1.3. Interim decision in relation to sanguinarine

1. Interim decisions on proposed amendments referred to the Advisory Committee on Medicines Scheduling (ACMS #27, June 2019)

Interim decision in relation to sanguinarine

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 sanguinarine as follows:

Proposed date of effect of the proposed amendment

1 February 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 | Australian regulations | International regulations | Substance summary | Summary of pre-meeting public submissions | Summary of ACMS advice/recommendations to the Delegate | Delegate's considerations | Reasons for the interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to create a Schedule 10 entry for sanguinarine 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:

• Sanguinaria canadensis (also known as 'bloodroot') is a key ingredient of black salve. Sanguinarine derived from the root of S. canadensis and is purported as a treatment for cancer, including skin cancer.
• Sanguinarine leads to the indiscriminate death of normal and cancerous cells and results in extensive tissue necrosis and the formation of a thick black scab (eschar) which eventually sloughs off, leaving an open wound.
• Multiple case studies have shown that sanguinarine is not selective for tumour cells and that extensive tissue damage can result as well as a recurrence or metastasis of skin cancer.
• Sanguinarine has the potential to cause epidemic dropsy, a severe form of oedema that results from ingesting sanguinarine.
• Sanguinarine is in two listed medicines on the ARTG as components of S. Canadensis and in six listed medicines, one complementary medicine and one export only medicine as a component of Chelidonium majus.
• There has never been a published controlled clinical trial conducted in black salve's 160-year history of clinical use.

Current scheduling status

Sanguinarine is not specifically scheduled in the current Poisons Standard and has not been previously considered for scheduling. Therefore a scheduling history is not available.

Australian regulations

Sanguinarine is currently not scheduled. However, it is an active alkaloid found in the plant species S. canadensis and C. majus.

• According to the TGA Ingredient Database, S. canadensis is available for use as an active ingredient in: export only, listed medicines, over the counter and prescription medicines. S. canadensis is also available for use in listed medicines as a homoeopathic ingredient only and as an excipient ingredient in prescription medicines. It is not available as an equivalent ingredient in any application.
• According to the TGA Ingredient Database, C. majus is available for use as an active ingredient in: export only, listed medicines, over the counter and prescription medicines. C. majus is also available for use in listed medicines as a homoeopathic ingredient only and as an excipient ingredient in prescription medicines and listed medicines. It is not available as an equivalent ingredient in any application.
• There are two (2) listed medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[9] that contain S. canadensis as an active homeopathic ingredient. These include two non-prescription medicines:
  • XXXXXXX - oral uncoated tablet, listed medicine for temporary relief of osteoarthritic pain. Contains S. canadensis (Homeopathic) - 450 micrograms; and
  • XXXXXXX - oral liquid, listed medicine for temporary relief of dry cough/nasal congestion. S. canadensis (Homeopathic) 1 microlitre/mL (1:1000 dilution therefore 0.1% concentration).
• There are six (6) listed medicines, one (1) complementary medicine and one (1) export only medicine containing C. majus on the ARTG
• The current Therapeutic Goods (Permissible Ingredients) Determination No. 2 of 2019^[10] contains S. canadensis as follows:

  Item	Ingredient name	Purpose	Specific requirements
  4398	SANGUINARIA CANADENSIS	Homoeopathic preparation ingredient (H) - an ingredient that is a constituent of a homoeopathic preparation	Only for use as an active homoeopathic ingredient. The potency must be more than 4X.

• The current Therapeutic Goods (Permissible Ingredients) Determination No. 2 of 2019^[11] contains C. majus (4387) as follows:

  Item	Ingredient name	Purpose	Specific requirements
  1305	CHELIDONIUM MAJUS	Active ingredient (A) - a medicine that has the same meaning as in the Regulations. Excipient (E) - a medicine that means an ingredient that is not an active ingredient or a homoeopathic preparation ingredient. Homoeopathic preparation ingredient (H) - an ingredient that is a constituent of a homoeopathic preparation	When for oral or sublingual use, the medicine requires the following warning statement on the medicine label: (CELAND) 'WARNING: Greater Celandine may harm the liver in some people. Use only under the supervision of a healthcare professional'.

