F1 rats. Estimate the NOEL to be 100 mg/kg/day. Toxicokinetics Under in use conditions in human volunteers, hydroquinone is released to a relative level (compared to the arbutin + hydroquinone content) as high as 11.8 % (w/w). Phototoxicity and Little phototoxicity potential. Did not possess photoallergic photosensitisation potential under test conditions.

SCCP Identified Issues • In acidic medium, arbutin is easily hydrolysed into hydroquinone. This is of relevance in situations where arbutin is incorporated in aqueous lotions with a slightly acidic pH, facilitating hydrolysis into hydroquinone within the formulation. • Hydrolysis has been described to significantly take place with oral ingestion of arbutin (stomach acids), but also to a lesser extent after dermal exposure. In addition, enzymatic biotransformation may be expected in both cases. • In light of the above, it also needs to be noted that the ratio hydroquinone/(arbutin + hydroquinone) in the skin amounted up to 11.77 per cent in a skin metabolism study

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in human volunteers which was considerably higher than the ratio of the two substances in the applied product. • Although this finding was not considered alarming by the performing laboratory because the absolute levels of arbutin and hydroquinone in the skin were considered relatively small and their contribution to the total body burden was considered negligible, it needs to be considered that this study was of limited size (18 volunteers) with only one type of formulation and that dermal absorption will be influenced by the vehicle used. • Moreover, the dermal absorption of hydroquinone is reported to be 57 per cent, which is much higher than the dermal absorption value observed for arbutin. • These considerations raise questions as to the safety of the use of 7 per cent arbutin in cosmetic products for skin bleaching purposes. If hydroquinone is released in sufficient amounts either in the product or on contact with the skin, the product could not be considered safe, since hydroquinone has been assessed as being unsafe for use in skin lightening applications due to the danger of ochronosis and leukomelanoderma and consequently has been banned for this use in the EU. The hydroquinone levels at which ochronosis has been described is 1 per cent and higher. • As no data was available on concentration levels below 1 per cent, a lower threshold for the occurrence of ochronosis was difficult to establish. Although the risk for ochronosis may be relatively low, the occurring cases can be severe and irreversible. • In the case of release of hydroquinone, the aspect of skin sensitisation has to be considered, since hydroquinone has been identified to be a skin sensitiser. Also, the concerns about cancer risks then become an issue. • The use of arbutin at 7 per cent in skin bleaching products induces a complex situation for which the local application level and the bioavailability of hydroquinone cannot be generalized.

Brief Summary of Safety Concerns Relating to Hydroquinone (see also item 11.7)

Topical hydroquinone may cause transient erythema and a mild burning sensation. Occasionally hypersensitivity has occurred. Concentrations of 2 to 4 per cent are commonly used; higher concentrations may be irritants and increase the risk of ochronosis. Ochronosis is an autosomal recessive metabolic disorder that causes an excess of homogentisic acid, resulting in adverse pigmentation, calcification, and inflammation of cartilagenous and related tissue throughout the body.

The Committee also noted the following matters previously considered relating to hydroquinone: • Hydroquinone was included in Schedule 4 in 1969 due to concerns about skin lightening creams which were being targeted to the PNG and indigenous Australian populations. The Committee agreed that, due to the highly toxic nature of this substance and the potential for ADRs, free availability was not warranted.

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• The February 1971 meeting agreed to allow an exemption from scheduling for preparations of hydroquinone containing 2% or less. This was reconsidered at the May 1986 and May 1987 where it was agreed to foreshadow creation of a new Schedule 2 entry for preparations of 2% or less for human therapeutic or cosmetic use. Members agreed that the safety profile of preparations of 2% or less warranted inclusion in Schedule 2 with an accompanying Appendix F warning statement entry. This was confirmed at the July 1987 meeting. • The June, October and February 2009 meetings noted that the USFDA was reviewing the safety of hydroquinone products because of concerns about carcinogenicity with regard to topical use. The Committee’s consideration of this concern was deferred until such time as the USFDA review was finalised.

Members also recalled that a 1998 SCCNFP opinion regarding hydroquinone as a skin depigmenting agent concluded that: • Clinical adverse effects of skin bleachers based on hydroquinone and its ethers are represented by two main aspects: exogenous ochronosis and leukomelanoderma. Ochronosis is the darkening of skin accompanied by changes in the papillary dermis, which may became ochre-like coloured, with cellular degeneration. Leukomelanoderma is a depigmentation of the skin more or less uneven, giving a confetti-like pattern. This effect is related to the activity of hydroquinone which suppress melanogenesis by inhibiting the enzymatic oxidation of tyrosine. • The SCCNFP was of the opinion that hydroquinone should not be used as depigmenting agent in cosmetic products due to observed clinical side effects.

Hydroquinone was banned from use as a skin lightening agent in the UK and the EU as of January 2001. It also appears to have been banned from use for cosmetic purposes in Japan and South Africa (in 1998).

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extent and patterns of use, (e) dosage and formulation and (g) potential for abuse.

A Member asserted that arbutin itself had low toxicity and that the concentration of liberated hydroquinone was likely to be low in cosmetics. The Member also advised that there were already cosmetics on the market containing arbutin with no evidence of harm being reported. The Member advocated that there was therefore no need to schedule low concentrations of arbutin for non-therapeutic use.

Other Members disagreed, noting that it was the risks from the liberated hydroquinone rather than the inherent toxicity of arbutin itself which was of concern. A Member also noted that the effect often sought by specifically including arbutin in dermal cosmetics was that achieved by liberating hydroquinone (i.e. modification of skin pigmentation).

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A Member recalled that there is currently no exemption from the Schedule 2 hydroquinone entry apart from the 0.3% or less for hair preparations, noting that such hair preparations may have less of an exposure risk than that posed by dermal cosmetic products. However, exposure to low levels of arbutin via ingestion is considerable, given that arbutin is present in a number of fruits and this fact may provide weight to the proposals to exempt low concentrations of arbutin from scheduling.

A Member noted that, while the XXXXX pre-meeting submission had proposed an exemption cut-off of 7 per cent, the SCCP conclusion was that the use of arbutin at 7 per cent in skin bleaching products induces a complex situation for which the local application level and the bioavailability of hydroquinone cannot be generalized. Several Members asserted that, given this uncertainty regarding the level of hydroquinone generated from arbutin, it was difficult to extrapolate to propose a possible cut-off. The Committee generally agreed that this created difficulties in considering separate scheduling for arbutin as the actual risk was unknown.

The Committee generally agreed that until more robust data was available regarding the actual risk of arbutin, then it remained appropriate to take a conservative approach and control arbutin under the current scheduling for hydroquinone as a derivative (i.e. cosmetic use would be captured by Schedule 2 or 4, requiring cosmetic use to be subject to Therapeutic Goods Administration approval). Members agreed that the scheduling of arbutin could be revisited when sufficient data was available.

RESOLUTION 2009/56 - 6

The Committee decided to: • confirm that arbutin for cosmetic use should continue to be scheduled as a derivative of hydroquinone; • cross arbutin with glycosolated hydroquinone in the SUSDP index.

SUSDP 25 Index – New Cross References

ARBUTIN

See HYDROQUINONE

GLYCOSYLATED HYDROQUINONE

See HYDROQUINONE

11.2 XXXXX

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11.3 SCHEDULING OF OTC PRODUCTS CONTAINING CODEINE

PURPOSE

The Committee considered the scheduling of over-the-counter (OTC) products containing codeine.

BACKGROUND

At its June and October 2005 meetings, the Committee noted concerns relating to the codeine+ibuprofen bi-layer tablet reportedly being cut in half to access the codeine. Given that the product had been withdrawn by the sponsor and replaced with a single layer formulation, the Committee agreed that concerns of abuse had been resolved.

At the June 2007 meeting, the Committee noted claims of an apparent increase in the incidence of codeine+ibuprofen abuse where the codeine was being easily separated by simple dissolution in water. The Committee asked the TGA to investigate dissolution rates of the products in question. The Committee noted at the February 2008 meeting that the results of the dissolution investigation were not yet available and agreed to foreshadow consideration at the June 2008 meeting.

At the June 2008 meeting, the Committee formed a working party (the Codeine Working Party - CWP) to review the availability of all OTC combination analgesics containing codeine (CACC) and the definition of ‘compounded’. The Committee also agreed to foreshadow consideration of a reduction in the Schedule 2 codeine+ibuprofen pack size limit and to include a Schedule 3 pack size limit.

At the October 2008 meeting, the Committee noted the CWP’s progress on the definition of ‘compounded’, including the likelihood of recommendations being tabled at the February 2009 meeting (on that issue) but deferred consideration of codeine+ibuprofen pack sizes until the CWP had progressed further, noting the importance of resolving this issue without undue delay.

At the February 2009 meeting, the Committee considered a number of proposals from the CWP, together with the findings of a separate evaluation of OTC CACC. Members agreed to foreshadow amendments including (but not limited to) a proposal to delete the Schedule 2 codeine entry and amend the Schedule 3 entry by: • limiting the recommended daily dose (maximum daily dose) to a maximum of 100 mg codeine; • limiting pack size to a maximum of 5 days supply; • restricting divided preparations to a maximum of 12 mg codeine per dosage unit; and • restricting undivided preparations to a concentration of ≤ 0.25 per cent codeine.

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The Committee also decided to seek advice from the TGA regarding the efficacy of codeine in OTC combination products intended for pain relief, and the appropriateness of the fixed dose combinations currently registered.

DISCUSSION - SUBMISSIONS

Pre-meeting Comments

A total of 66 pre-meeting comments were received by the gazetted closing date and one late comment was also received: XXXXX Brief Overview of Pre-meeting Comments by Topic

Proportion of CACC users at risk of harm • Many of the submissions agreed that there were legitimate concerns relating to safety due to misuse of CACC but many also felt that the extent of misuse/abuse was extremely low in comparison to total use. One submission, however, stated there was little evidence to support the view that the easy availability of CACC has led to only very limited misuse. • Most submissions from organisations involved with the supply chain of CACC asserted that excessive consumption and subsequent harm are very limited because only a very small proportion of users are consuming at levels that pose a risk. The vast majority of people use combination analgesics safely for short term treatment. This argument was predicated on an assumption that OTC CACC are more efficacious than paracetamol or ibuprofen alone. • However, a Member noted that there were only limited published data as to extent to which the addition of codeine (< 30 mg) to non-narcotic analgesics, such as paracetamol and ibuprofen, resulted in greater efficacy over paracetamol or ibuprofen alone. Jurisdictional uniformity • Many submissions asserted that it was imperative that all jurisdictions complied uniformly with the current scheduling requirements as this would preclude the current situation where larger pack sizes of CACC are available as Schedule 2 in some states (NSW has no pack size limit for Schedule 2, also noting that some jurisdictions do not allow Schedule 2 self-selection). Codeine+ibuprofen • A number of submissions claimed that codeine+ibuprofen combination products seemed to be those most frequently associated with problems and supported consideration of differential scheduling according to the non-codeine analgesic active.

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Retention of CACC in Schedule 2 • Submissions were divided between those that supported retention of a Schedule 2 entry and those that did not. • Most submissions from organisations involved with the supply chain of CACC argued that, rather than address the misuse/abuse issue using mechanisms such as removal of CACCs from Schedule 2 (which would limit access for the vast majority of ‘safe’ users), the Committee should focus on changes that would address those at risk of excessive use i.e. education, warning statements etc. • On the other hand, there was universal support from organisations involved with addiction medicine for removal of CACC products from Schedule 2. These organisations were generally silent on the issue of the need for access to short term analgesia for the general population. Efficacy • A number of the submissions that supported removal of codeine from Schedule 2 noted that there was little evidence for the efficacy of many of the current formulations that contain relatively low amounts of codeine. Unit dose, maximum daily dose and pack size • Most submissions from clinicians and those in alcohol and drug services supported a maximum OTC quantity of 10 mg codeine base per dosage unit and a maximum daily dose of 60 mg codeine. The majority of these submissions also supported a limit of 24 dosage unit or 3-5 days supply in order to increase the ‘shopping time’, thus deterring use by those who misuse large quantities, while still enabling people to manage short term pain. • Several clinicians indicated that their submissions on this issue were driven by the need to reduce harm from abuse of codeine. The efficacy argument i.e. that a higher dose may be needed to ensure that OTC products contain an efficacious dose of codeine, was not a consideration. • Most of the submissions from industry and pharmacy retail groups opposed any scheduling changes that would result in restrictions on pack sizes of CCAC. Undivided preparations • Several submissions supported restricting undivided preparations to ≤ 0.25 per cent codeine. XXXXX recommended that all undivided preparations containing codeine be moved to Schedule 3 and that the current Schedule 2 limits for concentration and maximum daily dose be used in that Schedule 3 entry, with a pack size limit of 200 mL. Codeine combinations for coughs and colds • None of the submissions that mentioned codeine combination products for coughs and colds supported a change to scheduling. Those submissions asserted that:

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− There was no evidence indicating a problem of misuse of these products. − Colds and flu are transient, self-limiting conditions whereas pain conditions can be acute or chronic. − Re-scheduling all phenylephrine+codeine combinations to Schedule 3 would position them in direct competition with pseudoephedrine+codeine combinations, potentially leading to a rebound in the sales of the latter, with adverse consequences. Real-time monitoring system • XXXXX asserted that scheduling changes to codeine would not address the issue of misuse/abuse. • XXXXX instead recommended a real-time monitoring system (NotifyRx), similar to that used for the sale of pseudoephedrine, would assist in managing the risks and potential for abuse associated with CACC. • XXXXX recommended deferral of any decision on the scheduling of codeine until the Pharmacist Only Medicines Notifiable (POMN) sub-schedule of Schedule 3 can be trialled in the Northern Territory. A Member advised that a Northern Territory trial had merely been proposed at this stage and had yet to be agreed to. • However XXXXX objected to any Project Stop type software being applied to the sale of CACC. XXXXX. • A Member noted that the real-time monitoring proposal raised a number of governance issues including ownership of the data. Another Member was of the opinion that the proposed system was impractical for several reasons: − costs of software installation and maintenance; − possible delays in implementing such a system; − difficulty in assessing effectiveness; − the highly sensitive nature of the information being captured possibly limiting the extent to which it can be used; − the parties proposing this software potentially having a vested interest in its use. • Members agreed that, at this time, the consideration should remain focused on limiting access, rather than in introducing some sort of real-time monitoring system. It was noted that, should the POMN proposal be adopted in the future, it would be open for applicants to submit rescheduling submissions at that time. • A Member noted that, while supportive of obligatory recording of sales of Schedule 3 products, he was less sure of the benefits of using real-time monitoring systems. The Member asserted that these initiatives appeared to be driven more by policing issues than by public health concerns. Face to face counselling from a pharmacist should be

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viewed as the primary tool for mitigating the risk of abuse. Another Member asserted that recording, while possibly generating good monitoring data, would not, in and of itself, address the risk of abuse. • A Member also noted that the 2001 Review of Drugs, Poison and Controlled Substances Legislation (the Galbally Review) recommended against a “recordable” schedule as this should be a professional practice issue (www.tga.gov.au/docs/html/rdpdfr.htm). Advertising • A number of submissions asserted that advertising of CACC should be prohibited as this places these products in the realm of normal items of commerce, rather than medicines. It was asserted that there was no public health benefit in the advertising or promotion of CACC and that promotion and advertising could imply to consumers that these products were without risk. Warnings • Of 13 submissions from clinicians and drug and alcohol services, 9 proposed that warnings about the risk of addiction should be included on packs and that there should be more explicit statements about the serious risks of exceeding the recommended dose of CACC, especially those containing ibuprofen. Education campaigns • A number of pharmacy and industry submissions supported an education campaign to raise awareness of the risks associated with the overuse of CACC.

Summary of Main Points from Individual Pre-meeting Submissions

Professional bodies

Points made by XXXXX included the following. • All OTC CACC should be Schedule 3. Pack sizes of 24, 48 dosage units or 5 days supply, with a 10 mg codeine per dose limit, were the most widely supported options. • Project STOP was not supported as recording sales was time-consuming and alienated regular customers. • A ban on the advertising of OTC CACC was supported. There was also a view that it was unprofessional to discount these products, as this put these products in the realm of normal items of commerce, rather than being medicines, for which sales should be supervised.

XXXXX submission included the following recommendations. • Arrangements across jurisdictions for all CACC products including (but not limited to) scheduling, pack sizes, storage requirements, supply and recording should be standardised.

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• A comprehensive national electronic data system to collect information on the provision of CACC in Schedule 3 should be established. • A national public awareness and education campaign on the appropriate use of OTC analgesics with the support of government, industry, consumers and pharmacy organisations should be established. • The current scheduling arrangements for CACC in Schedule 2 should be retained. • The current scheduling arrangements for CACC in Schedule 3 should also be retained (noting that this was integrally linked to the recommendations above), but with mandatory recording of the supply of CACC in Schedule 3. • The current scheduling for codeine combinations for coughs and colds should be retained.

XXXXX made the following recommendations: • retain the codeine Schedule 2 entry including the current limits on codeine content, CACC maximum daily dose and pack size limits at 25 dosage units for divided preparations. • continue to differentiate between CACC and those preparations intended for other purposes (such as codeine combinations for coughs and colds) in the Schedule 2 entry. Introduce pack size limits for products intended for other purposes in Schedule 2. • move undivided preparations containing codeine to Schedule 3 (irrespective of intended use) and retain the current concentration and maximum daily dose limits specified in Schedule 2 in the Schedule 3 entry. Specify a pack size limit of 200 mL for those undivided preparations. • amend part (a) of the existing Schedule 3 entry for codeine by adding a pack size limit of 48 dosage units. • retain part (b) of the existing Schedule 3 entry for codeine relating specifically to its combination with paracetamol.

XXXXX recommended that the Committee delay any final decision relating to the scheduling of codeine to allow time for the evaluator’s report to be fully considered by the CWP and for the POMN proposal to be implemented. The submission also: • agreed that there were legitimate concerns relating to patient safety due to misuse of CACC and some action needed to be taken although, the overall prevalence of misuse was most likely to be extremely low in comparison to total use; • asserted that changes to the scheduling of CACC would not effectively address the risk of misuse and would disadvantage the majority of consumers who used these products appropriately but a real-time monitoring system would provide a fast and efficient mechanism to record and monitor sales, in order to identify misuse of these products and allow for assistance to be offered;

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• stated that it was imperative that there was consistency of access to CACC across all jurisdictions and this should be addressed before any changes to scheduling occurred; • endorsed the development of a consumer education program to raise awareness of the risks associated with overuse of CACC to provide support to community pharmacists and pharmacy assistants in counselling their customers; • argued that any changes should be limited to CACC only and not affect codeine combinations for coughs and colds, as there was no evidence of a problem of misuse of Schedule 2 codeine combinations for coughs and colds; and • asserted that had the evaluator’s report been available in full for consideration by the CWP in its development of its advice to the Committee, this might have impacted on its recommendations.

XXXXX stated the following. • The evaluator’s report was a realistic assessment of the present state of affairs. • Whilst most pharmacies had large stocks of CACC, with codeine+ibuprofen being the most common, the only convincing efficacy data seems to be in dental pain (McQuay, HJ et al., 1989, ‘Codeine 20 mg increases pain relief from ibuprofen 400 mg after third molar surgery. A repeat-dosing comparison of ibuprofen and an ibuprofen- codeine combination’ Pain, vol 37, pp 7-13). − A Member asserted that this reference was not particularly relevant to the scheduling of OTC CACCs as these combinations are not approved for post- operative acute pain. • While there were sound arguments for a Schedule 3 classification, this could present logistical difficulties for pharmacists in meeting their obligations to counsel each patient who sought this combination. • Advertising and mass merchandising of codeine+ibuprofen should be discontinued, noting that a Schedule 3 classification would facilitate this. • All codeine+ibuprofen formulations in Schedule 2 should be transferred to Schedule 3 and all formulations in Schedule 3 should be transferred to Schedule 4. • Similar problems of abuse were not evident with codeine+paracetamol and while industry may take the view that the same scheduling should apply to codeine+paracetamol as codeine+ibuprofen, the principal analgesic components do have different properties and misuse of the former is not seen at present.

XXXXX supported a POMN sub-schedule in Schedule 3. The submission also: • asserted that if scheduling changes were made, then large packs of analgesics would not be offered, leading patients to buy multiple packs at greater cost or seek prescriptions from their GPs, and resulting in increased costs to the Pharmaceutical Benefits Scheme (PBS), the Medicare Benefits Scheme (MBS) and the patient;

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• suggested that the proposed scheduling changes would inconvenience bona fide consumers by decreasing accessibility to CACC; and • put forward that a POMN sub-schedule could be used to enhance recording and reporting of codeine usage, identify at-risk patients and prevent the possibility of misuse through purchase at multiple pharmacies.

XXXXX provided a submission XXXXX supporting a POMN sub-schedule to address problems of inappropriate use of CACC. This submission also: • did not support scheduling changes that would result in a restriction on pack sizes of CACC; • did support an appropriate Schedule 2 entry for CACC in smaller pack sizes; • did not support any scheduling changes to codeine combinations for coughs and colds which are currently Schedule 2, as at this stage there was no evidence these products represented a risk to the community; and • did support an alternative approach to address the problem of misuse of codeine through the implementation of a mandatory real-time monitoring system by community pharmacies for Schedule 3 CACC in larger pack sizes.

Clinicians XXXXX

XXXXX, an addiction medicine clinical nurse consultant, provided details of a case study of a patient treated in ICU following excessive use of CACC. The submission also made the following points. • Mechanisms that make it more difficult for patients dependent on CACC to access higher dosages of these products would help minimise the risk of developing a dependency and assist those with an existing dependency to seek help. • The individual dose available in divided preparations should not be increased beyond 10 mg and the recommended maximum daily dose should be not more than 60 mg. • Limiting the pack size to 24 or less would also increase ‘shopping time’ and deter use by those who misuse large quantities by would still enable people to manage their short term pain. • A warning of the risk of dependency and the risks associated with excessive doses should be included on packets of CACC.

XXXXX, a consultant pharmacist, welcomed the proposed re-scheduling to Schedule 3 which would still ensure availability and self-medication but with the added benefit of professional assessment for the need for an analgesic and of the risks of addiction. The submission also stated that: • the maximum unit dose should be 10 mg codeine; • the maximum daily dose of codeine should be 60 mg;

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• the maximum pack size should be limited to 5 days supply; • smaller pack sizes increase ‘shopping time’ and may encourage dependent individuals to seek help and treatment; • warning labels about risks of addiction (as per the UK); and • codeine+ibuprofen (c.f., codeine+paracetamol) seems to be more frequently associated with problems of abuse.

XXXXX supported changes to scheduling to prevent serious harm from non-steroidal anti-inflammatory drug (NSAID) side effects arising from high doses of ibuprofen secondary to codeine addiction. The submission also: • supported the proposal to delete the Schedule 2 codeine entry; • recommended maintaining the current maximum unit dose of 10 mg codeine; • recommended maintaining the current maximum daily dose of 60 mg; • recommended that the pack size be limited to 24 tablets; • recommended the addition of a warning about the risk of addiction (similar to the UK); and • recommended a warning on codeine+ibuprofen of ‘keep to the recommended dose - you may be at serious risk of stomach perforation or bleeding or kidney failure if you exceed the recommended dose’.

XXXXX, clinicians with an alcohol and drug service, supported deletion of the Schedule 2 codeine entry, restriction of pack sizes and pack warnings of addiction. The submission also asserted the following. • Claims that ready availability of OTC CACC had only led to a small degree of misuse were unfounded. • There was little evidence to support the efficacy of combined moderate dose codeine with paracetamol or ibuprofen preparations over paracetamol or ibuprofen alone. • Pharmacist intervention was a deterrent to excess codeine use and provided the opportunity for pharmacists to make appropriate referrals. • Limiting pack sizes engendered the inconvenience of having to shop at multiple pharmacies which was a strong motivator to seeking treatment. • Smaller pack sizes would limit the amount of product being ‘stored’ by consumers and this would lead to less misuse.

XXXXX, clinician with an alcohol and drug service, supported changes to scheduling as there was no evidence that CACC had any benefits over ibuprofen or paracetamol alone, and asserted that the codeine serves purely to increase the risk of physiological and psychological dependence with substantial physical morbidity.

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XXXXX, representative of the Faculty of Pain Medicine of the Australian and New Zealand College of Anaesthetists (ANZCA), supported the proposal to delete the Schedule 2 codeine entry and noted the following. • It was unclear whether there was any evidence of analgesic benefit for preparations with less than 30 mg of codeine phosphate and so potentially the amount of codeine in currently available CACC products had no analgesic purpose but increased the risk of physiological and psychological dependence and, consequently, morbidity. It was therefore concluded that these products should be withdrawn. • Seven per cent of the population were ultra rapid metabolisers who would get a euphoric effect from the pulse of morphine when they take codeine and it was hypothesised that these are the patients who develop dependency on these low dose CACC preparations. • The maximum daily dose of codeine should be 60 mg. • The maximum pack size should be 5 days supply. • The maximum dose per unit should be 10 mg of codeine. • An addiction warning should be added to all packs of OTC CACC products. • Recommended a warning on codeine+ibuprofen packs such as ‘keep to the recommended dose’, ‘You may be at serious risk of stomach perforation, bleeding, liver/kidney failure or death if you exceed the recommended dose’.

XXXXX, a clinician with an alcohol and drug service, agreed that while people should be able to manage symptoms by self-medicating (provided the medicines are safe), they should also be fully informed about the risks. The submission made the following points. • There should be a warning on all packs of CACC that there is a risk of addiction. Additionally there should be a warning on all packs of CACC containing ibuprofen that if the recommended dose is exceeded there is a risk of serious harm. • There should be no increase in the dose of codeine above 10 mg in each dose unit. • There should be no increase in the maximum daily dose of codeine above 60 mg. • The pack size should be limited to 24 tablets as this would increase the number of visits to the pharmacy by addicted patients which may cause them to seek treatment.

XXXXX, a clinician with a hospital alcohol and drug service, made the following points. • The current maximum unit dose of 10 mg codeine should be maintained. • The current maximum daily dose of 60 mg codeine should be maintained. • The pack size of CACC be limited to no more than 24 tablets. Anyone requiring analgesia for more than 2 or 3 days should seek medical advice.

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• CACC should be in Schedule 3 requiring profession assessment by a pharmacist which would not alter therapeutic use of these preparations by would limit their misuse. • Schedule 2 allows advertising and promotion and this may contribute to increased used. There is no public health benefit from advertising or promotion of CACC products. • Appropriate warnings of dependence should be included on the packs.

XXXXX, an addiction medicine physician, supported the deletion of the Schedule 2 codeine entry as this would prevent promotion and advertising which seemed to suggest to consumers that these products are relatively safe. The submission also made the following points. • The current maximum unit dose of 10 mg codeine should be maintained. • The current maximum daily dose of 60 mg codeine should be maintained. • The pack size should be limited to no more than 24 units per pack was recommended. • Warnings on packs of CACC regarding the risk of addiction and serious risks from exceeding the recommended dose should be mandated.

XXXXX, an addiction medicine physician, supported the deletion of the Schedule 2 codeine entry. The submission also supported: • warnings on packs of CACC of the risk of addiction. • a warning regarding excessive doses of NSAIDS for some CACC products. • maintaining the current maximum unit dose of 10 mg codeine. • maintaining the current maximum daily dose of 60 mg codeine. • limiting pack sizes to 24 dosage units. • the introduction of a special levy or tax on CACC to contribute to education campaigns directed to consumers and prescribers, and full PBS availability of buprenorphine for the outpatient management of opiate withdrawal.

XXXXX, a pharmacist, recommended: • the removal of codeine from Schedule 2; • an addiction warning on packs of CACC products; • a specific warning of risks of exceeding the maximum daily dose of ibuprofen;. • maintaining the current maximum unit dose of 10 mg codeine; • maintaining the current maximum daily dose of 60 mg of codeine; and • limiting pack sizes to 24 dosage units.

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XXXXX, an addiction medicine physician, supported the deletion of the Schedule 2 codeine entry based on experience with patients using excessive amounts of codeine+ibuprofen to support a codeine addiction but suffering consequent gastroenterological complications due to the ibuprofen. The submission supported any proposal that would make CACC products Schedule 3 but did not support any proposal that would increase the maximum daily dose, maximum dose per tablet or pack size.

