3.1 Interim decision in relation to caffeine

3. Interim decision on proposed amendment referred to the Advisory Committee on Medicines and Chemicals Scheduling in joint session (Joint ACCS/ACMS #23, November 2019)

3.1. Interim decision in relation to caffeine

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision to amend the current Poisons Standard in relation to caffeine as follows:

Proposed date of effect of the proposed amendment

1 June 2020

Reasons for the interim decision (including findings on material questions of fact)

In this section: Applicant's scheduling proposal and reasons for the proposal | Current scheduling status | Scheduling history | Australian regulations | International regulations | Summary of pre-meeting public submissions | Summary of Joint ACCS-ACMS advice/recommendations to the Delegate | Delegate's considerations | Reasons for interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to amend the Poisons Standard with respect to caffeine was considered.

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

The Applicant's main points provided in support of the proposed amendments were as follows:

• The dietary ingestion of caffeine has led to it being the most widely consumed psychoactive compound worldwide (Cappelletti et al., 2018).^[199] Caffeine powder is readily available for sale and consumption on the Australian market via the internet and numerous pure or highly concentrated (>98%) caffeine powders have been advertised for sale online either on Australian websites or international websites that are available to the Australian public.
• A recent fatality associated with inadvertent caffeine overdose suggests the current availability of pure or highly-concentrated caffeine powder presents a risk of poisoning.
• Appropriate labelling and control of all concentrated caffeine products would reduce the risk of inadvertent overdose.
• The toxicity of orally administered caffeine in rats is within the Australian Health Ministers' Advisory Council (AHMAC) Scheduling Policy Framework for Schedule 6. Potentially fatal doses (reported at 5 g) are easily exceeded with the availability of pure or highly-concentrated caffeine products and intentional ingestion of such products will be reduced if labelled as a 'POISON'.
• The Australian Regulatory Guidelines for Over-The-Counter (OTC) Medicines (ARGOM) and the Therapeutic Goods (Permissible Ingredients) Determination specify appropriate restrictions for internal caffeine within the low risk framework of listed medicines and OTC medicines. Internal human therapeutic use outside of these restrictions should be considered for prescription-only scheduling.

Current scheduling status

Caffeine is not specifically scheduled in the current Poisons Standard. However, caffeine is included in the Schedule 4 aspirin and salicylamide entries and the Schedule 2 paracetamol entry of the Poisons Standard. See green text below:

Scheduling history

Caffeine as a single active ingredient

In November 1986, the National Drugs and Poisons Schedule Committee (NDPSC) discussed a letter from the Australian Federation of Consumers Organisations (AFCO) raising a number of concerns including the use of caffeine as an additive in foods and the open sale of XXXXX caffeine tablets. The Committee considered that AFCO had not provided sufficient evidence of a problem with these tablets to warrant scheduling action.

In June 2006, the NDPSC considered the issues of potential misuse of stimulant/alerting caffeine products and the scheduling of single active caffeine following receipt of an inquiry that raised concerns about the misuse and ease of availability of an OTC product (XXXXXXXXXXXX) containing 100 mg caffeine. The NDPSC considered advice from both the Adverse Drug Reactions which had not received any reports of abuse from any caffeine-containing products and the drug Strategy Branch of the Department of Health and Aging that caffeine did not appear to be an issue. Members also noted that:

1. according to information from the Sports Dieticians Australia website, in January 2004 caffeine had been removed from the 2004 World Anti-Doping Agency (WADA) Prohibited List; and
2. FSANZ had established an Expert Working Group to examine the wider aspects of the safety of dietary sources of caffeine.

The Committee agreed that single active caffeine did not warrant scheduling at that time given evidence for long term detrimental or toxic effects from abuse of caffeine was generally lacking and that the Australian Guidelines for Registration of OTC Medicines required all OTC medicines using caffeine as a stimulant or alerting agent to have an adult dose compliant with 'a 100 mg/dose maximum, which may be repeated at 3 hourly intervals. Do not exceed 600 mg in 24 hours.'

Caffeine in combination with analgesics

In the 1960s - 70s in Australia, analgesic combinations containing aspirin, phenacetin (paracetamol from 1975) and caffeine, or aspirin, salicylamide and caffeine were found to be associated with a high risk of analgesic abuse and consequent analgesic nephropathy. Combinations of any two or more of paracetamol, aspirin, salicylamide, caffeine or any derivatives of these substances were rescheduled from OTC to Prescription Only following a recommendation from the National Health and Medical (NHMRC) Research Council in 1977.

In October 2003, the NDPSC considered a request to include paracetamol +caffeine in Schedule 2. Members agreed that the scheduling of paracetamol + caffeine as Schedule 4 remained appropriate given the inadequate evidence provided to demonstrate that paracetamol + caffeine was safe and also given that caffeine had potential side effects at high doses. The Committee also felt that the stimulating nature of caffeine might encourage excessive use or abuse of these combination products.

In February 2007, the NDPSC considered the scheduling of aspirin compound analgesics containing paracetamol, caffeine or salicylamide. After consideration of all submissions, the Committee agreed that due to the risk of nephrotoxicity, the current Prescription Only scheduling of aspirin when in combination with paracetamol, caffeine or salicylamide remained appropriate. The Committee also agreed to foreshadow the consideration of paracetamol when in combination only with caffeine for the June 2007 NDPSC Meeting as this was an ongoing harmonisation issue with New Zealand which needed to be resolved.

