Consultation: Proposed amendments to the Poisons Standard - ACCS, ACMS and Joint ACMS/ACCS meetings, March 2020

CAS Number

66357-35-5

Alternative names

(E)-1-N'-[2-[[5-[(dimethylamino)methyl]furan-2-yl]methylsulfanyl]ethyl]-1-N-methyl-2-nitroethene-1,1-diamine (IUPAC)

Applicant

Private applicant

Current scheduling

Ranitidine is currently listed in Schedules 4 and 2 and Appendix F of the Poisons Standard as follows:

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

Key uses/expected use

Medicines

Reasons for the proposal put forward by the Applicant

• The proposed amendment to the Schedule is to allow the provision of up to a 16 day supply of oral dose forms containing 150 mg ranitidine and 300 mg ranitidine outside of the pharmacy i.e. general sale and up to 42 days' supply of oral dose forms containing 150 mg ranitidine and 300 mg ranitidine as Pharmacy Only (Schedule 2) medicines.
• The number of dosage units for a 42 day supply will be no more than 84 tablets for 150 mg ranitidine and no more than 42 tablets for 300 mg ranitidine. There are no other changes proposed to the Poisons Standards requirements for the 150 mg and 300 mg ranitidine tablets other than the increase in pack size.
• The same information will appear on the labelling for all of the proposed larger pack sizes with respect to ranitidine, use, warnings and directions for use and storage information. The signal headings of Pharmacy Only will apply to pack sizes greater than 16 days' supply.
• The rescheduling to unscheduled or Pharmacy Only for the larger pack sizes will not expose the patient to any additional risk of misuse or masking a serious disease as justified below. The proposed 42 days' pack size will be accessible only via a pharmacy, ensuring that the patient continues to have access to a healthcare professional regarding counselling on the safe use of the product by a health care professional. For the pack sizes up to 16 days' supply, safe use of the medicine will be maintained by the labelling and packaging instructing the user to not use the product for more than 14 continuous days and to seek professional advice if symptoms persist or recur within two weeks.
• The Scheduling Policy Framework for Medicines and Chemicals (v1.0 January 2018) sets out general factors for scheduling consideration in order to determine the relevant schedule for a substance. The factors for Pharmacy Only medicines have been described below, with focus on ranitidine 150 mg and 300 mg as Schedule 2 in pack sizes not exceeding 42 days' supply. Factors in support of pack sizes up to 16 days' supply as Unscheduled are also provided:
  • The quality use of ranitidine will be achieved by labelling, packaging, and/or provision of other information. For all pack sizes, consumers will be instructed to not use the product beyond 14 consecutive days and for the pack sizes up to 42 days' supply, the availability of a pharmacist at the point of sale supports the consumer in selecting and using ranitidine in the appropriate manner. In purchasing the larger pack sizes up to 42 days' supply, consumers will still have the opportunity to be counselled by a pharmacist not to use the product for more than 14 days continuously, to seek professional consult should the symptoms persist beyond this time period and to reinforce aspects of the safe use of the medicine. Ranitidine is used for the relief of gastro-oesophageal reflux symptoms, including heartburn and acid indigestion, symptoms that can easily be recognised and are unlikely to be confused by the consumer with other more serious diseases or conditions. Treatment can be managed by the consumer without the need for medical intervention.
  • The use of ranitidine is substantially safe for short term treatment and the potential for harm from inappropriate use is low. In support of the low risk of misuse due to a larger pack size, a study of consumer understanding of ranitidine product label and usage patterns of treatment has been identified. The study concluded that 90% of consumers adhered to instructions of taking no more than the label directed dosage and 96% complied with the direction not to take the maximum dose for more than 14 consecutive days. Further, in an open-label consumer study with over the counter (OTC) omeprazole for frequent heartburn, data supports consumers compliance with a 14-day regimen in a self-managed setting and appropriately sought physician involvement for longer-term management of frequent heartburn. Both studies indicate consumer awareness with compliance of self-managed label products and the need for healthcare professional consult for persistent symptoms;
    • Ranitidine is does not produce dependency at either the established therapeutic dose or at supra-therapeutic doses;
    • The risk profile of ranitidine is well defined, and the risks can be identified and managed through the appropriate packaging and labelling. To purchase a pack size greater than 16 days' supply, and thus beyond the recommended period of 14 consecutive days use, the consumer will have the opportunity to consult with a pharmacist to discuss ongoing symptoms or concerns regarding symptom alleviation.
    • The use of ranitidine at established therapeutic dosage levels is not likely to mask the symptoms or delay diagnosis of a serious condition, and not to any greater extent than the currently available medicines for the relief of heartburn and indigestion. Early studies have shown the odds ratio of gastric cancer amongst people taking the H2 antagonist, cimetidine, to be similar for antacids and that erosive changes were found in almost equal portions of a study in patients with dyspepsia and controls. In an endoscopic study involving 562 people with dyspepsia who self-medicated with the OTC H2 antagonist, famotidine, no cases of gastric cancer were found. However, pharmacist-consumer consultation will remain available to detect the risk of masking a serious disease or compromising medical management of a disease, and to deal with it appropriately. The patient is still required to limit the use to not more than 14 consecutive days and should symptoms not alleviate on or before that time period, patients are to seek further advice, thereby allowing for the pharmacist to discuss the nature of persistent, and if applicable, the potential of a more serious underlying condition. In support of users complying with label instructions to seek professional advice in the absence of symptom relief, a community based cross-sectional study evaluating information on healthcare seeking and gastrointestinal symptoms was conducted. The study reported that dyspeptic patients presented to a physician when relief by an H2-receptor antagonist was not achieved, and moreover, the frequency of professional consult did not change with the availability of the H2 antagonist as an OTC. This study further supports that the risk of ongoing self-managed H2 antagonist use in masking a more serious condition is minimised by users seeking physician advice when gastrointestinal symptoms are not alleviated.

Australian regulations

• According to the TGA Ingredient Database,^[1] ranitidine, ranitidine bismuth citrate, ranitidine hydrochloride are:
  • available as active ingredients in: biologicals, export only, over the counter and prescription medicines;
  • available for use as an excipient ingredient in: biologicals, devices, prescription medicines; and
  • available for use as an equivalent ingredient in: prescription medicines (excluding ranitidine bismuth citrate).
• There are a total of 98 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[2] that contain ranitidine as an active ingredient. These include 44 prescription and 51 non-prescription medicines.
• Ranitidine is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination^[3] No.3 of 2019.
• The TGA prescribing medicines in pregnancy database^[4] classifies ranitidine as:

• The Therapeutic Goods (Medicines Advisory Statements) Specification 2019^[5] requires the following warning statements pertaining to ranitidine to be included on the labelling:

• Ranitidine is an approved active ingredient in 2 preparations listed on the Public Chemical Registration Information System Search (PubCRIS).^[6] There are 2 registered products containing ranitidine on PubCRIS.
• There were no adverse experiences were recorded for ranitidine in the APVMA Adverse Experience Reporting Program database (AERP)^[7] between 2009-2019.

International regulations

• In the United States, ranitidine is available as an over the counter and prescription medicine, according to the United States Food and Drug Administration Approved Drug Products Database (Drugs@FDA).^[8] Ranitidine is not used in pesticides according to the United States Environmental Protection Agency's (US EPA) Office of Pesticides Programs.^[9]
• In Canada, ranitidine is available as an over the counter medicine, prescription medicine and ethical medicine^[10] according to the Canadian (Health Canada) Drug Product Database.^[11] Ranitidine is not used in pesticides as it is not registered with Canada's Pest Management Regulation Agency.^[12]
• In Europe, the European Chemicals Agency (ECHA)^[13] has the following hazard classification & labelling for ranitidine 'Danger! According to the classification provided by companies to ECHA in Classification, Labelling and Packaging (CLP) notifications this substance causes serious eye irritation, is harmful if swallowed, may cause an allergic skin reaction, may cause allergy or asthma symptoms or breathing difficulties if inhaled, causes skin irritation and may cause respiratory irritation.'
• Ranitidine is not used in cosmetics in Europe according to the European Commission database for information on cosmetic substances and ingredients database.^[14] It is not used as an ingredient in pesticides.^[15]
• In New Zealand, ranitidine is available as a prescription medicine, pharmacy only medicine and for general sale according to the MedSafe.^[16] Ranitidine hydrochloride is an approved hazardous substance and is listed on the New Zealand Inventory of Chemicals (NZIoC).^[17]

Applicant

Delegate of the Secretary of the Commonwealth Department of Health

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

Reasons for proposal

• Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs commonly used to treat depression and anxiety disorders. SSRIs act by blocking the reuptake of serotonin, thereby increasing the levels of serotonin in the brain. Serotonin is a natural mood stabiliser that controls wellbeing and happiness. Insufficient levels of serotonin are thought to contribute to depression.
• There are a number of individual SSRIs captured in Schedule 4 of the Poisons Standard, including; citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline.
• The seriousness, severity and frequency of adverse effects and drug interactions associated with SSRI use are such that monitoring and intervention by a medical practitioner is required to minimise the risk of harm to patients.
• The Poisons Standard does not contain a group entry for SSRIs. A group entry exists to capture a substance that is considered to be a member of a group of related substances and is not captured as a salt or derivative of any specifically scheduled substance. Therefore, emerging SSRIs that are not derivatives of specifically scheduled SSRIs are effectively unscheduled.
• An SSRI group entry would automatically capture future unnamed or unscheduled SSRI variants in Schedule 4 and afford consumers the regulatory protections under the care of a medical practitioner.
• The proposed group entry would also clarify the scheduling status of SSRIs not specifically scheduled in the Poisons Standard for travellers intending to enter Australia with an SSRI not specifically scheduled in the Poisons Standard. The traveller will be required to bring a prescription with them or have a letter from their doctor that outlines what they are taking and how much they are bringing. The proposed group entry will also mean that anyone intending to import an SSRI not specifically scheduled in the Poisons Standard under the personal importation scheme will require a prescription from an Australian-registered medical practitioner for the medicine. This is important due to the seriousness, severity and frequency of adverse effects and drug interactions associated with SSRI use.