XXXXX provided a copy of a 2008 report ‘Investigation of Pharmaceutical Misuse Amongst Drug Treatment Clients’ (available at http://www.turningpoint.org.au/library/pharmaceutical_misuse_report.pdf ). The report included the following references to misuse of OTC CACC. • In a survey administered to a sample of recent entrants to Alcohol and Other Drug (AOD) treatment services who had reported misuse of pharmaceuticals prior to treatment entry, approximately one third reported using an OTC analgesic in the 4 weeks before entering treatment, with approximately ten per cent of the sample using them daily. The most common brand reported was Nurofen Plus, used by 48 per cent of those using OTC analgesics. • Approximately half of the study group reported lifetime misuse of OTC analgesics and about one quarter of participants reported misuse in the four weeks prior to treatment entry. • In the retrospective clinical case note analysis of 25 selected case files of individuals reporting pharmaceutical misuse, six cases involved OTC CACC. • The report recommended better screening by AOD treatment services for pharmaceutical misuse and that screening should include medications that are not currently routinely considered, such as OTC CACC, as misuse of these drugs appears to be an emerging issue. • Key experts also reported a group of pharmaceutical misusers who did not present for treatment at traditional AOD treatment services, with these primary pharmaceutical misusers being thought to be a ‘hidden population’ of pharmaceutical misusers. XXXXX

XXXXX proposed that there should be no change to the current scheduling of codeine on the basis that there was widespread use of CACC but the overall incidence of serious reactions have been relatively low. The submission supported: • limiting the maximum daily dose to a maximum of 100 mg codeine; • limiting the pack size to a maximum of 5 days supply; • restricting divided preparations to a maximum of 12 mg codeine per dosage unit; and • restricting undivided preparations to a maximum concentration of 0.25 per cent codeine.

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XXXXX recommended that the present scheduling arrangements for codeine combinations for coughs and colds remain unchanged, small pack sizes (3 to 4 days’ supply) of CACC be retained in Schedule 2, existing larger pack sizes be restricted to Schedule 3 and that the Committee explore with industry, pharmacy and State/Territory regulatory authorities the design and operation of a system to monitor sales of CACC. The following points were also raised. • CACC play an important role in the management of strong pain for a large number of consumers in Australia. They have been available without a prescription for many years. For the vast majority of users, they are effective and have an excellent safety profile. • It is acknowledged that a small number of people misuse or abuse analgesics containing codeine and have suffered serious adverse events as a result. • The needs and interests of the vast majority of responsible consumers need to be balanced against the risk of harm to a very small number of individuals. For responsible consumers, including the elderly and those who suffer with recurring episodic pain the proposed restrictions would present unjustifiable difficulties in accessing quantities of analgesics to manage their pain. • Restricting access to these products is unlikely to have any impact on the problem of addiction or abuse. It was uncertain what the potential unintended consequences of the restrictions foreshadowed by the Committee would be on the self-management of pain in the community. • Codeine combinations for coughs and colds should be excluded from any consideration of measures aimed at addressing CACC issues. No evidence of inappropriate use had been identified in relation to these products. The hypothesis that the problem of abuse/misuse would shift to codeine combinations for coughs and colds, in the event of restrictions being imposed on analgesic combinations, was entirely untested. • The low risk of potential harm to the general community should not preclude access to small pack sizes (3 –4 days supply) in Schedule 2 stored within the professional services areas of pharmacies. • With respect to larger pack sizes, it was proposed that these be retained nationally/uniformly in Schedule 3 to ensure mandatory intervention by a pharmacist. • A real-time monitoring mechanism to track the supply of the products in Schedule 3 should be implemented. This would help identify potential problem users and support pharmacists in their professional service delivery.

XXXXX, while in general agreement with the above submission, made the following additional points: • The proposed scheduling changes would present a huge and unnecessary disadvantage to the vast majority of users who use CACC products appropriately and without adverse events.

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• The potential to divert intentional misusers of CACC products to other substances of abuse and the negative consequences of these actions needed to be carefully considered prior to making any changes in scheduling. • Changes in scheduling would not address the need for public education. It would perhaps be of benefit to provide consumers with information and resources to make better informed choices about the OTC products they use rather than simply restricting their access without explanation. This was of particular importance given the apparent discrepancy in public understanding of the consequences of paracetamol overdose versus ibuprofen overdose. • Any change should be phased-in so as not to disadvantage the many legitimate users of CACC products. The Committee could then assess the impact of such phased strategies at a future meeting.

XXXXX supported the proposal to limit the maximum daily dose to 100 mg codeine; restrict divided preparations to a maximum of 12 mg codeine per dosage unit and restrict undivided preparations to a maximum concentration of 0.25 per cent codeine. In addition the submission included the following points. • Any decision to limit the pack size to a maximum of 5 days supply should be amended to include undivided preparations in Schedule 3 to a maximum of 5 days supply at the maximum dose, or alternatively the maximum pack size for undivided preparations could be limited to 200 mL. • The proposal to delete the Schedule 2 entry for codeine was supported. • The proposal to restrict undivided preparations to a maximum concentration of 0.25 per cent was supported. Furthermore, no objection would be made to a lower level of 0.1 per cent. • Limiting the pack size to a maximum of 5 days was not supported - limiting the pack size by adult dose was not appropriate for products that are intended for use only in children.

XXXXX submission concentrated on codeine combinations for coughs and colds. The Committee was urged to separate these products from CACC re-scheduling considerations and maintain the current scheduling of phenylephrine+codeine combinations in Schedule 2. The following points were raised. • Re-scheduling all phenylephrine+codeine combinations would move the phenylephrine+codeine cold tablet range from Schedule 2 to Schedule 3 which will compete directly with pseudoephedrine+codeine combinations. It was asserted that this would lead to a rebound in sales of pseudoephedrine+codeine combinations with adverse consequences for the community. • Colds and flu were self-limiting conditions as opposed to pain conditions which may be acute or chronic.

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• Any linking of codeine combinations for coughs and colds with abuse of codeine in CACC was purely speculative and no evidence had been presented to support this. The content of codeine in combinations for coughs and colds was less than 10 mg per unit dose and the likelihood of a dependent person switching to codeine combinations for coughs and colds was remote.

XXXXX made the following points. • The majority of support for a change in scheduling appeared to be for rescheduling of codeine+ibuprofen specifically, particularly in larger packs of 72 and 75. • The NSW Health Regulatory Impact Statement for the proposed Poisons and Therapeutic Goods Regulation 2008, stated that drug misuse and poisoning causing serious illness would be expected to lead to hospital admission (http://www.health.nsw.gov.au/resources/aboutus/legal/poison_ris_pdf.asp ). However, the Chief Health Officer’s Report in the Statement did not show that CACC were a common cause of poisoning leading to hospitalisation over the period 1998-99 to 2004-05. • The sponsor’s post-marketing surveillance data over the last 4 years for its products showed 173 cases, 34 serious or approximately 8.5 per year. − A Member noted that if this rate were extrapolated to the full market, it would equate to at least 42 serious adverse reactions to OTC CACC per annum in Australia. Indeed, the actual rate was likely to be much greater as these data did not involve any products containing ibuprofen and this ingredient appeared to be the major cause of harm at present. • The post-marketing data also indicated that scheduling (Schedule 2 or Schedule 3) had little impact on the incidence of ADRs including misuse or abuse. • For the vast majority of the community, CACC continued to be safe and effective medicines. Short-term therapy for pain with CACC remained appropriate as Schedule 2 at the current daily dosages. • There was considerable variability in what should be considered short-term therapy. The British National Formulary states, in relation to dental pain, use is 1-7 days therapy whereas the New Zealand Medicines Classification Committee (MCC) view is 10 days. − A Member advised that the MCC was currently consulting on a 5 day duration limit for OTC CACC. • Rescheduling was not warranted because diversion had not been identified and post- marketing surveillance had not identified any new or changed abuse safety signals. • Anecdotal evidence of misuse/abuse of codeine+ibuprofen products required verification.

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• An amendment to scheduling for Schedule 2 CACC was suggested to restrict to no more than 3 days therapy. The Committee should also consider strengthening the mandatory warnings for Schedule 2 CACC. • The uniform jurisdictional implementation of codeine scheduling and ‘recording’ of Schedule 3 codeine medicines was supported.

XXXXX recommended that the proposals to re-schedule codeine-containing medicines should not apply to codeine combinations for coughs and colds for the following reasons. • There was no evidence to date indicating that abuse had occurred with codeine combinations for coughs and colds. • Codeine combinations for coughs and colds were generally used for short term symptomatic relief of self-limiting conditions. • Re-scheduling codeine combinations for coughs and colds to Schedule 3 would not be cost-effective. Pharmacists would be required to spend time supplying medicines for the treatment of mild, uncomplicated conditions. • Scheduling was not an effective mechanism to prevent abuse. A public education program would be a more effective strategy in dealing with abuse.

XXXXX made the following points. • The level of misuse/abuse of codeine+ibuprofen was very low and there is only anecdotal evidence that it was increasing, with no evidence of an escalating risk to public health. − A Member noted however that XXXXX failed to provide any data, similar to the XXXXX post marketing surveillance data, to support this assertion. The Member was further concerned that the comment included the statement ‘XXXXX does not support protecting a very small minority who, often due to their own addictive personality and pattern of other substance abuse, expose themselves to potential harm’. • There was no evidence that taking CACC for short term pain led to addiction. Misuse/abuse for long periods was required for addiction to develop. • CACC products had provided thousands of consumers world-wide with effective relief from strong pain, over and above the relief afforded by the use of single analgesic active alone. • The risks associated with misuse/abuse of CACC should be weighed against the effect a change in scheduling would have on the vast number of non-abusing patients. • Re-scheduling would not solve the problem of opioid abuse but would simply cause people to shop around to maintain their habit.

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• Developing and implementing a major education program was planned to assist pharmacists and pharmacy assistants to recognise and manage drug-seeking behaviour and to educate consumers about appropriate use.

XXXXX

Submissions were received from XXXXX who have had personal experience of addiction to CACC. Both submissions supported the proposal to further restrict the availability of codeine. Members particularly noted the following. • A detailed account of the impact of addiction from the partner of a person struggling with an 8-year codeine+ibuprofen addiction (48 to 60 tablets a day). This submission supported CACC products being made Schedule 4 or that a real-time monitoring system be implemented. • A detailed account of a 6 year addiction. At one time the individual was consuming 24 codeine+ibuprofen tablets at a time, two to three times a day. This submission recommended more restrictions on the sale of CACC, particularly a real-time monitoring system. • Both submissions asserted that pharmacists’ interactions and advice had been inadequate in dealing with the addiction aspects of CACC. • Both submissions asserted that the mental and physical impact of addiction to codeine was large. • Both submissions asserted that when the sponsor company had been approached for advice, the response was to see a local GP and that the company had no responsibility regarding the misuse/abuse of these products. XXXXX

A form letter was received from 23 pharmacies, banner groups and wholesalers which made the following points. • These submissions supported the evaluator’s assessment that there was potential for significant harm from CACC if used excessively but based on the available evidence it was not possible to accurately estimate the associated risk. They agreed that the proportion of all users that abuse CACC was low. • The current scheduling arrangements remained appropriate for the majority of consumers that use CACC appropriately for the treatment of short term pain. • It was imperative that all jurisdictions complied with current scheduling so that larger pack sizes were not available as Schedule 2 products. • XXXXX proposal to implement a real-time monitoring system for Schedule 3 CACC in larger pack sizes as an alternative to the proposed scheduling changes was strongly supported.

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• Consumer education program to raise awareness of the risks associated with overuse of CACC was endorsed should be developed. • Schedule 2 codeine combinations for coughs and colds should be excluded from any scheduling changes. • The Committee should delay any final decisions relating to the scheduling of codeine to allow time for the evaluator’s report to be fully considered by the CWP and the real-time monitoring solution to be fully explored.

XXXXX also forwarded comments on behalf of 13 pharmacy banner groups and wholesalers (XXXXX). These all made the following points. • Any scheduling changes that would result in a restriction on pack sizes of CACC would not be supported. • The maintenance of an appropriate Schedule 2 entry for CACC in smaller pack sizes was supported. • Any scheduling changes to codeine combinations for coughs and colds would not be supported. • XXXXX proposal of a real-time monitoring system to identify people at risk of misuse of these products was supported.

Late submission

XXXXX, a consultant psychiatrist provided a late submission XXXXX. The following points were noted. • The problems caused by OTC codeine (and the increasing frequency of these problems) had been particularly apparent for the last year or so. OTC codeine was a significant problem. • Preparations containing codeine should only be available on prescription, or alternatively, should only be allowed in pack sizes of 8 with a real-time monitoring system implemented.

ADRAC Information

XXXXX.

An updated table of specific adverse events was noted. A Member noted that the updated table listed 31 cases ranging from intentional overdose, renal and hepatic failure, ulceration of the gastro-intestinal tract, hypokalaemia and death.

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February 2009 CWP Considerations

The CWP submitted two proposals for consideration at the February 2009 meeting: Schedule 2 (compounded) Schedule 3 (compounded) Current Tablets / individual powders, Single non-opiate analgesic single non-opiate analgesic: • Divided, ≤ 10 mg/dose, maximum daily • ≤ 10 mg/dose, ≤ 25/pk, CRC etc dose ≤ 60 mg, no pack limit (packaging etc left to TGA) Other therapeutic active: • Divided ≤ 10mg/dose, ≤ 25/pk With paracetamol • Undivided ≤ 0.25% • Divided ≤ 12 mg/dose, ≤ 12/pk, 60 < maximum daily dose ≤100 mg CRC maximum daily dose ≤ 60 mg No S3 undivided Option 1 DELETED ≥1 therapeutic actives (or single non- opiate analgesic) maximum daily dose ≤ 100 mg, ≤ 5 days • Divided ≤ 12 mg/dose, • Undivided ≤ 0.25% (packaging etc left to TGA) Option 2 ≥1 therapeutic actives (or single ≥1 therapeutic actives (or single non- non-opiate analgesic) maximum opiate analgesic) maximum daily dose ≤ daily dose ≤ 60 mg, ≤ 5 days 100 mg, ≤ 5 days • Divided ≤ 10 mg/dose, • Divided ≤ 12 mg/dose, • Undivided ≤ 0.25% • Undivided ≤ 0.25% (CRC packaging etc left to TGA) 60 < maximum daily dose ≤ 100 mg (packaging etc left to TGA)

The February 2009 meeting noted the two CWP options. While there was majority support for Option 1, Members were unable to reach a clear consensus and so agreed that while the Committee would foreshadow deleting the Schedule 2 entry it would welcome pre-meeting comments on both options.

The following points from the CWP meetings (December 2008 and February 2009) were also noted at the February 2009 meeting: • Efficacy – the TGA had not evaluated efficacy data for any OTC product containing codeine. While efficacy data were critical to an assessment of overall risk-benefit efficacy per se was not a primary issue for consideration under section 52E. The CWP felt that the TGA was best placed to address questions about efficacy. • Literature review – a literature search failed to locate any scientifically rigorous data on efficacy beyond that which had already been considered by the CWP and the NDPSC. • Scope – The CWP noted that while case reports of abuse or misuse related mainly to codeine+ibuprofen, it would be reasonable to extrapolate that, should substantial

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restrictions be placed on access to OTC codeine+ibuprofen, this could give rise to codeine-seeking behaviour being directed to codeine+paracetamol or codeine+aspirin combinations. • The CWP also generally agreed that, as codeine scheduling was not currently indication-specific, it was appropriate for the Committee’s consideration to remain at the level of reviewing the current OTC codeine scheduling. Indication-specific concerns could be pursued later, if this was deemed appropriate by the NDPSC. • NZ’s position – at its November 2008 meeting, the MCC had confirmed that >15 mg codeine base per dose should be prescription only, decided to seek further advice from addiction specialists about local experience with codeine abuse, and considered that pack size limitation might be the only way to minimise risk. The NZ representative stated that it would be appropriate to limit OTC availability to treatment of acute pain, with large pack sizes (i.e. > 36 or 40) being prescription medicines. • XXXXX. • UK report – A 2007 UK report provided to the CWP ‘An inquiry into Physical Dependence and Addiction to Prescription and Over-the-Counter Medication’ (http://www.mhra.gov.uk/home/groups/l-cs-l/documents/committeedocument/con n028602.pdf) gave, in one Member’s opinion, the best summary to date of this issue, and included a number of case reports highlighting the various routes to codeine habituation. The Member felt that this report supported the view that restricting by duration was the best approach to take. The CWP noted that Recommendation 3.4 was that access should be restricted for CACC by reducing pack sizes (to 18) and making them available only after consultation with a pharmacist. • Pack size / total codeine content – The CWP agreed that there was merit in limiting supply of OTC codeine combinations to a specific duration, as the abuse risk appeared to be directly linked to longer term use. In particular: − A CWP Member asserted that a uniform pack size limit would provide for greater consistency across the various combinations and products available eg 24 tablets, regardless of strength. The CWP in general, however, felt that uniformity in number of tablets was not necessarily a useful outcome. − It was noted that setting a total codeine content limit did not appear relevant to the risk of habituation, only to diversion. A CWP Member noted, however, that those actively abusing OTC codeine did seem to be attracted to high total content products. The CWP therefore agreed that it would be important to set a maximum daily dose for OTC supply. • CWP’s Option 1: − All OTC codeine Schedule 3, with a five day duration limit, but allowing the maximum daily dose to be increased to 100 mg to allow more efficacious use of codeine.

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− It was asserted that this would be appropriate for most patients, particularly those using products intermittently, while the requirement of pharmacist involvement would assist in limiting multiple purchases and identifying those misusing and at risk of habituation. − A maximum pack size limit was not necessary, noting that setting a maximum daily dose and limit on treatment duration would effectively limit the pack size. There was no differentiation regarding the various combinations (except that CACC would continue to be restricted to ‘single non-opiate’). − A CWP Representative noted that setting a five day limit could have a regulatory impact given that certain CACC products have separate dosage instructions for adults and for children aged 7 to 12 years of age (ie a product containing five days supply for an adult would exceed five days supply for a child). − The current Schedule 2 limit for undivided preparations (≤ 0.25%) should be replicated in the new Schedule 3 entry to prevent the current Schedule 2 undivided preparations becoming Schedule 4 when the Schedule 2 entry was deleted. It was noted that while this was up-scheduling, there was also an increase in the maximum daily dose allowable (in Schedule 3 this would be ≤ 100 mg while currently undivided preparations with maximum daily dose > 60 mg move from Schedule 2 to Schedule 4). • CWP’s Option 2: − Retain Schedule 2 and Schedule 3 entries for OTC codeine but amend these to incorporate a limit on treatment duration. − The CWP noted that both Schedule 2 and Schedule 3 products were indicated for short term use and both had risks of habituation from longer use. The CWP therefore agreed that the differentiation between these schedules should only be by maximum daily dose and unit dose. It was agreed that the limits suggested for Option 1 remained appropriate for the Schedule 3 entry under Option 2. − The current Schedule 2 limit of 10 mg per dosage unit was supported as was the current Schedule 2 60 mg maximum daily dose. − A CWP Member was, however, concerned that the removal of a pack size restriction from Schedule 2 could result in increased pack sizes (suggested that up to 40 tablets of a current paracetamol product could then be allowed). It was asserted that manufactures may deliberately reduce the codeine content in a tablet so that more tablets could be allowed per day while remaining compliant with the maximum daily dose ≤ 60 mg of codeine condition. Another CWP Member asserted, however, that the possibility of any significantly increased pack size achieved through reduced codeine content would also lead to efficacy questions, and that the appropriateness of such product presentations was best left to the regulator.

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− The CWP also agreed to maintain the current Schedule 2 ≤ 0.25% limit for undivided preparations with maximum daily dose ≤ 60 mg in Schedule 2, and allowing ≤ 0.25% with 60 < maximum daily dose ≤ 100 mg in Schedule 3. • Obligations under the Single Convention were discussed in relation to combining codeine with only one other (non opiate) analgesic. The CWP agreed that schedule wording should make clear that OTC codeine: − must not be combined with any other opiate; and − must by compounded with one or more therapeutic substances, only one of which may be another analgesic substance.

February 2009 OTC CACC evaluation report

The following from an evaluation report on OTC CACC was noted at the February 2009 meeting: • Based on currently available information from Australia the evaluator concluded that there was potential for significant harm, even death, from OTC CACC. It was not possible to accurately estimate the risk, although the following were reasonably assumed: − the proportion of all users that abuse OTC CACC was low. − the risk of harm among all users of OTC CACC was low. − the risk of harm among abusers of OTC CACC was high. • At the very least, the appropriateness of OTC CACC as a Schedule 2 product might be called into question. Therefore, in the interests of harm minimisation, the evaluator felt that it would be reasonable to up-schedule OTC CACC in order to restrict (without pharmacist intervention) access to large quantities of OTC CACC. • Notwithstanding that the evidence base for the analgesic efficacy of codeine in doses of ≤ 30 mg was weak, the evaluator felt that up scheduling of OTC CACC could occur without affecting the use of these products by ‘genuine’ (non-abusing) patients for the ‘short-term treatment of acute pain’ (the currently approved indication). In this context the evaluator felt that ‘short term’ would constitute a few days, certainly no more than one week.

Additional February 2009 discussion

Members also recalled following from the February 2009 discussion: • Members agreed that, as the issue was codeine abuse, all codeine combinations should have similar scheduling (noting that currently there are non-opioid analgesic combinations and, separately, other therapeutically active combinations – mostly for cough suppressant activity).

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• A Member asserted that it was important that any scheduling change did not impact on the codeine+phenylephrine combinations made available as a substitute for pseudoephedrine products. The Member asserted that the public health benefit of reducing the OTC pseudoephedrine supply outweighed the risk of abuse of codeine+phenylephrine. It was suggested that the June 2009 consideration include a proposed specific Schedule 2 entry for codeine+phenylephrine. Members therefore agreed that the June 2009 pre-meeting Gazette Notice should indicate that the foreshadowed proposal would affect all OTC codeine, not just analgesics, as this would encourage relevant public comment.

Other matters

On the 15 April 2009 the Chair received a request from XXXXX, for access to the evaluator’s report commission by the CWP. Following a teleconference held on the 23 April 2009 the CWP members agreed to release a de-identified copy of the evaluator’s report to all persons/agencies that have previously made a submission to the NDPSC since the February 2008 meeting. A copy was provided to all interested parties on 1 May 2009.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extent and patterns of use, (e) dosage and formulation, (f) the need for access, and (g) potential for abuse.

The Members generally agreed that a number of core issues had emerged that needed to be resolved in order to progress the consideration of the scheduling of OTC codeine combinations. These were as follows. • Was any change necessary for codeine combinations for coughs and colds? • Should all OTC CACC be considered together or be differentiated by the other analgesic active i.e. ibuprofen+codeine? • Should a Schedule 2 CACC entry be maintained or should OTC CACC be restricted to Schedule 3 only? • Should pack sizes be determined by a limit on treatment duration or by a specific pack size limit? What should this be? • What should the maximum unit dose (divided) or concentration (undivided) be? • What should be the maximum permitted daily dose of codeine (60 mg or 100 mg)? • What specific schedule wording should be adopted, noting the various suggestions from the CWP to improve clarity?

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Codeine combinations for coughs and colds

Members noted that there was no support in pre-meeting comments for changes to codeine combinations for coughs and colds currently captured by the Schedule 2 codeine entry.

A Member noted that there may be an issue of non uniformity with respect to the other codeine combination products, but conceded that this was not a major concern. These products generally had less codeine per unit dose. Further, these products had multiple therapeutically active ingredients and these together might diminish the abuse/misuse potential of these preparations. Indeed, a Member observed that none of the pre-meeting submissions made note of the fact that, when included in combinations for coughs and colds, the amount of codeine may in fact be sub-therapeutic.

A Member suggested that the Schedule 2 entry could be sufficiently restricted to codeine combinations for coughs and colds by specifying that the entry captured preparations for coughs and colds, and requiring that the codeine had to be compounded with at least one decongestant. Other Members suggested that, rather than ‘at least one decongestant’, the entry should instead specify ‘with phenylephrine’.

A Member suggested that, while supportive of retaining the current scheduling conditions for codeine combinations for coughs and colds captured under the Schedule 2 codeine entry, there was perhaps a need to review this at a future date to ensure that there was no shift of the misuse/abuse problem to these products.

The Committee decided that the current scheduling of codeine combinations for coughs and colds remained appropriate. The Committee also agreed to review the misuse/abuse of Schedule 2 codeine combinations for coughs and colds 12 months after the implementation of the CACC rescheduling discussed below.

All CACC or differentiated by the other analgesic

Members recalled that the Committee had previously agreed that, as the issue was codeine abuse, all CACC should have similar scheduling. A Member asserted, however, that most reports of harm from CACC (in the form of case reports or small surveys) indicated that the harm was more likely to arise from consumption of ibuprofen+codeine than paracetamol+codeine. The Member therefore advocated an approach that focused on increasing control specifically on ibuprofen+codeine (as Schedule 3) rather than uniformly applying increased controls across the board, although some tightening of controls for the non-ibuprofen CACC also appeared to be warranted.

Several other Members disagreed and argued that their concerns were that it was the presence of codeine that encouraged misuse of CACC products (i.e. large amounts) and this problem did not depend on the other analgesic. It was asserted that any differentiation would merely see a shift in the pattern of the products being misused/abused.

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A Member also suggested that adverse event reports for paracetamol+codeine may not have been as high as for ibuprofen+codeine because users were going to the small effort of separating the codeine from the paracetamol. Another Member suggested that the difference in reported adverse events may also directly relate to the greater sales of the ibuprofen+codeine rather than this combination being intrinsically more dangerous.

A Member thought it would be particularly dangerous to create a situation which may encourage a shift to paracetamol, noting that an acute overdose of paracetamol can be lethal. The Member thought that scheduling differentiation may lead the public to the assumption that paracetamol combinations were safer. A Member also noted that there were risks from excessive use of aspirin. The Committee agreed that there were risks from excessive use of all NSAIDs and resolved to consider variations to the scheduling and labelling of all OTC CACC.

Schedule 2 and 3 or restrict CACC to Schedule 3 only

A Member reiterated that the challenge was to balance the needs of legitimate users versus the harm to a small number of abusers and particularly recalled a conclusion from the February 2009 evaluation report that there was little evidence to allow a quantitative determination of the risks. While the evidence to date warranted some action, the Member advocated an incremental approach in light of the large potential regulatory impact of a rescheduling decision. The Member asserted that scheduling was a blunt instrument for addressing addiction and suggested that education, label warnings and warnings in advertising would be a sufficient first step. The Member therefore advocated that there was a role for maintaining both a Schedule 2 and Schedule 3 CACC entry. Another Member suggested that there was scope for a limited Schedule 2 entry for small packs of OTC CACC.

Several Members asserted, however, that warnings and small packs, by themselves, were inadequate in addressing the misuse/abuse concern. These Members contended that there was sufficient justification for considering a need to tighten access controls by removing Schedule 2 access to CACC. A Member noted that while up-scheduling all OTC CACC to Schedule 3 would not stop the addiction problem, it would help mitigate it. In particular it would ensure pharmacist involvement and provide an opportunity to pick up signals of misuse or abuse. The alternative (if seeking to more fully address the addiction concern) would be to remove all CACC from the OTC market (ie Schedule 4), which the Committee generally felt was not warranted.

A Member noted arguments that making all OTC CACC Schedule 3 would increase the costs of these products. The Committee generally agreed, however, that questions of cost were not a directly relevant consideration for a scheduling decision.

A Member also asserted that those comments opposing deletion of a Schedule 2 entry for CACC had not provided a clear argument as to why an up-scheduling to Schedule 3 would be burdensome for the public. The Member noted that legitimate users would still have access without the need for a prescription, but this would require the involvement of

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the pharmacist. The Member noted that several comments from addiction specialists indicated that such interactions were a significant trigger for addicts to eventually seek help.

A number of Members also revisited the efficacy question and expressed concern that the public may be exposed to the risk of these products with little evidence that they are any more effective at relieving the symptoms of short term pain than the non-codeine containing analgesics. A Member asserted that this was an issue that should be referred to the TGA.

The Committee decided that it was appropriate that OTC CACC be removed from Schedule 2.

Duration or specific pack size limit

Duration of treatment or specific pack size

Members noted the various proposals from pre-meeting comments (discussed above) which covered a spectrum of pack size and/or treatment duration limits. Members also recalled that the treatment duration limit proposals were based on the indication for use of OTC CACC – short-term treatment of acute pain.

A Member asserted that a small pack size would have little effect in discouraging addicts as they would just “pharmacy shop” to get sufficient product for their needs. Another Member disagreed, noting the advice from addiction specialists that increased “shopping time” was a factor in getting someone to admit that they had a problem and subsequently seek help.

A Member asserted that a limit on duration of treatment rather than a specific pack size limit made more sense as the number of dosage units per day differed by formulation (as dosing interval depended on the other analgesic active). The Committee confirmed its view from the February 2009 meeting that it was more appropriate to specify limit on treatment duration rather than a specific pack size (noting that a duration limit and maximum daily dose would effectively give rise to a pack size limit).

Limit size

A Member noted that the proposed treatment duration limit of ≤ five days supply could lead to increases in the pack sizes for some products. Other Members noted, however, that this was a maximum limit and there was nothing stopping sponsors from offering a smaller pack size on the market. Indeed, it was noted that the Schedule 3 ibuprofen+codeine products currently included a spectrum of pack sizes despite the fact that there were currently no maximum pack size limit. As such, there would continue to be flexibility for sponsors to market smaller packs. Another Member noted that the concern over the ‘potential’ for larger pack sizes (for current Schedule 2 products) was being balanced by an increased control on access through up-scheduling to Schedule 3. A

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 58

Member also noted that duration of supply did not mean a patient had to use the entire pack in a single period. These products were often used by consumers on an as-needed basis.