In June 2007, the NDPSC agreed to down-schedule paracetamol + caffeine from Schedule 4 as the indications for use, safety profile and potential for misuse met the Schedule 2 criteria. The Committee was of the opinion that it would be inappropriate to consider paracetamol + caffeine for exemption from scheduling until market experience had been gained with use as a Schedule 2 preparation.

In October 2009, the NDPSC considered a request from the XXXXXXXXXXXXX (XXX) for the Committee to reconsider its June 2007 decision to include paracetamol + caffeine in Schedule 2, on the grounds of potential toxicity of the formulation when used in excess. It was noted that the Committee had undertaken extensive deliberations in June 2007 and the concerns raised by the XXX were also comprehensively reviewed at that time. Consequently, the Committee decided that the scheduling of paracetamol + caffeine remained appropriate.

In November 2014, the Advisory Committee on Medicines Scheduling (ACMS) considered a proposal to amend the Schedule 2 entry to exempt paracetamol when compounded with caffeine, in a powder or granule product containing 1000 mg or less of paracetamol and in tablets or capsules containing 500 mg or less of paracetamol when paracetamol is the only therapeutic active constituent and when supplied in primary packs of not more than 20 tablets/caplets or 10 sachets of powders/granules. The Delegate's final^[200] decision was consistent with the ACMS advice that that the scheduling of paracetamol when compounded with caffeine remained appropriate.

Australian regulations

• On 20 September 2019, a media release - external site^[201] from the Commonwealth Department of Health announced that the Australian Government '...is taking decisive action towards banning the sale of pure and highly concentrated caffeine food products (including pure caffeine powder) for personal consumption.'
• The TGA are currently working on a consultation on sports supplements: 'Proposed clarification that certain sports supplements are therapeutic goods' which is anticipated to be release sometime in October 2019.
• According to the TGA Ingredient Database - external site,^[202] caffeine, caffeine citrate, caffeine hydrate and purine alkaloids calculated as caffeine (of Paullinia cupana) are included as follows:
  • Caffeine:
    • is available for use as an active ingredient in: biologicals, export only, listed medicines, over the counter and prescription medicines;
    • is not available as a homoeopathic ingredient in listed medicines;
    • is available for use as an excipient ingredient in: biologicals, devices, export only, listed medicines, over the counter and prescription medicines; and
    • is available for use an equivalent ingredient in: export only, listed medicines.
  • Caffeine citrate:
    • is available for use as an active ingredient in: biologicals and prescription medicines;
    • is available for use as an excipient ingredient in: biologicals, devices, and prescription medicines; and
    • is not available for use an equivalent ingredient in any application.
  • Caffeine hydrate:
    • is available for use as an active ingredient in: biologicals and prescription medicines;
    • is available for use as an excipient ingredient in: biologicals, devices and prescription medicines; and
    • is not available for use an equivalent ingredient in any application.
  • Purine alkaloids calculated as caffeine (of Paullinia cupana):
    • is not available for use as an active ingredient in any application;
    • is not available for use as an excipient ingredient in any application; and,
    • is available for use an equivalent ingredient in: export only, over the counter and prescription medicines.
• There are 77 medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[203] that contain caffeine as an active ingredient. These include two (2) prescription medicines, 27 non-prescription medicines, 47 listed medicines and one (1) export only medicine.
• Appendix 5 of the Australian Regulatory Guidelines for OTC Medicines (ARGOM)^[204] limits caffeine in OTC products to a maximum daily dose of 600 mg for adults and children 12 years and over. Further, labels for OTC medicines containing caffeine are must carry the following warning statements:
  • Limit the use of caffeine-containing products (including tea and coffee) when taking this product. One tablet/capsule contains about the same amount of caffeine as x cups of instant coffee.
  • Caffeine may cause sleeplessness if it is taken up to several hours before going to bed.
• The Prescribing medicines in pregnancy database^[205] classifies caffeine as:

  Drug name	Category	Classification Level 1	Classification Level 2	Classification Level 3
  Caffeine	A	Central Nervous System	CNS stimulants	-
  Category A - Drugs which have been taken by a large number of pregnant women and women of childbearing age without any proven increase in the frequency of malformations or other direct or indirect harmful effects on the foetus having been observed.

• The Database of Adverse Event Notifications (DAEN) - external site^[206] contains 340 reports of adverse events for products containing caffeine as an active ingredient, with 263 cases where there was a single suspected medicine. There was one (1) case where death was a reported outcome.
• As of 9 August 2019 there are three (3) entries for caffeine listed on the Public Chemical Registration Information System Search (PUBCRIS) - external site.^[207] Two entries are caffeine active constituent approvals (XXXXX and XXXXX) and one is for a veterinary medicine (XXXXX) containing 1.2% caffeine citrate (equivalent to 0.6% caffeine base) in combination with other active constituents for use as a restorative and appetite stimulate.
• There are no warning statements pertaining to caffeine in the Medicines Advisory Statement Specification 2019 (RASML No. 2- Schedule 1).^[208]