International regulations

• In the United States (U.S), New Zealand (NZ) and Canada, citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline are all available as prescription only medicines.
• The European Chemicals Agency (ECHA)^[18] identifies the following uses and/or regulations for:
  • Citalopram: used at industrial sites and in manufacturing. However, the ECHA has no public registered data indicating whether or in which chemical products citalopram might be used.
  • Dapoxetine (hydrochloride): no specific uses or regulations are listed on the ECHA database.
  • Escitalopram: used at industrial sites and in manufacturing. The ECHA has no public registered data indicating whether or in which chemical products escitalopram might be used. Escitalopram is registered and can be placed on the European Economic area (EEA) market by those companies with a valid registration.
• Sertraline (hydrochloride), paroxetine (hydrochloride), fluvoxamine (maleate) and fluoxetine (hydrochloride) are predicted as likely to meet the criteria for category 1A or 1B carcinogenicity, mutagenicity, or reproductive toxicity according to the Annex III: criteria for 1 - 10 tonne registered substances.^[19]

CAS Number

83799-24-0

Alternative names

2-[4-(1-Hydroxy-4-{4-[hydroxy(diphenyl)methyl]-1-piperidinyl}butyl)phenyl]-2-methylpropanoic acid (IUPAC)

Benzeneacetic acid, 4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyl]-α,α-dimethyl-

Carboxyterfenadine

Applicant

Private applicant

Current scheduling

Fexofenadine is currently listed in Schedules 4 and 2 of the Poisons Standard as follows:

Fexofenadine is cross-referenced in the Appendix F, Part 3 entry under antihistamines as follows:

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

Key uses/expected use

Medicines

Reasons for the proposal put forward by the Applicant

• Allergic diseases are the most common chronic conditions lasting throughout a sufferer's life. They not only cause significant deterioration in the quality of life of patients but also lead to significant absenteeism and reduced productivity, resulting in very high costs for society. Effective and safe treatment of allergic diseases is therefore one of the main challenges for public health and should be carried out by all the specialists in family medicine, internists and paediatricians in collaboration with allergists, otorhinolaryngologists and dermatologists.
• Australia has one of the highest rates of allergies in the developed world with approximately 3.1 million sufferers.^[20] Although most commonly experienced between the ages of 15 to 54, children as young as two are equally susceptible to the chronic and debilitating symptoms. Regardless of age group, the symptoms can significantly impact the daily lives of those affected including sleep disturbances, concentration, learning and function and affect childhood behaviour and development. Many consumers with seasonal allergic rhinitis (SAR) are chronic sufferers who are highly knowledgeable on their condition and treatment options. SAR is generally self-limiting and easy access to treatment to provide immediate relief of symptoms is essential for effective self-management of the condition.
• This application requests fexofenadine for the relief of SAR symptoms when supplied in packs of no more than 5 days' supply, restricted by dosage unit, labelled with a recommended daily dose not exceeding 180 mg be exempt from scheduling for adults and children over 12 years of age. For the relief of SAR symptoms within the paediatric population 6 to 11 years age group, this application requests fexofenadine when supplied in packs of no more than 10 days' supply, restricted by dosage unit, labelled with a recommended daily dose not exceeding 60 mg be exempt from scheduling.
• The benefits of the 180 mg strength of fexofenadine available in the general sales environment, aside from to relieve symptoms immediately from exposure to a trigger, is supporting treatment for sufferers experiencing intermittent episodes over a longer period in areas of Australia where the distance or duration of travel to a pharmacy during business hours may not be pragmatic. Similarly, broader options for access to the 30 mg paediatric dose by being available in the general sales environment makes it more convenient for not only the administering adult but potentially more rapid relief for a child suffering from SAR.
• Any potential risk to the misuse of the higher 180 mg strength outside the pharmacy sales environment in the proposed pack size, a total of 900 mg, is no greater than the current risk of the 120 mg dosage unit available in the 10 days' supply, 1,200 mg. Similarly, there is no greater risk to the consumer by the proposed exemption of the 30 mg tablet available in a pack size of 20 to be available in the general sales environment for ages 6 - 11 as it is the same restriction on dosage, and will be purchased and managed by the administrating adult.
• This submission provides information to support a risk/benefit profile in favour of the proposed rescheduling and provides mitigation actions such as revised labelling and warning statements to strengthen consumer awareness and to minimise the risk of misuse of fexofenadine.
• Consequently, the benefits of broadening the availability of fexofenadine 180 mg for adults and children over 12 years of age and fexofenadine 30 mg for children between 6 and 11 years to general sale outweighs any potential risks associated with its purchase outside the pharmacy environment.

Australian regulations

• According to the TGA Ingredient Database,^[21] fexofenadine hydrochloride is:
  • available for use as an active ingredient in: biologicals, export only, over the counter, prescription medicines;
  • available for use as an excipient ingredient in: biologicals, devices, prescription medicines; and
  • not available as an equivalent ingredient in any application.
• There are 64 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[22] that contain fexofenadine hydrochloride as an active ingredient. These include 63 non-prescription and one export only medicines.
• Fexofenadine is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination^[23] No. 3 of 2019.
• The Prescribing medicines in pregnancy database^[24] classifies fexofenadine as:

• The Therapeutic Goods (Medicines Advisory Statements) Specification 2019^[25] requires the following warning statements pertaining to fexofenadine to be included on the labelling:

• The Database of Adverse Event Notifications (DAEN)^[26] contains 236 reports of adverse events for products containing fexofenadine as an active ingredient, with 177 reports where fexofenadine was the single suspected medicine. There were two reports of deaths associated with fexofenadine use.
• There are no products containing fexofenadine listed on the Public Chemical Registration Information System Search (PubCRIS).^[27]

International regulations

Canada

• In Canada, fexofenadine is available over the counter according to the Canadian (Health Canada) Drug Product Database.^[28] Fexofenadine is not used in pesticides as it is not registered with Canada's Pest Management Regulation Agency.^[29]

New Zealand

• In New Zealand, fexofenadine is available as follows:

Europe

• The European Chemicals Agency (ECHA) hazard classification and labelling for fexofenadine is as follows: 'According to the notifications provided by companies to ECHA in REACH registrations no hazards have been classified. Fexofenadine is not used in cosmetics in Europe according to the European Commission database for information on cosmetic substances and ingredients database.^[30] It is not used as an ingredient used in pesticides.^[31]

United States (U.S)

• In the US, fexofenadine is available over the counter. Fexofenadine hydrochloride is available as a prescription medicine.
• Second generation antihistamines (such as fexofenadine) were developed to limit sedation as an adverse effect. The minimal risk of sedation occurs because these products have limited penetration of the central nervous system. In 1998, a Citizen Petition was submitted to US Food and Drugs Administration (FDA) requesting that cetirizine, loratadine and fexofenadine be switched from prescription to non-prescription status. The Joint Advisory Committees on Non-prescription Drug Products and Pulmonary and Allergy Drug Products met in 2001 and in 2002 to discuss the concept of switching second generation antihistamines for over-the-counter (OTC) use for symptoms of upper respiratory allergies and hives. The Committees recommended that the safety profiles of loratidine, cetirizine and fexofenadine made them appropriate candidates for non-prescription use for these indications.

CAS Number

5104-49-4

Alternative names

2-(2-fluoro-4-biphenylyl)propionic acid; [1,1'-Biphenyl]-4-acetic acid, 2-fluoro-α-methyl- hydratropic acid.

Applicant

Private applicant

Current scheduling

Flurbiprofen is currently listed in Schedules 2 and 4 of the Poisons Standard as follows:

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

Key uses/expected use

Medicines

Reasons for the proposal put forward by the Applicant

• Flurbiprofen lozenges are a low-dose topical analgesic and anti-inflammatory medicine for the relief of pain, swelling and inflammation associated with sore throats. The use of flurbiprofen lozenges exposes the painful and inflamed mucosal region of the throat to the analgesic and anti-inflammatory actions of flurbiprofen while minimising systemic exposure.
• Lozenges are the most commonly used dosage form for the management of sore throats and providing the public with wider access to a lozenge with both analgesic and anti-inflammatory activity has the potential to both improve self-management of sore throats and reduce the inappropriate use of antibiotics.
• The Therapeutic Guidelines for management of Acute Pharyngitis/Tonsillitis recommends analgesics as a first line approach for managing acute sore throat and for the management of pain recommends that analgesics be used at the lowest effective dose for the shortest possible time. Use of flurbiprofen lozenges to relieve the pain of acute sore throat is entirely consistent with these guidelines and the quality use of medicines. The flurbiprofen dose in lozenges is significantly lower than alternative unscheduled oral NSAIDs which are also used to manage the pain of a sore throat.
• The systemic exposure of flurbiprofen in a lozenge format is minimal and significantly lower than alternative oral analgesics (oral NSAIDs and paracetamol), as buccal absorption of flurbiprofen is low, with blood levels around 10% of those obtained from the same dose of flurbiprofen taken orally and swallowed.
• The proposed limited pack size of 16 dosage units, represents 2 days' therapy for patients taking the maximum dose (8 lozenges per day) compared to unscheduled oral analgesic (ibuprofen where 24 units represents 4 days' supply at the maximum dose and paracetamol 20 units representing 2.5 days' supply).
• The use of flurbiprofen lozenges in managing the pain of an acute sore throat would present a better risk benefit profile compared with use of systemic oral analgesics used for the same purpose purely based on the minimal systemic absorption and the clinical efficacy of these lozenges.