A Member noted that, for legitimate users, 3-5 days supply should be sufficient since most conditions requiring the treatment of short term acute pain should resolve in this period. Another Member noted that too short a treatment duration (less than five days in the Member’s opinion) could see legitimate customers routinely seeking to purchase multiple packs at a time, which could undermine messages regarding the safe use of Schedule 3 medicines.

A Member noted that a five day duration limit of supply was being proposed by the NZ MCC on the basis that most acute conditions resolved within five days. The Member asserted that short term supply in the UK was accepted as five days.

A Member also asserted that a five day maximum duration would also allow industry to make commercially viable pack sizes.

The Committee decided to limit the duration of treatment with OTC CACC preparations to no more than five days supply. An alternative proposal to limit to no more than three days was not supported by the Committee.

Unit dose / concentration

Divided

A Member suggested that in addition to the removal of OTC CACC from Schedule 2, there was sufficient evidence of risk to justify a conservative approach to the maximum unit dose. The Member suggested that an 8 or 10 mg maximum dose per unit might be appropriate.

Another Member supported a maximum dose per unit of 12 mg codeine. Other Members noted that there was support in various pre-meeting comments for restricting this to 10 mg codeine (although often proposed in conjunction with maintaining the current less restrictive access control for lower dose products i.e. Schedule 2). Another Member reiterated that this would be a maximum limit but sponsors could always formulate using a lower amount – noting the precedent that several OTC CACC products currently on the market have codeine in amounts less than the current maximums.

The Committee decided to limit the maximum unit dose of codeine in OTC CACC to no more than 12 mg. Alternative proposals of 8 or 10 mg for the maximum unit dose were not supported by the Committee.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 59

Undivided dose preparations

The Committee noted that the current concentration limit for undivided codeine combinations in Schedule 2 was 0.25 per cent (with a maximum daily dose of ≤ 60 mg). Members therefore considered a proposal to include a similar limit in the new Schedule 3 entry so that undivided CACC products did not automatically revert to Schedule 4 when they were deleted from Schedule 2.

Members noted, however, that the current Schedule 2 entry had no limit on the volume of the undivided preparation (just a maximum daily dose limit). Members agreed that the maximum duration of therapy for OTC CACC of five days supply would effectively set such a limit. However, a point for XXXXX pre-meeting comment was noted – that there was perhaps some ambiguity in specifying the maximum treatment duration to five days supply, particularly with regards to undivided preparations. Members generally agreed that the proposal should be amended to limit the pack size of undivided preparations to a maximum of five days supply at the maximum dose.

The Committee decided to limit undivided OTC CACC preparations to no more than five days supply at the maximum daily dose and at a concentration of no more than 0.25 per cent.

Maximum daily dose

A Member argued that the rationale for removing OTC CACC from Schedule 2 was to reduce harm, so perhaps there was scope for reducing the Schedule 3 maximum daily dose to the current Schedule 2 limit (≤ 60 mg). Other Members disagreed and felt that restricting access through inclusion in Schedule 3 was sufficient to send a message about potential harm and that the maximum daily dose limit for the Schedule 3 entry should be ≤ 100 mg.

A Member also asserted that many of the public submissions did not appear to reflect an understanding that there may be a need to allow sponsors to consider new product formulations. The Member asserted that a ≤ 60 mg maximum daily dose limit could curb such developments and therefore supported a ≤ 100 mg maximum daily dose limit.

The Committee decided to limit the maximum daily dose of codeine in OTC CACC to no more than 100 mg. Members also agreed that the same maximum daily dose limit should apply to divided and undivided preparations equally.

Advertising

A Member suggested that advertising should continue to be permitted through an Appendix H listing (perhaps with a caveat regarding abuse potential). The Member noted that an Appendix H listing did not mean free advertising – the approval of the Therapeutic Goods Advertising Code Council (www.tgacc.com.au) would also be required for all brand advertisements. Another Member noted that the situation involved

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movement from an environment in which some products would be advertised (for the current Schedule 2 CACC products) to a possible advertising ban. Several Members agreed that this was a different situation to the usual Appendix H consideration resulting from a down-scheduling decision.

A Member also suggested curbing advertising only for those CACC products with high codeine content or when containing ibuprofen. The Committee generally did not support this suggestion.

A Member asserted that there was little evidence of a particular harm arising from the current advertising. Several Members, however, noted comments from addiction specialists that visual cues and sales promotions could stimulate desire in habituated individuals. A Member asserted that while advertising may not lead directly to people becoming addicted (although any increase in use of a product would probably increase the risk of off-label, longer term, use which was linked to habituation) it would affect those who were already addicted. Another Member also noted concerns with some of the current promotion practices for CACC, particularly through pharmacy brochures etc.

Several Members queried the public benefit of advertising CACC. A Member asserted that the main benefit would be awareness-raising as to product availability. Another Member, however, noted that there was already a high awareness of these products in the community and felt that further awareness-raising may not be of public benefit. A Member was also concerned that any advertisers may be tempted to make ‘pharmacy strength’ type advertising claims.

There was also discussion about whether advertising of OTC CACC would increase pressure on pharmacists to supply these products, noting that moving these products into Schedule 3, a pharmacist would need to be involved in every sale. A Member asserted, however, that in this case the (Schedule 2) products are currently freely advertised environment so no additional pressure would be anticipated.

Several Members noted that the default position in Schedule 3 was not to permit advertising unless there was a demonstrated public benefit (as opposed to the suggestion that advertising should be allowed unless there was evidence of harm). A number of Members felt that advertising would be inconsistent with the removal of OTC CACC from Schedule 2.

The Committee decided not to include codeine in OTC CACC in Appendix H.

Implementation date

A Member noted that there would be substantial regulatory impact from the decisions on this issue and suggested that a deferred implementation date may be appropriate. The Member suggested 1 June 2010.

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Members generally agreed that a deferred implementation was justified but felt that 1 May 2010 would be more appropriate, as this would be the date of implementation of Amendment 3 to SUSDP 24. This would represent an additional four months from the standard date of implementation.

Schedule Wording

Members agreed to draft the exact schedule wording to implement the Committee’s decisions on OTC codeine combinations out-of-session.

Additional discussion

Warning labels

Several Members noted suggestions from a number of pre-meeting submissions regarding the need for label warning about the potential for addiction for all products containing codeine (such as is required in the UK). Members noted that there was concern that the current warning was too passive i.e. ‘Never exceed the recommended dose – treatment of pain for mare than a few days at a time without medical supervision can be dangerous – you must consult your doctor for treatment of persistent pain’.

A Member also suggested that warning labels should be required regarding the potential harm from excessive use for all products containing ibuprofen such as ‘keep to the recommended dose’, ‘you may be at serious risk of stomach perforation, bleeding, liver/kidney failure or death if you exceed the recommended dose’.

A Member advised that industry supported label warnings.

Members agreed to draw the TGA’s attention to the various suggestions in the pre- meeting submissions regarding warning labels.

RESOLUTION 2009/56 - 8

The Committee decided: • that the current scheduling of codeine combinations for coughs and colds remained appropriate; • that OTC CACC be removed from Schedule 2; • to limit the duration of treatment for OTC CACC to no more than 5 days; • to limit the maximum unit dose of codeine in OTC CACC to no more than 12 mg; • to limit undivided OTC CACC preparations to no more than 5 days supply at a maximum daily dose of 100 mg and at a concentration of no more than 0.25 per cent; • to limit the maximum daily dose of codeine in OTC CACC to no more than 100 mg; • not to include codeine in OTC CACC in Appendix H; and

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 62

• to defer implementation of this resolution until 1 May 2010.

Schedule 2 – Amendment

CODEINE – Amend entry to read:

CODEINE in preparations for the treatment of coughs and colds when:

(a) not combined with any other opiate substance;

(b) compounded with one or more other therapeutically active substances, of which at least one is phenylephrine and not more than one is an analgesic substance:

(i) in divided preparations containing 10 mg or less of codeine per dosage unit; or

(ii) in undivided preparations containing 0.25 per cent or less of codeine;

(c) labelled with a recommended daily dose not exceeding 60 mg of codeine; and

(d) in packs containing not more than 5 days of supply at the maximum dose recommended on the label.

Schedule 3 – Amendment

CODEINE – Amend entry to read:

CODEINE when:

(a) not combined with any other opiate substance;

(b) compounded with one or more other therapeutically active substances, of which not more than one is an analgesic substance:

(i) in divided preparations containing 12 mg or less of codeine per dosage unit; or

(ii) in undivided preparations containing 0.25 per cent or less of codeine; and

(c) labelled with a recommended daily dose not exceeding 100 mg of codeine; and

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 63

(d) in packs containing not more than 5 days of supply at the maximum dose recommended on the label,

except when included in Schedule 2.

11.4 MAGNESIUM SULFATE

PURPOSE

The Committee considered the scheduling of magnesium sulfate, including the foreshadowed proposal to list divided preparations of magnesium sulfate for constipation in Schedule 3.

BACKGROUND

Magnesium sulfate (MgSO4) is often available as the heptahydrate complex, MgSO4.7H2O, commonly called Epsom salts. Anhydrous magnesium sulfate is used as a drying agent. Epsom salts have been traditionally used as a component of bath salts. Oral magnesium sulfate can be used as an osmotic or saline laxative. Epsom salts have been available for many years as an unscheduled powder with directions for use as a laxative, relaxing bath additive, fertilizer and fabric softener.

A capsule presentation containing 950 mg of dried magnesium sulfate was listed on the ARTG in July 2007 under the Electronic Listing Facility (ELF). The product originally included the following indications: ‘for weekly bowel conditioning, for the relief of constipation, for bowel preparation prior to colonoscopy’. However, due to safety concerns, the sponsor changed the indications to: ‘for the relief of occasional constipation, magnesium sulfate is a naturally occurring mineral that has been used for many centuries for bowel cleansing’.

In April 2008, the Adverse Drug Reactions Advisory Committee (ADRAC) concluded that there was a considerable risk to consumers from these magnesium sulfate capsules because of the following: • Although the use of Epsom salts as a laxative has fallen out of favour, the availability of this product may lead to a resurgence of its use as a laxative and expose problems not currently seen e.g., a potential resurgence of hypermagnesemia. • In the absence of intervention by a healthcare professional, it was likely that the product would be used inappropriately and present safety risks in those with known renal impairment, undiagnosed renal impairment, as well as dehydration in children, the elderly and in those taking other medicine/s. • The potential for gastric erosion was a concern. • There was concern over swallowing safety i.e. risk of oesophageal obstruction with such a large recommended dose of capsules (15 capsules).

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• Nephrologists advised of the risk of the development of volume depletion and consequent worsening of renal failure in chronic kidney disease patients. There was also a risk for patients with undiagnosed kidney disease, especially if they are concurrently on non-steroidal anti-inflammatory drugs (NSAIDs), angiotensin- converting enzyme (ACE) inhibitors or angiotensin II receptor blockers.

At its July 2008 meeting, the ADRAC recommended that consideration should be given to scheduling products such as these in Schedule 3. ADRAC acknowledged that other products containing magnesium sulfate (but not used for constipation) may be affected by this recommendation but considered this a matter for the NDPSC. ADRAC suggested wording for a schedule entry of ‘when indicated for constipation or other bowel disorders’.

XXXXX agreed that the matter should be referred to the NDPSC for possible inclusion in Schedule 3 when used for human therapeutic purposes.

The matter was considered at the February 2009 meeting and the Committee decided to foreshadow consideration of the inclusion of magnesium sulfate in Schedule 3 for human therapeutic use in divided oral preparations for constipation.

DISCUSSION - SUBMISSIONS

Pre-Meeting Submissions

XXXXX supported the foreshadowed proposal. The submission stated that pharmacists possessed the necessary skills to make appropriate recommendations regarding the use of magnesium sulfate capsules. The submission also addressed the following points under section 52E(1): (a) Toxicity and safety, (b) Risks and benefits, (c) Potential hazards • Supported the concerns of ADRAC, as mentioned in the February 2009 Record of Reasons, including the potential resurgence of hypermagnesemia and inappropriate use in those with renal impairment. • Asserted that provision under the supervision of a pharmacist would allow for counselling and reinforcement of all safety concerns and also allow for advice to be given on use and the dangers of misuse of laxatives. Additionally, appropriate questioning would take place to determine if consumers were at risk of renal problems and make appropriate recommendations. (e) Dosage and formulation • Stated that, even though a reduced dose was advised by ADRAC, it was still a large number of capsules. Adequate fluid intake was vital to ensure capsules do not become lodged in the oesophagus which could lead to obstruction and / or erosion.

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(f) Need for access • Noted that similar saline laxatives such as sodium phosphate, sodium picosulfate and polyethylene glycol (macrogol 3350) are currently Schedule 3.

XXXXX also supported the foreshadowed proposal. However, it was noted that such products may also be used for bowel cleansing prior to diagnostic medical and surgical procedures as well as for ‘weekly bowel cleaning’. Given these additional indications, it was suggested that the Schedule 3 entry be amended to incorporate these indications (as was the case with saline laxatives such as sodium picosulfate and sodium phosphate).

XXXXX supported the proposal to include magnesium sulfate for human therapeutic use in divided preparations for constipation in Schedule 3.

The Committee noted that the sponsor of the complementary medicine had not provided a pre-meeting submission.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (c) potential hazards, (d) extent and patterns of use, (f) the need for access, (g) potential for abuse and (h) purpose for which a substance is to used.

A Member noted that ADRAC’s recommendation was based on concerns about potential adverse events rather than reports of actual events in Australia. The Member also noted that this substance had been unscheduled for a long time and the proposal to reschedule from unscheduled to Schedule 3 was significant. Another Member noted however, that it was undivided preparations (such as Epsom salts) that had been available without restriction and this divided preparation was new.

It was noted that overuse could arise if this product were used as part of a ‘cleansing diet’. Another Member noted that the divided preparation in question was of particular concern because the encapsulated formulation masked the taste of the magnesium sulfate. A Member asserted that the risks were therefore significantly different to the risks associated with use under medical supervision.

A Member supported the suggestion to include additional indications in the proposed Schedule 3 entry for bowel cleansing prior to diagnostic medical and surgical procedures. The Member advised that at least one surgeon was known to be using magnesium sulfate capsules for pre-operative bowel cleansing.

A Member noted, however, that a Schedule 3 listing would ensure that these types of products underwent more thorough evaluation before being approved for registration. Marketing approval would require the supply of data demonstrating the safety and efficacy of products. Another Member was concerned that without a specific indication, other products that contained magnesium sulfate might be inadvertently captured. It was

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noted, however, that the Schedule 3 entry should at least specify human therapeutic use (and divided oral preparations).

The Committee agreed to include magnesium sulfate in Schedule 3 for human therapeutic use in divided oral preparations and the TGA would determine the appropriateness of proposed indications.

Appendix H

A Member reiterated that the ADRAC’s recommendations had not been as a result of any actual report of an adverse event in Australia and this scheduling decision effectively placed a ban on products that could previously be freely advertised.

A Member asserted, however, that the risks associated with this particular presentation were such that it was not appropriate for it to be advertised. The Committee generally agreed that professional advice was required before a consumer should access such a presentation. It was noted that the other Schedule 3 bowel cleansers are not currently in Appendix H.

Several Members noted that no convincing argument for a public health benefit from advertising had been made. A Member noted that none of the pre-meeting submissions had proposed an Appendix H listing for divided preparations of magnesium sulfate.

The Committee therefore agreed that it was not appropriate to include magnesium sulfate in Appendix H.

RESOLUTION 2009/56 - 9

The Committee decided to: • include magnesium sulfate in Schedule 3 for human therapeutic use in divided oral preparations; and • exclude magnesium sulfate from Appendix H.

Schedule 3 – New entry

MAGNESIUM SULFATE for human therapeutic use in divided oral preparations.

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11.5 PIPER METHYSTICUM (KAVA)

PURPOSE

The Committee considered the scheduling of Piper methysticum (kava).

BACKGROUND

The active ingredients of kava are kavalactones (or kava pyrones) which are pharmacologically active compounds naturally present in the kava plant. Nineteen kavalactones have been isolated from the kava root, of which six are the major constituents of kava (kawain, dihydrokawain, methsticin, dihydromethsticin yangonin, and demethoxyangonin). The kavalactone content varies from 3 to 20 per cent dry weight, even within the same subspecies.

Kava’s primary action is as a mild sedative. Other actions include local anaesthesia of the mouth and tongue, analgesia, ocular effects, anticonvulsive effects and antimycotic properties. It has been reported as an effective anti-anxiety treatment.

At the October 2003 meeting, the Committee noted a report prepared by the Kava Evaluation Group from the TGA’s Office of Complementary Medicines on kava containing medicines and decided there was a need to restrict the use of alcohol/acetone extracts of kava, including those for bulk supply to health care practitioners, due to the potential risk of liver toxicities.

At the June 2004 meeting, the Committee agreed to include kava in Schedule 4, as well as adopting exemptions as specified in the TGA Regulations 1990. The decision made all kava Schedule 4 except dried whole or peeled rhizome, its aqueous dispersions or extracts, tablets of 125 mg or less of kavalactones per tablet, teabags of up to 3 g kava, and not more than 25 mg of kavalactones per dose.

At the February 2008 meeting, in light of an Australian Government kava policy decision, the Committee reconsidered the restrictions for kava and concluded that the potential for abuse and the hazard to public health of the whole or peeled rhizome meant that this form of kava should no longer be exempt from scheduling. The Committee therefore amended the Schedule 4 entry so that only some products on the ARTG were not captured.

At the February 2009 meeting, the Committee noted a request from XXXXX that kava be rescheduled to its pre-February 2008 status. The Committee noted that this matter had not been gazetted. Members expressed concern that the public had not had the chance to make a comment. The Committee therefore agreed that the issue be foreshadowed for consideration at the June 2009 Meeting to allow gazettal and public comment.

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DISCUSSION - SUBMISSIONS

Pre-meeting Submission

Only one pre-meeting submission was received. XXXXX supported the current scheduling due to public health and safety issues. It also fully supported the World Health Organisation (WHO) position that kava be a prescription substances in order to better monitor its use and to apply necessary controls.

February 2009 submission

The Committee particularly recalled the following from the XXXXX submission: (a) Toxicity and Safety

• LD50 of kava resin given by intra peritoneal injection to mice, rats and rabbits ranged from 300 to 4000 mg/kg. With oral administration the LD50 in mice was 920 mg. Doses of 50 mg dihydromethysticin, administered 3 times a week to rats produced no evidence of chronic toxicity, however attempts to duplicate the findings have had limited success. The applicant claimed that clinical trials of kava have not revealed any hepatoxicity, but also state that ‘kava has a tendency to have a toxic effect on the liver’. (b) Risks and Benefits • Kava is used traditionally to treat anxiety, sleep disorders and other complaints. The applicant claimed that kava lactones have been shown to affect a range of neurotransmitter systems, and that they have ‘dose dependent effects on the central nervous system, including anti-epileptic properties’. (c) Potential Hazards • The applicant claimed that the WHO has found only two reports of possible adverse reactions to kava use. The applicant claimed that this figure was out of over ‘12 billion discreet doses prepared in the traditional way over 20 years’ (the source for this figure was not cited). The applicant also claimed that when kava was taken in doses from 100 to 210 mg of kava lactones per day the users had few adverse reactions. Adverse reactions included kava dermopathy of the hair nails and skin, rare allergic reactions including hearing loss and anorexia and possible extrapyramidal side effects such as involuntary oral and lingual reflexes and twisting movements of the head and trunk. • The applicant reported that liver function tests could be elevated after 3 to 8 weeks of use, and may be followed by hepatomegaly; that kava can exacerbate hepatitis, but that this spontaneously resolves on cessation. (d) Extent and Patterns of Use • The traditional use of kava was described and the inappropriate use of kava by NT remote indigenous communities was mentioned.

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(e) Dosage and Formulation • Aqueous extract/suspension consumed in 100 mL measures. (f) Need for Access • The applicant claimed that the scheduling of kava denied Australians of Pacific Islander origin their traditional and cultural use of kava. − The Committee noted that the ban was imposed by Customs on all kava imports, except those under medical or scientific research licence. • The applicant claimed that kava’s closest alternative was alcohol with its related anti- social behaviour and associated health risks and that no deaths have been attributed to kava consumption. • Fewer than 350 people in the NT have been identified as being at risk of abusing kava. • The applicant reiterated the argument that the number of abusers of kava was ‘insignificant’ that it was not right to restrict the use of kava for others. (h) Purpose for which the substance is to be used • The applicant reiterated the original use of the substance in the Pacific Islands. Additional Matters: – Economic and Trade Considerations • The applicant reported that kava is a primary cash crop for Vanuatu, Tonga and Samoa, accounting for up to 30 per cent of their GDP, and infer that the ban imposed by Australia may influence other countries to ‘harmonise’ their policy to kava in line with Australia’s. It was noted that Australian is a signatory to the Agreement on Technical Barriers to Trade (World Trade Organisation), and may be subject to legal challenges (from kava producing countries) to remove technical barriers to the kava trade.

The application included an extensive bibliography, including fifteen articles by Alan Clough. The articles were selected to present a picture of kava use in the remote NT. Members noted that some of these references actually appeared to argue against the applicant’s position. The following summaries are from the three papers included in the application as attachments: • Clough, AR 2003, ‘Health effects of kava use in eastern Arnhem Land Aboriginal Community’, Internal Medicine Journal, vol 33, pp. 336-340: examined the links between various health effects including sudden cardiac arrest and heavy kava use, in a cross-sectional study in Arnhem Land. Health effects such as abnormal liver function, kava dermopathy and decreased lymphocytes were observed. The author stated ‘the general increase in IgE and IgG levels and CRP reflect the burden of infectious pathogens associated with the continuing socioeconomic disadvantage of those living in remote Aboriginal communities. Elevated CRP is increasingly recognized as a marker of risk for cardiovascular disease, and the generally high

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levels of CRP and homocystine across all groups in this Aboriginal community are of great concern. Markers for cardiovascular disease were higher in the indigenous population, but not higher in kava users’. • Clough, AR 2003, ‘Case-control study of the association between kava use and pneumonia in eastern Arnhem Land Aboriginal communities Northern Territory, Australia’, Epidemiol Infect., vol 131, pp. 627-635. Kava, consumed in Arnhem Land since 1982, may be a risk factor for infectious disease including pneumonia. The author found statistically significant associations between pneumonia admission and alcohol use, cannabis use and with petrol sniffing suggested that the effects of other substances, or combinations, may compound kava’s effects in ways not yet understood. He postulated that if Aboriginal people continue to drink kava it would be prudent for them to moderate consumption even though an association with pneumonia has not been shown. • Clough, AR, ‘Emerging Patterns of Cannabis and other substance use in Aboriginal Communities in Arnhem Land, Northern Territory: A study of two Communities’. This study examined the effects of a variety of substances including kava, cannabis, alcohol, tobacco and petrol sniffing. The research focussed on cannabis and made only brief mention of kava. The conclusion was that action was required to reduce cannabis use especially in relation to other drugs.

Members also recalled that in the applicant’s supporting data, it was claimed that a disproportionate ‘amount’ of papers on kava have come from Dr Clough during the past 20 years. It was claimed that because Dr Clough was responsible for this research, ‘the body of research has been skewed’. The following are summaries of other relevant articles listed by the applicant in the bibliography, but not attached to the application: • Clough, AR et al., 2006, ‘Letters to the Editor’, eMJA, vol 184 (2), pp. 91-92. Clough and colleagues reported their concern that the NT’s introduced regulations for kava control (under the Kava Management Act 1998) were not working in that: − Kava licence areas permitted retailers to sell more than double the safe weekly limit of kava per person. − The illegal trade added up to perhaps $2 million per annum. − The social, economic and health effects were unknown in the long term and had lead to a decline in participation in traditional ceremonies. − Kava is the psychoactive substance with the greatest impact on the financial resources of communities and individuals in Arnhem Land. − Kava’s health effects include seizures and extreme weight loss, resulting in immunosuppressive effects, possible cardiovascular disease and potential fatal hepatotoxicity. − The letter recommended that the kava supply and outlets supplying kava be reduced, the amount per person be halved, quantities imported be limited, kava prices be reviewed, illegal sale of kava be rigorously enforced and that the Kava

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Management Act 1998 be reviewed. Clough also disclosed that he had been a member of the NT Licensing Commission, the body responsible for licensing kava in the NT. • Clough, AR, 2003, ‘Enough! or too much. What is excessive kava use in Arnhem Land?’, Drug Alcohol Rev, vol 22, pp. 43-51. The study described parameters for use in monitoring health, social and economic effects of kava use in Arnhem Land Aboriginal communities in the Northern Territory. Interview data combined with health worker assessments were compiled. Kava, supplied illegally, was still being used in Arnhem Land in 2001-02. In 2000 cases included dermopathy, abnormally low body mass index, low blood lymphocytes and abnormally high y-glutamyl transferase, characteristic of heavy use, occurred more frequently with increased kava use. Acute effects emerged at average consumption levels of from 310-440 g/week of kava powder. When kava users in one community began to consume it at an average of 240-425 g/week from mid-1990, 19 per cent of available cash resources were spent on kava with 11 per cent of cash resources leaving the local community economy. The proportion of men drinking kava reached 70 per cent and women 62 per cent from mid-1990, with 20 per cent of the population spending unprecedented amounts of time (14 + hours/week) in activities where kava was consumed. Their association with increased kava use suggested that approaches to minimizing harm from its abuse may begin fruitfully with controlling supply. The article supported the banning of kava from Australia because of the negative health, economic and social effects on indigenous communities. • Clough, AR, 2000, ‘Kava in Arnhem Land: a review of consumption and its social correlates. Comprehensive Review’, Drug and Alcohol Review, vol 19, pp. 319-328. The paper stated that the way Aboriginal people drink kava had been confounded by claims, based on anecdote, of imputed health effects. The perception that dosage levels among Aboriginal people are much greater than in Pacific island societies is based only on anecdotal evidence. This paper reviews published data about kava consumption, and evaluates it with respect to information collected from observation of one Aboriginal community in Arnhem Land where people tended to consume kava at a steady tempo; 37g of kava powder containing around 3800 mg of kavalactones in 670 ml of water in an hour. The highest levels of consumption in Arnhem Land were reported to be up to 900g/week of kava powder with heavy consumers drinking at least 610g/week, levels comparable to estimates for Pacific-island societies. Results of the research included the finding that heavy users of kava in Fiji may consume over 701 and 1800 g/week, far more than in Arnhem Land. This paper questioned the anecdotal information that Aboriginal people are high consumers of kava, and placed their consumption in perspective compared to South Pacific countries, recommending that assumptions about usage need to be revisited. It did not support the continuation of the practice of drinking kava in indigenous communities.

The submission attachments also included the following: • Cairney, S, 2003, ‘Brain dysfunction associated with petrol sniffing and kava drinking in Arnhem Land Aboriginal Communities’, unpublished PhD thesis, La

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 72

Trobe University, Victoria (as viewed on 11 March 2008 at www.healthinfonet.ecu.edu.au/html/html_resources/theses/cairney.htm). The author found, despite collecting data from reportedly the heaviest users of kava in the world, no impairment in saccade or cognitive function in individuals who were currently heavy users and had been for up to 18 years, nor in users who been heavy users, but had abstained for longer than 6 months. Current and ex-users showed a higher rate of kava dermopathy, lower body mass index, lowered blood lymphocytes and, in addition kava users showed elevated liver enzymes. This paper supported the need for further research into the health effects of kava. • Cairney, S, 2003, ‘Saccade and Cognitive Function in Chronic Kava Users’, Neuropsychopharmacology, vol 28, pp. 389-396. The author’s findings were the same as those of the previous paper: that current and ex users showed a higher rate of kava dermopathy, lower body mass index, lowered blood lymphocytes and, in addition kava users showed elevated liver enzymes. The author concluded that, despite health consequences such as an increased risk of serious infection, potentially fatal liver damage, and loss of body fat and dermopathy, these data suggest that chronic kava use causes no disruption to human saccade and cognitive processes. The paper supported the need for further research into the effects of kava on liver function. • Pittler, MH & Ernst, E, 2003, ‘Kava extract versus placebo for treating anxiety’, Cochrane Database of Systematic Reviews, Issue 1. Compared with placebo, kava extract is an effective symptomatic treatment for anxiety although, at present, the size of the effect seems small. The effect lacks robustness and is based on a relatively small sample. The data available from the reviewed studies suggest that kava was relatively safe for short-term treatment (1 to 24 weeks), although more information was required. The author concluded that trials with large sample sizes and long term safety studies were needed to clarify the resultant effects of kavas consumption. • Escher, M, January 2001, ‘Hepatitis associated with kava, an herbal remedy for anxiety’ BMJ, vol 322, p. 139. This article describes the history of a patient, in previous good health, with no pattern of drug or alcohol use, through a rapid onset of liver failure, to a liver transplant. The patient took 3 to 4 capsules of kava extract daily for 2 months, to treat slight anxiety. He presented with jaundice, and dark coloured urine, and a ‘tanned’ skin colour. The patient's condition deteriorated within 48 hours. He developed stage IV encephalopathy and had to be intubated. This paper provided evidence to support further clinical studies on effects of kava on the liver and potential risks of liver disease resulting from kava ingestion are needed. • Ernst, E, 2002, ‘The Risk-Benefit Profile of Commonly Used Herbal Therapies: Ginkgo, St.John’s Wort, Ginseng, Echinacea, SawPalmetto, and Kava’, Ann Intern, vol 136, pp. 42-53. The author provided a clinically oriented overview of the safety and efficacy of kava and other herbs. He reported that kava is an efficacious short term treatment for anxiety, but not without side effects. Serious adverse effects have been reported but seem to be rare. Two postmarketing surveillance studies involving more than 6000 patients found adverse effects in 2.3% and 1.5% of patients taking

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120 to 240 mg of standardized extract. The author reported that problems arise when kava is self administered and when it is taken with other medication that acts on the central nervous system or with alcohol. It did not support the potential for kava to be safely used in indigenous communities.