• The Database of Adverse Event Notifications (DAEN)^[12] contains no reports of adverse events for products containing sanguinarine or the plant S. canadensis as an active ingredient in products that are listed on the ARTG. There are nine (9) reports of adverse events between 01/01/1971 - 21/02/2019 for ARTG products containing C. majus, with eight (8) as a single suspected medicine and no reported deaths.
• As at June 2012, the TGA^[13] has received four notifications of adverse events involving the use of products described as 'black salve', 'red salve' or 'cansema'. Each of these reports describes damage to the skin, subcutaneous tissue and, in one case, muscle following the application of these products. Three of the reported cases required medical intervention or follow up and in two of the cases significant scarring resulted.
• There are no products containing sanguinarine listed on the Public Chemical Registration Information System Search (PUBCRIS)^[14].
• The Medicines Advisory Statement Specification 2019 (RASML No. 5)^[15] does not include warning statements pertaining to sanguinarine to be included on the labelling.

International regulations

• The European Chemicals Agency (ECHA) has stated for sanguinarine, 'According to the majority of notifications provided by companies to ECHA in CLP notifications no hazards have been classified'.
• The United States Food and Drug Administration (U.S. FDA) has issued warnings regarding 'scams' involving black salves. In 2009 (lasted updated 27/09/2018), the U.S. FDA website posted a warning regarding how black salves are 'offered with the false promise of drawing cancer out from the skin, but they are potentially corrosive to tissues'.
• It does not appear that sanguinarine is regulated in the European regulations. However, there are two (2) regulation entries for a rhizome/root extract of the plant Sanguinaria Canadensis - CAS number 84929-48-6. The uses described in the European regulation include cleansing, refreshing, skin conditioning and tonic functions. There are no identified ingredients or substances listed for the two entries.
• In December 2013, Medsafe New Zealand published a safety alert on 'black salve' as part of the Trans-Tasman Early Warning System. In this publication, the Medsafe website states the black salves that are available in New Zealand are unregulated products.

Substance summary

Sanguinarine is a benzylisoquinoline alkaloid and isoquinoline derivative that has strong escharotic properties.

Table 1: Chemical information for sanguinarine

Property	Sanguinarine
Chemical structure
Molecular formula	C20H14NO4
Molecular weight	332.335 g/mol
CAS name	Sanguinarine
CAS number	2447-54-3
IUPAC and/or common and/or other names	IUPAC: 13-Methyl[1,3]benzodioxolo[5,6-c][1,3]dioxolo[4,5-i]phenanthridin-13-ium Other: [1,3]Benzodioxolo[5,6-c]-1,3-dioxolo[4,5-i]phenanthridinium, C20H14NO413-methyl-; Pseudochelerythrine;, sanguinarin;, sangvinarin.

Summary of pre-meeting public submissions

Nine (9) public submissions were received in response to the notice published under regulation 42ZCZK advising of the proposed amendment. Four (4) submissions were in support, three (3) that opposed and two (2) that provided general comments to the proposed amendments.

The main points in support of the proposed amendment were:

• Doctors have reported serious harms to their patients from the use of sanguinarine and consider it is a noxious and dangerous product.
• There are websites marketing black salves with claims of curing skin cancer, amongst other cancer types, which have not been scientifically tested. This presents a significant risk to self-treating patients, particularly those with low health literacy or those more vulnerable to this type of information.
• There are a number of cases documented in the literature where the use of black salve has had detrimental outcomes for patients, including:

  'The tumour appeared initially to disappear but recurred several years later requiring extensive surgery. The patient later developed metastasis (secondary growth), residual tumour found on biopsy although it appeared initially to have gone, severe scarring'.

• An article by Cliff Rosendahl titled 'Science or Snake Oil, what is black salve?' concluded:

  'In the future laboratory studies and ethical clinical trials might discover a beneficial role for blood-root products. But at present the use of black salve has no justifiable place in medical practice'.