Australian regulations

• According to the TGA Ingredient Database:^[32]
  • Flurbiprofen is available for use as an active ingredient in biologicals, export only, over the counter and prescription medicines, as an excipient ingredient in biologicals, devices and prescription medicines and is not available as an equivalent ingredient in any application; and
  • Flurbiprofen sodium dihydrate is available for use as an active ingredient in biologicals, export only, over the counter and prescription medicines, as an excipient ingredient in biologicals, devices and prescription medicines and is not available as an equivalent ingredient in any application.
• There are three (3) non-prescription medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[33] that contain flurbiprofen as an active ingredient and one (1) prescription medicine that contains flurbiprofen sodium dihydrate as an active ingredient.
• Flurbiprofen is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination (No. 3) of 2019.^[34]
• The TGA prescribing medicines in pregnancy database^[35] classifies flurbiprofen as:

• The Therapeutic Goods (Medicines Advisory Statements) Specification 2019^[36] requires the following warning statements pertaining to flurbiprofen to be included on the labelling:

• The Database of Adverse Event Notifications (DAEN)^[37] contains six (6) reports of adverse events for products containing flurbiprofen as an active ingredient, with five (5)reports where flurbiprofen was the single suspected medicine. There were no reports of deaths associated with flurbiprofen use.
• There are no products containing flurbiprofen listed on the Public Chemical Registration Information System Search (PubCRIS).^[38]

International regulations

Globally flurbiprofen lozenges are available in 73 countries. In the majority of these countries they are available for self-selection in pharmacy. The lozenges are available as unscheduled medicines in four countries including two recent down-scheduling decisions in Europe, specifically in Denmark and the Netherlands. Other countries with General Sales List (GSL) access are Botswana and Iraq.

Scheduling status of topical oral flurbiprofen in comparable markets:

United States:

• According to the United States (US) Food and Drug Administration (FDA)'s Approved Drug Database,^[39] flurbiprofen,^[40] is currently available as a prescription oral tablet at 50 mg and 100 mg strengths. Flurbiprofen sodium,^[41] as a 0.03% solution/drops is also available as a prescription medicine for ophthalmic use.
• There are no references to flurbiprofen^[42] in the United States Federal Regulations.^[43]

Canada:

• According to the Canadian (Health Canada) Drug Product Database,^[44] flurbiprofen oral tablets, 50 mg and 100 mg strength, are available as prescription medicines.

European Union:

• The European Commission database for information on cosmetic substances and ingredients database^[45] does not contain any listing for flurbiprofen.^[46]
• According to the European Medicines Agency (EMA)'s^[47] list of nationally authorised medicinal products (containing flurbiprofen) (pdf,221kb)^[48], flurbiprofen 8.75 mg lozenges are available in number of member states including Germany, Austria, Belgium, Finland, Latvia, Slovenia, Spain, Sweden, and the Netherlands.

United Kingdom (UK):

• In the UK, according to the Electronic Medicines Compendium (ECM),^[49] flurbiprofen, 50 and 100 mg tablets are available as prescription only medicines and flurbiprofen 8.75 mg lozenges are available as pharmacy medicines and flurbiprofen sodium, 0.03% eye drops solution, is available as a prescription only medicine.

New Zealand:

• Flurbiprofen is included in the New Zealand Medicines and Medical Devices Safety Authority (MedSafe)'s^[50] Classification Database as a pharmacy only medicine when 'in locally acting oromucosal preparations containing 10 mg or less per dosage unit', and as a prescription for all other uses.

CAS Number

99614-02-5

Alternative names

1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one

Applicant

Private applicant

Current scheduling

Ondansetron is currently listed in Schedule 4 of the Poisons Standard as follows:

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

According to the Scheduling Policy Framework Schedule 3 medicines will be included in Appendix H unless it is determined that there are reasons for not permitting the advertising of a particular substance. Therefore, the scheduling delegate has included a proposal to create a new Appendix H entry for ondansetron as follows:

Key uses/expected use

Medicines

Reasons for the proposal put forward by the Applicant

• Ondansetron in oral formulations is only TGA-indicated for the prevention and treatment of nausea and vomiting induced by cytotoxic therapy and radiotherapy. However, since being registered in Australia and other countries there has been an increased use of this substance for all forms of nausea and vomiting. It would appear that ondansetron has, despite its TGA-indication, become the default drug of choice for nausea and vomiting irrespective of aetiology.
• Since the development of the Appendix M to Schedule 3 there have been many suggestions by pharmacy organisations and others^[51] that ondansetron should be a high priority for down-scheduling.
• Medical practitioners are already prescribing ondansetron "off-label".
• The likelihood that a patient will actually have nausea due to chemotherapy or radiation is highly unlikely given that their oncologist would have already provided them with sufficient prescriptions for an antiemetic.

Australian regulations

• According to the TGA Ingredient Database,^[52] ondansetron, ondansetron hydrochloride and ondansetron hydrochloride dihydrate are:
  • available for use as active ingredients in biologicals, export only and prescription medicines;
  • available for use as excipient ingredients in biologicals, devices and prescription medicines;
  • available for use as an equivalent ingredient in prescription medicines. Ondansetron hydrochloride and ondansetron hydrochloride dihydrate are not available as equivalent ingredients in any application.
• There are 110 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[53] that contain ondansetron, ondansetron hydrochloride or ondansetron hydrochloride dehydrate listed as an active ingredient. These include 104 prescription and 6 export only medicines.
• Ondansetron is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination^[54] No.3 of 2019.
• The TGA prescribing medicines in pregnancy database^[55] classifies ondansetron as:

• There are no warning statements pertaining to ondansetron in the Therapeutic Goods (Medicines Advisory Statements) Specification 2019.^[56]
• The Database of Adverse Event Notifications (DAEN)^[57] contains 734 reports of adverse events for products containing ondansetron, ondansetron hydrochloride or ondansetron hydrochloride dihydrate as an active ingredient, with 268 reports where ondansetron, ondansetron hydrochloride or ondansetron hydrochloride dihydrate were the single suspected medicine. There were 22 reports of deaths associated with the use of these medicines.
• There are no products containing ondansetron listed on the Public Chemical Registration Information System Search (PubCRIS).^[58]

International regulations

United States (US)

• In the US, ondansetron is only available as a prescription only medicine according to the US Food and Drug Administration (FDA) Drugs@FDA search.^[59]
• In 2011, the US FDA informed the public^[60] of an ongoing safety review of the anti-nausea drug ondansetron, ondansetron hydrochloride and their generics. Ondansetron may increase the risk of developing abnormal changes in the electrical activity of the heart, which can result in a potentially fatal abnormal heart rhythm.
• In 2012, the US FDA notified health care professionals^[61] that the 32 mg, single intravenous (IV) dose of the anti-nausea drug ondansetron hydrochloride would no longer be marketed because of the potential for serious cardiac risks.

Canada

• In Canada, ondansetron is available as prescription medicine according to the Canadian (Health Canada) Drug Product Database.^[62] Ondansetron is not used in pesticides as it is not registered with Canada's Pest Management Regulation Agency.^[63]

Europe

• In Europe, the European Chemicals Agency (ECHA)^[64] has the following hazard classification & labelling for ondansetron "Danger! According to the classification provided by companies to ECHA in CLP notifications this substance is toxic if swallowed, is very toxic to aquatic life with long lasting effects, is very toxic to aquatic life, causes serious eye damage, may cause harm to breast-fed children, causes skin irritation and may cause respiratory irritation."
• Ondansetron is not used in cosmetics in Europe according to the European Commission database for information on cosmetic substances and ingredients database.^[65] It is not used as an ingredient used in pesticides.^[66]

New Zealand

• In New Zealand, ondansetron is available as a prescription medicine, according to the New Zealand Medicines and Medical Devices Safety Authority (MedSafe).^[67]

CAS Number

145202-66-0

Alternative names

N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indole-3-ethanamine monobenzoate; 1H-Indole-3-ethanamine, N,N-dimethyl-5-(1H-1,2,4-triazol-1-ylmethyl)-; N,N-Dimethyl-2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1H-indol-3-yl]ethanamine (IUPAC)

Applicant

Private applicant

Current scheduling

Rizatriptan is currently listed in Schedule 4 of the Poisons Standard as follows:

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

Key uses/expected use

Medicines

Reasons for the proposal put forward by the Applicant

• This application proposes to reschedule rizatriptan from Schedule 4 (Prescription Only) medicine, to Schedule 3, (Pharmacist Only) for the supply of rizatriptan 5 mg in pack sizes of two tablets for the acute relief of migraine attacks with or without aura in patients who have a stable, well-established pattern of symptoms.
• Rescheduling would permit consumers who fit the criteria for safe and appropriate supply, to access highly effective treatment in a timelier manner that would be more therapeutically effective. Rescheduling would also align the scheduling classification with New Zealand.
• Migraine has a considerable impact on the health and wellbeing of Australians, while also resulting in a significant economic and productivity cost to the country. Clinical evidence and treatment recommendations for the management of acute, episodic migraine, highlights the importance of taking effective agents early in the migraine development to achieve the best outcomes. The 5HT1 agonists or 'triptans' have a pre-eminent position in the management of migraine, but are currently only available in Australia with a prescription.
• An abundance of clinical evidence demonstrates that triptans are more therapeutically effective in reducing progression, severity and duration of migraine when taken within an hour of the onset of a headache. Studies also demonstrate how consumers have an active role in decision-making about the management of their migraine, and often wait to assess symptoms they're experiencing will or do lead to a migraine attack.
• This application contends that not only does the requirement to see a medical practitioner for assessment and a prescription reduce access and increases cost of treatment, but that the delays caused by mandating patients see their GP prevent them from receiving the maximum benefit of treatment and increases the risk of more severe and debilitating pain, as well as the risk of developing chronic migraine
• A long history of clinical use of triptans world-wide, including over-the-counter provision by pharmacists in many countries, has demonstrated their safety and tolerability. Pharmacists are already experienced in assessing headache and migraine on a daily basis in practice, and with guidance to reinforce a low-risk population of episodic migraine suffers, can provide this effective treatment safely and appropriately.