The applicant also disagreed with the findings of an article (Hughes, H, October 2007, ‘Kava and after in the Nhulunbuy hinterland’, Issue Analysis, the Centre for Independent Studies, Australia, vol 88, pp. 1-12) previously presented to the Committee in February 2008. The applicant claimed that the paper by Hughes was misleading in that it cited the WHO as recommending kava be available on prescription only. The applicant felt that the Committee relied too heavily on this reference in its February 2008 deliberations. Specifically:

• The Hughes paper stated – the study found mixed evidence of liver damage from the use of kava in medications, but WHO recommended that kava products should only be available on prescription. • The WHO paper (2007, ‘Assessment of the risk of hepatotoxicity with kava products’, p. 5), stated – it would seem advisable that all kava products, prepared as pharmaceuticals, be available on prescription only in order to better monitor the use and apply necessary controls. • The applicant also argued that the paper by Hughes did not address section 52E. Members noted, however, that the paper was not, and was not intended to be, an application to the NDPSC. There was therefore no expectation that it specifically address matters under section 52E. • Points made by Hughes were: that the available limit of kava for legal consumption had been twice the safe limit per week of between 240 g and 400 g per week; that the interaction of kava with the other drugs of addiction was a known health risk; that due to the negative social and health outcomes of kava abuse, that the Australian Government had no choice but to ban its use allowing limited imports for medical and scientific research and 2 kg per person as accompanied baggage; that commercial interests in kava promotion were the protagonists of perpetuating the sale of kava in the NT and Australia wide.

Previous Committee Discussion

Members recalled that, from June 2006, the previous Australian Government had serious concerns about abuse of kava in the NT following abuse in remote indigenous communities. Kava was consumed by some indigenous communities at up to 100 times the usual rate. At least eight communities in Arnhem Land, comprising about 7,700 people, identified significant kava use as a problem. Heavy use of kava caused weight loss, malnutrition, liver damage, hypertension and skin disorders. These health issues represented a real concern to the then Government and to the jurisdictional health departments. The following restrictions came into force under the Australian Customs

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Service as a result of the previous Australian Government’s decision to restrict access to kava: • The unaccompanied importation of kava without a permit issued by the Office of Chemical Safety & Environmental Health, Treaties and Compliance Section, is an offence. • Consistent with the existing regulations, kava importation is now only permitted for medical or scientific purposes. • Importation of 2 kg of dried or root kava per adult is permitted with accompanied baggage in recognition of cultural significance of kava use by people of South Pacific Islander descent.

Information was received from Food Standards Australia and New Zealand (FSANZ). The status of kava in terms of the FSANZ Food Standard for kava was: • The Australia New Zealand Food Standards Code includes a specific standard for kava i.e. Standard 2.6.3. • FSANZ was aware of recent changes to the SUSDP and to the Customs (Prohibited Imports) Regulations 1956.

• XXXXX

Members also recalled that the New Zealand Food Safety Authority (NZFSA) issued a ‘Privileged Statement’ in August 2002 advising that people should consider carefully when using dietary supplements containing kava, noting the TGA’s recall of all complimentary medicines containing kava after the death of a woman from liver failure. The statement pointed out that ‘traditional forms’ had not been associated with serious liver damage, as opposed to the concentrated form.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extent and patterns of use, (f) the need for access, and (g) potential for abuse.

Members generally agreed that the submission had not established a case for overturning the previous decision to restrict access to kava products. A Member noted that support for Pacific Island economies was not a relevant consideration under section 52E.

RESOLUTION 2009/56 - 10

The Committee decided that the current scheduling for Piper methysticum remains appropriate.

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11.6 SOMATROPIN

Item withdrawn.

11.7 HYDROQUINONE

PURPOSE

The Committee consider the scheduling of hydroquinone for therapeutic and cosmetic use.

BACKGROUND

Hydroquinone is used as a skin depigmenting agent and also used in hair preparations. Hydroquinone increases melanin excretion from melanocytes and may also prevent its production. Topical hydroquinone may cause transient erythema and a mild burning sensation. Occasionally hypersensitivity has occurred. Concentrations of 2 to 4 per cent are commonly used; higher concentrations may be irritants and increase the risk of ochronosis.

Hydroquinone was first included in Schedule 4 in 1969 due to concerns about skin lightening creams being targeted to the Papua New Guinea and indigenous Australian populations. It was agreed that, due to the highly toxic nature and potential for ADRs, free availability of hydroquinone was not warranted.

At the February 1971 meeting, the Committee agreed to an exemption for ≤ 2 per cent hydroquinone. This was reconsidered at the May 1986 and May 1987 meetings which agreed to foreshadow that the safety profile of ≤ 2 per cent for human therapeutic or cosmetic use warranted inclusion in Schedule 2. This was confirmed at the July 1987 meeting.

The June 2008 meeting was advised of United States Food and Drug Administration (USFDA) concerns about possible carcinogenicity from prolonged use of hydroquinone. The Committee noted, however, that a USFDA final ruling on hydroquinone was not expected before the end of 2008. The Members therefore decided to foreshadow consideration of hydroquinone.

At the October 2008 meeting, the Committee again foreshadowed consideration of the rescheduling of hydroquinone including possible up-scheduling in preparations for human external use (excluding hair dyes) to Schedule 3.

At the February 2009 meeting, the Committee decided: • To defer a decision on hydroquinone in skin bleaching products until the USFDA’s final action was known.

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• To amend the exemption for hair preparations containing hydroquinone from 1 per cent to 0.3 per cent or less. • That the scheduling of hydroquinone remains appropriate with respect to salts and derivatives. • To foreshadow specific scheduling entries for arbutin at the June 2009 meeting (see item 11.1 – arbutin).

DISCUSSION - SUBMISSIONS

Status of the USFDA Review

The Committee recalled the following: • A USFDA OTC drug review establishes conditions under which OTC drugs are considered generally recognized as safe and effective. After a final rule is issued, only OTC drugs meeting the conditions of the monograph, or having an approved new drug application, may be legally marketed in the US. • In 2006, based on data regarding potential carcinogenicity and reports of ochronosis, the USFDA proposed to reclassify skin bleaching products (specifically containing hydroquinone) as drugs and make them available by prescription only. The USFDA’s ‘Skin Bleaching Drug Products for Over the Counter Human Use, Proposed Rule’ was released in 2006 for comment. • The USFDA advised that response submissions had raised many issues that were being addressing in writing the final rule. To resolve these issues, the USFDA needed to review a substantial amount of data. • At the February 2009 NDPSC Meeting a Member expressed concern that the USFDA decision might take years, however it was confirmed that the final decision was expected to be handed down in May 2009. Members agreed that it was important to wait for the decision of the USFDA, in order to consider its findings before making their decision. • The February 2009 NDPSC Meeting therefore supported deferring a decision on the scheduling of hydroquinone in skin bleaching products (for external therapeutic use) until the USFDA report was available (expected in May 2009) and thus anticipated addressing the issue at the June 2009 NDPSC Meeting.

Members were advised that the USFDA had yet to release its final rule. Members noted, however, that hydroquinone was included in the June 2009 pre-meeting gazette notice as it had been anticipated that the USFDA report would be available for the June 2009 meeting. A number of pre-meeting comments have therefore been received.

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Pre-meeting Comments

A pre-meeting comment was received from XXXXX regarding hydroquinone and arbutin. Members particularly noted the following regarding hydroquinone from this comment: Conclusion • The current scheduling of hydroquinone and its salts and derivatives remains appropriate, regardless of the decision of the USFDA. • Requested that any decision as a consequence of the USFDA’s action be foreshadowed to allow sufficient time for informed public comment. Background • XXXXX products are sold through pharmacies to ‘assist in fading age spots, freckles and brown skin blemishes’ i.e. for therapeutic rather than cosmetic use. They are not indicated for use in general skin lightening. Discussion • These products perform a useful role in helping people deal with some of the visible signs of hyper-pigmentation including ageing. The importance of this to the wellbeing and self esteem of the elderly should not be underestimated and could be compared to the use of therapeutic acne treatments to help teenagers deal with the visible signs of puberty. Up-scheduling of hydroquinone would severely limit people’s access to these very low-risk, effective medicines. • Asserted that while the USFDA’s decision was of interest, it should be remembered that that the regulatory framework in the US is not the same as in Australia. • There was a long history of use of hydroquinone as a medicine in Australia and the level of adverse effects reports was very low. Asserted that the ADRAC summary covering 1960 to May 2009 includes only 6 reports of skin sensitivity where hydroquinone was ‘suspected’ and no reports of ochronosis or leukomeloderma. XXXXX • The incidence of ochronosis from exposure to hydroquinone in the USA also appears to be very low - a literature review of exogenous ochronosis and clinical studies employing hydroquinone (involving over 10,000 exposures under clinical supervision) reveal an incidence of only 22 cases in more than 50 years.

Members also noted the following from a pre-meeting comment from XXXXX: Conclusion • Asserted that, from experience selling hydroquinone products over the past 25 years, the strict conditions of Schedule 2 has allowed consumers to have reasonable access to effective products while ensuring negligible side effects as a result of informed usage.

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• There appeared to be no sound reason why the current scheduling for topical products containing ≤ 2 per cent hydroquinone should be altered in any way. Discussion • The scheduling status of topical hydroquinone had been reviewed by NDPSC on numerous previous occasions. It was asserted that such reviews have never been based on concerns of reported misuse in Australia but rather as a result of restrictions being applied in other countries, misuse in other countries or lobbying by the cosmetic industry. • In Australia, hydroquinone products have been responsibly and effectively used for over 25 years as treatments for correcting various forms of pigmentation irregularities that occur in the skin under the influence of genetics, sun exposure and hormones. Surveys would suggest that around 90% of the population over the age of 18 suffer from some form of hyper-pigmentation. • Asserted that in other parts of the world, especially where there is a significant proportion of the population with dark skin, products containing ≤ 2 per cent hydroquinone are predominantly used for overall cosmetic ‘skin lightening’. This had led to some reported cases of excessive overuse resulting in a number of problems occurring in dark skin. The problem was exacerbated in those countries where hydroquinone creams are sold as cosmetics with unrestricted consumer access and with no label warning statements as they were assumed to be harmless by consumers. • Countries such as South Africa, the United Kingdom and the European Union have reacted to this situation by restricting use of hydroquinone and changing the classification of hydroquinone products from an approved ingredient for cosmetic use to medicines available only on prescription. In some cases, this was because they did not have a Schedule 2 equivalent in their regulatory framework. • It should be noted that various skin types have different forms of melanin pigment to colour the skin as well as different mechanisms whereby the melanocytes transfer the melanin to the skin cells above. This gives rise to problems in some specific skin types and not others if excessive overuse of hydroquinone occurs. Side-effects • Asserted that, from personal experience formulating and marketing 2 per cent hydroquinone creams for over 25 years in Australia, the reported side effects from Australian products have been confined to mild inflammation which has disappeared after a few days once treatment has ceased. XXXXX. • Confirmed that there has not been a single incident reported during this time of more serious problems such as depigmentation, ochronosis, or leukomelanoderma. • While the phenol ring in the hydroquinone molecule has from time to time been linked to skin cancer stimulation, the absence of any reported cases during the

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extensive use of this molecule over the past 40 years should conclusively debunk this suggestion. US Situation • While the USFDA was again undertaking a review of hydroquinone in cosmetics, there are significant differences between the US and the Australian markets: − The US has large black and hispanic populations whose skin reacts differently to hydroquinone than caucasians. − There is no intermediate schedule (such as Schedule 2) operating in the US which meant products must be safe enough for sale anywhere and without advice / supervision or they have to be restricted to prescription only. The potential for misadventure from incorrect use of products containing hydroquinone at 2 per cent is greater in the US where its access is unrestricted.

A pre-meeting submission from XXXXX asserted that consideration of scheduling for human external use should be deferred until the final report of the USFDA is made available publicly and relevant stakeholders have had the opportunity to consider the outcomes.

A pre-meeting submission from XXXXX addressed the issue of the February 2009 hair dyes decision and did not comment on the current dermal use consideration.

USFDA’s 2006 Proposed Rule

Members recalled the following from the USFDA’s 2006 ‘Proposed Rule’: • The actual risk to humans from the use of hydroquinone has yet to be fully determined. There was, however, evidence of carcinogenicity related to hydroquinone in animals and disfiguring effects (ochronosis) in humans. • Under these circumstances, the use of hydroquinone as an active ingredient in OTC skin bleaching drug products cannot be justified. The USFDA found that because of the carcinogenic and ochronotic potential of hydroquinone, its use in skin bleaching drug products should not be available OTC but should be restricted to prescription use only, and users of such products should be closely monitored under medical supervision. • The USFDA tentatively concluded that the benefits of OTC skin bleaching drug products were insignificant when compared to the potential risks and that this proposed rule would benefit society because it would eliminate a potentially unsafe drug product. The benefit of removing OTC skin bleaching drug products from the market would be a reduction in the number of cases of ochronosis that would otherwise occur each year.

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European Controls on Cosmetic Use

In Europe the use of hydroquinone in cosmetic preparations for skin lightening has been banned, but it was still available for prescription as a medicine. This ban followed a February 1998 opinion from the Scientific Committee on Cosmetic and Non-Food Products (SCCNFP) which concluded that hydroquinone should not be used as depigmenting agent in cosmetic products due to observed clinical side effects (ochronosis and leukomelanoderma). Hydroquinone was listed in Annex III - Part 1 ‘List of Substances which cosmetic products must not contain except subject to restrictions and conditions laid down’ to European Council (EC) Directive 76/768/EEC of 27 July 1976 of the Cosmetics Directory.

Other Recent NDPSC Considerations

Members recalled the following from the October 2008 meeting discussion regarding use on skin: • The Committee noted that the US drug classification system does not include a pharmacist-only schedule and the use patterns in the US were not necessarily comparable to use patterns in Australia. • The Members noted that hydroquinone is known to carry some risk and is of limited benefit. Further, the point was made that chloasma and other hyperpigmentation conditions should not be self-diagnosed by consumers. The Committee believed that use of hydroquinone on the skin at least required a pharmacist’s supervision and so agreed to foreshadow up-scheduling hydroquinone in preparations for human external use (excluding hair dyes) to Schedule 3.

Members additionally recalled that at the June 2008 meeting that a Member suggested that it was not uncommon to find hydroquinone containing products which were sourced from overseas being imported into Australia. The Member stated that there was a high demand for skin lightening type products in certain sections of the community.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extent and patterns of use, (f) the need for access taking into account its toxicity compared with other substances available for a similar purpose and (g) potential for abuse.

A Member asserted that there had been no adverse reports in Australia in relation to products for external therapeutic use which would justify rescheduling. Members recalled that the current inclusion of the term ‘cosmetic use’ in the Schedule 2 and 4 hydroquinone entries meant that any cosmetic containing hydroquinone was scheduled in a medicines schedule and therefore captured by therapeutic goods legislation. It was noted that many of the concerns arose in the context of patterns of use that were quite

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different to those in Australia. Additionally, a Member asserted that literature relating to this may not be current.

A Member noted that this issue had been deferred a number of times over the last year and the Member asserted that there was already sufficient evidence before the Committee for a decision to be made. The Member suggested that any decision could then be reconsidered once the USFDA findings were final. Indeed, given the differences in patterns of use between Australia and the US, it seemed unnecessary to wait for an outcome from the USFDA.

The Committee generally agreed that the scheduling of hydroquinone remained appropriate.

RESOLUTION 2009/56 - 11

The Committee decided to confirm that the current scheduling of hydroquinone for human external therapeutic or cosmetic use remains appropriate. The Committee also committed to a subsequent review of this matter once the USFDA findings were final.

11.8 CLARIFICATION OF THE SCHEDULING OF CODEINE IN COMBINATION WITH MENTHOL & AMMONIUM CHLORIDE

PURPOSE

The Committee considered the scheduling of a codeine cough linctus.

BACKGROUND

Australia is a signatory to the United Nations Single Convention on Narcotic Drugs, 1961 (the Single Convention) (http://www.unodc.org/pdf/convention_1961_en.pdf). As such, Australia must adhere to the provisions of the International Narcotics Control Board’s (INCB) list of narcotic drugs under international control. This list only exempts codeine from the strictest controls when it is ‘compounded with one or more other ingredients and containing not more than 100 milligrams of the drug per dosage unit and with a concentration of not more than 2.5 per cent in undivided preparations’.

Where the exemption does not apply, codeine preparations are subject to Schedule II of the Single Convention. Thus, as per the intention of the Single Convention (which bases its exemption less on the potential for harm to an individual and more on the potential for illicit diversion) all single (active) ingredient undivided preparations of codeine are not exempted from any provision of the Single Convention. In Australia this has been interpreted to mean that such preparations must be classified as Schedule 8 substances.

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At the November 1984 meeting, the Committee noted that some jurisdictions were experiencing abuse problems with codeine linctus. At this time codeine linctus was considered to be a compounded liquid and thus Schedule 2 by the scheduling limits at the time.

At the August 1991 meeting, the Committee confirmed that codeine linctus preparations were Schedule 8 products. However, because of wider legal implications for the jurisdictions, the question of interpretation of the schedule classification, along with the existence of a definition for “compounded” (a decision of the August 1991 meeting), it was agreed that this should be referred to the NCCTG. The June 2009 meeting noted that there was no evidence of further action being taken.

At the May 1998 meeting, the Committee considered the interpretation of “compounded” and “therapeutically active substance” as they related to the various codeine (and dihydrocodeine) schedule entries. The Members noted that this matter arose because “therapeutically active” was not defined in the SUSDP, and that some substances (e.g. sucrose or glycerol) might therefore be inappropriately considered to be therapeutically active ingredients. A Member suggested that one option would be to re-examine products in the marketplace with a view to removing the phrase “other therapeutically active substances” from schedule entries and replacing it with a specific list of acceptable combinations. Members agreed that although this issue needed to be resolved, it was not urgent and a paper exploring the above option could be prepared for consideration at a future Meeting. The June 2009 meeting noted that there was no evidence of further action being taken on this matter.

A similar issue was considered at the February 2006 meeting, where the Committee confirmed that scheduling of codeine required any single active preparation of codeine, including liquid preparations, to be captured by Schedule 8.

At the October 2008 meeting, Members discussed the inclusion of menthol and ammonium chloride in a particular codeine formulation (XXXXX) intended to suppress coughs. The ARTG entry listed the active ingredients in the following quantities: ammonium chloride 10 mg/ml, codeine phosphate 1.5 mg/ml and menthol 0.1 mg/ml. It was noted that, as per the Martindale monograph, a therapeutic dose of ammonium chloride is around one to two grams every four to six hours and this particular formulation contains only 100 mg/10mL. Given that menthol is mostly used via inhalation, its presence in an oral formulation intended for systemic effect (c.f. lozenge or pastille) may not be appropriate. The Committee decided to ask the Sponsor to provide information to justify this product being considered a Schedule 2 medicine and to gazette this issue for consideration at the February 2009 meeting.

At the February 2009 meeting, the Committee agreed to defer further consideration of the scheduling of this matter until matters relating to the scheduling of codeine and the definition of “compounded” had been resolved.

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DISCUSSION - SUBMISSIONS

Advice from TGA

Members recalled the following information from the TGA: • There was only one product on the ARTG with menthol and ammonium chloride as active ingredients. • Two other entries listed ammonium chloride, menthol, diphenhydramine and sodium citrate as active ingredients. • All three products were grandfathered onto the ARTG in 1991 and it appeared that no formal evaluation of these products had taken place. • The ARTG had over five hundred products which list ammonium chloride as an active ingredient. • Ammonium chloride was a common active ingredient listed in OTC medicines. Menthol was listed in products as an active to a similar scale. Many of these products had been grandfathered onto the ARTG.

Sponsors justification for inclusion in Schedule 2

The sponsor (XXXXX) provided a final response which included a large number of references, not all of apparent relevance to the issue of the appropriateness of inclusion of ammonium citrate and menthol in a cough suppressant was not clear). Members noted the following from the sponsor’s submission regarding the claim that the ammonium chloride and menthol were therapeutically active ingredients: • Two Cochrane reviews were cited, but results were not discussed: − Smith SM, Schroeder K, Fahey T, 2008, ‘Over-the-counter medications for acute cough in children and adults in ambulatory settings’, Cochrane Library, Issue 1. − De Sutter AI, Lemengre M, Campbell H, 2009, ‘Antihistamines for the common cold’, The Cochrane Library, Issue 2). • The sponsor claimed that ‘…it is important to bear in mind, however, that lack of evidence for efficacy does not mean that there is a lack of efficacy’. This was followed by a statement to the effect that the Smith et al. Cochrane review found little evidence of efficacy of menthol or ammonium salts (although the review also concluded that most OTC cough preparations appeared to be safe). • Information pertaining to the physiological effects which may be induced by a placebo and the possible effects of a bitter taste or distinctive smell. Information on the effects of sweet tasting medicines was also provided. • Descriptions of the pharmacological, placebo the physiological effects of cough medicines. Members noted that none of these went to the question of clinical efficacy of the ingredients.

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• Other arguments put forward concerning the availability of this formulation insupporting the current policy of reducing reliance on antibiotic treatment for common colds and minor infections. Members noted that there was no evidence provided on the therapeutic activity and efficacy of ammonium chloride or menthol.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (e) dosage and formulation and (g) potential for abuse.

Several Members noted that the current provisions of the Schedule 2 codeine entry required that the codeine must be compounded with one or more therapeutically active substances i.e. have a therapeutic purpose and be present at a concentration which would achieve the therapeutic purpose.

A Member asserted, and the Committee generally agreed, that the levels of menthol and ammonium chloride in this particular formulation were not therapeutically active. As such, there was no other therapeutically active substance compounded with the codeine and the formulation was therefore captured by the Schedule 8 codeine entry.

RESOLUTION 2009/56 - 12

The Committee confirmed that this product should be considered a Schedule 8 medicine.

12. PROPOSED CHANGES/ADDITIONS TO THE STANDARD FOR THE UNIFORM SCHEDULING OF DRUGS AND POISONS

12.1 SUSDP, PART 4

12.1.1 FEXOFENADINE

PURPOSE

The Committee considered the scheduling of fexofenadine, including a proposal to exempt fexofenadine in preparations for oral use for the short term treatment of seasonal allergic rhinitis (SAR).

BACKGROUND

Fexofenadine is an orally active non-sedating histamine H1-receptor antagonist. It is the carboxylic acid metabolite of terfenadine.

At the May and August 1996 meetings, the Committee considered a request to initially schedule fexofenadine as per terfenadine (Schedule 3) given that fexofenadine is a terfenadine prodrug. The Committee noted, however, that simply because a drug was an

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active metabolite and there was experience with the parent compound did not mean that experience necessarily yielded adequate safety data on the metabolite. It was agreed that there was insufficient evidence to make a decision in regard to the toxicity of fexofenadine and in view of this the Committee agreed that a Schedule 4 entry was appropriate at that time.

At the November 1996 meeting, the Committee noted interactions of fexofenadine with ketoconazole and erythromycin but did not consider these to be clinically significant. The Committee, being satisfied with respect to the safety of fexofenadine, decided that it should be in Schedule 3 in divided preparations as the only therapeutically active substance.

At the February 1997 meeting, the Committee considered a post-meeting submission seeking a temporary Schedule 4 entry for all pack sizes so that the initial availability of fexofenadine would be under greater control. However, the Committee noted that a major reason for its Schedule 3 decision was that it had been satisfied that the available evidence indicated that fexofenadine was a safer drug than the prodrug, terfenadine, and that much was already known about terfenadine. The Committee also noted that the applicant had included a fexofenadine monograph which provided information on overdose and reported that single doses of up to 800 mg and 690 mg twice daily for one month in healthy volunteers had been administered without the development of clinically significant adverse effects. The Committee agreed that the decision to include fexofenadine as Schedule 3 remained appropriate.

At the August 1998 meeting, the Committee agreed that it was appropriate for fexofenadine to be included in Appendix H.

At the November 1998 meeting, the Committee deferred a request to reschedule fexofenadine from Schedule 3 to Schedule 2. At the February 1999 Meeting the proposal was again considered. Members considered that it was incongruous that sedating antihistamines were more freely available than the non-sedating antihistamines. Members also noted that the possible causal links between fexofenadine and arrhythmias were now sufficiently resolved that rescheduling to Schedule 2 was appropriate. It was also noted that in New Zealand all antihistamines were in the equivalent of Schedule 2, except when used as sedatives. Members additionally noted that abuse was not seen as an issue with the non-sedating antihistamines. The Trans-Tasman Harmonisation Working Party had also recommended that fexofenadine be re-scheduled to Schedule 2. In view of all this, the Committee agreed that fexofenadine be rescheduled to Schedule 2.

DISCUSSION - SUBMISSIONS

XXXXX submitted an application requesting exemption of oral fexofenadine (10 dosage units or less) from scheduling when used for short-term treatment (not more than 5 days) of seasonal allergic rhinitis (SAR) in adults with a maximum daily dose of 120 mg.

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An evaluation of this application recommended that the application for re-scheduling be rejected. This evaluation was supplied to the applicant for comment prior to the June 2009 meeting. Part of the applicant’s comment, however, relied on data not contained in the original application (despite it being a requirement, as set out in the NDPSC Guidelines, that new data not be included in such a comment). Member’s noted that: • A company, XXXXX, provided (prior to the cut-off for public pre-meeting submissions) data from a market research report commissioned on behalf of XXXXX. This new data was used as the basis for a comment in the applicant’s response to the evaluation report. • The applicant was advised: XXXXX data − This data did not constitute a valid pre-meeting submission. XXXXX was not acting as a separate interested party in this matter, its involvement entirely stemmed from acting as an agent for the applicant. − The applicant was advised that it was not the Secretariat’s role to exclude this data from consideration by the June 2009 meeting. The Committee was free to consider information from any source. The Secretariat simply advised that the XXXXX data was not a valid pre-meeting submission and as such the Committee was in no way bound to consider it. Additionally, XXXXX was not entitled to any possible post-meeting submission rights with regard to this consideration. Use of this data by the applicant in commenting on the evaluation report − The applicant was reminded that the invitation for providing a comment on the evaluation report advised that ‘comments should only address issues raised in the evaluation report. Any new or additional data should not be included as it will not be considered’. − The applicant was also advised that it was not the Secretariat’s role to exclude this data from consideration. It was up to the Committee’s discretion whether or not it considered this data. However, as stated in the NDPSC Guidelines, the applicant was advised that ‘inclusion of new or additional data is likely to be grounds for consideration of the rescheduling application by the NDPSC to be deferred to a later meeting to allow assessment of this information’. • Members noted that the applicant subsequently indicated a preference for the data not to be considered by the Committee rather than risk the possibility of the Committee deferring consideration of this issue.

While a number of pre-meeting submissions had been received, Members agreed that there was no point considering these or the majority of data in the application, the evaluation report or the applicant’s response to the evaluation report, until the issue of the XXXXX data had been resolved.

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DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extent and patterns of use, and (f) the need for access.

With regard to the XXXXX data, a Member asserted that as it had not come to the Committee appropriately, it should be disregarded. Other Members asserted that while the data were not presented to the Committee through the established processes, they may be relevant to the evaluator’s findings.

While noting the applicant’s preference for the new data not to be considered by the Committee if this would risk a deferral of a decision, the Members generally agreed that the XXXXX data should not be excluded. The Committee considered that the XXXXX data may be directly relevant to concerns raised by the evaluator. The Committee also agreed that this deferral was in no way establishing a precedent. Data before the Committee which had not been presented in compliance with the Committee’s established processes would continue to be dealt with on a case-by-case basis. Specifically, the Committee would retain the option of not considering such data, at its discretion.

Members also discussed if the October 2009 consideration should be re-opened to pre- meeting submission through inclusion in the October 2009 pre-meeting gazette notice. It was generally agreed that this was not necessary as deferment was only to allow additional time for the evaluation of the XXXXX data, and that ample time had been allowed for public submissions through the pre-June Gazette notice.