• All exposures to sanguinarine or black salve reported to the NSW Poisons Information Centre (PIC) have resulted in significant tissue damage and required management in hospital. The NSW PIC have received four (4) calls in the past four (4) years, two (2) of these were errors where veterinary black salve was used instead of ichthammol ointment and two (2) were self-treatment alternative therapy for skin cancers
• This highly toxic substance has high risk of accidental and intentional exposures which will always result in the need for hospital management. Restricting its access will reduce both of these risks.
• Although there are a number of in vitro studies demonstrating the apoptotic and anti-proliferative effects of sanguinarine, clinical evidence for its efficiency as a treatment for skin cancer is lacking. Similarly, the risks and full side effect profile of its use in humans have not been determined.

The main points in opposition of the proposed amendment were:

• Adding sanguinarine to Schedule 10 may have the impact of automatically restricting these herbal medicines, depending upon the exact concentration of sanguinarine in finished preparations.
• S. candaensis could be limited by its route of administration and/or dosage form to restrict topical use. This can be implemented at the time of listing or application for registration.
• May unintentionally and needlessly restrict other herbal medicines currently available in Australia.
• Chelidonium majus is an approved herbal ingredient in Australia for use in listed and registered medicines (seven separate complementary medicines). This herbal ingredient is known to contain a range of benzylisoquinoline alkaloids including chelidonine, chelerythrine, coptisine, berberine, stylopine, sanguinarine and others at a total quantity of between 0.1-1% in the dried aerial parts. It is theoretically possible for the sanguinarine content in a preparation containing C. majus to exceed the proposed limit of 0.1%.
• Chelidonium majus is an ingredient of a registered medicine on the ARTG, specifically XXXXXXX (XXXXXXX). The efficacy and safety of XXXXXXX have been proven in extensive preclinical studies (including long-term studies), randomized double-blind clinical studies, non-interventional studies, cohort studies and surveys of more than 50,000 patients and in the treatment of more than 80 million people since the product was launched.
• Despite the presence of sanguinarine, there is no evidence of Chelidonium majus being used in the production of black salve and no suggestion that it might be.
• Eschscholzia californica (also an approved herbal ingredient in Australia) contains between 0.5-1.2% total alkaloids including eschscholtzine, eschscholtzidine, californidine, norargemonine, bisnorargemonine, laurotetamine, protopine, chelidonine, chelerythrine, and sanguinarine (amongst others). The European Medicines Agency (EMA) states that 'no major safety concerns can be derived in relation to the use of E. californica in the recommended posology and conditions of use'.
• A search of the ARTG database shows that Eschscholzia californica is found in an additional 13 products, and Chelidonium majus in another 7 products. This is not including herbal liquid extracts and dry herbal material for extemporaneous dispensing by herbalists and naturopaths.
• S. canadensis (but not the isolated sanguinarine) is included as an ingredient in two products (ARTG numbers XXXXXX and XXXXXX). However, both products are homeopathic oral preparations and are not recommended for topical use in the treatment of skin cancers.
• Such consultation should consider how to effectively limit this inappropriate usage but simultaneously avoid unnecessary restriction of other safe and valuable herbal medicines containing sanguinarine.
• The upper content limit of sanguinarine of 0.1% would render S. canadensis and potentially other herbs such as Chelidonium majus, a completely restricted substance, irrespective of plant part, route of administration and professional use.
• S. Canadensis is available and supplied as a liquid extract for extemporaneous compounding. These are not required to be listed, but are required to be manufactured under good manufacturing practice (GMP) conditions.
• Like many plant constituents, there is significant natural variability and sanguinarine content is dependent on harvesting time, ranging between 2.81-3.96% in the dried rhizome.
• The TGA should pursue those companies and individuals manufacturing, supplying and importing medicines into Australia that are not registered on the ARTG. There are sufficient provisions that allow for this under section 19B of the Therapeutic Goods Act 1989.
• The TGA should review a series of products marketed and sold as black salve, analysing the actual composition of these preparations. Once this is known, a sense of the risk posed by these products will be easier to calculate, and targeted and appropriate regulatory action can be taken.
• Use the Permissible Ingredient Determination to mandate any label warning statements for products containing S. canadensis that the Committee finds appropriate.
• A raw material which contained sanguinarine above the Schedule 10 cut-off could not be imported, could not be sold to a finished product manufacturer and could not be used in the (legitimate) manufacture of therapeutic goods.
• Should the ACMS find the scheduling of sanguinarine necessary, it is recommended that preparations containing less than 2% of sanguinarine only be appropriate by prescription and otherwise available for use in herbal medicine preparations.