Australian regulations

• According to the TGA Ingredient Database,^[68]:
  • Rizatriptan is available for use as an active ingredient in biologicals, export only and prescription medicines. Including the above uses, rizatriptan benzoate is additionally available for use as an active ingredient over the counter.
  • Rizatriptan and rizatriptan benzoate are available for use as excipient ingredients in biologicals, devices and prescription medicines.
  • Rizatriptan is available for use as an equivalent ingredient in prescription medicines, whereas rizatriptan benzoate is not available as an equivalent ingredient in any application.
• There are 35 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[69] that contain rizatriptan and rizatriptan benzoate as active ingredients. These 35 products are all prescription medicines.
• Rizatriptan is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination^[70] No.3 of 2019.
• The TGA prescribing medicines in pregnancy database^[71] classifies rizatriptan as:

• There are no warning statements pertaining to rizatriptan in the Therapeutic Goods (Medicines Advisory Statements) Specification 2019.^[72]
• From 1 January 1971 until 1 September 2019, the Database of Adverse Event Notifications (DAEN)^[73] had 25 reports of adverse events for products containing rizatriptan as an active ingredient, with 18 reports where rizatriptan was the single suspected medicine. There were no reports of deaths associated with rizatriptan use.
• There are no products containing rizatriptan listed on the Public Chemical Registration Information System Search (PubCRIS).^[74]

International regulations

United States (U.S)

• In the US, rizatriptan is available as a prescription only medicine according to the US Food and Drugs Administration (FDA) website.^[75]
• According to a FDA review on rizatriptan benzoate, rizatriptan has been marketed in the US for adult migraine patients since 1998. It has a well characterized safety profile. No new or unexpected adverse events were discovered in the course of the development program of rizatriptan in the adolescent population. The overall risk to benefit ratio of rizatriptan in adolescents 12 to 17 years of age is therapeutically acceptable.^[76]

Canada

• In Canada, rizatriptan is available as a prescription medicine according to the Canadian (Health Canada) Drug Product Database.^[77] Rizatriptan is not used in pesticides as it is not registered with Canada's Pest Management Regulation Agency.^[78]

Europe

• In Europe, the European Chemicals Agency (ECHA)^[79] has the following hazard classification and labelling for rizatriptan "Danger! According to the classification provided by companies to ECHA in CLP notifications this substance causes damage to organs through prolonged or repeated exposure, may damage fertility or the unborn child, causes serious eye irritation, is suspected of damaging fertility or the unborn child, is harmful if swallowed and may cause drowsiness or dizziness."
• Rizatriptan is not used in cosmetics in Europe according to the European Commission database for information on cosmetic substances and ingredients database.^[80] It is not used as an ingredient used in pesticides.^[81]

New Zealand

• According to MedSafe^[82] rizatriptan is available in New Zealand as follows:

CAS Number

73-31-4

Alternative names

N-[2-(5-methoxy-1H-indol-3-yl)ethyl]acetamide , N-[2-(5-methoxyindol-3-yl)ethyl]acetamide

N-Acetyl-5-methoxytryptamine

Applicant

Private applicant

Current scheduling

Melatonin is currently listed in Schedule 4 of the Poisons Standard as follows:

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

According to the Scheduling Policy Framework Schedule 3 medicines will be included in Appendix H unless it is determined that there are reasons for not permitting the advertising of a particular substance. Therefore, the scheduling delegate has included a proposal to create a new Appendix H entry for melatonin as follows:

Key uses/expected use

Medicines, veterinary and cosmetic use.

Reasons for the proposal put forward by the Applicant

• Down-scheduling of melatonin 2 mg modified release will harmonise with New Zealand where melatonin has recently been down-scheduled.
• Patients with primary insomnia will benefit from greater access to a proven, Australian Register of Therapeutic Goods (ARTG)-registered product with a better safety profile than alternative prescription-only products such as benzodiazepines, Z-drugs or other Schedule 3 products such as promethazine or doxylamine.

Australian regulations

• According to the TGA Ingredient Database,^[83] melatonin is:
  • Melatonin (CAS 73-31-4) is available for use as an active ingredient in biologicals, export only and prescription medicines, as an excipient ingredient in biologicals, devices and prescription medicines and is not available as an equivalent ingredient in any application.
• There are 15 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[84] that contain melatonin as an active ingredient. These include 10 prescriptions and 0 non-prescription medicines. The remaining 5 medicines are export only medicines.
• Melatonin is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination^[85] No.3 of 2019.
• The TGA prescribing medicines in pregnancy database^[86] classifies melatonin as:

• There are no warning statements pertaining to Melatonin in the Therapeutic Goods (Medicines Advisory Statements) Specification 2019.^[87]
• The Database of Adverse Event Notifications (DAEN)^[88] contains 86 reports of adverse events for products containing melatonin as an active ingredient, with 68 reports where melatonin was the single suspected medicine. There was one (1) report of death associated with melatonin use.
• There are two (2) products containing melatonin listed on the Public Chemical Registration Information System Search (PubCRIS).^[89] One product has an approved status with an active constituent product type while the other product is registered under an endocrine system product type.
• In 2009-2019 no adverse experiences were recorded for melatonin in the APVMA Adverse Experience Reporting Program database (AERP).^[90]

International regulations

• In Canada, melatonin is a medicinal ingredient in many products on the Licensed Natural Health Products Database^[91]. There are currently no products listed on the Prescription Drug List for either human use or veterinary use. On the Canadian (Health Canada) Drug Product Database^[92] there is an over the counter (OTC) melatonin product for veterinary use.
• According to MedSafe^[93] melatonin is available in New Zealand as follows:

• This classification has been effective since 24 June 2019^[94]. Melatonin is also on the New Zealand Inventory of Chemicals (NZIoC).^[95]
• In the United States the entries for melatonin products on the National Drug Code Directory^[96] are classified as 'human prescription drug' and 'human OTC drug' on the directory. The products are indicated for administration via oral route (i.e. spray, liquid, tablet etc.) or indicated for administration via injection (i.e. intramuscular; intravenous; parenteral; subcutaneous etc.). All products on the register are in the market category of either 'unapproved drug other' or 'unapproved homeopathic'. There are no entries for 'melatonin' on the United States Food and Drug Administration Approved Drug Products Database (Drugs@FDA).^[97]
• In Europe, melatonin is indicated on the European Commission database for information on cosmetic substances and ingredients database^[98] as an antioxidant in cosmetic products. The European Chemicals Agency (ECHA)^[99] provides that the majority of notifications provided by companies to ECHA in CLP notifications no hazards have been classified for melatonin.

CAS Number

106685-40-9

Alternative names

6-(3-(adamantan-1-yl)-4-methoxyphenyl)-2-naphthoic acid

6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthoic acid

Applicant

Private applicant

Current scheduling

Adapalene is currently listed in Schedules 4, Appendix F, Part 3 and Appendix L, Part 2 of the Poisons Standard as follows:

Proposed scheduling

The Applicant's proposed amendments to the Poisons Standard are:

Key uses / expected use

Medicines

Reasons for the proposal put forward by the Applicant

• Adapalene is a safe and effective substance that fulfils the criteria for Schedule 3 and is available in the USA as an OTC product and in New Zealand without a prescription.
• [Down-scheduling adapalene] will provide a safer and less irritant alternative to tretinoin for acne sufferers. There is some contention over its teratogenicity with the FDA determining that this is not a valid reason why it should not be available as an OTC product in the USA. The suggested inclusion in Appendix M should address this issue and will be consistent with the New Zealand "prescription only except when" listing.
• The down-scheduling of adapalene topical preparations for the treatment comedo, papular and pustule acne [would] harmonise with New Zealand where adapalene has been available from a pharmacist without a prescription since 2016.
• Acne is a condition that can be diagnosed by a consumer with advice from their pharmacist. By making adapalene available from a pharmacist as Schedule 3 Appendix M acne sufferers will have access to a safe and effective treatment which will prevent scarring, social withdrawal, distorted body image, low self-confidence and self-esteem and depression.
• Adapalene is a safe and effective treatment for acne vulgaris but is less irritating than tretinoin. An Appendix M requirement that the pharmacist must verify that the patient is not intending to become pregnant, is pregnant or is breastfeeding and to record the supply of adapalene in the pharmacy dispense system as well as upload to the My Health Record will ensure that adapalene is not used inappropriately.
• A Schedule 3 entry will provide access to an effective treatment for patients. Acne has an emotional and social impact on patients and can lead to social withdrawal, preoccupation with their condition, distorted body image, low self-confidence and self-esteem. Early diagnosis and treatment of acne can be provided by community pharmacy which will prevent possible scarring and psychological impacts that acne can cause.