High-moderate risk changes to permissible ingredients - Caffeine

• Following a safety review, new requirements for caffeine and caffeine-containing ingredients^[209] within listed medicines are specified in the Therapeutic Goods Amendment (Permissible Ingredients) Determination (No. 1) 2019 - external site.^[210] This was an unincorporated amendment in the Therapeutic Goods (Permissible Ingredients) Determination (No. 2) 2019 - external site. A delay to implementation of these changes was considered likely to pose an imminent or serious safety risk to consumers (see High-moderate risk changes^[211]). As such, the Delegate of the Minister of Health has considered it appropriate to make this change to the Determination commencing 2 September 2019.
• Caffeine as an individual ingredient remains only for oral use and at a maximum daily dose of 100 mg. However, caffeine, when present as a component of other herbal ingredients, will now have dosage restrictions so that the medicine does not provide more than 400 mg total caffeine per day. A maximum dose of 100 mg per three hours will also be required. These limits consider consumption from other sources such as food, and the adverse effects which are seen with caffeine intake exceeding 400 mg/day and more frequent dosing.
• The additional restrictions have been included to be consistent with all caffeine containing ingredients and cover routes of administration where caffeine is present from other ingredients.
• The warning statement (CAFF) has been adjusted to increase consumer awareness of caffeine intake. An additional warning statement of (CAFFPREG) addresses concerns for caffeine use in pregnancy and lactation. Caffeine as an individual ingredient currently has the requirement for a warning statement for 'Adults only'. The same concerns for caffeine intake for children apply to other ingredients containing caffeine and this statement has been applied to all caffeine containing ingredients above 10 mg daily dose.
• For doses greater than 80 mg/day (which equates to a cup of instant coffee), additional warning statements will be required to address specific safety concerns of inadvertent misuse, interactions with other medicines which may lead to increased caffeine plasma levels or interactions between medicines, and potential adverse effects due to high caffeine intake.
• A caffeine concentration of 1% in undivided preparations was considered acceptable given that 30 g (estimated equivalent of a heaped tablespoon) would deliver only 300 mg of caffeine, which sufficiently reduces the likelihood of inadvertent overdose. A concentration of 33% is considered acceptable in divided preparations that do not require the consumer to measure dosage. This is considered to pose a lower risk of inadvertent overdose and is in line with the highest caffeine concentration in existing OTC products.
• The new requirements for caffeine^[212] have been applied to the following ingredients for internal use or oral use application in listed medicines and are specified in the Therapeutic Goods (Permissible Ingredients) Determination (No. 4) 2019 - external site:^[213]
  • Caffeine
  • Cammellia sinensis
  • Coffea arabica
  • Coffee
  • Cola acuminate
  • Cola nitida
  • Ilex paraguariensis
  • Paullinia cupana
  • Theobroma caco
• The following requirements will have immediate effect:
  • Undivided preparations (e.g. bulk powders) must not contain a concentration of total caffeine greater than 4%.
  • Divided preparations (e.g. tablets) must not contain a concentration of total caffeine greater than 33%.
• For the following requirements, sponsors of existing listed medicines will have until March 2021 to bring affected products into compliance while any new listed medicines will need to comply immediately:
  • The maximum recommended daily dose must not provide more than 400mg of total caffeine from all ingredient sources. NOTE: The existing 100mg maximum daily dose limit for caffeine as an individual ingredient still applies.
  • Undivided preparations must not contain a concentration of total caffeine greater than 1%.
  • The maximum recommended dose must not provide more than 100 mg of total caffeine within a 3-hour period.
  • When the maximum recommended daily dose provides greater than 10 mg of total caffeine, the following warning statements are required:
    • (ADULT) 'Adults only' (or words to that effect).
    • (CAFF) 'Contains caffeine [state quantity per dosage unit or per mL or per gram of product] total caffeine [per dosage unit or per mL or per gram]. A cup of instant coffee contains approximately 80mg of caffeine.'
    • (CAFFPREG) 'Caffeine intake more than 200 mg per day is not recommended during pregnancy or breastfeeding.'
  • When the maximum recommended daily dose provides greater than 80 mg of total caffeine, the following warning statements are required:
    • (CAFFLIMIT) 'Limit the use of caffeine-containing products (including tea and coffee) when taking this product.'
    • (CAFFCYP) 'Caffeine interacts with the liver enzyme CYP1A2. Consult your health professional before taking with other medicines' (or words to that effect).

Food Standards Australia and New Zealand (FSANZ)