RESOLUTION 2009/56 - 13

The Committee agreed to defer consideration of the scheduling of fexofenadine until the October 2009 meeting to allow data presented after the application had been evaluated to be duly considered by the evaluator.

12.1.2 HMG-COA REDUCTASE INHIBITORS (STATINS)

PURPOSE

The Committee considered the scheduling of HMG-CoA reductase inhibitors (‘statins’), including a proposal for a Schedule 4 class entry.

BACKGROUND

HMG-CoA reductase inhibitors (more commonly known as ‘statins’) are inhibitors of 3- hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the rate-determining enzyme for cholesterol synthesis. They reduce cholesterol by stimulating an increase in low-density-lipoprotein (LDL)-receptors on hepatocyte membranes, thereby increasing the clearance of LDL from the circulation. Their main effect is to reduce LDL-

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cholesterol, but they may also reduce triglycerides to a modest extent and increase high- density-lipoprotein (HDL)-cholesterol.

The NDPSC has previously considered atorvastatin, cerivastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin and these have all been included in Schedule 4. The Committee was of the view that the medical condition that these substances are indicated for (hypercholesterolemia) requires medical oversight and the contraindications of these agents require that they be monitored by a medical practitioner.

Other statins such as lovastatin and mevastatin have not yet been considered by the Committee. It should be noted that there are no products currently on the ARTG containing either lovastatin or mevastatin. Cerivastatin was withdrawn from sale worldwide in August 2001 by its sponsor following increasing reports of rhabdomyolysis, both in combination with gemfibrozil and when used in monotherapy.

The Committee recalled that, at the February 2009 meeting, phosphodiesterase-5 inhibitors (PDE5) inhibitors were included in Schedule 4 as a class entry to capture those substances that had not yet been evaluated by TGA for safety and efficacy. The Committee noted that while a class entry would capture all PDE5 inhibitors, it would not preclude scheduling new PDE5 inhibitors as they are evaluated through TGA registration processes.

DISCUSSION - SUBMISSIONS

This matter had been referred by XXXXX. The Committee was asked to consider the appropriateness of a class entry for these agents, given the purposes for which they are used. Statins are used to reduce LDL-cholesterol, apoliprotein B and triglycerides and to increase HDL-cholesterol in the treatment of hyperlipidaemias. They are indicated for hypercholesterolaemias, combined (mixed) hyperlipidaemia (type IIa or IIb hyperlipoproteinaemia), hypertriglyceridaemia (type IV), primary dysbetalipoproteinaemia (type III) and may also be used as an adjunct in patients with homozygous familial hypercholesterolaemia who have some LDL-receptor function (Martindale: The Complete Drug Reference 32nd Ed; Kathleen Parfitt et al, 1999, Pharmaceutical Press).

In regards to the safety and efficacy of these substances as a class, multiple well- controlled clinical trials have documented the efficacy and safety of simvastatin, pravastatin, lovastatin and atorvastatin in reducing fatal and nonfatal CHD events, strokes, and total mortality (Law, MR, Wald, NJ, Rudnicka, AR Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease and stroke: systematic review and meta-analysis BMJ, 2003, 326; 1423). In this paper of three meta- analyses (164 short term RCTs of six statins and LDL reduction; 58 randomised trials of cholesterol lowering by any means and IHD events; and nine cohort studies with the same 58 trials on stroke), rates of adverse events in statin trials were the same in the placebo groups and in the groups receiving the drug. The main outcome measure was LDL cholesterol reduction according to statin and dose and reduction in IHD events and

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stroke for a specified reduction in LDL cholesterol and conclusions were that statins can lower LDL cholesterol concentration by an average of 1.8mmol/L which reduces the risk of IHD events by about 60 per cent and stroke by 17 per cent.

The major adverse effect of clinical significance associated with statin use is myopathy. Between 1987 and 2001, the US FDA recorded 42 deaths from rhabdomyolysis induced by statins (except cervastatin, which has been withdrawn from the market worldwide). In the same time period, 3 deaths were reported to the Adverse Drug Reaction Advisory Committee (ADRAC). Within that same time period, reports of rhabdomyolysis and other muscle disorders to the ADRAC were as follows: Reports from 1/1/1987 to 31/12/2001 Total number Muscle disorders* Rhabdomyolysis** Atorvastatin 751 147 10 Fluvastatin 244 59 1 Lovastatin 0 NA NA Pravastatin 352 83 4 Simvastatin 2293 460 52

*Number of reports describing one or more of the following terms: myalgia, myopathy, myositis, rhabdomyolysis ** Number of reports describing rhabdomyolysis (other muscle disorders may also be described in these reports)

Case line listings were also provided to the Committee for fluvastatin, atorvastatin, pravastatin and simvastatin. No cases were reported for lovastatin (as it was not currently registered in Australia).

In the statin trials described in Law et al 2003, rhabdomyolysis occurred in eight active drug recipients versus five placebo subjects. Among active drug recipients, 0.17 per cent had creatine kinase (CK – commonly monitored in patients taking statins) values exceeding ten times the upper limit of normal, the value commonly used to define statin- induced rhabdomyolysis. Among placebo-treated subjects, the incidence was 0.13 per cent. Only 13 out of 55 drug-treated subjects and 4 out of 43 placebo subjects with greater than tenfold elevations of CK reported any muscle symptoms. The Committee noted that the safety of statins during pregnancy had not been established.

The Committee noted that a class entry for statins would not preclude consideration of new substances within this class as they were evaluated by the TGA as part of the registration process. The scheduling of each new substance as it is registered would ensure the SUSDP provided useful information to stakeholders as to whether a particular statin had been considered by this Committee. The class entry for the statins would, like the PDE5 inhibitors class entry, capture all statins that are yet to be considered for scheduling.

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Pre-Meeting Submissions

XXXXX provided a pre-meeting submission. The submission supported a Schedule 4 class entry, as any drug in this class should only be provided under medical supervision. The submission further stated that upon review of the relevant product information documents, the adverse effects, precautions and contraindications for statins, it was appropriate that any drug in this class to be included in Schedule 4.

A pre-meeting submission was provided by XXXXX. It is stated that including wording such as ‘HMG-CoA reductase inhibitors (‘statins’) not otherwise included in this or any other schedule’ would provide a safety net, should other statins become available. In event of prosecution or should the matter be challenged, expert advise would need to be obtained that a particular substance was a member of the class.

XXXXX provided a pre-meeting submission. The submission did not object to the proposal. However, it was requested that the existing individual entires for specific drugs remain to assist in the use of the SUSDP.

A submission was received from XXXXX. The submission requested that the NDPSC assess the suitability of red yeast rice as a Schedule 3 substance (containing Monacolin- K, more commonly known as lovastatin). The proposed indication was to reduce blood cholesterol levels and for ongoing assistance in maintenance of healthy blood cholesterol levels. Against each of the criteria for S3 listing set down in the Interim Guidelines, the submission made the following claims (in relation to red yeast rice products, containing lovastatin): • Lovastatin was substantially safe but guidance from a pharmacist would assist consumers. • As lovastatin had a measurable pharmacological effect, pharmacist advice was warranted. • The need for use could be determined by the consumer through the use of an approved cholesterol measurement kit. • Lovastatin had no potential for abuse. • Lovastatin, at low doses, presented no risk of harm from overdose. • Clinical data indicates severe adverse effects were extremely rare, not sudden and were dose related (Bradford et al, Expanded clinical eval of lovastatin study results: two-year efficacy and safety follow-up, Am J Cardiol 1994; 74:667-673). • There was very low potential for minor interactions with medicines or some foods. • Lovastatin had a high therapeutic index. • Lovastatin could not mask symptoms of a serious disease nor could it compromise medical management. • Known contra-indications could be dealt with by a pharmacist.

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• Pharmacists would be able to provide counselling. • No intervention or close medical supervision was required. • Marginally elevated blood cholesterol levels could be assessed by consumers. • Results could be seen by consumer in short term, with a pharmacist’s assistance using an approved diagnostic kit.

Against the provisions of section 52E(1), the following claims were made: (a) Toxicity and safety of the substance • In vitro genotoxicity studies, in vitro cytotoxicity studies, acute toxicity mice studies, reproductive toxicity mice studies, a 12 week (human) safety and efficacy clinical trial, a 40 week follow-up safety and efficacy trial and clinical trials using comparable products (Herber et al, Cholesterol lowering effects of a proprietary Chinese red yeast rice dietary supplement, Am J Clin Nutr, 1999 69: 231-6) were all outlined. (b) Risks and benefits associated with use • Benefits listed included demonstrated effectiveness in lowering LDL cholesterol, total cholesterol and triglyceride while increasing HDL: LDL ratio, demonstrated low level of AEs, well established history of traditional use in Asian populations, no demonstrated change in CK levels, appropriate concentration of monacolins (i.e. lovastatin). Risks listed were no established safety data on interaction with other substances or use in pregnancy. (c) Potential hazards associated with use • Potential for dose-related interaction with inhibitors of CYP3A4. (d) Extent and patterns of use • Quoted article on traditional use of red yeast rice in Asia (Ma et al, Constituents of Red Yeast Rice, a Traditional Chinese Food and Medicine, J Ag Food Chem 2000). Other published articles also referenced. Provided sales data on food supplements sold in the USA containing red yeast rice. (e) Dosage and formulation • Listed the (typical) constituents in red yeast rice. (f) Need for access • Submission contended that red yeast rice offered consumers a safe and effective way to assist with marginally elevated blood cholesterol levels. It pointed out that cardiovascular health is a National Health Priority and so this treatment had an important preventive healthcare role in Australia. (g) Potential for abuse • Based on pharmacological action, no abuse potential existed.

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(h) Purposes for use • The intended indication of reducing blood cholesterol levels and ongoing assistance in the maintenance of healthy blood cholesterol levels was listed. (i) Other matters • The OTC availability of simvastatin in the UK was stated as relevant, given the similar regulatory framework which existed there. Three expert comments were commissioned and are included in the attachments.

A list of attachments were also included with this submission including various product specs, animal reproduction toxicity report, 12 week trial and 40 week follow-up trial reports, proposed labelling and PI, summaries of US sales data for red yeast rice and UK OTC simvastatin data as well as three expert reports.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under Section 52E (1) included (a) toxicity and safety, (b) risks and benefits, (c) potential hazards, (d) extent and patterns of use, (e) dosage and formulation, (f) the need for access, (g) potential for abuse and (h) purpose for which the substance is to be used.

The Committee agreed that precedents existed for class entries in the SUSDP, most recently regarding PDE5 inhibitors. XXXXX. The Committee noted that a situation could arise where a product which contained a substance which would ordinarily require a prescription could potentially be available for sale. Therefore it was appropriate to for the Committee to consider a class entry for these substances.

While a Member asserted that there was currently no evidence that lovastatin has the safety profile appropriate for a Schedule 3 listing, another Member pointed out that the issue of whether lovastatin should be a Schedule 3 substance is separate to whether or not a Schedule 4 class entry for HMG CoA reductase inhibitors was appropriate.

The Committee considered the risk / benefit profile for HMG CoA reductase inhibitors as a class. It was agreed that a patient generally could not self-diagnose hypercholesteraemia. Further, should a patient incorrectly self-diagnose (and take an HMG CoA reductase inhibitor), the patient would be unnecessarily exposed to the risk of side-effects (including the very serious risk of rhabdomyolysis). Furthermore, given that this class of substances is used to lower blood cholesterol in order to decrease the risk of heart-attack or stroke, oversight by a medical practitioner was appropriate to look at the entirety of the matter.

RESOLUTION 2009/56 - 14

The Committee agreed to include an entry for all HMG-CoA reductase inhibitors (‘statins’).

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Schedule 4 – New entry

HMG-CoA REDUCTASE INHIBITORS (“statins”) except when separately specified in these Schedules.

12.1.3 LOPERAMIDE

PURPOSE

The Committee considered the scheduling of loperamide including a proposal to reschedule loperamide in undivided preparations for therapeutic use containing no more than 0.02 per cent of loperamide in a pack size no greater than 100 mL with a recommended daily dose of not more than 16 mg for patients 12 years and over.

BACKGROUND

Loperamide is a synthetic piperidine derivative which binds to the opiate receptor in the gut wall. Consequently, it inhibits the release of acetylcholine and prostaglandins, thereby reducing propulsive peristalsis and increasing intestinal transit time. Studies suggest that loperamide may increase the tone of the anal sphincter, reducing incontinence and urgency. Due to its high affinity for the gut wall and its high first-pass metabolism, loperamide hardly reaches the systemic circulation. In humans, as a constipating agent, loperamide on a mg to mg basis is about three times more potent than diphenoxylate hydrochloride and 25 times more potent than codeine phosphate. Given orally, it is an antidiarrhoeal as well as an adjunct in the management of both acute and chronic diarrhoea. Loperamide may also be used in reducing the volume of discharge in patients with colostomies or ileostomies.

At the November 1978 meeting, the Committee recommended loperamide be included in Schedule 4.

At the August 1986 meeting, the Committee considered an application to have loperamide rescheduled from Schedule 4 to Schedule 3. The Committee recalled that at the May 1983 NDPSC meeting it rejected a similar request to down-schedule. The Committee also noted concerns with possible risks with the use in early pregnancy and decided to retain loperamide in Schedule 4. At the August 1986 DPSC meeting, the Committee noted in the evaluator’s report that in June 1981 loperamide was considered following an application for marketing for loperamide syrup in children. The application was rejected as the Committee believed that paediatric formulations of this type of drug were not appropriate. The Committee agreed to include loperamide in Schedule 3 in packs of 8 dosage units or less each containing 2 mg or less of loperamide with an Appendix F Part 1 entry stating ‘Not to be taken by children under 12 years, during pregnancy or lactation or beyond 48 hours except on advice of a medical practitioner’.

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At the November 1996 meeting, the Committee considered a request to down-schedule loperamide from Schedule 3 to Schedule 2. The Committee noted that from March 1994 to February 1995 there were only 62 adverse reports received out of an estimated 87 million patients treated worldwide. The Committee agreed that this provided assurance of a safety profile appropriate for a Schedule 2 medicine. The Committee recommended inclusion of loperamide in Schedule 2 in packs of 8 dosage units or less, each dosage unit containing 2 mg or less of loperamide.

At the August 2000 meeting, the Committee decided that it would harmonise with New Zealand and increase the Schedule 2 pack size limit of loperamide from eight dosage units to a maximum of 20 dosage units.

DISCUSSION - SUBMISSIONS

XXXXX made a submission proposing that loperamide in undivided preparations (1 mg/5 ml) in pack sizes of 100 mL (i.e. 20 doses) or lower be included in Schedule 2. The applicant put forward that a liquid formulation was needed as there are no such products available on the Australian market. It was further stated that liquid formulations are preferred by certain age populations and could be advantageous to those who have problems with swallowing tablets or capsules. It would also provide additional choice to consumers.

The applicant addressed the following criteria under Section 52 E (1): (a) Toxicity and safety of a substance • The applicant believed that toxicity and safety data was not relevant for this scheduling application as loperamide was already available in tablet and capsule formation in equivalent dosages. Further, the applicant believed this information was not necessary as liquid preparations were available in various countries under a lower schedule. A summary of the review article ‘Loperamide Therapy for Acute Diarrhea in Children: Systematic Review and Meta-Analysis’ (Li, S Grossman, D & Cummings, P 2007, PLoS Medicine, vol 4, issue 3, pp 495-505) was included, which concluded that serious side effects were reported only in children below 3 years of age. The applicant also referred to MIMS 2007 entry for loperamide. It was stated that the adverse effects for current formulations containing loperamide, reported in clinical investigations, are difficult to distinguish from the symptoms of diarrhoea itself. Further, adverse reactions were considered mainly minor, self limiting and common in the treatment of chronic diarrhoea. (b) Risk and benefits associated with the use of the substance • The applicant identified accidental ingestion and misuse in children as possible risks with the liquid formulation. The applicant proposed to reduce the risks of accidental ingestion by ensuring a maximum pack size of less than or equivalent to 20 adult doses or 100 mL at a concentration of 0.02 per cent. Further the preparation was to be packed in a container with a child-resistance closure. The applicant proposed to reduce misuse in children by ensuring the Schedule 2 listing for loperamide oral

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liquid have further restrictions i.e. that its use be limited to adults and children over 12 years of age and also include a warning statement from Appendix F of the SUSDP to the effect of ‘WARNING: This product should not be given to children under 12 years’. The applicant chose the above age group based on existing loperamide products. • The applicant identified the benefits of a liquid formulation as: ease of use for people who have difficulty swallowing tablets, may provide better absorption, already available in overseas OTC markets. (c) Potential hazards associated with the use of a substance • The applicant requested that the product be only used for children 12 years or older. Therefore, the applicant identified, the potential hazards of loperamide hydrochloride liquid being related to the potential use by children as either misuse or accidental ingestion, as per criterion (b) risks and benefits. (d) Extent and patterns of use of a substance • The applicant stated that loperamide was currently available in various dosage forms for the symptomatic treatment of acute diarrhoea, the treatment of chronic diarrhoea, antipropulsive control and the reduction of discharge in patients with intestinal resection. (e) Dosage and formulation of a substance • The applicant stipulated that the dosage and formulation of loperamide liquid would be as an undivided preparation with 1 mg/5 ml per dose, be packaged in a container with a child-resistant closure, contain 20 mg or less of loperamide being equivalent to 100 ml. (f) Need for access to a substance taking into account its toxicity compared with other substances available for a similar purpose • The applicant felt that this criterion was not applicable as loperamide was available in other dose forms as Schedule 2. (g) Potential for abuse of a substance • The applicant provided information from the website RxList – the Internet Drug Index (www.rxlist.com/imodium-drug.htm) in relation to this criterion. It stated that ‘a specific clinical study designed to assess the abuse potential of loperamide at high doses resulted in a finding of extremely low abuse potential’. In regards to dependence, the website referred to studies of morphine-dependent monkeys taking loperamide at higher than recommended doses resulting in the prevention of the signs of morphine withdrawal. Conversely, in humans there was a nil response to the naloxone challenge pupil test after a single high dose or after more than two years of therapeutic use of loperamide. The website further concluded that loperamide, when orally administered, is highly insoluble and poorly penetrates the central nervous system. Moreover, the applicant noted that if there are concerns with abuse that

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available loperamide products such as melts and chewable tablets, approved as Schedule 2, may fall into the same category. (h) Purpose for which the substances is to be used • The applicant stated that loperamide was for the control and symptomatic relief of acute non-specific diarrhoea. It was further noted that current loperamide products state they are also indicated for chronic diarrhoea associated with inflammatory bowel disease and reducing the volume of discharge from ileostomies. The applicant also provided justification for the suggested dosage with it being based on current loperamide preparations. Therefore, the liquid preparation equated to ‘…4 teaspoonfuls after the first loose stool… then 2 teaspoonfuls after each loose stool that follows. Take no more than …8 teaspoonfuls in 24 hours.’ A recommendation that subsequent daily dosages be only administered after a loose stool and not exceed recommended dosages for the first day was also stipulated. (i) Additional matters • These included abbreviated technical information and an extract from a review article ‘Loperamide: a pharmacological review’ (Baker DE, 2007 Rev Gastroentrol Disord., 7 Suppl 3:S11-18). The Li, S Grossman, D & Cummings, P (2007) article, ‘Loperamide therapy for acute diarrhea in children: Systemic review and meta– analysis’ was also supplied.

NDPSC Evaluation Report

It was the evaluators view that the Committee consider if there was a adequately justifiable need for an OTC liquid loperamide preparation, given that an easy to swallow preparation currently exists in the form of loperamide ‘melts’. It was further stated that a scheduling decision may be better informed upon the provision of appropriate TGA registration information. The evaluator gave the following reasons for these recommendations: • It was unclear from the submission if the applicant had applied for TGA approval of a liquid loperamide product. A search of the ARTG found that there were no liquid preparations currently listed. It was also unclear how the proposed liquid was to be presented as information regarding package size, labelling and dosage recommendations were not clearly stated. Absence of such information meant the NDPSC cannot adequately assess the submission as per the provisions of Section 52E. • A literature search was conducted by the applicant, however only the results of a meta-analysis (Li, S Grossman, D & Cummings, P 2007) were mentioned in the submission. Also, while some articles from the literature search were provided, many of the listed articles could not be assessed as they were not in English. • The applicant argued that, since loperamide was already sold in Australia at the same strength but in a different dosage form, details of toxicity and safety were not relevant for this application. Thus the submission did not address Section 52E in any great

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detail. For toxicity in children, the applicant provided a summary (descriptive only) of the results of a systemic review by Li, S Grossman, D & Cummings, P (2007) of trials of loperamide versus placebo for acute diarrhoea in children 12 years and younger. It was concluded from the results that serious adverse events occurred only among children younger than 3 years. The evaluator felt that, although these statements were true, the context of the comparison was inappropriate for the current consideration (included mainly trials of inpatient treatment of acute diarrhoea i.e., patients were under medical supervision which is vastly different from the provision of loperamide in a Schedule 2, OTC context). No data addressed safety or toxicity of loperamide as a Schedule 2 substance (particularly relating to children). • No data was provided regarding the safety of chronic loperamide use as a Schedule 2 medicine. Further, the need for access to the substance was not discussed. The evaluator stated that a comparison of the risks and benefits of loperamide liquid with other Schedule 2 liquid preparations for acute diarrhoea would have been useful. • It was noted that loperamide was already available in Australia in a sublingual dissolving tablet formulation known as ‘melts’. This formulation already provides the benefits outlined in the application (i.e. ease of use for people who cannot swallow tablets, faster systemic absorption and availability in overseas markets as an OTC product) but with potentially lower risks of inappropriate use in young children. • The evaluator stated that inappropriate in young children would be more likely with liquid preparations compared with solid dosage forms.

Pre-Meeting Response from Applicant

The applicant included two full text articles with its submission: ‘Surveillance of Loperamide Ingestions: An analysis of 216 Poison Center Reports’ (Litovitz, T et al 1997, Clinical Toxicology, vol 35. issue 1, pp 11-19) and ‘Safety and Efficacy of Loperamide’ (Ericsson, C & Johnson, P 1990, The American Journal of Medicine, vol. 88 suppl. 6A, pp 10s-14s). In the initial application, only an extract was provided for one of the articles Litovitz, T et al (1997) while the other article (Ericsson & Johnson (1990)) was referred to within Li, S et al (2007). The Committee considered whether inclusion of the full text of either these articles constituted introduction of new data. The following points were made: • The applicant confirmed that no application to register liquid loperamide on the ARTG had been made but that there was an intention to do so before June 2010, pending the outcome of this consideration. Collating of data had commenced to support a future application should rescheduling of the liquid dosage form as a Schedule 2 product be confirmed.

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• The applicant clarified the proposed product, as requested by the evaluator. The following proposed characteristics were listed: Strength 1 mg/5 mL loperamide hydrochloride. Dose For adults and children 12 years and over, 20 mL of loperamide after each loose stool and 10 mL after each loose stool, but no more than 40 mL of loperamide in a 24 hour period. Pack size 100 mL. Pack sizes >100 mL for Schedule 4. Pack Amber bottle, PVC child resistant cap, bottle label, measuring presentation cup (or dropper), carton, CMI leaflet.

• The point raised by the evaluator regarding the context of the comparison of the systematic review by Li, S et al (2007) as being inappropriate for this consideration, as patients were under medical supervision which is vastly different to the Schedule 2 OTC context, was refuted by the applicant. The applicant noted that the meta analysis stated that children who were malnourished, moderately/severely dehydrated, had bloody diarrhoea or were systemically ill were often excluded from trials. Therefore the applicant felt the meta analysis covered consumers that would use liquid loperamide in an OTC context. Further, results of the meta analysis are claimed by the article authors to be consistent with that of a previous review on efficacy and safety in adults by Ericsson & Johnson (1990). • The applicant also referred to the abstract of a paper by Litovitz et al (1997) provided in the initial application. The paper analysed 216 poison centre reports pertaining to loperamide overdose and management. Amounts ingested ranged from 0.03 – 0.94 mg/kg with children aged 1-3 years accounting for 57.0 percent of ingestions. No related symptoms were life-threatening and no fatalities occurred. The summary stated that ‘paediatric acute poisoning profile seen with loperamide formulations demonstrates limited clinical manifestations of toxicity’. • The applicant highlighted that the product would include a child resistant cap, diminishing the likelihood of accidental ingestion, as well as having a maximum pack size of 100 mL. This would be equivalent to just over the maximum recommended adult daily dose which the TGA have approved at 16 mg/day (80 mL of a 1mg/5mL formulation). • The applicant also reiterated that loperamide was not well absorbed orally and does not penetrate well into the brain, resulting in a large proportion of the drug excreted in faeces. • The applicant provided further information in response to the evaluator’s comments regarding the omission of a comparison between the risks and benefits of loperamide liquid preparation with other Schedule 2 liquid preparations for acute diarrhoea. The applicant stated that the greatest risk was with individuals who may take loperamide to treat diarrhoea that they believe to be non-specific when it was, in fact, the result of a serious underlying condition such as malignancy, bacterial enterocolitis or acute

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dysentery. This risk applies to all loperamide products and other antidiarrheal OTC products currently available. The applicant stated that if a consumer with such a condition took loperamide it would only be for a short period of time as the required warning advises consumers to seek medical advice after 24 hours if symptoms persist. The 100 mL pack size would also limit the number of doses available. • In response to the evaluators comments on the lack of data regarding the safety of loperamide use in the community as a Schedule 2 medicine, the applicant referred to Li, S et al (2007) and its citation of Ericsson & Johnson (1990). It was concluded in this article that loperamide is effective and safe for the treatment of diarrhoea. Further, the large number of studies and reviews included in the original application (which covered a large spectrum of ages, populations and geographical locations) concluded that loperamide is safe and effective as an OTC product for the treatment of acute diarrhoea. The applicant also provided a table of OTC liquid loperamide formulations currently available in overseas markets. • The applicant acknowledged the current availability of the loperamide ‘melt’ product, but considered this to be a solid dosage form. The applicant felt that reclassification would encourage self-care, lessen the reliance on health professionals and allow more choice for sufferers in how they safely manage this condition.

Pre-Meeting Submissions

XXXXX provided a pre-meeting submission. The submission asserted no knowledge of any commercially available product containing loperamide in undivided preparations. It was also noted that an undivided preparation containing not more than 0.02 percent and not exceeding 100 ml would be equivalent to the smaller packs of divided preparations currently sold in Australia. If such an undivided preparation was made available, there would be no objections to its inclusion in Schedule 2.

A pre-meeting submission was received from XXXXX. The submission did not support a Schedule 2 listing but rather the inclusion of liquid preparations in Schedule 3 (at least) when packaged with a Child Resistant Closure (CRC). To support this statement, the following provisions of Section 52E (1) were addressed: • Under (a) toxicty and safety, (c) potential hazards and (e) dosage and formulation: − it was felt that the packaging of liquid preparations should include a CRC to minimise accidental ingestion by young children. Further, in overdose, children may be more sensitive to central nervous system effects than adults. Ingestion of large doses would also increase the possibility of adverse drug reactions such as fluid and electrolyte depletion, gastrointestinal upset and urinary retention. − there were concerns that a liquid formulation may infer that the product was suitable for children under the recommended age i.e < 12 years of age. Even if a dose was not listed on the packaging for younger children, parents or carers may be tempted to administer a smaller dose that they think is appropriate. Administration of a tablet formulation to an infant was less likely. Having the

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product in Schedule 3 would allow pharmacist interaction to reinforce that the product is contraindicated in children under 12 years of age. • Under (b) risks and benefits: − It was stated that this liquid preparation may be useful for adults and children over 12 years who have difficulty swallowing tablets and capsules. It was also noted that there is a currently a loperamide sublingual tablet available. Further, supply under Schedule 3 would ensure the risks and benefits of the liquid preparation were fully explained to the consumer by a pharmacist.

XXXXX provided a pre-Meeting submission. The submission did not oppose the proposal for children 12 years or over. However, concerns were raised that if a liquid preparation was made available, there was a possibility that parents/carers of children under 12 years may assume that it was suitable for children. Should this product become available in Australia, it was highly recommended that it be labelled with a specific statement that it NOT be used in children under 12 years of age.

XXXXX provided a pre-meeting submission. The submission did not object to the proposal with the caveat that the liquid preparation was intended for adults who are unable to swallow tablets of capsules.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under Section 52E (1) included (a) toxicity and safety, (b) risks and benefits, (c) potential hazards, (d) extent and patterns of use, (e) dosage and formulation, (f) the need for access, (g) potential for abuse and (h) purpose of use.

The Committee discussed the data relating to side effects occurring in children under 3 years of age. A Member noted that this was not useful in determining whether this formulation was appropriate as a Schedule 2 medicine given the data were derived from a hospital population which is not comparable to the demographic who might access OTC loperamide. Further, the applicant’s claims that a liquid preparation ‘may be’ better absorbed was not accepted. Data had not been submitted to support this claim and this was inconsistent with the applicant’s statement that the dosing regimen of the liquid preparation was similar to divided dosage preparations, thereby implying bioequivalence.