Australian regulations

• According to the TGA Ingredient Database,^[100] adapalene is:
  • available for use as an active ingredient in biologicals, export only, prescription medicines;
  • available for use as an excipient ingredient in biologicals, devices, prescription medicines; and
  • not available as an equivalent ingredient in any application.
• As of 5 December 2019, there are six (6) medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[101] that contain adapalene as an active ingredient. These include six (6) prescription and no non-prescription medicines.
• Adapalene is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination^[102] No.3 of 2019.
• The TGA prescribing medicines in pregnancy database^[103] classifies adapalene as:

• There are no warning statements pertaining to adapalene in the Therapeutic Goods (Medicines Advisory Statements) Specification 2019^[104]
• The Database of Adverse Event Notifications (DAEN)^[105] (Jan 1971 - Sep 2019) contains 13 reports of adverse events for products containing adapalene as an active ingredient, with 10 reports where adapalene was the single suspected medicine. There were no reports of deaths associated with adapalene use.
• There are no products containing adapalene listed on the Public Chemical Registration Information System Search (PubCRIS).^[106]

International regulations

• In Canada, adapalene is a prescription medicine for human use on the Canadian (Health Canada) Drug Product Database^[107]. Adapalene or its salts or derivatives, is on Health Canada's Prescription Drug List^[108] for human use and veterinary use.
• In Europe, a public assessment report regarding Retinoids containing medicinal products (pdf,283kb)^[109] was published by the European Medicines Agency (EMA) in 2018. Adapalene is not listed on the European Commission database for information on cosmetic substances and ingredients database.^[110]
• Adapalene is listed on the European Chemicals Agency (ECHA)^[111] database with the following:
  • Hazard classification & labelling: Warning! According to the classification provided by companies to ECHA in CLP notifications this substance is suspected of damaging fertility or the unborn child, causes serious eye irritation, is harmful if swallowed, is suspected of causing cancer, may cause harm to breast-fed children, causes skin irritation, may cause an allergic skin reaction and may cause respiratory irritation.
  • Properties of concern: Some data submitters indicate they consider this substance as Skin sensitising
• In New Zealand (Medicines and Medical Devices Safety Authority (MedSafe),^[112] adapalene is classified as 'prescription medicine except' in medicines containing 1 milligram or less per millilitre or gram and when supplied by a pharmacist in a pack containing not more than 30 grams for the treatment of comedo, papular and pustular acne (acne vulgaris) of the face, chest or back', following recommendations by the Medicines Classification Committee in May 2016^[113]
• In the United Kingdom, adapalene is available as a prescription medicine. The products listed on the Medicines & Healthcare products Regulatory Agency (MHRA) Medicines Information: List of products^[114] include topical preparations for human use.
• In the United States, adapalene is available for human use as over the counter and prescription (for topical application) products on the United States Food and Drug Administration Approved Drug Products Database (Drugs@FDA).^[115]

CAS Numbers and alternative names

Applicant

Delegate of the Secretary of the Commonwealth Department of Health

Current scheduling

Arbutin is not specifically scheduled in the Poisons Standard but it is cross referenced to hydroquinone in the index of the Poisons Standard as follows:

Hydroquinone is listed in Schedule 2, 4 and 6 and Appendices E and F the Poisons Standard as follows:

Proposed scheduling

The proposed amendments to the Poisons Standard are:

Key uses/expected use

Medicines and cosmetics

Reasons for proposal

• Arbutin is a naturally occurring β-D glucopyranoside consisting of a molecule of hydroquinone bound to glucose (the beta-_D-glucopyranoside of hydroquinone).^[116] It is extracted from the dried leaves of bearberry plant in the genus Arctostaphylos and other plants commonly in the Ericaceae family.^[117]
• Arbutin is found in foods, over-the-counter drugs and herbal dietary supplements. Most commonly, it is an active ingredient in skincare and cosmetic products as a skin-lightening agent for the prevention of melanin formation in various skin conditions that involve cutaneous hyperpigmentation or hyperactive melanocyte function.^[118]
• The risks and benefits of the use of arbutin in cosmetic and topical dermal therapeutic products have not been considered by the Australian regulatory system.
• Specific consideration is warranted on whether different and/or additional controls should be applied for different arbutin derivatives for external use (i.e. alpha-arbutin, beta-arbutin and deoxyarbutin).
• The European Commission's Scientific Committee on Consumer Safety (SCCS) concluded that:
  • the use of alpha-arbutin safe for consumers in cosmetic products in a concentration up to 2% in face creams and up to 0.5% in body lotions;^[119]
  • the use of beta-arbutin to be safe for consumers in cosmetic products in a concentration up to 7% in face creams provided that the contamination of hydroquinone in the cosmetic formulations remain below 1 ppm;^[120] and
  • the use of deoxyarbutin up to 3% in face creams is not safe.^[121]

Australian regulations

• According to the TGA Ingredient Database:
  • Arbutin is not available for use as an active ingredient or excipient in any application. However, arbutin is available for use as an equivalent ingredient in export only and listed medicines.
  • Alpha-arbutin is available for use as an active ingredient in biologicals and prescription medicines; available for use as an excipient ingredient in biologicals, over the counter and prescription medicines; and not available as an equivalent ingredient in any application.
  • Hydroquinone derivatives calculated as anhydrous arbutin are not available for use as an active ingredient or excipient in any application. However, it is available for use as equivalent ingredients in export only and over the counter medicines.
  • The following plant extracts are sources of arbutin and are available for use as follows:
    • Achillea millefolium: available for use as an active ingredient in export only, listed medicines, over the counter, and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in export only, listed medicines, over the counter, and prescription medicines. Not available as an equivalent ingredient in any application.
    • Arctostaphylos uva-ursi: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in export only, listed medicines, over the counter and prescription medicines. Not available as an equivalent ingredient in any application.
    • Kalmia latifolia: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Ledum palustre: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Origanum majorana: available for use as an active ingredient in export only, listed medicines, over the counter, and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Pyrus communis: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in devices, export only, listed medicines, over the counter and prescription medicines. Not available as an equivalent ingredient in any application.
    • Pyrus pyrifolia: available for use as an active ingredient in listed medicines and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Rhododendron ferrugineum: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Turnera diffusa: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in export only, listed medicines, over the counter and prescription medicines. Not available as an equivalent ingredient in any application.
    • Vaccinium vitis-idaea: available for use as an active ingredient in listed medicines and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
• As of 6 December 2019, there are no medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[122] that contain arbutin, alpha-arbutin or hydroquinone derivatives calculated as anhydrous arbutin as an active ingredient. However, the following plants, which are known sources or arbutin, are found on the ARTG as follows:
  • Achillea millefolium: 14 products;
  • Arctostaphylos uva-ursi: 16 products;
  • Kalmia latifolia: 2 products;
  • Ledum palustre: 3 products;
  • Origanum majorana: 12 products;
  • Pyrus communis: 3 products;
  • Turnera diffusa: 42 products; and
  • Vaccinium vitis-idaea: 1 product.
• There are a number of plant extracts which are sources of arbutin (beta) and are permitted to be included in listed medicines according to the Therapeutic Goods (Permissible Ingredients) Determination^[123] No.3 of 2019.
• The Database of Adverse Event Notifications (DAEN)^[124] contains no reports of adverse events for products containing arbutin as an active ingredient. However, the following plant sources of arbutin have reported adverse events between 01/01/1971 and 01/09/2019, where the plant extract was one of the listed active medicines:
  • Achillea millefolium: 2 reported cases and 2 with a single suspected medicine;
  • Arctostaphylos uva-ursi: 38 reported cases and 33 with a single suspected medicine;
  • Kalmia latifolia: 4 reported cases and 4 with a single suspected medicine;
  • Ledum palustre: 4 reported cases and 4 with a single suspected medicine; and
  • Turnera diffusa: 69 reported cases and 63 with a single suspected medicine.
• There are no requirements for arbutin in Medicines Advisory Statement Specification 2019 (RASML No. 5)^[125]. However, products containing hydroquinone when included in Schedule 2 of the Poisons Standard are required by Required Advisory Statements for Medicine Labels (RASML) No. 5 to include several label statements as follows:

• Arbutin is not listed in the TGA prescribing medicines in pregnancy database.^[126]
• There are no products containing arbutin listed on the Public Chemical Registration Information System Search (PubCRIS).^[127]
• Arbutin is not included on the NICNAS Australian Inventory of Chemical Substances (AICS).^[128] However, arbutin is mentioned on the NICNAS website^[129] as follows:

  'Skin-whitening products — cosmetic or therapeutic good?

  Products that produce a skin-whitening effect by colouring the skin may be regulated as cosmetics.

  If the following applies to your product, the product is not a cosmetic and it may be regulated as a therapeutic good:

  The product influences, inhibits or modifies a physiological process to produce the skin-whitening effect. This sort of product does not meet the definition of a cosmetic under the Industrial Chemicals (Notification and Assessment) Act 1989.

  An example of a skin-whitening product that does not meet the definition of a cosmetic is one that contains hydroquinone (arbutin), which inhibits the physiological process of melanin production.'

International regulations

• The European Chemicals Agency (ECHA) hazard classification for arbutin is, 'Warning! According to the classification provided by companies to ECHA in CLP notifications this substance causes serious eye irritation, causes skin irritation and may cause respiratory irritation'.
• The European Commission Scientific Committee on Consumer Safety (SCCS) has published opinions on alpha-arbutin (pdf,1.62Mb),^[130] beta-arbutin (pdf,1.34Mb)^[131] and deoxyarbutin (pdf,1.14Mb).^[132]
• According to the European Commission database for information on cosmetic substances and ingredients database (CosIng):^[133]
  • alpha-arbutin is approved for use for antioxidant, bleaching and skin conditioning; and
  • arbutin is approved for use for antioxidant, bleaching and skin conditioning.
• Arbutin is not listed on the United States Food and Drug Administration (US FDA) Approved Drug Products Database (Drugs@FDA).^[134] Hydroquinone is available as prescription medicine in a 4% cream.
• Arbutin is not listed on New Zealand Inventory of Chemicals (NZIoC).^[135] Hydroquinone is listed on NZIoC and was added to the inventory 1 December 2006.
• Arbutin is not listed on New Zealand Medicines and Medical Devices Safety Authority (MedSafe).^[136] Hydroquinone is listed as follows:

• Canadian (Health Canada) Drug Product Database^[137] had one homeopathic medicine listed for arbutin. However, this product was cancelled post market in 1996. Hydroquinone is listed on the Health Canada website as an over the counter medicine in 2% cream/gel/lotion. It is also available as a prescription medicine in 3.5%, 4% and 8% cream/gel/lotion.

CAS Number

96-91-3

Alternative names

6-amino-2,4-dinitrophenol; Picramic acid; Phenol, 2-amino-4,6-dinitro.

Applicant

Delegate initiated application from information provided by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS)

Current scheduling

PICRAMIC ACID (including its salts) is not specifically scheduled in the current Poisons Standard.

Proposed scheduling

Key uses/expected use

Cosmetic, industrial use etc.