• According to FSANZ - external site,^[214] there is no recognised health-based guidance value, such as an acceptable daily intake (ADI) for caffeine. However, a 2000 literature review conducted by a FSANZ Working Group on the safety aspects of dietary caffeine (pdf,344kb) - external site^[215] concluded that based on the available data:
  • enhanced performance and mood effects may be seen at doses of 37.5 mg (0.54 mg/kg bw/day in 70 kg adults);
  • increased anxiety levels can occur in children at doses of 95 mg (3 mg/kg bw/day in children aged 5-12 years with a mean bodyweight of 32 kg) and at 210 mg in adults (3 mg/kg bw/day in 70 kg adults); and
  • caffeine has been reported to reduce the ability to sleep at doses of 100 mg (1.4 mg/kg bw/day in 70 kg adults) at bedtime.
• The Food Standards Code - external site^[216] restricts how much caffeine can be added to cola-type soft drinks and energy drinks. Foods containing added caffeine must also have a statement on the label - external site^[217] stating that the product contains caffeine. In cola-type drinks, the total caffeine content must not exceed 145 mg/kg (36 mg/ 250 mL serve) in the drink as consumed. Formulated caffeinated beverages (including energy drinks) are regulated under Standard 2.6.4 - external site^[218] of the Code. Standard 2.6.4 stipulates that the maximum amount of caffeine (in any form) that these products can contain is 320 mg/L and includes additional labelling requirements - external site^[219] advising the products are not suitable for young children, pregnant or lactating women and individuals sensitive to caffeine. 'Energy shots' marketed as dietary supplements or supplemented foods have been found to contain caffeine and other substances in small volumes at concentrations above the limits prescribed in the Code and therefore do not meet the requirements of Standard 2.6.4.
• In June 2014, a Ministerial Policy Guideline on the Regulatory Management of Caffeine in the Food Supply^[220] was endorsed. Recommendations were included in the guidance that the regulatory management of caffeine in the food supply should:
  1. be based on risk analysis ensuring consideration of general population and taking into account vulnerable population groups including children, adolescents, pregnant and lactating women and caffeine sensitive consumers;
  2. consider exposure to caffeine from all dietary sources; and
  3. be informed by emerging evidence and the regulation of caffeine in overseas jurisdictions.
• On 10 July 2019, the Minister for Health, the Hon Greg Hunt and the Minister for Aged Care and Senior Australians and Minister for Youth and Sports, Senator the Hon Richard Colbeck asked FSANZ to look into the safety of caffeine powders and high caffeine content food products - external site.^[221] The Ministers also asked FSANZ to consider the need for appropriate warning labels and consumer safety information for these products.
• On 30 August 2019, Mark Booth, CEO of FSANZ wrote a report - external site in response to the request from Ministers Hunt and Colbeck on pure and highly concentrated caffeine products.^[222] The report covers the current regulatory framework and permissions for use of caffeine in the Australia New Zealand Food Standards Code; identifies high risk areas where regulation should be strengthened; and, preliminary recommendations regarding the safety of high caffeine products based on consultation with key stakeholders (the report discusses current actions being taken by the TGA (i.e. amendments to the Permissible Ingredients Determination as discussed above and this scheduling application). The report identified that 'the immediate and acute risk is the sale to consumers of pure or highly purified forms of caffeine that require a very small safe dose to be measured from a potentially lethal amount'.
• On 20 September 2019, Minister Colbeck released a response - external site to the report and agreed to all recommendations made by FSANZ to enhance consumer safety with regards to caffeine powder and high caffeine content food.^[223] The recommendations are as follows:
  • RECOMMENDATION ONE: That FSANZ develop and declare as urgent a proposal to amend the Code to prohibit the retail sale of pure and highly concentrated caffeine food products.
  • RECOMMENDATION TWO: That FSANZ consider developing a maximum limit of caffeine in foods, based on the outcomes of the current review of Standard 2.9.4 - Formulated Supplementary Sports Foods.
  • RECOMMENDATION THREE: That a coordinated inter-agency consumer information campaign on safe caffeine consumption be developed and implemented in conjunction with the implementation of recommendation one, if adopted.
  • RECOMMENDATION FOUR: That, prior to or in parallel with the consumer information campaign, guidance on the regulation of products containing pure or high concentrations of caffeine, and high caffeine content products, be developed by Implementation Subcommittee for Food Regulation (ISFR) for, and agreed by, enforcement agencies to inform compliance action.
  • RECOMMENDATION FIVE: That targeted research on caffeine consumption across the Australian and New Zealand population, including consumption by specific vulnerable population groups, continue to be undertaken, including as part of the upcoming Intergenerational Health and Mental Health Study.^[224]
• In September 2019, FSANZ also published a food issues brief for consumers on caffeine - external site.^[225] Topics covered include caffeine levels in common foods, safe caffeine limits, how caffeine is regulated and what the government is doing about caffeine powders and high caffeine content products.
• In November 2019, FSANZ published an urgent proposal - external site^[226] for public consultation on a proposal to amend the Food Standards Code (the Code) to prohibit the retail sale of pure and highly concentrated caffeine products. Proposal P1054 (pdf,1.06Mb) - external site^[227] was prepared after reviewing and reporting to Ministers Hunt and Colbeck on the current availability and regulation of caffeine, and on options for strengthening regulations and consumer warnings in relation to pure and highly concentrated caffeine food products. One of the five recommendations contained in the report to the Ministers was the recommendation that FSANZ, 'develop and declare as urgent a proposal to amend the Code to prohibit the retail sale of pure and highly concentrated caffeine food products.'^[228] The draft variation which is the subject of this consultation, proposed to 'prohibit the sale of foods in which total caffeine is present in a concentration of 5% (5 g/100 g) or more, in the product presented at retail sale, unless that sale or presence was expressly permitted by the Code.'^[229] The proposed amend to the code would not affect the continued use of caffeine as an ingredient in foods such as formulated caffeinated beverages and cola beverages.

International regulations

• In June 2016, the International Agency for Research on Cancer (IARC), the cancer agency of the World Health Organization (WHO), released the findings of an international Working Group of 23 scientists convened to evaluate the carcinogenicity of drinking coffee (pdf,52kb) - external site^[230] (and hot beverages and maté). The Working Group found no conclusive evidence for a carcinogenic effect of drinking coffee. Consequently, coffee was reclassified from possibly carcinogenic to humans (Group 2B) to not classifiable as to its carcinogenicity to humans (Group 3).