The Committee discussed the risks and benefits of a liquid loperamide formulation. It was noted that the benefits of a liquid preparation, as stated by the applicant, would be for those who cannot swallow tablets. The Committee agreed that the number of people in the general population who cannot swallow tablets was small and a smaller subset of those might need to access OTC loperamide. The Committee also discussed the risk of paralytic ileus in paediatric populations being known and significant.

The Committee discussed the proposed packing of the liquid preparation. A Member noted that not only did the proposed label state ‘for children over 12 years of age’ but

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also included a dropper. It was agreed that both references to children on the label and the inclusion of a dropper would increase the likelihood of inappropriate administration to children. The Committee agreed that loperamide was contraindicated in treatment of diarrhoea in children.

The Committee considered the need for access. The Committee agreed that the sublingual loperamide preparation currently available provided the required formulation for those aged over 12 year who are unable to take tablets.

A Member contested that potential inappropriate use in paediatrics could be addressed with appropriate labelling. The Member stated that bona fide consumers who would benefit from this presentation should be considered. The Committee generally disagreed that labelling would address such concerns as a liquid formulation intrinsically infers that use in paediatrics is appropriate. The Committee agreed that a solid dosage form was already available for adults who cannot swallow and this formulation was not one that might infer that paediatric use was appropriate. Given that anti-motility drugs have no place in the treatment of acute diarrhoea in children, the risk of inappropriate use was a significant consideration and one which lead the Committee to conclude that a Schedule 2 listing for a liquid presentation of loperamide was not warranted. Thus the current scheduling should remain.

Members did agreed, however, to include the word ‘divided’ in the Schedule 2 loperamide entry for consistency with similar entries and to further clarify that liquid preparations are Schedule 4.

RESOLUTION 2009/56 - 15

The Committee decided that the current scheduling of loperamide remains appropriate. The Committee also decided to amend the current Schedule 2 entry for loperamide to include the word ‘divided’ to further clarify that liquid preparations are Schedule 4.

Schedule 2 – Amendment

LOPERAMIDE in divided preparations for oral use in packs of 20 dosage units or less.

12.1.4 RABEPRAZOLE

PURPOSE

The Committee considered the scheduling of rabeprazole.

BACKGROUND

ATPases are a class of enzymes that catalyses the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion, releasing energy. The

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hydrogen potassium ATPase is a member of the P-type ATPase superfamily, a large family of related proteins that transport ions, most usually cations, across biological membranes in nearly all species.

Rabeprazole is a proton pump inhibitor (PPI) indicated for the treatment of peptic ulcer disease and gastro-oesophageal reflux disorder (GORD). PPIs suppress gastric acid secretion by inhibiting the hydrogen potassium ATPase irreversibly, blocking the final step in gastric acid secretion. PPIs have more prolonged suppression of gastric acid secretion than the H2 receptor antagonists (H2As). Rabeprazole is extensively metabolised in the liver by cytochrome P450 isoenzymes CYP2C19 and CYP3A4 to the thioether, thioether carboxylic acid, sulfone, and desmethylthioether. The plasma half- life is about 1 hour, increased two to three fold in hepatic impairment, 1.6 times in CYP2C19 slow metabolisers and by 30 per cent in the elderly.

The August 2000 Australian Drug Evaluation Committee (ADEC) meeting recommended the registration of enteric-coated tablets, containing 10 mg and 20 mg rabeprazole sodium, for the treatment and prevention of relapse of GORD; treatment of duodenal ulcers; and treatment of gastric ulcers.

At the November 2000 meeting, the Committee considered the scheduling of rabeprazole. The Committee supported the inclusion of rabeprazole in Schedule 4 based on the fact that rabeprazole was a new substance and required medical management and also to ensure harmonisation with New Zealand’s classification of rabeprazole.

DISCUSSION - SUBMISSIONS

XXXXX provided a submission separately addressing two proposals for rabeprazole: • Rescheduling, in preparations containing ≤ 10 mg for the relief of heartburn and other GORD symptoms, in packs containing ≤ 14 days supply, from Schedule 4 to Schedule 3. • Listing in Appendix H.

Rescheduling submission

Members noted the following summary of general points from the rescheduling submission: • Asserted that rabeprazole is a safe and effective treatment in the OTC environment for people who experience frequent heartburn. GORD affects between 15 and 20 per cent of Australian adults at least once a week. Pathological disease associated with GORD includes oesophagitis, oesophageal ulcers, strictures and Barrett’s oesophagus. Most patients present to their doctor with non-erosive disease having only symptomatic GORD. • Symptomatic GORD has been considered by the Committee for another PPI, pantoprazole (downscheduled, in June 2008 to Schedule 3, oral preparations

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containing ≤ 20 mg for the relief of heartburn and other GORD symptoms, in packs containing ≤ 14 days supply). Rabeprazole has been available in Australia (Schedule 4) and NZ (Prescription) since 2000. Internationally, Sweden has down-scheduled lansoprazole and pantoprazole while omeprazole has been down-scheduled in Sweden, UK, USA and Norway. • The approved indications for PPIs include: symptomatic treatment of GORD; treatment and prevention of relapse of GORD; treatment of duodenal ulcers; treatment of gastric ulcers, and in combination with clarithromycin and amoxicillin for eradication of Helicobacter pylori and healing of peptic ulcers in patients with Helicobacter pylori associated ulcers. • The registered dosage for the treatment of GORD is one 10 mg tablet once daily when needed. The applicant stated that it did not seek to extend the indications beyond what is currently being treated by other OTC medicines. There are also a range of symptoms (dysphagia, painful swallowing, hematemesis, choking attacks and weight loss) which indicate that referral to a doctor may be necessary.

The applicant also provided an overview of the current treatments in Australia for GORD associated heartburn: • Antacids for mild, infrequent heartburn and acid indigestion. • H2As such as ranitidine, unscheduled (150 mg for 14 days); famotidine and nizatidine (not more than 14 days supply) in Schedule 2; cimetidine (not more than 14 days supply) in Schedule 3; for GORD symptoms. • PPIs, currently available as Schedule 4 (except pantoprazole which is Schedule 3), for treatment of heartburn and other symptoms of GORD if the symptoms are more frequent (i.e. > 2 times a week). PPIs are recommended by the Gastrointestinal Society of Australia Guidelines for Clinicians as the treatment choice for the management of GORD. The applicant also distinguished between on-demand (begin treatment with onset of symptoms and end when symptoms resolve) therapy and intermittent (over a fixed period at onset of symptoms) therapy, although both have been found to be effective.

The rescheduling submission also addressed matters under section 52E(1), as summarised below: (a) Toxicity and safety • The adverse event profile is similar to pantoprazole’s. The most common adverse events were mild to moderate with serious events at a low level of incidence. • Provided the following toxicity data: − In a 2 year carcinogenicity mouse study, oral doses up to 100 mg/kg/day did not produce tumours. The highest dose produced a systematic exposure equated to 1.6 times the human exposure at the recommended daily dose for GORD (20 mg/day).

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− In rats, doses of 5, 15, 30 and 60 (male) and 5, 15, 30, 60 and 120 mg/kg/day (female) produced gastro enterochromaffin-like (ECL) cell hyperplasia in both sexes and ECL cell carcinoid tumours in female rats at all doses; male rats had no treatment related tumours. Similar outcomes have been seen with pantoprazole. − Positive in assays for gene mutations and the AMES test. Negative in assays for chromosomal damage and in vitro and ex vivo rat hepatocyte unscheduled DNA synthesis tests. Intravenous doses of about 10 times the human exposure (20 mg/day) were found to have no effect on fertility and reproductive performance of rats. − No studies in lactating women, although rats during gestation and lactation had pups with decreased body weight gains. The applicant suggested that in humans the drug should not be taken while nursing and would be labelled to reflect this concern. − The only PPI with Category B1 pregnancy classification (others are B3). No adequate, well-controlled studies in pregnant women have been carried out. • Members recalled the following definitions of Pregnancy Category B1 and B3: − B1: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have not shown evidence of an increased occurrence of foetal damage. − B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human foetus having been observed. Studies in animals have shown evidence of an increased occurrence of foetal damage, the significance of which is considered uncertain in humans. • The applicant also provided a comparative table between rabeprazole and pantoprazole, based on information from the approved PIs. The results indicated that in the ‘common’ (≥ 1 and ≤ 10 per cent) and ‘uncommon’ (≥ 0.1 and ≤ 1 per cent) system organ classes, rabeprazole may have a higher incidence of events than pantoprazole, which appears to have a higher incidence of adverse events in the rare and very rare categories. • The rabeprazole PI also indicated: − During clinical trials the observed side effects have generally been mild or moderate and transient in nature. In the majority of cases, the incidence of the adverse events was equal to or less than that observed in the placebo control treatment group. − Only headaches, diarrhoea, abdominal pain, asthenia, flatulence, rash and dry mouth have been associated with the use of rabeprazole.

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• From post marketing experience, erythema and rarely bullous reactions, urticarial skin eruptions and acute systemic allergic reactions, for example facial swelling, hypotension and dyspnoea, have been reported in patients treated with rabeprazole. These usually resolved after discontinuation of therapy. • Erythema multiforme, interstitial nephritis, gynecomastia, myalgia and potential allergic reactions including anaphylactic reactions have been reported rarely. Blood dyscrasias including thrombocytopenia, neutropenia, leukopenia, pancytopenia, agranulocytosis and bicytopenia have been reported rarely. There have also been reports of increased hepatic enzymes and serious hepatic dysfunction such as hepatitis and jaundice. Rare reports of hepatic encephalopathy have been received in patients with underlying cirrhosis. • There have been very rare reports of toxic epidermal necrolysis and Stevens-Johnson syndrome. (b) Risks and benefits • Described data from two studies. The first assessed the efficacy of ‘on demand’ maintenance therapy with 10 mg daily rabeprazole for 6 months: − The patients had non-erosive reflux disease and 83 per cent showed complete symptom relief after 4 weeks of open acute treatment. − Twenty one per cent of all patients in the acute phase experienced at least one adverse event, usually mild abdominal pain, diarrhoea and headache. − Patients experienced a superior result during the on demand phase, when compared to the placebo. The rate of discontinuation due to lack of heartburn control was 6 per cent for patients on rabeprazole (p<0.00001)). • The second study was a placebo controlled trial of 10 or 20 mg tablets once daily in subjects with GORD, to assess safety over a 4 week period. The findings included: − Time until complete heartburn free interval was significantly shorter with either dose strength of rabeprazole than with the placebo, but shorter with the 10 mg tablet. − Rabeprazole performed better for the secondary endpoints (2 and 4 weeks heartburn interval) than the placebo, with 10 mg performing better that the higher dose. − Both strengths were equally safe with slightly lower incidence of adverse effects amongst the rabeprazole 10 mg group (21.5 vs 25 per cent for 20 mg). (c) Potential hazards • Asserted that there is a low risk of poisoning considering the wide therapeutic index of rabeprazole and the pack size will be limited to 14 tablets (140 mg). • Stated that the NSW Poisons Information Centre 2007 report listed 68 exposures including adults, children and animals with 2,023,284 PBS claims for the drug over

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the same period. This is compared to antacids at 224 exposures and pantoprazole with 111 exposures. • Claimed that the potential for masking more serious disease is low because the product will be available through Schedule 3 via the pharmacist. • Asserted that having rabeprazole in Schedule 3 will help to identify people who have not sought help for GORD symptoms in the past and yet may have a serious condition. The applicant hypothesises that the ability to purchase rabeprazole from the pharmacist under Schedule 3 will convince a patient with GORD, or other symptoms, to seek medical attention. The supposition is that when the 14 day pack fails to provide relief in the case of underlying disease, the patient will seek medical advice. The applicant also claims that the package labelling specifying ‘Stop using this product and see your doctor or pharmacist if you need to take for more than 14 days’, would turn GORD suffers towards medical intervention. • Claimed that data on rabepazole exposure in the elderly is extensive. It has been seen to be safe and well tolerated in this population. ADR reporting to date indicates that no special precautions are required for the elderly. (d) Extent and patterns of use • The justification for down-scheduling was in terms of patterns of use and on the premise that PPIs are considered safe and effective medicines which have been available for consumer self selection in some countries for up to nine years with a low risk factor. The same use pattern may be expected for rabeprazole. The following points were made: − A Cochrane review (Khan, M, et al, 2008, ‘Medical treatments in the short term management of reflux oesophagitis (Review)’, The Cochrane Library, Issue 4) compared the efficacy of different PPIs and found no significant differences in their healing effect. − Pantoprazole is available as Schedule 3 as ≤ 20 mg tablets for symptoms of GORD in packs containing not more than 14 days supply. − A product labelling study was described. The study revealed that participants were willing to purchase the product on this basis alone. At the end of a 3 month period the study showed that consumers could accurately self select an OTC PPI, complying with pack instructions and seeking medical care when appropriate. (e) Dosage and formulation • A description of the tablet, its packaging and pack size, was included. A clinical trial, of a 28 day trial pack size of rabeprazole was described. (f) Need for access • Claimed that because rabeprazole has ‘superior efficacy’ to currently available OTC medication and has a favourable safety profile, it should be down-scheduled to provide an additional choice for consumers who may not tolerate pantoprazole.

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(g) Potential for misuse/abuse • Claimed that the potential for misuse was very low as it was not an addictive substance and that the small pack size minimised the risk of abuse. (h) Purpose for use • Reiterated that the product will be used in an OTC setting for treatment of symptomatic GORD. Additional matters (pharmacy education) • Stated a commitment to develop educational programs for consumers, pharmacy staff and pharmacists.

Appendix H submission

Members noted the following from the Appendix H submission (put forward by the applicant in terms of the NCCTG’s Schedule 3 Advertising Guidelines http://www.tga.gov.au/NDPSC/ndpsc3a.htm): Potential public health benefits • Advertising will create awareness of the disease symptoms and of the availability of an effective treatment, as well as of GORD itself. • Asserted that at this time, self treating consumers do not have the most effective treatment available to them and some may see heartburn as a minor ailment. • Consumers who currently self treat may be encouraged to see their pharmacist if they knew that such a treatment was available, perhaps resulting in referral to seek medical treatment if ‘alarm symptoms’ were detected by the pharmacist. • Asserted the consumers’ right to know what treatment options are available to them, and to choose an appropriate treatment depending on symptom severity. Appropriate use of scarce health care resources • Asserted that advertising will encourage people to seek pharmacy advice and free up general practitioners’ time. • Discussed a study which concluded that rabeprazole cost less, resulted in more symptom free days, had higher quality adjusted life year gains and was more effective than omeprazole (and other PPIs) intermittently for 4 weeks (Wahlqvist, P, et al, 2004, ‘Cost effectiveness of proton pump inhibitors in gastro-oesophageal reflux disease without oesophagitis, comparison of on demand esomeprazole with conventional omeprazole strategies’, Pharmacoeconomics, vol 20, no. 4, pp 267-77). • First time users and those currently self treating with antacids and H2As are most likely to ask for rabeprazole.

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Inappropriate patterns of use • Advertising is unlikely to lead to inappropriate patterns of use because: − Consumers are already exposed to heartburn and reflux product advertising (i.e. antacids and H2As) and advertising rabeprazole will add to their ‘knowledge base’. − The small pack size and premium price will mitigate against misuse. − It is ‘more than likely’ that the consumer will seek advice from the pharmacist if they are not getting satisfactory relief. − Rabeprazole is not an addictive substance. Therapeutic Goods Advertising Code (TGAC) and advertising for an indication other than those included in the ARTG • Asserted that it will comply with the provisions of the TGAC and gave an assurance that advertising will be limited to the indications relevant to the ‘symptomatic treatment of GORD’ and not for short term treatment. • Provided assurances that pharmacists would remain actively involved in the supply of the product and counselling of consumers about the products suitability, distinguishing between patients with more frequent symptoms who would benefit from the use of a PPI and those needing referral to a doctor. The words ‘Your pharmacists advice is required’ would also be included on all advertisements. Consumer education • Listed numerous opportunities for the provision of education materials to consumers, pharmacist and pharmacy staff. They also confirmed that Consumer Medicine Information (CMI) will be included in the packs. • Referred to the ‘desire of consumers to manage their own medication’, and asserted that nearly a third of consumers do not consult a doctor to treat upper gastric illness (i.e. arguing that advertising is a means of keeping these consumers informed).

Evaluation Report

Evaluation of the rescheduling submission

The evaluation report for the rescheduling submission recommended: • That the application be approved on the basis that the Committee had already listed in Schedule 3 a clinically equivalent (and largely interchangeable) product and also on the basis of the high benefit-to-risk ratio of short-term OTC rabeprazole 10 mg availability. • The new scheduling entry should make explicit that the treatment excludes children (any person aged less than 18 years).

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Additional points from the rescheduling evaluation included: (a) Toxicity and Safety • Rabeprazole is a well-tolerated agent with a high therapeutic index with the most common adverse events being headache, dizziness, nausea, vomiting, diarrhoea, flatulence, abdominal pain, dry mouth, insomnia and fatigue, but these are usually not serious and self-limiting. • Rabeprazole has a similar safety profile to pantoprazole and safety data have now accumulated from a few million patient-years of post-marketing surveillance with results from the latest periodic safety update reports (PSURs) and the Adverse Drug Reactions Advisory Committee (ADRAC) not indicating any new safety concerns. • Although rabeprazole undergoes hepatic metabolism via the cytochrome p450 system, it does not appear to have clinically significant interactions with other drugs metabolised by the same system. Known interactions include changes to levels of digoxin (increased), ketaconazole (decreased) and clarithromycin (increased). There is no need for dose adjustment in the elderly, nor in patients with renal or hepatic disease. (b) Risk and benefits • The evaluator noted that, in terms of benefits, there was robust evidence to suggest that compared to placebo, rabeprazole provides effective treatment of GORD symptoms. • To the evaluator’s knowledge, there have been no head-to-head randomised controlled trials of rabeprazole 10 mg and pantoprazole 20 mg for treating GORD symptoms. Nonetheless, in clinical practice, the two agents at these doses are mostly considered equivalent. (c) Potential Hazards • Experience with deliberate or accidental overdose is currently limited. Reports of poisoning are uncommon in Australia, relative to use. As mentioned, rabeprazole has a high therapeutic index and it has been used in doses of up to 180 mg daily without obvious adverse effects. • The applicant claimed, appropriately, that the likelihood of rabeprazole masking more serious disease is limited as patients will still need to consult a pharmacist, and the proposed rescheduling is for a maximum duration of 14 days. • Largely because of a lack of adequate data from human studies, rabeprazole’s Pregnancy Category is B1. Of note, pantoprazole is classified as Pregnancy Category B3. There was no data regarding the use of rabeprazole in breast-feeding women or children, the latter for whom the product was explicitly not recommended. (d) Extent and Pattern of Use • The evaluator was unsure what the applicant meant regarding the claim ‘without pharmacist intervention…for up to nine years’ in other markets. Perhaps it was the

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notion that because OTC access in other markets has not lead to safety concerns, none should be expected in Australia if rabeprazole was listed as Schedule 3. The evaluator felt that this would not be an unreasonable assertion. (f) Need for Access • Reiterated points made under (b) ‘Risks and Benefits’. Noted the applicant’s claim that rabeprazole may potentially have a faster onset of action than pantoprazole, but the evaluator considered that this was speculative. • The evaluator concluded that the applicant has not provided specific evidence that there is a need for greater access to OTC PPIs than is currently available. Other than the claim about potentially faster onset of action, it states that OTC rabeprazole would provide an alternative to patients who are intolerant of OTC pantoprazole, but there were no data cited indicating the extent of this intolerance. (g) Potential for Abuse • There appeared to be very little potential for abuse. (h) Purposes for Which a Substance is to be Used • The evaluator felt that it was unlikely that pharmacists would always make the distinction between GORD and no GORD, with the diagnosis being based only on arbitrarily (and poorly) defined thresholds for the frequency and severity of GORD symptoms. • Hence it was likely that, in the event that this application were successful, rabeprazole would be used for GORD symptoms that do not actually qualify as GORD. Strictly speaking, this would constitute use outside of its approved indication. The same ‘leakage’ was possibly occurring at present for OTC pantoprazole.

Evaluation of the Appendix H submission

The evaluation report for the Appendix H submission recommended: • The evaluator was unconvinced that advertising of OTC rabeprazole will lead to greater public health benefits and has some concern about it fuelling potential ‘inappropriate’ use. • Therefore, the evaluator recommended against the Appendix H proposal.

Additional points from the Appendix H evaluation included: Potential public health benefits • The evaluator asserted that there was not convincing evidence that the current level of awareness of GORD in the community was lacking. There is already advertising of many other GORD treatments. Furthermore, the symptoms are usually easily identified. Consumers who consult their pharmacists about treatment options would be informed about all available OTC treatments, including PPIs.

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• The applicant claimed that, despite advertising of OTC rabeprazole leading to increased interaction with pharmacists and doctors overall, there would be channelling of healthcare provision from Medicare-reimbursed doctors to pharmacists, such that there would be a net decrease in demand for doctors’ services. This is a not a reasonable assertion. Nevertheless, there may be healthcare savings (purely from the Government’s perspective) in terms of having a currently PBS- reimbursed medication listed as Schedule 3, as long as there is no offset from greater PBS-reimbursed prescription of rabeprazole arising from more diagnoses of GORD in general. Whatever the case, use of rabeprazole to treat GORD would at least be cost- effective. Inappropriate patterns of use • The evaluator felt that the usage patterns for OTC rabeprazole may go beyond approved indications, as may already be occurring with OTC pantoprazole. This being the case, advertising would presumably increase such ‘inappropriate’ use. Advertising for an indication other than those included in the ARTG • The applicant stated that any advertising will be limited to the indications relevant to the submission, i.e. ‘symptomatic treatment of GORD’, or in consumer terminology ‘relief of heartburn and reflux’. Related to the above discussion, ‘heartburn and reflux’ in themselves do not constitute GORD, which is the approved indication. Other criteria addressed by the applicant • The evaluator had no comments on other parts of the application.

Applicant's response to the evaluation report

Members noted the following points from the applicant’s response to the evaluation report: Potential ‘leakage’ to other TGA-approved indications • The applicant acknowledged the evaluator’s concern above over the potential ‘leakage’ of OTC PPIs. The applicant asserted, however, that any potential ‘leakage’ will be addressed with the availability of a Pharmaceutical Society of Australia (PSA) diagnostic tool (based on the current PSA diagnostic tool for OTC pantoprazole) and other additional training programs for pharmacists. Use in children • The proposed packaging will include the statement ‘Do not use in children under 18 years of age’.

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Pre-meeting comments

XXXXX pre-meeting comment: Recommendation • Supported the rescheduling proposal based on the safety profile of rabeprazole and its proposed short term use. • Opposed listing in Appendix H as there was no data or information available in relation to its OTC use in Australia. Discussion • Interaction with clopidogrel – was aware of a number of recent reports, some of which are conflicting, regarding the possible increase in risk of adverse cardiovascular events for patients on clopidogrel and PPIs. Association between PPIs and hip fractures have also been reported. However, these reports have been in relation to medium- to long-term use of PPIs. In addition, data on rabeprazole is less readily available, given its shorter history of use. Given these issues, close consideration and monitoring of the use of PPIs will be required. • Suggested that if rabeprazole was down-scheduled, the applicant should work with the pharmacy profession in providing current evidence-based information on PPIs and GORD and ongoing education in the provision of PPIs. This should include any new evidence or developments relating to the issues above.

XXXXX pre-meeting comment: Recommendation • Supported the rescheduling proposal. • Opposed Appendix H listing since pantoprazole was not listed in Appendix H. Discussion • Noted the Schedule 3 availability of pantoprazole and supported a similar scheduling for rabeprazole for use in adults over the age of 18 years. • Asserted that PPIs are generally considered the mainstay of GORD treatment, having good efficacy, tolerability and safety profiles. As a class, PPIs are the most potent inhibitors of gastric acid secretion available. • Although there are differences among PPIs in relation to their pharmacokinetics, pharmacodynamics, interactions with food and antacids as well as potential for drug interactions, it was not always evident whether these differences were clinically relevant. • Raised the issue of training materials for pharmacists, noting that comprehensive training materials were developed for Schedule 3 pantoprazole. Asserted that the applicant should produce material of a similar quality for rabeprazole.

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• Although comprehensive counselling would take place at the time of sale, it was noted from the Gastrointestinal Therapeutic Guidelines that referral was recommended if long-term maintenance or a higher dose was required. • Described OTC PPI availability internationally.

XXXXX pre-meeting comment: Recommendation • The rescheduling proposal is somewhat premature. It would be preferable to see such a decision delayed until more experience with the Schedule 3 availability of pantoprazole has been gained. • However, should the Committee see fit to approve this proposal, it would be appropriate for the sponsor of any product subsequently marketed to be required to provide equivalent educational resources for pharmacists to those that were provided for the down-scheduling of pantoprazole. • Noted that the Committee opposed the recent application to list pantoprazole in Appendix H on the basis that such an application was premature. The same reasoning should be applied to rabeprazole. Discussion • Noted that there have been many studies published recently regarding the potential for PPIs to impair the antiplatelet effect of clopidogrel. Some studies suggest that this may be a class effect whilst others suggest that it may be limited to specific drugs within this group. This serves to highlight the fact that PPIs are a relatively new class of medications and that not all is known about them. • Experience with the OTC availability of pantoprazole is limited at this point in time. • Appendix H listing and subsequent direct-to-consumer advertising hinders the ability of pharmacists to satisfactorily fulfil their professional responsibilities in relation to the supply of Schedule 3 medicines.

XXXXX pre-meeting comment expressed reservations about transferring PPIs out of Schedule 4 but given the previous decision for pantoprazole, it would be difficult to treat rabeprazole and other PPIs differently. Appendix H listing for these drugs was opposed.

XXXXX pre-meeting comment: Recommendations • Opposed the rescheduling proposal on the grounds that drug interaction issues have the potential to compromise patient welfare and safety and therefore make this particular PPI unsuitable for use in a non-prescription environment. • Opposed Appendix H listing on the grounds that there is no in-use data as a Schedule 3 medicine in the Australian market place and for consistency with the recent rejection of a similar proposal for pantoprazole.

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Discussion • Pharmacokinetic behaviour and the potential to interact with other drugs are the most important safety issues in relation to anti-secretory medication. Many patients taking heartburn products use them ‘on demand’ which can mean that drug interactions, and potential consequences, become highly unpredictable. • Asserted that the profile of pantoprazole is unique among the PPI class. No clinically significant metabolic drug interactions have been reported for pantoprazole and a recent review found that pantoprazole had the lowest potential for interactions with other drugs of all the PPIs (Blume H, Donath F, Warnke A, & Schug BS 2006, ‘Pharmacokinetic drug interaction profiles of proton pump inhibitors’, Drug Saf, vol 29(9), pp 769-84). • Interaction with digoxin: − Asserted that it was already established that rabeprazole had a clinically relevant metabolic interaction with digoxin (Stanghellini, V April 2003, ‘Management of gastroesophageal reflux disease’, Drugs of today, vol 39 Suppl A, pp 15-20). − While data from in vivo studies suggested that rabeprazole had no noteworthy effect on the metabolism of other drugs, it was suggested that this be read with caution due to a lack of investigations about possible effects on the cytochrome P- 450 enzymes (Fuhr U & Jetter A September 2002, ‘Rabeprazole: pharmacokinetics and pharmacokinetic drug interactions’, Pharmazie, vol 57(9), pp 595-601). − Asserted that while the interaction with digoxin was expected to be clinically relevant only in isolated cases, it still raised questions as to the suitability of OTC supply. • Interaction with clopidogrel: − Concerns have been raised about the interaction between rabeprazole and clopidogrel and associated adverse cardiovascular outcomes. Previous evidence had suggested that some PPIs, including rabeprazole, can inhibit cytochrome P- 450 2C19. This cytochrome plays a major role in the anti-platelet effect of clopidogrel. Inhibiting it may alter the pharmacokinetics of clopidogel. However the clinical significance of this interaction has only recently been quantified. − A retrospective cohort study to assess cardiovascular outcomes in patients taking clopidogrel with or without PPIs (Ho, MP et al. 2009 ‘Risk of Adverse Outcomes Associated With Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome’, JAMA, vol 301(9), pp 937-944) found a consistent association between omeprazole and rabeprazole with adverse cardiovascular outcomes. The association amongst other PPls was not explored due to limited patient numbers. − Another study amongst patients (who had previously had an acute mycocardial infarction) prescribed clopidogrel and who were also exposed to PPIs (Juurlink,

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DN et al. March 2009 ‘A population-based study of the drug interaction between proton pump inhibitors and clopidogrel’, CMAJ, vol 180, pp 713-718) found that current use of omeprazole, lansoprazole or rabeprazole (but not pantoprazole), was associated with an increased risk of reinfarction. − As the above two articles only appeared this year (after the cut-off for June 2009 NDPSC scheduling applications), it was an important matter for consideration when determining whether rabeprazole should be down-scheduled. − Asserted that the TGA, USFDA and Health Canada are currently evaluating this data and implications for the use of these PPIs. The comment was that consideration of this rescheduling application should be postponed until an international and local consensus on the clinical significance of this issue is reached. • Collaboration with the pharmacy profession: − Recalled that the implementation date for the original decision to down-scheduled pantoprazole 20 mg was deferred to provide time for collaboration with the pharmacy profession regarding the generation and provision of educational materials and protocols. [Member’s noted that this was not correct. The deferred implementation was in response to the sponsor’s request to this effect (although the sponsor’s reasons for submitting this request were based on wishing to have additional time in which to develop educational materials and protocols).] − Asserted that a demonstration of such collaboration should be required prior to implementing a rescheduling of rabeprazole. In particular, it was argued that the applicant should demonstrate how patients on clopidogrel will be identified in the pharmacy setting and how they will be counselled as to the use of rabeprazole. • With regards to the Appendix H listing proposal, noted that the Committee, in its recent rejection of an Appendix H listing proposal for pantoprazole despite the availability of OTC data from other markets, was of the opinion that the lack of Australian data on pantoprazole as an OTC medicine meant that no conclusions on the likelihood of improvements in health outcomes could be drawn from Appendix H listing. The submission requested that the Committee be consistent in its requirements for adequate Australian OTC data with PPIs before Appendix H listing is granted.