Reasons for proposal

• These chemicals are reported to be used in hair dyes in Australia. They are skin sensitisers. The European Union (EU) and the Association of Southeast Asian Nations (ASEAN) have restricted the use of these chemicals in hair dyes to a maximum on-head concentration of 0.6% to mitigate skin sensitisation risk.
• Furthermore, these chemicals may cause harmful effects on repeated oral exposure at low concentrations. They are particularly toxic to the male reproductive system. The margin of safety (MOS) of 155 derived for these chemicals based on dermal absorption and 90-day repeat dose study in rats, is not far above the threshold generally considered safe (MOS of 100) for use in cosmetics (SCCS, 2016). Given the haematotoxicity, testicular toxicity and the adverse effects seen in the stomach, intestines, liver and kidney on repeated exposure, the MOS of 155 derived for these chemicals remains a concern.
• The chemicals are acutely toxic or harmful via all routes of exposure.

Australian regulations

• Picramic acid (including its salts) is not identified in the following databases:
  • TGA Ingredient Database;^[138]
  • Australian Register of Therapeutic Goods (ARTG);^[139]
  • Therapeutic Goods (Permissible Ingredients) Determination^[140] No.3 of 2019;
  • Prescribing medicines in pregnancy database;^[141]
  • Therapeutic Goods (Medicines Advisory Statements) Specification 2019;^[142]
  • Database of Adverse Event Notifications (DAEN);^[143] and
  • Public Chemical Registration Information System Search (PubCRIS).^[144]
• Picramic acid and sodium picramate are included on the NICNAS Australian Inventory of Chemical Substances (AICS).^[145]
• Picramic acid and sodium picramate have undergone a Human health tier II assessment by NICNAS using the Inventory Multi-tiered Assessment and Prioritisation (IMAP) framework. The assessment examined both picramic acid (CAS No. 96-91-3) and its sodium salt, sodium picramate (CAS No. 831-52-7) as the toxicokinetics and toxicity of these chemicals were expected to be similar. NICNAS noted that there may be differences 'between the free acid and the sodium salt with respect to the local effects, the speciation of the chemicals in biological fluids will be dependent on pH but independent of the original chemical form'.
• Picramic acid is classified as explosive (division 1.1) in the Hazardous Chemical Information System (HCIS), and is subject to regulations set in the Explosives Act 2003 administered by Safe Work Australia (Safe Work Australia).
  • Picramic acid is classified as hazardous, with the following hazard categories and hazard statements for human health in the HCIS (Safe Work Australia):
  • Acute toxicity—Category 4; H302 (Harmful if swallowed);
  • Acute toxicity—Category 4; H312 (Harmful in contact with skin); and
  • Acute toxicity—Category 4; H332 (Harmful if inhaled).
• Sodium picramate is not listed on the HCIS.

International regulations

• In Europe, picramic acid is listed in the European Chemicals Agency (ECHA)^[146] database as follows:
  • Hazard classification & labelling: Danger! According to the classification provided by companies to ECHA in CLP notifications this substance is harmful if swallowed, is harmful in contact with skin, is harmful if inhaled and is harmful to aquatic life with long lasting effects. This substance is covered by several Harmonised Classifications and Labelling's (CLH) entries approved by the European Union.
• In Europe, sodium picramate is listed in the European Chemicals Agency (ECHA)^[147] database as follows:
  • Hazard classification & labelling: Danger! According to the classification provided by companies to ECHA in REACH registrations this substance is toxic if swallowed and may cause an allergic skin reaction.
  • Properties of Concern: A majority of data submitters agree this substance is Skin sensitising; Some data submitters indicate they consider this substance as Persistent, Bioaccumulative and Toxic.
• In the European Commission database for information on cosmetic substances and ingredients database,^[148] picramic acid is listed as having a hair dyeing function. In September 2012, the European Scientific Committee on Consumer Safety (SCCS) adopted an opinion on picramic acid and sodium picramate.^[149] The SCCS Committees conclusion was as follows:

  'The SCCS is of the opinion that the use of picramic acid/sodium picramate with a maximum on-head concentration of 0.6% in oxidative and non-oxidative (see SCCS/1227/10) hair dye formulations does not pose a risk to the health of the consumer, apart from its sensitising potential.'

• In the United States, picramic acid and sodium picramate are not registered as an ingredient on the United States Food and Drug Administration Approved Drug Products Database (Drugs@FDA) or on the USA Federal Regulations^[150] database.^[151]
• In New Zealand, there are entries for picramic acid and sodium picramate on the New Zealand Inventory of Chemicals (NZIoC)^[152] (added Dec 2006). Several synonyms are listed for these substances.
• In Canada, sodium picramate is listed under the Hazardous Products Regulations^[153] in Schedule 4 (Subsections 2(3) to (5)) Prescribed Classification. The classification is as follows: Sodium picramate, wetted with not less than 20.0% water, by mass with the classification Physical Hazards Not Otherwise Classified - Category 1. Sodium picramate is also listed on the Cosmetic Ingredient Hotlist- List of Ingredients that are Restricted for Use in Cosmetic Products^[154] with the maximum concentration permitted being 0.1% - no further restrictions were listed for sodium picramate in this database.
• Picramic acid and sodium picramate are listed on the Annexes of the ASEAN cosmetic directive under ANNEX III-Part 1-List of substances which cosmetic products must not contain except subject to restrictions and conditions laid down (pdf,3.63Mb)^[155] as follows:
  • Field of application and/or use: (a) Hair dye substance in oxidative hair dye products (b) Hair dye substance in non-oxidative hair dye products Use for dyeing eyelashes and eyebrows is not permitted.
  • Maximum authorised concentration in the ready for use preparation: (b) 0.6 %
  • Other limitations and requirements: (a) After mixing under oxidative conditions the maximum concentration applied to hair must not exceed 0.6 % (a) and (b): The direction for use "wear suitable gloves" must be included in label or leaflet text.
  • Conditions of use and warning which must be printed on the labels: (a) To be printed on the label: The mixing ratio. "Hair colorants can cause severe allergic reactions. Read and follow instructions. This product is not intended for use on persons under the age of 16. Temporary 'black henna' tattoos may increase your risk of allergy. Do not colour your hair if: you have a rash on your face or sensitive, irritated and damaged scalp, you have ever experienced any reaction after colouring your hair, you have experienced a reaction to a temporary 'black henna' tattoo in the past." (a) and (b) Do not use to dye eyelashes or eyebrows.

CAS Number

74070-46-5

Alternative names

2-chloro-6-nitro-3-phenoxyaniline (IUPAC)

Benzenamine, 2-chloro-6-nitro-3-phenoxy- (9CI)

Applicant

Australian Pesticides and Veterinary Medicines Authority (APVMA)

Current scheduling

Aclonifen is not specifically scheduled in the current Poisons Standard.

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

Key uses/expected use

Herbicide

Reasons for the proposal put forward by the Applicant

• The proposal is to consider a new substance, aclonifen, which it is considered appropriate for inclusion in Schedule 6 of the Poisons Standard, based on sufficient toxicological data being available to recommend a scheduling decision.
• Aclonifen has low acute toxicity by oral, dermal and inhalational routes and is not a slight skin and eye irritant and although it was a skin sensitiser in the guinea pig via the guinea pig maximisation test (GPMT), it was not under the Buehler method, a method considered more relevant for occupational exposure.
• The active is not a developmental or reproductive toxicant, and is not genotoxic in a battery of in vivo and in vitro assays. However, it did demonstrate a potential to bind chromatin in an as yet unspecified assay in rats reported by reliable oversees regulators (without demonstrating such potential in a DNA adduct study in mice), and induced a relatively rare neoplastic lesion (malignant astrocytoma) in a second, more recent carcinogenicity study in rats at the high dose tested.
• The available evidence demonstrates a plausible mode of action involving impairment of the blood-brain-barrier but without discernible white matter myelopathy (as judged by histopathological analysis), and altered chromatin packaging state that ultimately leads to the silencing of oncogene suppressors. There is a clear threshold for this effect. While aclonifen poses a moderate hazard from repeated use and moderate risk of producing irreversible toxicity, these risks are manageable via traditional exposure and risk assessment methodologies on a product-by-product basis.
• Therefore, it is considered that the toxicity profile of aclonifen is consistent with a Schedule 6 classification. A cut-off to Schedule 5 may being justifiable in acknowledgement of the clear threshold for carcinogenicity induction, however no cut-off is recommended at this time.

Australian regulations

• Aclonifen is not currently approved for use in Australia as a herbicide as it is not an approved active ingredient in the Public Chemical Registration Information System Search (PubCRIS).^[156]
• Aclonifen is not available for use as an active ingredient in human therapeutic products as it is not listed on the TGA Ingredient Database.^[157]
• There are currently no medicines active on the Australian Register of Therapeutic Goods (ARTG)^[158] that contain aclonifen as an active ingredient.
• Aclonifen is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination^[159] No.3 of 2019.
• Aclonifen is not identified in the TGA prescribing medicines in pregnancy database.^[160]
• There are no warning statements pertaining to aclonifen in the Therapeutic Goods (Medicines Advisory Statements) Specification 2019.^[161]
• There have been no reports of deaths associated with aclonifen use according to the Database of Adverse Event Notifications (DAEN).^[162]

International regulations

• In 2009, aclonifen was approved for use in Europe with the European Union Pesticides Database.^[163]
• The European Chemicals Agency (ECHA)^[164] hazard classification and labelling identifies aclonifen as 'Warning! According to the harmonised classification and labelling (ATP05) approved by the European Union, this substance is very toxic to aquatic life, is very toxic to aquatic life with long lasting effects, is suspected of causing cancer and may cause an allergic skin reaction.'. Aclonifen is predicted as likely to meet criteria for category 1A or 1B carcinogenicity, mutagenicity, or reproductive toxicity according to the Annex III: criteria for 1 - 10 tonne registered substances.^[165]
• The ECHA identifies properties of concern for aclonifen as a possible carcinogen and skin sensitising agent.
• Aclonifen is not identified on the European Commission database for information on cosmetic substances and ingredients database^[166] or the European Commission Comitology Register.^[167]
• Aclonifen is not registered for use in the United States according to the United States Environmental Protection Agency's (US EPA) Office of Pesticides Programs,^[168] the United States Food and Drug Administration Approved Drug Products Database (Drugs@FDA)^[169] and the United States Federal Regulations.^[170]
• Aclonifen is not registered for use in New Zealand according to the New Zealand Inventory of Chemicals (NZIoC)^[171] and the New Zealand Medicines and Medical Devices Safety Authority (MedSafe).^[172]
• According to Canada's Pest Management Regulation Agency^[173] and the Canadian (Health Canada) Drug Product Database,^[174] aclonifen is not registered as an active ingredient an any products.