Canada

• As of 9 August 2019, Health Canada has approved 21 products that contain caffeine^[231] for use in humans. All approved medicines are tablets for oral use and are either un-scheduled (1), or scheduled as OTC (15) or narcotic (controlled substances) (8), medicines. The unscheduled preparation contains 200 mg caffeine as the sole active ingredient and is approved for use as a diuretic. The 15 OTC medicines, approved for use as analgesics and antipyretics include caffeine at 15 mg (4), 32 mg (2) and 65 mg (9) in combination with one or more of the following: acetylsalicylic acid, codeine phosphate, acetaminophen (paracetamol) and pyrilamine maleate.
• In Canada, when used in food, caffeine is regulated as a food additive - external site^[232] under the Food and Drugs Regulations and requires a thorough safety assessment by Health Canada before any new uses are permitted. Health Canada's Marketing Authorisations allows for the use of caffeine and caffeine citrate as food additives - external site^[233] in cola-type beverages and non-alcoholic carbonated water-based flavoured sweetened beverages (which includes carbonated soft drinks) to a maximum level of 200 ppm when used singly or in combination with caffeine citrate, 150 ppm, calculate as caffeine - external site^[234], in the finished product, respectively. Caffeinated energy drinks are considered a food and require a Temporary Marketing Authorisation Letter (TMAL) to allow for use of caffeine.
• In October 2018, Health Canada released a monograph on caffeine in natural health products - external site.^[235] While not a comprehensive review of the medicinal ingredient, the monograph provides guidance for industry for product licence applications (PLA) and labels for natural health product market authorisations. The monograph discusses routes of administration, dosage forms and doses, indications and contraindications, quantities, directions for use, duration of use, required caution and warning statements and adverse reactions.
• In March 2010, Health Canada released preliminary guidance for industry on the labelling of caffeine content in pre-packaged foods - external site^[236] to encourage food manufacturers to quantitatively label caffeine when present in certain pre-packaged foods such as beverages. In 2012, after a review of caffeine and its potential health effects, Health Canada reconfirmed that for the average adult, moderate daily caffeine intake at dose levels of 400 mg/day is not associated with any adverse effects. However, the data showed that women of childbearing age and children may be at greater risk from caffeine. Consequently, as a precautionary measure, Health Canada released recommended maximum caffeine intake levels for children and women of childbearing age. While there was insufficient data to develop definitive advice for adolescents, Health Canada suggests that daily caffeine intake for this age group be no more than 2.5 mg/kg body weight.^[237]

Europe

• According to the European Chemicals Agency (ECHA) - external site^[238], caffeine is manufactured and/or imported in the European Economic Area (EEA) in 1000 - 100 000 tonnes per year and is used in the manufacture of a range of consumer, professional and industrial products including: cosmetics and personal care products; perfumes and fragrances; laboratory chemicals; pharmaceuticals; washing liquids and detergents; automotive care products; paints and coatings; and as a processing aid in industrial situations. The ECHA recommended hazard classification and labelling statement for caffeine is, 'Warning…this substance is harmful if swallowed.'
• Caffeine, caffeine benzoate, caffeine carboxylic acid, caffeine carboxylol sh-Decapeptide-1, caffeine carboxylol tripeptide-37 and caffeine salicylate are included in the European Commission (EU)'s cosmetic ingredient database (CosIng) - external site^[239] without restriction, for use in skin conditioning and/or masking products.
• In May 2015, the European Food Safety Authority (EFSA) published its Scientific Opinion on the safety of caffeine - external site.^[240] The opinion addresses possible adverse health effects of caffeine consumption:
  • from all dietary sources, including food supplements, in the general healthy population and in relevant sub-groups (e.g. children, adolescents, adults, the elderly, pregnant and lactating women and subjects performing physical exercise); and
  • in combination with other substances present in "energy drinks" (D-glucurono-γ-lactone and taurine), alcohol or p-synephrine (present in diet products and sports supplements, to determine whether or not these substances modify the possible adverse health effects of caffeine and/or the doses at which such adverse effects may occur.
• Based on available data, EFSA - external site^[241] reached the following conclusions on caffeine intakes which do not give rise to safety concerns:
  • single doses of caffeine up to 200 mg (approximately 3 mg/kg bw for a 70 kg adult) from all sources do not give rise to safety concerns for the general healthy population;
  • caffeine intakes from all sources up to 400 mg (approximately 5.7 mg/kg bw per day for a70 kg adult) consumed throughout the day do not give rise to safety concerns for health adults in the general population, except for pregnant women;
  • in pregnant women, caffeine intake from all sources up to 200 mg per day consumed throughout the day do not give rise to safety concerns for the developing foetus;
  • single doses of caffeine up to 200 mg and habitual consumption at doses of 200 mg caffeine per day consumed by lactating women do not give rise to safety concerns for the breastfeed infant; and
  • insufficient information was available to derive a safe level of caffeine intake for children and adolescents. However, EFSA proposed that the single dose of caffeine considered to be of no concern for adults (3 mg/kg bw per day) may also be applied to children, as the rate at which children and adolescents process caffeine is at least that of adults, and the studies available on the acute effects of caffeine anxiety and behaviour in children and adolescents support this level.

New Zealand

• According to New Zealand's Medicines and Medical Devices Safety Authority (Medsafe) - external site,^[242] there are twelve (12) products containing caffeine - external site^[243] as the sole ingredient or in combination with other active ingredients (ergotamine, paracetamol, phenylephrine, ascorbic acid, glucose, nicotinic acid, thiamine) currently approved for use. These products are available as prescription only (1), pharmacy only (3) and general sales (8), medicines.
• In August 2019, MedSafe - external site released a consumer up-date on 'Too much caffeine' - external site^[244] alerting consumers of the wide variety of products containing caffeine and to the dangers of over-consumption. The article addresses health risks associated with caffeine over-dose and caffeine withdrawal and advises medical practitioners to question patients presenting with possible symptoms of caffeine overdose about their ingestion of caffeine from less obvious sources (e.g. dietary supplements, guarana preparations etc.).