XXXXX

XXXXX has provided advice regarding possible interactions between clopidogrel and PPIs. The advice indicated that the only discussion of any detail was at XXXXX: • It would be of value to inform prescribers of updated information on drug interactions with PPIs, which had received considerable attention in recent times (noted the Juurlink and Ho 2009 articles discussed by XXXXX pre-meeting submission, together with two other relevant articles: O’Riordan, M, March 2009 ‘More data support adverse clopidogrel and proton-pump inhibitor interaction’, Medscape review

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and Roughead, E et al. 2009 ‘Proton-pump inhibitors and the risk of antibiotic use and hospitalisation for pneumonia’, MJA, vol 190, pp 114-116). • Interactions appeared to occur with all PPIs available currently; adequate evidence was not available to support published claims that pantoprazole was any safer than other PPIs when used with clopidogrel. • Given that PPIs were used widely and for long periods, it would be useful to promulgate on the current knowledge of PPI safety profile including recent updates in safety information for PPIs and remind prescribers that the use of these drugs should be reviewed periodically (especially for those who have been taking them for a long period) and when new drugs are introduced.

XXXXX

XXXXX has advised that: • The sponsor of clopidogrel has updated the PI in relation to this interaction with information on pharmacogenetics and an interaction precaution. The sponsor has also distributed a Dear Healthcare Professional letter to all doctors advising of this situation and the changes to the PI. The sponsor is undertaking further studies internationally to properly qualify this interaction. • XXXXX. • An article (Sadowski, DC. 2009 ‘Proton Pump Inhibitors and Clopidogrel – What is the current status?’, Am Heart J, vol 157, pp 148e1-148.e5 available at http://www.cag-acg.org/uploads/ppis&clopidogreltalkingpoints.pdf) was provided.

DISCUSSION – RELEVANT MATTERS UNDER 52E

XXXXX.

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (c) potential hazards, (d) extent and patterns of use, (e) dosage and formulation and (f) the need for access.

In relation to the applicant’s response to the evaluation report, a Member asserted that the larger problem of leakage still stood and would only be addressed by having more definitive criteria for PPI eligibility (i.e. what constitutes GORD). The Member also asserted that it did not appear that the applicant had responded to the evaluator’s conclusion that an Appendix H listing was not appropriate.

Regarding possible interactions with clopidogrel, a Member asserted that: • It seemed that there was emerging data from both mechanistic and population studies to suggest that PPIs may diminish the beneficial antiplatelet effects of clopidogrel.

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• At present, the evidence appeared to not be strong, but it did raise potential safety issues. The potential significance of this was underpinned by the common use of clopidogrel and the severity of adverse outcomes. • More data was required to clarify the issue. • There appeared to be insufficient evidence to confirm that this interaction is / is not a class effect. At present, there was no certainty that pantoprazole (or any other PPI) was excluded from the interaction.

A Member provided a copy of a 29 May 2009 European Medicines Agency (EMEA) public statement on possible interaction between clopidogrel and PPIs (http://www.emea.europa.eu/humandocs/PDFs/EPAR/Plavix/32895609en.pdf). Members particularly noted the following from this statement: • The concern related to several recently published studies examining clinical outcomes of clopidogrel users. Taken together, these studies suggest that a significant interaction might occur between clopidogrel and PPIs, making clopidogrel less effective when given with these medicines. • One possible explanation for this is that some PPIs prevent the conversion of clopidogrel into its biologically active form in the body, reducing the effectiveness of clopidogrel and increasing the risk of heart attack or other conditions involving harmful clotting (e.g. strokes). However, as different PPIs have different capacity to affect the metabolism of clopidogrel and as the outcome studies have not fully reflected the different effect of PPIs on activation of clopidogrel, there may be more than one explanation for the effect of PPIs on clopidogrel. • As heartburn and stomach ulcers can occur as side effects of clopidogrel, patients taking clopidogrel often take PPIs to prevent or ease these symptoms. • Taking all the data into account, the EMEA’s Committee for Medicinal Products for Human Use (CHMP) and its Pharmacovigilance Working Party have recommended that the product information for all clopidogrel-containing medicines should be amended to discourage concomitant use of PPI and clopidogrel-containing medicines unless absolutely necessary. − A Member noted that, appropriately, these warnings were to be on clopidogrel products rather than PPIs. • Furthermore, CHMP recommended that further information is needed in relation to the inhibition of clopidogrel metabolism by other medicines, and in relation to the implications of genetic variation which results in a small proportion of individuals (so called ‘CYP2C19 poor metabolisers’) being unable to fully convert clopidogrel to its active form, regardless of interactions with other medicines.

A Member asserted that treatment of GORD requires a clinician’s involvement and as such no PPI should be Schedule 3 for this indication. Another Member disagreed, noting that H2A products were available unscheduled for the same indication and PPIs are

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arguably more effective than these for treating GORD symptoms. Further, previous scheduling decisions relating to both PPIs and H2As were on the understanding that while GORD may require initial medical diagnosis, it does not necessarily require close medical management.

A Member also asserted that there was some concern on the issue of a causal link between long term use of PPIs and osteoporosis. Another Member noted, however, that data on this were only in relation to medium- to long-term use of PPIs.

The argument was made that the potential interaction with clopidogrel was the only matter that separated this rescheduling application from the previous down-scheduling application for pantoprazole. A Member noted that it was not clear whether this interaction was a class effect rather than a problem peculiar to rabeprazole. Indeed, a Member suggested that should the interaction with clopidogrel be sufficient reason not to down-schedule rabeprazole, then the Committee might need to reconsider the appropriateness of pantoprazole’s inclusion in Schedule 3.

Several Members asserted, however, that the current data on the clopidogrel / PPI interaction were inconclusive. A Member suggested that the EMEA public statement was perhaps a precautionary measure. Other Members noted that the TGA was monitoring this issue.

A Member asserted that the concerns relating to PPIs potentially masking underlying disease dealt with when pantoprazole was down-scheduled. Further, both indications and labelling limit use to short term only. There are now extensive professional materials available to pharmacists on appropriate use of PPIs. The Member commented that pantoprazole and rabeprazole were virtually interchangeable and so their scheduling should be the same.

The Committee generally agreed that the current body of evidence supported rescheduling of rabeprazole, in preparations containing ≤ 10 mg for the relief of heartburn and other GORD symptoms, in packs containing ≤ 14 days supply, from Schedule 4 to Schedule 3. The Committee also agreed that, at this time, the data regarding the possible interaction with clopidogrel were not sufficient to rule out down- scheduling. Members noted that, should new data come to light, the scheduling status of rabeprazole (and, indeed, all PPIs) should be reconsidered.

A Member noted, with regard to the requested inclusion of rabeprazole in Appendix H, that no PPIs were currently in Appendix H. The Member felt that the public benefit case had not been established for advertising rabeprazole. Several Members asserted, and the Committee generally agreed, that no compelling argument for including rabeprazole in Appendix H had been made.

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RESOLUTION 2009/56 - 16

The Committee decided to down schedule rabeprazole in oral preparations containing 10 mg or less for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days supply, to Schedule 3.

Schedule 3 – New entry

RABEPRAZOLE in oral preparations containing 10 mg or less of rabeprazole for the relief of heartburn and other symptoms of gastro-oesophageal reflux disease, in packs containing not more than 14 days of supply.

Schedule 4 – Amendment

RABEPRAZOLE – Amend entry to read:

RABEPRAZOLE except when included in Schedule 3.

12.1.5 SUCCIMER (DMSA)

PURPOSE

The Committee considered the scheduling of succimer.

BACKGROUND

Succimer is an orally active, heavy metal chelating agent. The IUPAC chemical name for succimer is (R,S)-2,3-dimercapto-butanedioic acid, also known as meso 2,3- dimercaptosuccinic acid, often abbreviated to ‘DMSA’. It is a white crystalline powder with an unpleasant, characteristic mercaptan odour and taste. It is used in the treatment of lead poisoning as it forms water-soluble chelates with heavy metals. Succimer has also been used to treat arsenic and mercury poisoning. Succimer is structurally related to dimercaprol, another heavy metal chelating agent. When labelled with a radionuclide, succimer has also been used in nuclear medicine.

In the United States (US), succimer is indicated for the treatment of lead poisoning in paediatric patients with blood lead levels above 45 μg/dL. At present, no products containing succimer are listed on the ARTG.

Succimer has been used in Australia under the Special Access Scheme (SAS) through hospitals. XXXXX.

In August 1983, the Committee noted the increasing use of disodium edetate (EDTA) for chelation therapy and the unacceptable advertising of the substance. The Committee recommended a new Schedule 4 entry for edetic acid for human therapeutic use in preparations for injection or infusion.

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At its November 1998 meeting, the Committee agreed to include dimercaprol in Schedule 4. This decision was a result of a recommendation from the TTHWP.

DISCUSSION - SUBMISSIONS

XXXXX referred this matter to the Committee, suggesting that Schedule 4 would be appropriate for the following reasons: (a) Toxicity and safety • According to Martindale succimer may cause gastrointestinal disorders, skin rashes, increases in serum transaminase, flu-like symptoms, drowsiness, and dizziness. Mild to moderate neutropenia has been reported in some patients and regular full blood counts are recommended during therapy. Succimer should be used with caution in patients with renal impairment or a history of hepatic disease. • According to the USFDA approved product information (PI): − Succimer has low acute oral toxicity, with oral median lethal doses in rodents in excess of 3.6 g/kg. − In a 28-day toxicity study, dogs receiving 30 and 100 mg/kg/day had lower urinary specific gravity and an increase in renal tubular regenerative hyperplasia. − No renal toxicity was noted in dogs given 50 mg/kg/day orally for 14 consecutive days. − In a chronic 6-month oral toxicity study, one male dog died (out of 7) at a dose of 200 mg/kg/day attributed to associated renal toxicity. Treatment related renal tubule epithelial changes in this study were observed in dogs after chronic (6- month) exposure to 110 and 200 mg/kg/day for 17 days then to 80 and 140 mg/kg/day for the remainder of the study. These changes were dose-dependent and correlated with increased kidney weights in male and female dogs at the 10 mg/kg/day dose. − Nephropathy was not observed in dogs treated at 10 mg/kg/day. − Reduced platelet counts were noted in 5 of 7 dogs receiving either 80 or 140 mg/kg/day for 3 or 6 months, although group means were not statistically different from concurrent controls. Platelets had not been quantified in earlier studies. Normal megakarycocytes (bone marrow cells responsible for the production of platelets), plus the absence of fibrin degradation products or evidence of disseminated intravascular coagulopathy (a pathological process depleting the body of its platelets and coagulation factors, and resulting in an increased risk of haemorrhage), suggested an autoimmune-mediated thrombocytopenia, a finding common in dogs but not in other species. However, serum antibody tests were inconclusive. − Rats dosed chronically to 500 mg/kg/day developed no evidence of nephropathy or thrombocytopenia.

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(b) Risks and benefits • Risks – as above. • Benefits – it would appear that succimer is an effective lead chelator and is used in the management of lead poisoning. Succimer is also used in children with chronic lead exposure, and various dosage regimens have been studied. It is generally only indicated if blood-lead concentrations are greater than 45 μg per 100 mL although short-term studies in children with lower concentrations have shown effective reduction of blood lead, no effect on neurodevelopmental outcome has been shown in follow-up studies and treatment of such children remains controversial. The following references were considered: − Mann KV, Travers JD, 1991 ‘Succimer, an oral lead chelator’, Clin Pharm, vol 10, pp 914-22. − Farrar HC, et al. 1999, ‘A comparison of two dosing regimens of succimer in children with chronic lead poisoning’, J Clin Pharmacol, vol 39, pp 180-3. − American Academy of Pediatrics Committee on Environmental Health, 2005, ‘Lead exposure in children: prevention, detection, and management’, Pediatrics, vol 116, pp 1036-46. − Besunder JB, et al. 1995, ‘Short-term efficacy of oral dimercaptosuccinic acid in children with low to moderate lead intoxication’, Pediatrics, vol 96, pp 683-7. − Rogan WJ, et al. 2001, ‘The effect of chelation therapy with succimer on neuropsychological development in children exposed to lead’, N Engl J Med 2001, vol 344, pp 1421-6. − Dietrich KN, et al. 2004, ‘Effect of chelation therapy on the neuropsychological and behavioral development of lead exposed children after school entry’, Pediatrics, vol 114, pp 19-26. (c) Potential hazards • The USFDA approved PI noted in the ‘warnings’ section that mild to moderate neutropenia has been observed in some patients receiving succimer. While a causal relationship to succimer has not been definitively established, neutropenia has been reported with other drugs in the same chemical class. A complete blood count with white blood cell differential and direct platelet counts should be obtained prior to and weekly during treatment with succimer. Therapy should either be withheld or discontinued if the absolute neutrophil count (ANC) is below 1200/μL and the patient followed closely to document recovery of the ANC to above 1500/μL or to the patient’s baseline neutrophil count. • There is limited experience with re-exposure in patients who have developed neutropenia. Therefore, such patients should be rechallenged only if the benefit of succimer therapy clearly outweighs the potential risk of another episode of neutropenia and then only with careful patient monitoring.

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• Patients treated with succimer should be instructed to promptly report any signs of infection. If infection is suspected, the above laboratory tests should be conducted immediately. (d) Extent and patterns of use • The USFDA approved PI stated that the extent of clinical experience with succimer is limited and therefore, patients should be carefully observed during treatment. It also notes that elevated blood lead levels and associated symptoms may return rapidly after discontinuation because of redistribution of lead from bone stores to soft tissues and blood. • After therapy, patients should be monitored for rebound of blood lead levels, by measuring blood lead levels at least once weekly until stable. However, the severity of lead intoxication (as measured by the initial blood lead level and the rate and degree of rebound of blood lead) should be used as a guide for more frequent blood lead monitoring. All patients undergoing treatment should be adequately hydrated. Caution should be exercised in using succimer therapy in patients with compromised renal function. Limited data suggests that succimer can be removed from the body via dialysis, but that the lead chelates can not. • Transient mild elevations of serum transaminases have been observed in 6-10 per cent of patients during the course of succimer therapy. Serum transaminases should be monitored before the start of therapy and at least weekly during therapy. Patients with a history of liver disease should be monitored closely. No data are available regarding the metabolism of succimer in patients with liver disease. • Clinical experience with repeated courses is limited. The safety of uninterrupted dosing longer than three weeks has not been established and it is not recommended. • The possibility of allergic or other mucocutaneous reactions to the drug must be borne in mind on re-administration (as well as during initial courses). Patients requiring repeated courses of succimer should be monitored during each treatment course. (e) Dosage and formulation • The USFDA approved PI stated that the starting dose is 10 mg/kg or 350 mg/m2 every eight hours for five days. Initiation of therapy at higher doses is not recommended. Reduce frequency of administration to 10 mg/kg or 350 mg/m2 every 12 hours (two- thirds of initial daily dosage) for an additional two weeks of therapy. A course of treatment lasts 19 days. Repeated courses may be necessary if indicated by weekly monitoring of blood lead concentration. A minimum of two weeks between courses is recommended unless blood lead levels indicate the need for more prompt treatment. • Patients who have received EDTA with or without dimercaperol may use succimer for subsequent treatment after an interval of four weeks. Data on the concomitant use of succimer with EDTA with or without dimercaprol are not available, and such use is not recommended.

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(f) Need for access, taking into account toxicity compared with other substances available for a similar purpose • Succimer has the advantage of being orally administered whilst other commonly used chelating agents require intravenous administration. Other chelating agents used in heavy metal poisoning such as dimercaprol and edetic acid (EDTA) are included in Schedule 4. (g) Potential for abuse • While the likelihood of abuse of succimer is low, it has been used by complementary medicine therapists both in Australia and overseas in a therapeutic modality called ‘chelation therapy’ for the treatment of diverse conditions such as atherosclerosis and autism. While this is not a potential abuse, it is a potential misuse of the substance which is relevant to its possible scheduling as a Schedule 4 medicine. • The Member who referred this to the Committee stated that the impetus for recommending such a classification for succimer was that there were reports of this substance being used in Australia for the treatment of conditions such as autism and such use did not appear to have adequate medical oversight. • The Committee noted that a letter to the editor of the British Medical Journal (7 October 2006, www.bmj.com/cgi/content/full/333/7571/756?grp=1, as accessed on 3 June 2009) from several Australian doctors likely to be involved in the treatment of autistic patients which concluded that: − ‘Serious concern should arise about the ongoing use of chelation therapy in children with autism at this time, especially when the side effects of appropriate administration are well reported, a death has occurred with an error of administration, and the treatment incurs a cost for the families. The potential for vulnerable families to seek this as a promised miracle cure raises ethical and professional practice questions that need international consideration. • The Committee also noted an article (Mitka, M, 19 November 2008, ‘Chelation Therapy Trials Halted’, JAMA, vol 300, no. 19, pp 2236), regarding the cancellation or suspension of 2 clinical trials testing chelation therapy as a treatment for autism or coronary artery disease. Critics charged that the studies had little scientific merit and exposed participants to unacceptable safety risks. (h) Purpose for which a substance is to be used • Succimer is used for the treatment of heavy metal poisoning for which medical supervision and regular blood tests are required.

Pre-Meeting Submissions

A pre-meeting submission from XXXXX supported inclusion of succimer in Schedule 4. It was noted that succimer has been used as an oral chelating agent for the treatment of lead poisoning in both children and adults. Details of an oral capsule succimer product available in the US were discussed. The submission also noted that dimercaprol

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(currently Schedule 4) which can be used as an adjunct with sodium calcium edetate (also Schedule 4) in the treatment of lead poisoning, although this needs to be administered via injection. The submission also address a number of points under section 52E(1) as follows: (a) Toxicity and safety, (b) Risks and benefits, (c) Potential hazards • Chelation therapy should be under the supervision of a medical practitioner as the mortality rate of complications (such as lead encephalopathy) in paediatric patients is high. • Further, lead concentrations in the blood should be measured at commencement and after treatment as well as the monitoring of full blood counts and liver enzymes during treatment. • Succimer is not recommended for use during pregnancy or breastfeeding. • Succimer suppresses the immune system and can cause drowsiness and dizziness (and consequently can be very dangerous in overdose). • It also is crucial a patient receive appropriate counselling to identify and remove the source of lead poisoning. (d) Extent and Patterns of use, (h) purpose for which a substance is to used • An internet search had revealed succimer being use with various vitamin, mineral and herbal preparations to treat other conditions including autism. • Websites reported the many symptoms of autism are similar to that of mercury poisoning such as immune dysfunction, visual disturbance and motor/co-ordination defects. One internet site stated that “children who undergo chelation therapy have seen significant and sometimes dramatic improvement”. • If such a practise is or becomes common place in Australia then a Schedule 4 entry would ensure appropriate supervision by a medical practitioner.

A pre-meeting submission from XXXXX also supported inclusion of succimer in Schedule 4.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (a) toxicity and safety, (b) risks and benefits, (c) potential hazards, (d) extent and patterns of use, (f) the need for access, (g) potential for abuse and (h) purpose for which a substance is to used.

A Member asserted that the use of succimer clearly required medical oversight. The Member described a recent incident whereby a pharmacist had been asked to compound succimer capsules by a naturopath for treating autism. Members generally agreed that the use of chelating substances as a treatment for autism had no merit.

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A Member also put forward that diagnosis of lead poisoning required medical intervention and ongoing monitoring which is one reason why other substances for heavy metal chelating therapy are, appropriately, in Schedule 4.

A Member noted that heavy metal poisoning was not a common ailment and suggested that an Appendix D listing might be appropriate. Other Members disagreed, however, noting that other heavy metal chelating substances were not restricted by inclusion in Appendix D. Several Members also asserted that there was a need for access in emergency medicine and an Appendix D listing would be an unwarranted restriction in such circumstances.

The Committee agreed, for clarity, to add a cross reference from DMSA to succimer in the SUSDP 25 index.

RESOLUTION 2009/56 - 17

The Committee decided to include succimer in Schedule 4.

Schedule 4 – New entry

SUCCIMER.

12.2 SUSDP, PART 5

12.2.1 DI-IODOHYDROXYQUINOLINE (IODOQUINOL)

PURPOSE

The Committee considered the scheduling of di-iodohydroxyquinoline (commonly known as iodoquinol), including whether the Appendix C entry for di- iodohydroxyquinoline is captured by the Appendix C entry for clioquinol and other halogenated derivatives of 8-hydroxyquinoline.

BACKGROUND

The halogenated hydroxyquinolines have antibacterial, antifungal, and antiprotozoal activity. The halogenated hydroxyquinolines are also used for the treatment of acrodermatitis enteropathica (a rare skin disease). The four main halogenated 8- hydroxyquinolines are: iodochlorhydroxyquin (clioquinol), di-iodohydroxyquine (iodoquinol), broxyquinoline and chloroquinaldol. Because of the neurotoxic effects seen between 1955 and 1970, clioquinol and similar halogenated hydroxyquinolines had been taken off the market in many countries.

In the past clioquinol was given orally to treat intestinal amoebiasis and was also used for the prophylaxis and treatment of travellers’ diarrhoea. Iodoquinol has been used in the treatment of intestinal amoebiasis, in Dientamoeba fragilis infections, in balantidiasis (as

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an alternative to tetracycline), and in Blastocystis hominis infections. Currently, clioquinol and other halogenated derivatives of 8-hydroxyquinoloine for human internal use are included in Appendix C.

At its August 1982 meeting, the Committee noted that the Australian Drug Evaluation Committee (ADEC) had recommended market withdrawal of halogenated hydroxyquinolines for systemic use, because of their known toxicity and the availability of alternatives. As such, the Committee recommended that clioquinol and other halogenated 8-hydroxyquinoline derivatives for internal human use be included in the Prohibited Substances List – Part 2 (the precursor to Appendix C).

At its November 1991 meeting, the Committee considered a request from ADEC to place all topical preparations of clioquinol, iodoquinol and chlorquinaldol in Schedule 4 due to their potential side effects of neurotoxicity related to percutaneous absorption. Members noted that the compounds were taken by mouth mainly as gastrointestinal antiseptics specially for amoebiasis and other protozoal infections. It was also noted that in the 1950s and 60s there was a surge of neurotoxic adverse events in Japan, mostly attributed to use of clioquinol. The neurological conditions attributed to these drugs was sub-acute myelo-optico neuropathy (SMON) and is to a large extent irreversible. At the May 1992 meeting, clioquinol and other halogenated derivatives of 8-hydroxyquinolone for human external use were recommended to be listed in Schedule 4.

At its February 1999 meeting, the Committee agreed to a recommendation from the TTHWP to include iodoquinol for vaginal use in Schedule 3 and add a new entry to Appendix C to prohibit human internal use.

At the October 2005 meeting, the Committee considered the Appendix C entry for clioquinol. Given the safeguards that already existed for clinical trials conducted in Australia, the Committee agreed to amend the Appendix C entry for clioquinol and related compounds to allow its use in clinical trials which have met TGA requirements. Furthermore, the Committee agreed to foreshadow a similar exemption for all substances listed in Appendix C. The June 2009 meeting was advised that this latter action did not occur.

DISCUSSION - SUBMISSIONS

The Committee noted that although iodoquinol is a halogenated derivative of hydroxyquinoline (and therefore captured by the Appendix C entry for clioquinol etc.,), its separate, specific, Appendix C listing does not include an exemption for use in accordance with either the Clinical Trial Notification (CTN) scheme or the Clinical Trial Exemption (CTX) scheme. This inconsistency may have arisen when the exemption clause was added to the clioquinol Appendix C entry.

The Committee considered advice that there were a number of ways this seeming inconsistency could be resolved:

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• Firstly, it could confirm that iodoquinol is indeed a halogenated derivative of hydroxyquinoline and should also be exempted from Appendix C when the subject of a CTN or CTX i.e. deleting the specific Appendix C entry for iodoquinol. Cross- referencing iodoquinol in the index with the clioquinol Appendix C entry would further clarify this intention. • Alternatively, it may conclude that this exemption is not warranted for iodoquinol at this time i.e. specifically excluding iodoquinol from the clioquinol etc., Appendix C entry.

Members also noted information from Micromedex regarding the hydroxyquinolines.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (a) toxicity and safety, (c) potential hazards and (f) the need for access taking into account its toxicity compared with other substances available for a similar purpose.

A Member suggested, and the Committee generally agreed, that it was appropriate that iodoquinol for human internal use had the same restrictions as applied to clioquinol and other halogenated derivatives of 8-hydroxyquinoline for human internal use. The Committee therefore agreed to delete the specific Appendix C entry for iodoquinol i.e. reverting control on iodoquinol for human internal use to the clioquinol class entry.

Members also agreed, however, that the current Schedule 3 and 4 specific entries for iodoquinol remained appropriate. It was suggested that, in order to avoid potential confusion arising from iodoquinol being captured by both a group entry and its own specific entry, a cross reference in the SUSDP index would be useful.

RESOLUTION 2009/56 - 18

The Committee decided that the entry for di-iodohydroxyquinoline (iodoquinol) for human internal use be removed from Appendix C as it was appropriately captured by the Appendix C entry for clioquinol and other halogenated derivatives of 8- hydroxyquionoline. Further, the Committee agreed to cross-reference di- iodohydroxyquinoline with the clioquinol Appendix C entry in the SUSDP index.

Appendix C – Amendment

DI-IODOHYDROXYQUINOLINE (iodoquinol) – delete entry.

SUSDP 25 Index – New Entry

DI-IODOHYDROXYQUINOLINE (iodoquinol)

See also CLIOQUINOL

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 128

13. MATTHERS REFERRED BY THE REGISTRATION PROCESS FOR PRESCRIPTION MEDICINES

13.1 NEW SUBSTANCES (NOT SEEN BEFORE BY NDPSC)

13.1.1 DORIPENEM

PURPOSE

The Committee considered the scheduling of doripenem.

BACKGROUND

Doripenem monohydrate is a synthetic broad-spectrum carbapenem antibiotic structurally related to beta-lactam antibiotics. Doripenem exerts its bactericidal activity by inhibiting bacterial cell wall biosynthesis. It inactivates multiple essential penicillin-binding proteins (PBPs) resulting in inhibition of cell wall synthesis with subsequent cell death. In Escherichia coli and Pseudomonas aeruginosa, doripenem binds to PBP 2, which is involved in the maintenance of cell shape, as well as to PBPs 3 and 4.

Doripenem is similar to imipenem, however it is more stable to renal dehydropeptidase than imipenem and need not be given with an enzyme inhibitor such as cilastatin. It is used in the treatment of susceptible infections such as intra-abdominal infections and complicated urinary-tract infections, including pyelonephritis. It is claimed to have particular activity against Pseudomonas aeruginosa.

DISCUSSION - SUBMISSIONS

The Committee noted the relevant extract of the minutes of the February 2009 ADEC Meeting. The ADEC recommended registration of DORIBAX powder for injection containing the new chemical entity doripenem monohydrate 500 mg for the following indication:

• For treatment of following infections in adults caused by bacteria sensitive to doripenem, which are proven or suspected to be resistant to other antibiotics or in patients who are unable to tolerate other antibiotic: − Complicated intra-abdominal infections. − Nosocomial pneumonia, including ventilator-associated pneumonia. − Complicated urinary tract infections, including pyelonephritis and cases with concurrent bacteremia.

The Committee also noted that doripenem was not efficacious against methicillin- resistant Staphylococcus aureus (MRSA).