CAS Number

16118-49-3

Alternative names

(R)-1-(ethylcarbamoyl) ethylcarbanilate

Applicant

Australian Pesticides and Veterinary Medicines Authority (APVMA)

Current scheduling

Carbetamide is currently included under Appendix B, Part 3 of the Poisons Standard as follows:

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

Key uses/expected use

Herbicide

Reasons for proposal

• The proposal is to consider that the current listing for carbetamide in Appendix B be reviewed with a view to including it in Schedule 6 based on identified hazards related to carcinogenicity and developmental toxicity.
• There are currently no registered agricultural and veterinary (agvet) chemicals containing carbetamide available in Australia, however this proposal for re-scheduling of carbetamide has been submitted in support of a new herbicide product.
• The formulated product had low toxicity via the oral, dermal and inhalation routes of exposure, was a slight eye irritant but was not a skin irritant or skin sensitiser. Carbetamide is considered not to be non-genotoxic.
• Positive tumour responses in multiple tissues were seen in carcinogenicity studies in both rats and mice. In developmental toxicity tests, adverse outcomes were observed in rats and rabbits at doses that induced minimal maternal toxicity. It is therefore considered that, while carbetamide is of low acute toxicity, it presents a moderate risk of producing irreversible toxicity.
• The risks posed by carbetamide can be controlled by adequate warnings and safety directions recommended by the APVMA for inclusion on the product label. It is considered therefore that carbetamide meets the requirements for inclusion in Schedule 6.

Australian regulations

• According to the Public Chemical Registration Information System Search (PubCRIS),^[175] carbetamide is an approved active constituent in Australia. However, there are currently no registered products.
• Carbetamide is not available for use as an active ingredient in human therapeutic products and is not listed on the TGA Ingredient Database.^[1765]
• There are currently no medicines active on the Australian Register of Therapeutic Goods (ARTG)^[177] that contain carbetamide as an active ingredient.
• Carbetamide is not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination^[178] No.3 of 2019.
• Carbetamide is not listed on the TGA prescribing medicines in pregnancy database.^[179]
• There are no warning statements pertaining to carbetamide in the Therapeutic Goods (Medicines Advisory Statements) Specification 2019.^[180]
• There are no adverse events associated with carbetamide use according to the Database of Adverse Event Notifications (DAEN).^[181]

International regulations

• According to the New Zealand Inventory of Chemicals (NZIoC)^[182] and New Zealand Medicines and Medical Devices Safety Authority (MedSafe),^[183] there are no registered products containing carbetamide in New Zealand.
• Carbetamide was approved as a herbicide on 1 June 2011 in Europe according to the European Union Pesticides Database.^[184]
• The European Chemicals Agency (ECHA)^[185] hazard classification & labelling for carbetamide identifies it as 'Danger! According to the harmonised classification and labelling (ATP10) approved by the European Union, this substance may damage the unborn child, is toxic to aquatic life with long lasting effects, is harmful if swallowed and is suspected of causing cancer'. Carbetamide is predicted as likely to meet criteria for category 1A or 1B carcinogenicity, mutagenicity, or reproductive toxicity according to the Annex III: criteria for 1 - 10 tonne registered substances.^[186] In 2009, carbetamide was recorded as being intended to be registered by at least one company in the European Economic Area (EEA).
• Carbetamide is not identified as an ingredient used in cosmetics according to the European commission database for information on cosmetic substances and ingredients database.^[187]
• Carbetamide is not an approved active ingredient in the United States and Canada according to the United States Environmental Protection Agency's (US EPA) Office of Pesticides Programs,^[188] the Canadian (Health Canada) Drug Product Database^[189] and Canada's Pest Management Regulation Agency.^[190]

CAS Number

54-11-5

Alternative names

3-[(2S)-1-methylpyrrolidin-2-yl]pyridine [IUPAC]

Applicant

Private applicant

Current scheduling

Nicotine is currently listed in Schedules 4, 6 and 7 and Appendices F and J of the Poisons Standard as follows:

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

Key uses/expected use

Nicotine for use in alternative nicotine delivery product including heated tobacco products (HTPs)

Reasons for the proposal put forward by the Applicant

• Currently, the use of nicotine in tobacco, other than in 'tobacco prepared and packed for smoking', are included in Schedule 7 of the Poisons Standard as a result of the naturally occurring nicotine component of tobacco. This means that alternative nicotine delivery products, such as Heated Tobacco Products (HTPs), cannot be sold in Australia and the only option for smokers who would otherwise continue to smoke are combustible cigarettes (CCs) - the most harmful way to use tobacco.
• The current exemption 'tobacco prepared and packed for smoking' permits the consumption of tobacco and nicotine in its more dangerous form (i.e. cigarette smoke). Adding to the exemption 'tobacco prepared and packed for heating' would enable the availability of heated tobacco products (HTPs) as a better alternative for current Australian smokers who do not quit. HTPs were developed based on the fundamental proposition that if combustion is eliminated, the level of harmful chemicals generated and inhaled is significantly reduced.
• Delivery of nicotine in aerosol from a heated non-combusted tobacco product reduces the exposure to many of the chemicals found in cigarette smoke that are the main cause of tobacco smoking related disease. Specific HTPs have been reviewed by several regulators globally and accepted as a better alternative than continued smoking for adult smokers who do not quit.
• In addition to the United States, a HTP was authorised in countries such as Poland, Greece, Austria, and Portugal after thorough review of a scientific submission dossier. Furthermore, the scientific evidence was reviewed by the Committee of Toxicology (COT) in the United Kingdom both through a submission of the evidence and an oral presentation. The assessment concluded that, while still harmful to health, HTPs "are likely to be less risky than smoking conventional cigarettes" and also stated that: "There would likely be a reduction in risk for conventional smokers deciding to use heat-not-burn tobacco products instead of smoking cigarettes." (COT, 2017).

Australian regulations for HTPs

• The Australia Government supports the cessation of smoking rather than harm reduction.^[191]
• Australia is a Party to the World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC), which aims to protect present and future generations from the devastating health, social, environmental and economic consequences of tobacco consumption and exposure to tobacco smoke.^[192],^[193] Under the FCTC, Australia must adopt and implement effective measures for preventing and reducing tobacco consumption, nicotine addiction and exposure to tobacco smoke.
• The FCTC also obliges Australia to take steps to protect its tobacco control policy setting and implementation from interference from the tobacco industry and its interests. This obligation comes from Article 5.3 of the FCTC, which states:

  "In setting and implementing their public health policies with respect to tobacco control, Parties shall act to protect these policies from commercial and other vested interests of the tobacco industry in accordance with national law."

• On 1 November 2019, the Commonwealth Department of Health published 'Guidance for public officials on interacting with the tobacco industry'.^[194] The guide has been developed in light of Australia's obligations as a Party to the WHO FCTC. The guide applies to e-cigarettes and HTPs, as well as traditional tobacco products. Article 5.3 of the WHO FCTC requires public officials to protect public health policies in relation to tobacco control from commercial and other vested interests of the tobacco industry. Among other details, the guide notes that consultation with the tobacco industry should be limited to what is necessary for public officials or agencies to enact effective tobacco control measures.

Australian regulations on nicotine

• According to the TGA Ingredient Database,^[195] nicotine is:
  • available for use as an active ingredient in: biologicals, export only, over the counter, prescription medicines;
  • available for use as an excipient ingredient in: biologicals, devices, prescription medicines; and
  • not available as an equivalent ingredient in any application.
• According to the TGA Ingredient Database,^[196] nicotine betadex complex is:
  • available for use as an active ingredient in: biologicals, export only, over the counter, prescription medicines;
  • available for use as an excipient ingredient in: biologicals, devices, prescription medicines; and
  • not available as an equivalent ingredient in any application.
• According to the TGA Ingredient Database,^[197] nicotine bitartrate dehydrate is:
  • available for use as an active ingredient in: biologicals, export only, over the counter, prescription medicines;
  • available for use as an excipient ingredient in: biologicals, prescription medicines; and
  • not available as an equivalent ingredient in any application.
• According to the TGA Ingredient Database,^[198] nicotine polacrilex is:
  • available for use as an active ingredient in: biologicals, export only, over the counter, prescription medicines;
  • available for use as an excipient ingredient in: biologicals, devices, prescription medicines; and
  • not available as an equivalent ingredient in any application.
• There are 120 products currently active on the Australian Register of Therapeutic Goods (ARTG)^[199] that contain nicotine, nicotine betadex complex, nicotine bitartrate dehydrate and nicotine polacrilex as an active ingredient. These include 2 export-only medicines and 118 non-prescription medicines.
• According to the Therapeutic Goods (Permissible Ingredients) Determination^[200] No.3 of 2019, Nicotiana tabacum (cultivated tobacco) is permitted to be included in listed medicines as follows:

• Nicotine is listed on the TGA prescribing medicines in pregnancy database^[201] as follows:

• There are no warning statements pertaining to nicotine in the Therapeutic Goods (Medicines Advisory Statements) Specification 2019.^[202]
• Between 1971 and 2019, there have been 1346 reports of adverse event for nicotine recorded on the Database of Adverse Event Notifications (DAEN).^[203] Of these, 1236 cases where nicotine was the single suspected medicine and 3 cases where death was a reported outcome.
• Nicotine is not listed as an active ingredient on the Public Chemical Registration Information System Search (PubCRIS).^[204]

International regulations setting on HTPs

• The World Health Organisation (WHO)^[205] recommends that all forms of tobacco use are harmful, including HTPs. Tobacco is considered to be inherently toxic and contains carcinogens even in its natural form. Therefore, it is view of the WHO that HTPs should be subject to policy and regulatory measures applied to all other tobacco products, in line with the WHO Framework Convention on Tobacco Control (WHO FCTC).
• Europe: HTPs were first marketed in European Union in May 2014.^[206] They are treated as other tobacco products with regard to their sale, presentation and manufacturing. That is, the relevant provisions of the Tobacco Products Directive apply and should be enforced. This includes prohibiting suggestions that a particular tobacco product is less harmful than others.^[207],^[208]
• United Kingdom (U.K): HTPs are currently available in the U.K market.^[209] The UK was one of the first countries to assign a separate taxation category for HTPs.^[210]
• United States (U.S): In April 2019, the U.S Food and Drug Administration (FDA) approved an application to sell a HTP in the U.S, noting that it was appropriate for the protection of the public health because, among several key considerations, the products produce fewer or lower levels of some toxins than combustible cigarettes.^[211] The agency found that the aerosol produced by the HTP contains fewer toxic chemicals than cigarette smoke, and many of the toxins identified are present at lower levels than in cigarette smoke. The FDA has placed stringent marketing restrictions on the products in an effort to prevent youth access and exposure.
• The FDA is continuing its review of the application through the Modified Risk Tobacco Product (MRTP) pathway.^[212] In the U.S, claims of reduced risk (referred to as MRTP under U.S legislation) must be approved by the FDA before a tobacco company can market a product with reduced exposure or risk claims.^[213] In January 2018, the FDA Tobacco Product Scientific Advisory Committee recommended against FDA approval of reduced risk claims for the HTP.^[214]
• Japan: Japan is the largest market for HTPs.^[215] HTPs are sold as tobacco products and regulated by the Tobacco Business Act. The Japanese government has announced plans to restrict use of HTPs in certain public places; however, the restrictions will be less stringent than those on cigarettes 'because the risk to health posed by second hand smoking of such products remains unclear'.^[216]
• Canada: HTPs are regulated as tobacco products under the Tobacco and Vaping Products Act.^[217] As such, they are regulated in the same way as conventional cigarettes.^[218] Health Canada recently introduced changes which would mean that advertisers will not be allowed to make the claim that HTPs are a safer alternative to cigarettes.^[219] These changes mean that retail stores which sell HTPs could not use the product name as signage. In response to the legislative changes, retail stores selling HTPs were required to remove HTP product names from all shop signage.^[220]
• New Zealand: HTPs are regulated as tobacco products and they are permitted to be legally imported, sold and distributed in New Zealand.^[221]

CAS Number

76-74-4

Alternative names

Pentobarbitone; 5-ethyl-5-pentan-2-yl-1,3-diazinane-2,4,6-trione [IUPAC]

Applicant

Delegate of the Secretary of the Commonwealth Department of Health

Current scheduling

Pentobarbital is currently listed in Schedules 4 and 8 and Appendix K of the Poisons Standard as follows:

Proposed scheduling

It has been proposed to amend the Poisons Standard as follows:

Key uses/expected use

Veterinary medicine

Reasons for proposal

• This rescheduling proposal was initiated by a Delegate of the Secretary of the Department of Health as a result of the reported misuse of injectable pentobarbital and its involvement in suicides. Of particular note, the South Australian Coroner has made a request (pdf,372kb)^[222] for the Therapeutic Goods Administration (TGA) to reconsider the Schedule 4 (Prescription Only Medicine) entry for 'PENTOBARBITAL when packed and labelled for injection' and to move it to Schedule 8 (Controlled Drug).
• In revisiting the scheduling of pentobarbital, the Delegate notes that access controls for pentobarbital in Australia were most recently reviewed by the Joint Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS) in November 2016 and a decision was made to retain the current scheduling.^[223] It is noted that the last consideration of pentobarbital was initiated under similar circumstances to the current consideration: in response to the Queensland Coroner's recommendations in 2016 relating to a suicide involving pentobarbital. The Coroner's report recommended that injectable pentobarbital be moved from Schedule 4 to Schedule 8 thereby ensuring that all forms of the substance would be subject to restriction of manufacture, supply, distribution, possession and use to reduce abuse, misuse and physical or psychological dependence.

Australian regulations

• Pentobarbital was previously scheduled under the name pentobarbitone. As a result, the two names are used in the Australian regulations below.
• According to the TGA Ingredient Database,^[224] pentobarbital and the related substance, pentobarbital sodium, are available for use as active ingredients in: biologicals, export only and prescription medicines. They are also available for use as excipient ingredients in: biologicals, devices and prescription medicines. They are not available as equivalent ingredients in any application.
• There are no medicines (prescription or non-prescription) currently active on the Australian Register of Therapeutic Goods (ARTG)^[225] that contain pentobarbital, pentobarbital sodium or pentobarbitone sodium as an active ingredient.
• Pentobarbital and pentobarbitone are not permitted to be included in listed medicines as it is not included in the Therapeutic Goods (Permissible Ingredients) Determination^[226] No.3 of 2019.
• The TGA prescribing medicines in pregnancy database^[227] classifies pentobarbital (listed under pentobarbitone) as:

• There are no warning statements pertaining to pentobarbital or pentobarbitone in the Therapeutic Goods (Medicines Advisory Statements) Specification 2019.^[228]
• The Database of Adverse Event Notifications (DAEN)^[229] contains 18 reports of adverse events for products containing pentobarbital and pentobarbitone as an active ingredient, with 10 reports where pentobarbital/pentobarbitone was the single suspected medicine. There were 3 reports of deaths associated with pentobarbital/pentobarbitone use.
• Pentobarbital (as pentobarbital sodium) is as an approved active constituent according to the Public Chemical Registration Information System Search (PubCRIS).^[230] There are no registered products containing pentobarbital on PubCRIS.
• In addition to pentobarbital there is a separate entry in PubCRIS under pentobarbitone. Pentobarbitone (as pentobarbitone sodium) is listed as an approved active ingredient. There are 5 registered products containing pentobarbitone. The listed uses include euthanasiates and anaesthetics/analgesics.
• In 2009-2019 the following adverse experiences/incidences were recorded for pentobarbitone in the APVMA Adverse Experience Reporting Program database (AERP):^[231]
  • 1 report classified being probable and related to lack of effect reported in 2010.
  • 1 report classified being possible and related to low efficacy reported in 2013.
  • 5 reports classified being possible and related to lack of effect and abnormal breathing reported in 2014.
  • 1 report classified being possible and related to lack of effect reported in 2015.
  • 1 report classified as being related to efficacy reported in between 2016-2017.
  • 2 reports classified as being related to efficacy reported between 2017-2018.
  • 4 reports classified as being related to efficacy and human health reported between 2018-2019.
• There were no adverse experiences/incidences reported for pentobarbital between 2009-2019 recorded the in the AERP.

International regulations

United Nations (UN)

• Pentobarbital is classified as a Class III psychotropic substance^[232] under the United Nations Convention on Psychotropic Substances 1971 treaty.^[233] The United Nations Single Convention on Narcotic Drugs (1961) and the United Nations Convention on Psychotropic Substances (1971) treaties provide the legal basis for the international prevention of drug abuse, together with the United Nations Convention against the Illicit Traffic in Narcotic Drugs and Psychotropic Substances (1988).

United States of America (USA)

• Pentobarbital is a Schedule III controlled substance in the USA where it is classified as a depressant i.e. a substance having a depressant effect on the central nervous system. In the USA, Schedule III drugs, substances, or chemicals are defined as drugs with a moderate to low potential for physical and psychological dependence.
• Pentobarbital is not registered for use in pesticides according to the United States Environmental Protection Agency's (US EPA) Office of Pesticides Programs.^[234]
• Pentobarbital is available as a prescription medicine in the USA according to the United States Food and Drug Administration Approved Drug Products Database (Drugs@FDA).^[235]

Europe

• The European Chemicals Agency (ECHA)^[236] hazard classification & labelling for pentobarbital is 'Danger! According to the classification provided by companies to ECHA in REACH^[237] registrations this substance is toxic if swallowed, is harmful in contact with skin, is harmful if inhaled and is suspected of damaging fertility or the unborn child.'
• Pentobarbital is identified in the European Commission database for information on cosmetic substances and ingredients database^[238] in the group entry for barbiturates.^[239]
• According to the European Union Pesticides Database,^[240] pentobarbital is not used in pesticides in Europe.

Canada

• Pentobarbital (as pentobarbital sodium) is used in veterinary medicine and it is listed on Schedule IV of the Canadian Controlled Drugs and Substances Act.^[241] The Act serves as the implementing legislation for the Single Convention on Narcotic Drugs, the Convention on Psychotropic Substances, and the United Nations Convention Against Illicit Traffic in Narcotic Drugs and Psychotropic Substances.^[242]
• Pentobarbital is not used as an active ingredient in pesticides according to the Canada's Pest Management Regulation Agency.^[243]

New Zealand (NZ)

• On the NZ Medsafe Classification Database,^[244] pentobarbital is classified as follows:

• The NZ Misuse of Drugs Act 1975^[245] defines a Class C controlled drug 'drugs that pose a moderate risk of harm'.
• Pentobarbital (listed under pentobarbitone sodium) is identified as an approved chemical on the New Zealand Inventory of Chemicals (NZIoC).^[246]