United States

• In the United States (US), caffeine and caffeine citrate, either as the sole active ingredient or in combination with other active ingredients (including acetaminophen (paracetamol), aspirin, dihydrocodeine bitartrate, codeine phosphate, butalbital, and ergotamine) are present in a range of OTC (2) and prescription medicines (46) approved by the US Food & Drug Administration (FDA) - external site.^[245] These drugs are available as tablets and capsules for oral use as solutions for oral and intravenous use and as rectal suppositories.
• Caffeine is included in the US Code of Federal Regulations (CFR) - external site^[246] as follows: 'Food and Drugs, Part 340 - Stimulant drug products for over-the-counter (OTC) human use'. When used as an over the counter stimulant drug (i.e. helps to restore mental alertness or wakefulness during fatigue or drowsiness) in a form suitable for oral administration, caffeine is generally considered safe and effective when used within established dosage limits. Products containing caffeine must carry the following warning statements and dosing instructions:

  Warnings:

  • "The recommended dose of this product contains as much caffeine as a cup of coffee. Limit the use of caffeine-containing medications, foods, or beverages while taking this product because too much caffeine may cause nervousness, irritability, sleeplessness, and, occasionally, rapid heartbeat."
  • "For occasional use only. Not intended for use as a substitute for sleep. If fatigue or drowsiness persists or continues to recur, consult a (select one of the following: 'physician' or 'doctor')."
  • "Do not give to children under 12 years of age."

  Directions:

  • "Adults and children 12 years of age and over: Oral dosage is 100 to 200 milligrams not more often than every 3 to 4 hours."
• According to the US FDA's Food Additive Status List - external site,^[247] caffeine at 0.02 % in cola-type beverages is generally recognised as safe and is not considered to be a food additive.
• In April 2018, the US FDA released guidance for industry on highly concentrated caffeine in dietary supplements - external site^[248] after products consisting of or containing only pure or highly concentrated caffeine were linked to at least two (2) deaths. Many products that consist of only or primarily pure or highly concentrated caffeine are sold as dietary supplement (powdered and liquid preparations). According to the FDA, the difference between a safe amount and a toxic or life-threatening amount - external site^[249] of caffeine in these highly concentrated products is very small. FDA considers some such products to be adulterated under the Federal Food, Drug, and Cosmetic Act (FD&C Act), because they are dietary supplements that present a significant or unreasonable risk of illness or injury under the conditions of use recommended or suggested in the labelling or, if no conditions for use are suggested or recommended, under ordinary conditions of use.
• In April 2018, the US FDA released a consumer warning - external site^[250] about dietary supplements consisting of consisting of pure or highly concentrated caffeine, and recommends avoiding these products. In particular, the FDA is concerned about pure and highly concentrated caffeine, in powdered and liquid forms, sold in bulk containers and marketed directly to consumers, following the deaths related to the use of these products in otherwise healthy individuals. Consumers were advised that pure and highly concentrated caffeine is extremely toxic and that:
  • when encountering pure or highly concentrated caffeinated products they should be aware of the high potency of these products and that parents should be aware that teenagers and young adults may be drawn to these products for their perceived benefits and may not recognise their risks;
  • these products often closely resemble safe household items. Highly concentrated caffeine in a clear liquid form could be easily confused with commonly available liquids, such as water or distilled vinegar, and pure powdered caffeine could be easily confused with flour or powdered sugar and that the consequences of a consumer mistakenly confusing one of these products could be toxic or even lethal;
  • symptoms of caffeine overdose can include rapid or dangerously erratic heartbeat, seizures and death; vomiting, diarrhoea, stupor and disorientation are also symptoms of caffeine toxicity and these symptoms are likely to be much more severe than those resulting from drinking too much coffee, tea or other caffeinated beverages;
  • If consumers believe that they are having an adverse event related to caffeine, stop consuming it and seek immediate medical care or advice.
• In December 2018, US FDA released another consumer update - external site^[251] on the dangers of over-consumption of caffeine. The FDA estimates toxic effects, such as seizures, can be observed with rapid consumption of around 1200 mg of caffeine, or 0.15 tablespoons of pure caffeine. According to the FDA, the risk of caffeine overdose increases as the concentration of caffeine in the product increases, meaning even small dosages of a highly concentrated product could lead to dangerous effects. Just one teaspoon of pure powdered caffeine can contain the same amount of caffeine as 28 cups of coffee, and a half cup of a liquid highly concentrated caffeine product contains the equivalent of more than 20 cups of coffee. These are toxic amounts that can have serious health consequences, including death. While noting variations in how sensitive people are to the effects of caffeine and how fast they metabolise it, the US FDA consumer update - external site^[252] cites 400 mg caffeine per day (equivalent to 4-5 cups of coffee) as an amount not generally associated with dangerous, negative effects. While the US FDA has not set a level for children, the American Academy of Paediatrics - external site^[253] discourages the consumption of caffeine and other stimulants by children and adolescents.

Summary of pre-meeting public submissions

In response to the notice published under regulation 42ZCZK advising of the proposed amendment, three (3) submissions were received. All submissions supported the amendment.