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 129

The Committee additionally noted the following from the Martindale monograph for doripenem:

• Adverse Effects and precautions were similar to those for imipenem. • Probenecid inhibits the renal excretion of doripenem thereby increasing its plasma concentrations and prolonging its elimination half-life. • After intravenous infusion of doripenem 500 mg over 1 hour, a mean peak plasma concentration of 23 micrograms/mL is attained, falling to 10 micrograms/mL after 1.5 hours and 1 microgram/mL after 6 hours. • Doripenem was less than 10 per cent bound to plasma proteins and is widely distributed into body tissues and fluids. It is metabolised via hydrolysis of its beta- lactam ring by dehydropeptidase I to an open-ringed metabolite (doripenem-M1). The plasma elimination half-life is about 1 hour in adults; the half-life may be prolonged in patients with renal impairment. Doripenem is mainly excreted in the urine by tubular secretion and glomerular filtration. About 70 per cent and 15 per cent of a dose is recovered as unchanged drug and metabolite, respectively, in the urine within 48 hours. Less than 1 per cent is excreted in faeces. • For treatment of susceptible infections doripenem was given by intravenous infusion over 1 hour, in a usual adult dose of 500 mg every 8 hours.

• Administration in renal impairment: doses of doripenem given by intravenous infusion should be reduced in patients with renal impairment according to creatinine clearance (CC): CC 30 to 50 mL/minute: 250 mg every 8 hours CC greater than 10 to less than 30 mL/minute: 250 mg every 12 hours.

The Committee also noted the international status of doripenem:

• USA – approved in October 2007 for use as a single agent for the treatment of complicated intra-abdominal infections caused by Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacteroides caccae, Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Streptococcus intermedius, Streptococcus constellatus and Peptostreptococcus micros. It is also indicated for complicated urinary tract infections, including pyelonephritis caused by Escherichia coli including cases with concurrent bacteremia, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Acinetobacter baumannii. • EU - granted a marketing authorisation on 25 July 2008. Indicated for the treatment of the Nosocomial pneumonia (including ventilator–associated pneumonia), complicated intra-abdominal infections and complicated urinary tract infections. • New Zealand – not classified.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 130

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extent and patterns of use and (h) purpose for which the substance is to be used.

RESOLUTION 2009/56 - 19

The Committee decided to include doripenem in Schedule 4.

Schedule 4 – New entry

DORIPENEM.

13.1.2 JAPANESE ENCEPHALITIS VACCINE

PURPOSE

The Committee considered the scheduling of Japanese encephalitis vaccine.

BACKGROUND

Japanese encephalitis vaccine is used for active immunisation against encephalitis. Two types of inactivated Japanese encephalitis vaccine are generally used: either the Nakayama or the Beijing-1 strain. Beijing-3 strain has been used, but this has been replaced by the Chinese vaccination programme with a live, attenuated Japanese encephalitis virus (strain SA 14-14-2) vaccine.

Japanese encephalitis vaccines are widely used in China, Japan and other parts of Asia where the Japanese encephalitis is endemic. Vaccination is recommended for visitors to rural areas of South East Asia and the Far East where the visit is to be for more than one month.

DISCUSSION - SUBMISSIONS

The Committee noted the following points from previous considerations relating to vaccines: • November 1990. The Committee decided that oral vaccines should be given individual entires, but retained the Schedule 4 class entry for vaccines for human therapeutic use as it covered both oral and parenteral vaccines and could also be applied to homoeopathic vaccines. At the February 2001 meeting, it was again noted that the general principle regarding oral vaccines was that whenever possible substances should be listed separately in the schedules. • October 2007. The Committee considered the listing of Human Papillomavirus vaccine (HPV vaccine) as a Schedule 4 medicine. The Committee felt that there was

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 131

no reason for separately listing HPV vaccine as it would be captured under the class entry. Further, the Committee felt that to include a separate entry for every vaccine might be setting a precedent. Seemingly, this position was not in line with what was agreed at the November 1990 and February 2001 meetings. • February 2009. The Committee decided it was appropriate to include a class entry for phosphodiesterase type 5 (PDE5) inhibitors. The Committee noted that a class entry would capture all PDE5 inhibitors in Schedule 4 including those not yet considered for scheduling. The Committee was of the view that such a class entry would not and should not preclude scheduling new PDE5 inhibitors as they are evaluated through TGA registration processes. By listing the new substances as they are registered, the SUSDP would provide insight into whether a particular PDE5 inhibitor had been considered by the Committee. In other words, the Committee agreed that while a class entry was useful to capture any PDE5 inhibitors not yet considered for scheduling, it was important to separately and exhaustively list all PDE5 inhibitors which came before the Committee so that the SUSDP fully recorded all scheduling decisions on these substances.

The Committee also noted that at the December 2008 Australian Drug Evaluation Committee (ADEC) Meeting, approval was recommended for a submission from CSL Limited to register JESPECT® suspension for injection containing Japanese encephalitis virus 6 μg purified inactivated Japanese encephalitis virus strain SA14-14-2 per 0.5 mL dose. The following indications were specified: • Active immunisation against Japanese encephalitis virus for persons aged 18 years or older. • Considered for use in persons who plan to reside or travel to areas where Japanese encephalitis is endemic (common) or epidemic (seasonal). • For use in persons who work with the Japanese encephalitis virus in laboratories and in industry.

Safety and efficacy has not been established in people under 18 years of age. The primary vaccination series consists of 2 IM doses with the second dose administered 28 days after the first dose.

The ADEC members also recommended that approval should be subject to the provision of the results of a number of clinical, efficacy and safety studies, as soon as they are available.

Further, the ADEC members recommended that approval should also be subject to the finalisation of the Product Information (PI) to the satisfaction of the TGA. The PI and Consumer Medicine Information (CMI) should include a statement regarding the cross- reactivity (in relation to immunogenicity) with other flavivirus vaccines such as yellow fever vaccine.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 132

The Committee also considered a pre-meeting submission from XXXXX supporting the inclusion of Japanese encephalitis vaccine in Schedule 4.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extent and patterns of use and (h) purpose for which the substance to be used.

On the issue of the appropriateness of relying on the class entry for vaccines (and not separately listing each), a Member noted that unlike other therapeutic classes (such as PDE5 inhibitors which were structurally related), vaccines are an entirely heterogenous group of substances. Thus, listing each of the substances separately was appropriate.

A Member also highlighted that some people may not understand class entries, hence it would be valuable to list vaccines individually. Another Member noted that this was particularly important for enforcement officers in the field who may not have the technical skills to interpret descriptive rather than prescriptive entries.

A Member also noted that quite a number of vaccines, including Hepatitis A, Hepatitis B and measles, were currently listed separately. The Member further asserted that the class entry for vaccines was of use in ensuring that ‘novel’ treatments, including alternative vaccine practices, were appropriately scheduled, but that the class entry should not be relied upon for the scheduling of vaccines which have properly gone through registration processes.

Several Members asserted, and the Committee generally agreed, that there were benefits from having both class and specific entries for vaccines for human therapeutic use.

RESOLUTION 2009/56 - 20

The Committee decided to include Japanese encephalitis vaccine in Schedule 4.

Schedule 4 – New entry

JAPANESE ENCEPHALITIS VACCINE.

13.1.3 HUMAN PAPILLOMAVIRUS VACCINE

PURPOSE

The Committee considered the scheduling of human papillomavirus vaccine.

BACKGROUND

Human Papillomavirus (HPV) is a group of viruses that include approximately 100 different strains. HPV spreads by skin-to-skin or sexual contact. HPV strains are

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 133

responsible for causing growths like genital warts and abnormal cell changes. This can lead to cervical cancer in women as well as other genital and anal cancers in both genders. Cervical cancer is responsible for significant mortalities in third world and morbidity and cost in developed countries. Despite an extensive surveillance system in Australia, about one-third of affected women die.

HPV vaccine is a non-infectious, subunit, viral vaccine for use in immunization against infection caused by HPV. HPV vaccine is indicated for the prevention of cervical cancer, genital warts, cervical intraepithelial neoplasia, cervical adenocarcinoma in situ, vulvar intraepithelial neoplasia and vaginal intraepithelial neoplasia in women of certain age group.

DISCUSSION - SUBMISSIONS

The Committee noted the following points from previous considerations relating to vaccines: • November 1990. The Committee decided that oral vaccines should be given individual entires, but retained the Schedule 4 class entry for vaccines for human therapeutic use as it covered both oral and parenteral vaccines and could also be applied to homoeopathic vaccines. At the February 2001 meeting, it was again noted that the general principle regarding oral vaccines was that whenever possible substances should be listed separately in the schedules. • October 2007. The Committee considered the listing of HPV vaccine as a Schedule 4 medicine. The Committee felt that there was no reason for separately listing HPV vaccine as it would be captured under the class entry. Further, the Committee felt that to include a separate entry for every vaccine might be setting a precedent. Seemingly, this position was not in line with what was agreed at the November 1990 and February 2001 meetings. • February 2009. The Committee decided it was appropriate to include a class entry for phosphodiesterase type 5 (PDE5) inhibitors. The Committee noted that a class entry would capture all PDE5 inhibitors in Schedule 4 including those not yet considered for scheduling. The Committee was of the view that such a class entry would not and should not preclude scheduling new PDE5 inhibitors as they are evaluated through TGA registration processes. By listing the new substances as they are registered, the SUSDP would provide insight into whether a particular PDE5 inhibitor had been considered by the Committee. In other words, the Committee agreed that while a class entry was useful to capture any PDE5 inhibitors not yet considered for scheduling, it was important to separately and exhaustively list all PDE5 inhibitors which came before the Committee so that the SUSDP fully recorded all scheduling decisions on these substances.

The Committee also noted that at the February 2009 Australian Drug Evaluation Committee (ADEC) Meeting, ADEC Members recommended registration of HPV vaccine with the following conditions:

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 134

• There should be no objection to approval to register GARDASIL Injection suspension containing Human Papillomavirus (Types 6, 11, 16, 18) for the new indication: GARDASIL is indicated in females aged 27 to 45 years for the prevention of cervical, vulvar and vaginal cancer, precancerous or dysplastic lesions, genital warts and infection caused by HPV types 6, 11, 16 and 18 (which are included in the vaccine). • XXXXX.

The Committee also noted the international status of HPV vaccine: • USA – approved GARDASIL in September 2008 indicated in girls and women 9 thorough 26 years of age for the prevention of the following diseases caused by the HPV types. − Cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18 − Genital warts caused by HPV types 6 and 11. • European Commission – Committee for Orphan Medicinal Products in December 2007 granted orphan designation for human papilloma virus type 16E6/E7 synthetic long peptides for the treatment of epithelial neoplasia of the vulva, positive for human papilloma virus.

The Committee also considered a pre-meeting submission from XXXXX supporting a specific Schedule 4 listing for HPV vaccine.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extend and patterns of use and (h) purpose for which a substance is to be used.

On the issue of the appropriateness of relying on the class entry for vaccines (and not separately listing each), a Member noted that unlike other therapeutic classes (such as PDE5 inhibitors which were structurally related), vaccines are an entirely heterogenous group of substances. Thus, listing each of the substances separately was appropriate.

A Member also highlighted that some people may not understand class entries, hence it would be valuable to list vaccines individually. Another Member noted that this was particularly important for enforcement officers in the field who may not have the technical skills to interpret descriptive rather than prescriptive entries.

A Member also noted that quite a number of vaccines, including Hepatitis A, Hepatitis B and measles, were currently listed separately. The Member further asserted that the class entry for vaccines was of use in ensuring that ‘novel’ treatments, including alternative vaccine practices, were appropriately scheduled, but that the class entry should not be relied upon for the scheduling of vaccines which have properly gone through registration processes.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 135

Several Members asserted, and the Committee generally agreed, that there were benefits from having both class and specific entries for vaccines for human therapeutic use.

RESOLUTION 2009/56 - 21

The Committee decided to include human papillomavirus vaccine in Schedule 4.

Schedule 4 - New entry

HUMAN PAPILLOMAVIRUS VACCINE.

13.2 FOR INFORMATION (SUBSTANCES ALREADY SCHEDULED)

No items.

14. OTHER MATTERS FOR CONSIDERATION

No items.

15. MATTERS REFERRED BY THE MEDICINES EVALUATION COMMITTEE (MEC)

No items.

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

16.1.1 GOLIMUMAB

PURPOSE

The Committee considered the scheduling of the new medicine golimumab.

BACKGROUND

Golimumab is a human IgG1-kappa monoclonal antibody specific for human tumour necrosis factor alpha (TNFα) (a cytokine protein). Golimumab binds to both the soluble and transmembrane bioactive forms of human TNFα. This interaction prevents the binding of TNFα to its receptors, thereby inhibiting the biological activity of TNFα. Elevated TNFα levels in the blood, synovium, and joints have been implicated in the pathophysiology of several chronic inflammatory diseases such as rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. TNFα is an important mediator of the articular inflammation that is characteristic of these diseases.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 136

DISCUSSION - SUBMISSIONS

The Committee noted the relevant extract of the minutes of the November 2008 New Zealand Medicines Classification Committee (MCC). The MCC agreed to classify golimumab as a prescription medicine. The proposed indication was for: • the treatment of active rheumatoid arthritis in adult patients when used in combination with methotrexate; • the treatment of active psoriatic arthritis in adult patients when used alone or in combination with methotrexate; and • the treatment of ankylosing spondylitis in adult patients.

The Committee also noted that the USFDA approved golimumab in April 2009 for the treatment of: moderately to severely active rheumatoid arthritis in adults, in combination with methotrexate; active psoriatic arthritis in adults, alone or in combination with methotrexate and in active ankylosing spondylitis in adults.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extent and patterns of use and (h) purpose for which the substance is to be used.

RESOLUTION 2009/56 - 22

The Committee decided to include the new chemical entity golimumab in Schedule 4.

Schedule 4 – New entry

GOLIMUMAB.

16.1.2 LACOSAMIDE

PURPOSE

The Committee considered the scheduling of the new medicine lacosamide.

BACKGROUND

Lacosamide, a functionalised amino acid, is an antiepileptic medicine used as adjunctive therapy in partial seizures with or without secondary generalisation in patients aged 16 years and older. The precise mechanism by which locosamide exerts its antiepileptic effects in humans remains to be fully elucidated. In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 137

sodium channels, resulting in stabilization of hyperexcitable neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide binds to collapsin response mediator protein-2 (CRMP-2), a phosphoprotein which is mainly expressed in the nervous system and is involved in neuronal differentiation and control of axonal outgrowth. The role of CRMP-2 binding in seizure control is unknown.

DISCUSSION - SUBMISSIONS

The Committee noted the relevant extract of the minutes of the November 2008 New Zealand Medicines Classification Committee (MCC). The MCC agreed to classify lacosamide as a prescription medicine. The proposed New Zealand indications for lacosamide tablets were: • As adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older. • For the treatment of neuropathic pain associated with diabetic peripheral neuropathy in adults.

The Committee also noted that the proposed New Zealand indication for lacosamide oral solution was ‘as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older’ and that the proposed New Zealand indication for lacosamide injection was ‘as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in patients with epilepsy aged 16 years and older when oral administration is temporarily not feasible’.

The Committee also noted the international status of lacosamide: • USFDA: approved lacosamide on the 28 October 2008 as a prescription only medicine available in tablets and intravenous solution for use in partial-onset seizures. The tablets are indicated for adjunctive therapy in patients ≥17 years and the injection is indicated as short term replacement when oral administration is not feasible in these patients. • The European Commission: granted a marketing authorisation for lacosamide on 29 August 2008.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E (1) included (b) risks and benefits, (d) extent and patterns of use and (h) purpose for which a substance is to be used.

RESOLUTION 2009/56 - 23

The Committee decided to include the new medicine lacosamide in Schedule 4.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 138

Schedule 4 - New entry

LACOSAMIDE.

16.1.3 LIRAGLUTIDE

PURPOSE

The Committee considered the scheduling of the new medicine liraglutide.

BACKGROUND

Liraglutide is a human glucagon-like peptide (GLP-1) analogue that binds to and activates the GLP-1 inhibitor. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose dependent insulin secretion from the pancreatic beta cells. Unlike GLP-1, liraglutide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once daily administration. Liraglutide is indicated for use as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus.

DISCUSSION - SUBMISSIONS

The Committee noted the relevant extract of the minutes of the November 2008 New Zealand Medicines Classification Committee (MCC). The MCC agreed to classify liraglutide as a prescription medicine. The proposed indication was for use as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus.

The Committee also noted the international status of liraglutide. • The USFDA Endocrinologic and Metabolic Drugs Advisory Committee discussed a new drug application for liraglutide on 2 April 2009. The results of this meeting have yet to be released. • The EMEA Committee for Medicinal Products for Human Use on the 23 April 2009, adopted a positive opinion recommending to grant a marketing authorisation for liraglutide 6 mg/ml solution for injection in a pre-filled pen intended for treatment of type 2 diabetes mellitus.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extent and patterns of use and (h) purpose for which the substance is to be used.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 139

RESOLUTION 2009/56 - 24

The Committee decided to include the new chemical entity liraglutide in Schedule 4.

Schedule 4 – New entry

LIRAGLUTIDE.

16.1.4 PRASUGREL

PURPOSE

The Committee considered the scheduling of the new medicine prasugrel.

BACKGROUND

Prasugrel hydrochloride is a thienopyridine antiplatelet drug with similar properties to clopidogrel. It is an orally administered pro-drug requiring in vivo metabolism to form the active metabolite R-138727 that irreversibly inhibits platelet activation and aggregation mediated by the P2Y12 receptor.

DISCUSSION - SUBMISSIONS

The Committee noted the relevant extract of the minutes of the November 2008 New Zealand Medicines Classification Committee (MCC). The MCC agreed to classify prasugrel as a prescription medicine. The proposed New Zealand indications were: • the reduction of recurrent ischaemic events in patients with acute coronary (AC) syndromes including unstable angina (UA), non ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI) who are to undergo percutaneous coronary intervention. • The reduction of stent thrombosis following treatment for acute coronary syndromes.

The proposed indication was for use as an adjunct to diet and exercise to improve glycaemic control in patients with type 2 diabetes mellitus.

The Committee also noted the international status of prasugrel: • The USFDA Cardiovascular and Renal Drugs Advisory Committee, on the 2 February 2009, discussed a new drug application for prasugrel hydrochloride film coated oral tablets (5 mg and 10 mg) for the proposed indication of use in acute coronary syndrome. It was agreed that prasugrel should be approved to treat patients with acute coronary syndromes, presenting with either UA/NSTEMI or STEMI. • On 18 December 2008, the EMEA Committee for Medicinal Products for Human Use adopted a positive opinion recommending granting marketing authorisation for the

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 140

medicinal product prasugrel 5 mg and 10 mg film-coated tablets intended for prophylaxis against atherothrombotic events in patients with acute coronary syndrome undergoing primary or delayed percutaneous coronary intervention.

DISCUSSION – RELEVANT MATTERS UNDER 52E

The Committee agreed that the relevant matters under section 52E(1) included (b) risks and benefits, (d) extend and patterns of use and (h) purpose for which a substance is to be used.

RESOLUTION 2009/56 - 25

The Committee decided to include the new medicine prasugrel in Schedule 4.

Schedule 4 - New entry

PRASUGREL.

16.2 MEDICINES HARMONISED – FOR INFORMATION

16.2.1 ANIDULAFUNGIN

BACKGROUND

At the October 2008 meeting, the Committee agreed to include the new medicine anidulafungin in Schedule 4. The November 2008 MCC meeting classified anidulafungin as a prescription medicine through the New Zealand new medicines classification process. Anidulafungin is now fully harmonised.

RESOLUTION 2009/56 - 26

The Committee noted the harmonisation of anidulafungin.

16.2.2 BLOOD AND BLOOD PRODUCTS

BACKGROUND

Blood and blood products were considered at the October 2007 meeting. The resulting Appendix A listing had been discussed at the June 2008 MCC meeting and it was agreed that New Zealand would harmonise with Australia.

The wording for the proposed entry was amended at the February 2008 meeting to avoid inadvertent capture of recombinant versions of other naturally occurring human proteins. As such, the November 2008 MCC meeting reviewed the new wording and confirmed their decision to harmonise with Australia. Blood and blood products are now fully harmonised.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 141

RESOLUTION 2009/56 - 27

The Committee noted the harmonisation of blood and blood products.

16.2.3 DESVENLAFAXINE

BACKGROUND

At the October 2008 meeting, the Committee agreed that desvenlafaxine was a new medicine and should be included in Schedule 4. The November 2008 MCC meeting classified desvenlafaxine as a prescription medicine through the New Zealand new medicines classification process. Desvenlafaxine is now fully harmonised.

RESOLUTION 2009/56 - 28

The Committee noted the harmonisation of desvenlafaxine.

16.2.4 FLUORIDES

BACKGROUND

Flourides were subject to a review under the direction of the June 2007 meeting. As a result the MCC had withheld making a recommendation. This review, and the Committee’s subsequent deliberations and decisions, were finalised at the June 2008 meeting. The November 2008 MCC meeting agreed to the wording adopted by Australia. Entries for fluoride are now fully harmonised.

RESOLUTION 2009/56 - 29

The Committee noted the harmonisation of fluorides.

16.2.5 GLYCERYL TRINITRATE FOR RECTAL USE

BACKGROUND

At the June 2008 meeting, the Committee agreed to reschedule glyceryl trinitrate for rectal use from Schedule 2 to Schedule 3. At the November 2008 MCC meeting, it was agreed to reclassify glyceryl trinitrate, for rectal use, as a restricted medicine. Glyceryl trinitrate is now fully harmonised.

RESOLUTION 2009/56 - 30

The Committee noted the harmonisation of glyceryl trinitrate.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 142

16.2.6 KETOTIFEN FUMARATE 0.025 PER CENT FOR OPHTHALMIC USE

BACKGROUND

At the October 2008 meeting, the Committee agreed to down-schedule ketotifen from Schedule 3 to Schedule 2. At the November 2008 MCC meeting, a joint submission from XXXXX and XXXXX for the reclassification of 0.025 per cent ketotifen fumarate eye drops from restricted medicine to pharmacy-only medicine was received. Ketotifen was reclassified as a pharmacy-only medicine and is now fully harmonised.

RESOLUTION 2009/56 - 31

The Committee noted the harmonisation of ketotifen.

16.2.7 NITRIC OXIDE

BACKGROUND

At the June 2008 meeting, the Committee agreed to include nitric oxide for human therapeutic use in Schedule 4. At the November 2008 MCC meeting, it was agreed that nitric oxide be classified as a prescription medicine. Nitric oxide is now fully harmonised.

RESOLUTION 2009/56 - 32

The Committee noted the harmonisation of nitric oxide.

16.2.8 ROMIPLOSTIM

BACKGROUND

At the October 2008 meeting, the Committee agreed to include romiplostim in Schedule 4. At the November 2008 MCC meeting, romiplostim was classified as a prescription medicine through the New Zealand new medicines classification process. Romiplostim is now fully harmonised.

RESOLUTION 2009/56 - 33

The Committee noted the harmonisation of romiplostim.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 143

16.2.9 ROTIGOTINE

BACKGROUND

At the June 2008 meeting, the Committee agreed to include rotigotine in Schedule 4. At the November 2008 MCC meeting, rotigotine was classified as a prescription medicine through the New Zealand new medicines classification process. Rotigotine is now fully harmonised.

RESOLUTION 2009/56 - 34

The Committee noted the harmonisation of rotigotine.

16.2.10 TEMSIROLIMUS

BACKGROUND

At the June 2008 meeting, the Committee agree to include temsirolimus in Schedule 4. At the November 2008 MCC meeting, temsirolimus was classified as a prescription medicine through the New Zealand new medicines classification process. Temsirolimus is now fully harmonised.

RESOLUTION 2009/56 - 35

The Committee noted the harmonisation of temsirolimus.

17. MINUTES OF THE ADVERSE DRUG REACTIONS ADVISORY COMMITTEE (ADRAC)

No items.

18. MINUTES OF THE MEDICAL DEVICE EVALUATION COMMITTEE (MDEC)

No items.

19. INFORMATION ITEMS (PHARMACEUTICALS)

XXXXX

20. GAZETTAL NOTICES

The Committee noted the post-February 2009 Gazette Notice No. GN 13 dated 8 April 2009.

The Committee noted the pre-June 2009 Gazette Notice No. GN 15 dated 22 April 2009.

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 144

21. AMENDMENTS TO THE SUSDP

21.1 EDITORIAL CHANGES AND ERRATA

No items.

21.2 SUSDP 24 AMENDMENT 1 – EDITORIALS

PURPOSE

The Committee considered editorial changes to SUSDP 24 Amendment 1 (SUSDP 24/1).

BACKGROUND

A review of a draft SUSDP 24/1 by Members prior to the June 2009 meeting resulted in a number of proposed editorial changes which may more accurately reflect the intent of the decisions made at the February 2009 meeting which were to be included in SUSDP 24/1.

DISCUSSION - SUBMISSIONS

Members noted a number of suggested editorial changes to SUSDP 24/1 from XXXXX:

• GUAIPHENESIN − Amend the Schedule 2 entry to ready ‘…when not labelled for the treatment…’ rather than ‘…when labelled not for the treatment…’. − Amend the Schedule 4 entry to refer to the Schedule 2 entry first. • HYDROQUINONE − Amend the Schedule 2 entry to read ‘…hydroquinone except in hair preparations…” rather than ‘…hydroquinone except hair preparations…’. • ETHYLENE GLYCOL & DIETHYLENE GLYCOL − Amend listings to include the Appendix C symbol †.

DISCUSSION – RELEVANT MATTERS UNDER 52E

Members agreed that these editorial suggestions added clarity to the intent of the February 2009 decisions and should be incorporated into SUSDP 24/1 (with a note explaining that the relevant decisions also include editorial changes as identified at the June 2009 meeting under item 21.2).

RESOLUTION 2009/56 - 36

The Committee decided to editorially amend the relevant decisions from the February 2009 meeting as follows:

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 145

• Schedule 2 guaiphenesin entry – to read ‘…when not labelled for the treatment…’ rather than the current ‘…when labelled not for the treatment…’. • Schedule 4 guaiphenesin entry – move ‘when included in Schedule 2’ from (c) to (a) in the list of exemption conditions. • Schedule 2 hydroquinone entry – to read ‘…hydroquinone except in hair preparations…’ rather than ‘…hydroquinone except hair preparations…’. • Schedule 5 and Schedule 6 diethylene glycol entries – include the Appendix C symbol †. • Schedule 5 and Schedule 6 ethylene glycol entries – include the Appendix C symbol †.

Schedule 2 – New Entry

GUAIPHENESIN in a modified release dosage form of 1200 mg or less of guaiphenesin with a recommended daily dose of 2400 mg or less when not labelled for the treatment of children under 12 years of age.

Schedule 2 – Amendment

HYDROQUINONE – Amend entry to read:

HYDROQUINONE (excluding monobenzone and other alkyl ethers of hydroquinone included in Schedule 4) in preparations for human external therapeutic or cosmetic use containing 2 per cent or less of hydroquinone except in hair preparations containing 0.3 per cent or less of hydroquinone.

Schedule 4 – Amendments

GUAIPHENESIN – Amend entry to read:

GUAIPHENESIN for human therapeutic use except:

(a) when included in Schedule 2;

(b) in oral liquid preparations containing 2 per cent or less of guaiphenesin; or

(c) in divided preparations containing 200 mg or less of guaiphenesin per dosage unit.

Schedule 5 – New Entry

† DIETHYLENE GLYCOL (excluding its salts and derivatives) in preparations containing not less than 10 mg/kg of denatonium benzoate as a bittering agent except:

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 146

(a) in paints or paint tinters;

(b) in toothpastes or mouthwashes containing more than 0.25 per cent of diethylene glycol; or

(c) in other preparations containing 2.5 per cent or less of diethylene glycol.

Schedule 5 – Amendment

ETHYLENE GLYCOL – Amend entry to read:

† ETHYLENE GLYCOL (excluding its salts and derivatives) in preparations containing not less than 10 mg/kg of denatonium benzoate as a bittering agent except:

(a) in paints or paint tinters;

(b) in toothpastes or mouthwashes containing more than 0.25 per cent of ethylene glycol; or

(c) in other preparations containing 2.5 per cent or less of ethylene glycol.

Schedule 6 – New Entry

† DIETHYLENE GLYCOL (excluding its salts and derivatives) except:

(a) when included in Schedule 5;

(b) in paints or paint tinters;

(c) in toothpastes or mouthwashes containing more than 0.25 per cent of diethylene glycol; or

(d) in other preparations containing 2.5 per cent or less of diethylene glycol.

Schedule 6 – Amendment

ETHYLENE GLYCOL – Amend entry to read:

† ETHYLENE GLYCOL (excluding its salts and derivatives) except:

(a) when included in Schedule 5;

(b) in paints or paint tinters;

National Drugs and Poisons Schedule Committee Record of Reasons of Meeting 56 – June 2009 147

(c) in toothpastes or mouthwashes containing more than 0.25 per cent of ethylene glycol; or

(d) in other preparations containing 2.5 per cent or less of ethylene glycol.

22. CLOSURE AND NEXT MEETING

The Chair closed the Meeting at 16:00, 17 June 2009 and advised that the next meeting of the NDPSC will be held on 20-21 October 2009.

...... Ruth Lopert Date / / Chair National Drugs and Poisons Schedule Committee ______