The main points provided in support of the proposed amendment were:

• Caffeine can cause significant toxicity involving gastrointestinal, stimulant, metabolic and cardiac effects. Exposures of 15-30 mg/kg can cause mild to moderate toxicity and need referral to hospital for monitoring. Caffeine in high concentration preparations poses a greater risk of toxicity and requirement of medical management. A pure caffeine powder could produce toxicity in very small quantities (<1 gm in an adult and as little as 150 mg in a toddler).
• There have been 724 calls to the NSW PIC regarding exposures to caffeine (not energy drinks) since January 2014 and only 1/3 of these calls involved an accidental exposure. This shows wide use/misuse in the community which has remained constant over the last 5 years:

  Year	Calls to NSW PIC regarding intentional exposure to caffeine
  2014	90
  2015	88
  2016	88
  2017	93
  2018	89
  2019 to 15 Oct	86

• There have been calls regarding 9 exposures to caffeine powder since 2014 evenly spread over the 5 years. All these patients were symptomatic requiring medical management. Of these exposures, two were deliberate self-harm, two were therapeutic errors and the remaining 5 exposures were intentional exposures for weight-loss, body building or recreational purpose. The inclusion of caffeine powder in Schedule 6 will ensure appropriate labelling and reduce the likelihood of exposures such as these therapeutic errors and intentional misuse.
• Given the recent fatality associated with inadvertent caffeine overdose, the public submission agreed that the current availability of pure or highly-concentrated caffeine powder presents a risk of poisoning.
• The new proposed Schedule 4 entry will not result in the scheduling of caffeine that occurs naturally in foods or items covered by a Food Standard Code nor will it include stimulant preparations such as XXXXX that are labelled with a maximum recommended daily dose of no more than 600 mg of total caffeine.
• The XXXXXXXXXXXXXXXXXXXXXX has no objections to the proposed new Schedule 4 and 6 entries for caffeine.

Summary of Joint ACCS-ACMS advice/recommendations to the Delegate

The Committee recommended that caffeine be entered into Schedule 4 and Schedule 6 of the Poisons Standard as follows:

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

52E(1) Considerations	Reasons
a - the risks and benefits of the use of a substance	Risks Caffeine is toxic in high doses, not recommended for children and consumption should be limited in pregnancy. There are approximately 90 calls to NSW PIC annually for caffeine (excluding to energy drinks), with 9 relating to high-concentration caffeine powder. Benefits Small amounts of caffeine are widely available in foods and up to 600 mg per day has been safely used as a medicine. Caffeine is used in combination with analgesia ingredients and a stimulant.
b - the purposes for which a substance is to be used and the extent of use of a substance	Caffeine is widely consumed as a food ingredient, contained in work-out supplements and available in over-the-counter and prescription products as a stimulant and as an analgesic adjuvant. High concentration caffeine powders are widely available from internet-based vendors, including from within Australia.
c - the toxicity of a substance	Doses of up to 400 mg per day of caffeine are not generally considered to be associated with adverse effects. Single doses of 400-600 mg or more can have toxic effects such as vomiting, abdominal pain, and central nervous system symptoms such as agitation, altered conscious state, rigidity and seizures. There can be cardiovascular effects at high doses of caffeine. Caffeine exhibits dose dependent toxicity. Acute dose animal toxicity data is consistent with the SPF scheduling factors for Schedule 6. Human poisonings resulting in death have been reported after ingestion of single doses of, on average, 10 grams (5-20 grams).
d - the dosage, formulation, labelling, packaging and presentation of a substance	High-concentration caffeine powders can deliver a lethal dose with one teaspoon. It is difficult for a consumer to accurately measure a safe oral dose using high concentration caffeine powder. Caffeine packaged as a medicine with dose restrictions is considered sufficiently safe to remain exempt from scheduling. No evidence has been presented about any safety concerns where caffeine is included in products for external application (cosmetics or personal care products). There are currently 30 registered medicines containing caffeine on the ARTG including two Schedule 4 (Prescription Only Medicines) for treatment of apnoea in premature infants (up to 32 weeks).
e - the potential for abuse of a substance	There are currently 30 registered medicines containing caffeine on the ARTG including two Schedule 4 (Prescription Only Medicines) for treatment of apnoea in premature infants (up to 32 weeks).
f - any other matters that the Secretary considers necessary to protect public health	Amendments to the food standards in parallel with this scheduling amendment are intended to prohibit high concentration caffeine food products.

Delegate's considerations

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to caffeine;
• Joint Meeting of the Advisory Committee on Chemicals Scheduling and the Advisory Committee on Medicines Scheduling's advice;
• The public submissions made pursuant to regulation 42ZCZK by the first closing date.
• Section 52E of the Therapeutic Goods Act 1989, in particular (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018);
• Scheduling Handbook (V 1.1, July 2019);
• The new requirements for caffeine^[254] for internal use or oral use application in listed medicines as specified in the Therapeutic Goods (Permissible Ingredients) Determination (No. 4) 2019 - external site;^[255] and
• Food Standards Australia New Zealand's (FSANZ) proposed amendments to the Food Standards Code to prohibit the retail sale of pure and highly concentrated caffeine food products - external site.^[256]

Reasons for interim decision

I agree with the Joint ACMS-ACCS #23 (the Committee) findings that the relevant provisions of section 52E of the Therapeutic Goods Act 1989 are: (a) the risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use of a substance; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

In my view, the relevant parts of the SPF 2018 are the Scheduling Factors for Schedules 4, 6 and 7.

I have considered the information provided with the application and the advice of the Committee and have made the decision to include caffeine in Schedule 4 and Schedule 6 of the Poisons Standard.

Caffeine is naturally present in various plant-based foodstuffs such as tea, coffee and chocolate. Purified caffeine is also added to a range of products such as cola-type and energy drinks and pre-workout supplements. Therapeutically, caffeine is used as stimulant, an analgesic adjuvant (it augments the analgesic effects of pain relievers such as paracetamol) and is an Australian Pesticides and Veterinary Medicines Authority (APVMA) approved oral veterinary medicine. While caffeine in food and beverages and its use therapeutically is subject to regulatory oversight, pure and highly concentrated caffeine powder, which is not packaged or labelled in a way to reduce the risk of poisoning, can be purchased in Australia without restriction via web-based vendors. The inquest by the Coroner's Court of NSW into a recent fatality associated with inadvertent caffeine overdose, demonstrates that the current availability of pure and highly-concentrated caffeine powder presents a clear public health risk. Given that caffeine is so ubiquitous and is the most widely consumed psychoactive compound worldwide, it was important that I consider any unintended impacts with the proposed scheduling of this substance.

Caffeine exhibits dose dependent toxicity, with pure and highly concentrated caffeine (>98 %) having a moderate to high toxicity, which may cause death or severe injury if taken internally. Seizures can occur with doses of 1200 mg and while a lethal dose is generally considered to be between 5 and 10 g, death has been reported after a single dose of 3 g caffeine, supporting the need to limit access high-potency products. A single dose exceeding 400-600 mg has the potential to cause adverse effects such as tachycardia, palpitations, insomnia, restlessness, nervousness, tremor, headache, abdominal pain, nausea, vomiting, diarrhoea and diuresis. The acute oral LD₅₀ (rat) of 367 mg/kg bw is within the range for the SPF Scheduling Factors for Schedule 6 (i.e. 50 mg/kg - 2000 mg/kg) and potentially fatal doses (reported at 5 g) are easily exceeded with the availability of pure or highly concentrated caffeine products. While pure or highly concentrated caffeine poses a clear public health risk, it does not meet the SPF Scheduling Factors for inclusion in Schedule 7. However, I am satisfied that reasonably foreseeable harm to users from the known dangers of pure and/or highly concentrated caffeine can be sufficiently reduced via a Schedule 6 listing, requiring products to include strong label warnings (i.e. POISON) and extensive safety directions educating consumers on its potential dangers and safe use.

Caffeine is currently included within registered and listed medicines on the Australian Register of Therapeutic Goods (ARTG). The Australian Regulatory Guidelines for Over-The-Counter (OTC) Medicines (ARGOM)^[257] and the Therapeutic Goods (Permissible Ingredients) Determination^[258] specify appropriate restrictions for internal caffeine within the low risk framework of listed medicines and OTC medicines. Given the toxic effects of increasing doses of caffeine, it is my view that the weight of evidence supports the contention that internal human therapeutic use outside of these restrictions should be Prescription Only Medicines (i.e. Schedule 4). Taking into consideration the widespread dietary consumption of caffeine and caffeine containing products, there is an increased risk of inadvertent caffeine overdose associated with internal therapeutic caffeine use. Given the potential seriousness of adverse health effects, I am of the view that medical oversight is required to minimise the risk associated with caffeine's therapeutic use outside listed and OTC medicines.

While lethal consequences have been observed following inappropriate use of products containing high-concentrations of caffeine, the widespread ingestion of food products containing caffeine indicates appropriate concentration limits need to be specified so that these and other legitimate uses are not inadvertently captured by the proposed Schedule 4 and Schedule 6 entries. In determining a suitable concentration cut-off from Schedule 6, I have considered the Applicant's evidence in support of 4 per cent or less. However, the recent FSANZ review of pure and highly concentrated caffeine products^[259] has determined that products containing less than 5 per cent caffeine will not pose an unacceptably high acute risk to consumers. Also, given that the Foods Standard Code and the Poisons Standard sit side-by side and do not operate in isolation, I have decided that the proposed scheduling cut-off of 4 per cent be changed to less than 5 per cent to align with planned amendments to the Food Standard Code. Furthermore, the proposed Schedule 6 exemption for 'other preparations with a concentration of less than 5 per cent of caffeine' will mean that the single oral veterinary product (containing 6 g/L caffeine (as 12 g/L caffeine citrate)) that is currently available will not be inadvertently captured in Schedule 6 because the caffeine concentration is well below the cut-off (i.e. up to 0.6% concentration).

In light of standard doses of caffeine in food and therapeutic products, I am also satisfied that the 600 mg maximum daily dose exemptions from Schedule 4 and Schedule 6 for preparations for human internal therapeutic use are acceptable. These will continue to allow both ARTG listed and registered products to continue to be marketed without any scheduling restrictions. Although the 600 mg cut-off is higher than the dietary 400 mg recommended by FSANZ which was based on figures from the European Food Safety Authority (EFSA) from 2015[62], I am of the opinion that it is reasonable given that caffeine is being used as a medicine. Furthermore, the Australian Regulatory Guidelines for OTC Medicines (ARGOM) includes a 100 mg maximum dose and a 600 mg maximum daily dose recommendation (for adults and children over 12 years) for registered over-the-counter products. Following a safety review by the TGA, the Therapeutic Goods Amendment (Permissible Ingredients) Determination (No. 4) 2019^[260] now also specifies new requirements for caffeine, including label warning statements and limitations on caffeine concentrations in both divided and undivided medicines for caffeine and caffeine-containing ingredients within listed medicines. Together, I am satisfied that these requirements will help to ensure the safe and quality use of these medicines.

Caffeine is also widely used in cosmetics and personal care products, primarily for its hydrophilic and possible antioxidant properties. It is listed in the European Union Cosmetic Ingredients database with no restriction on concentration or type of cosmetic products in which it can be used. Given the lack of safety signals, I am satisfied that the exemption from Schedule 6 for preparations for external use will ensure no capture of cosmetic and personal care products containing caffeine. However, the scheduling will still capture high concentration caffeine before it is added to a cosmetic or personal care product, which I consider is appropriate.

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