General comments to the proposed amendment were:

• There are concerns about the potential unintended impacts that the proposal may have on existing therapeutic goods and their ingredients. Feedback received indicates that the current finished products included on the ARTG are unlikely to be impacted by the proposed Schedule 10 entry for sanguinarine. However, there are concerns regarding the raw materials used to produce these products, or in relation to other herbal species.
• A raw material that contained sanguinarine above the Schedule 10 cut-off could not be imported, could not be sold to a finished product manufacturer and could not be used in the (legitimate) manufacture of therapeutic goods.
• The content of alkaloids in the chelidonium extract used is monitored regularly and the average is well under the proposed limit of 0.1% for the Schedule 10 entry.

Summary of ACMS advice/recommendations to the Delegate

The Committee recommended that a new Schedule 10 entry for sanguinarine be created as follows:

The Committee also recommended an implementation date as soon as practicable.

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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice included:

1. risks and benefits of the use of a substance:
   • Purported benefits of black salve containing Sanguinaria canadensis (bloodroot) in the management serious conditions including skin cancer have not been substantiated.
   • Evidence that application of black salve containing bloodroot can lead to serious damage to the skin requiring medical treatment.
   • Evidence that attempted management of skin cancer with black salve containing bloodroot can lead to a delay in patients seeking proven management.
   • Sanguinarine is 50% of the benzophenanthridine alkaloid content in Sanguinaria canadensis. While sanguinarine is present in other herbal ingredients its percentage of all benzophenanthridine alkaloid content is much lower.
   • There is evidence that Sanguinaria canadensis in combination with zinc chloride has can have harmful effects in that its use can lead to indiscriminate death of normal and cancerous cells and may not eradicate tumour cells and therefore lead to recurrence and metastasis.
2. the purpose for which a substance is to be used and the extent of use:
   • Black salve containing sanguinarine is promoted for the management of skin cancer. Whilst use appears to be limited its characteristics as a natural product are likely to appeal to sections of the community.
   • Sanguinarine is an alkaloid contained in many herbal products and the up scheduling request relates to one herbal product (Sanguinaria canadensis) when combined with another product (zinc chloride). The use of this combination is evident when considering information from the internet and from adverse event reports.
3. the toxicity of a substance:
   • Potential to cause significant damage to the skin including hypertrophic and keloid scarring (possibly requiring scar revision surgery), granulomatous plaque formation (possibly requiring topical steroid treatment) and abnormal pigmentation changes (that may require biopsy).
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • Bloodroot is formulated as a paste/ointment when used topically for skin cancer.
   • Oral forms available.
5. the potential for abuse of a substance:
   • Nil.
6. any other matters that the Secretary considers necessary to protect public health:
   • Nil.

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 sanguinarine;
• Advisory Committee on Medicines Scheduling's advice;
• The public submissions received before the first closing date;
• Section 52E of the Therapeutic Goods Act 1989, in particular: (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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• The Australian Health Ministers' Advisory Council's Scheduling Handbook (V 1.0, January 2018).

Reasons for the interim decision

I agree with the Committee's finding that the relevant matters of section 52E of the Therapeutic Goods Act 1989 are: (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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the scheduling factors for Schedule 10.

I have made the decision to amend the current Poisons Standard by creating a new Schedule 10 entry for sanguinarine and I have set out my reasons below.

Having considered the SPF 2018, it is my view that sanguinarine meets the Schedule 10 scheduling factors. In making a recommendation for a Schedule 10 entry, I have taken into account the potential for sanguinarine to cause significant harm to members of the public who are seeking to use a product that they believe to be natural and therefore safe. I consider the critical risk to public health to be the escharotic properties of black salve containing sanguinarine, particularly when used for self-treatment of skin cancers. This can lead to a delay in patients seeking proven management. In assessing these risks, I have considered that there is a lack of evidence to support the use of black salve in the treatment of skin cancers, together with documented adverse events including severe scarring, tumour recurrence and metastasis.

In my deliberations, I considered that sanguinarine itself may not pose significant risk and that there is a lack of toxicity data to support this. I took into account the arguments made in the public submissions in opposition to the scheduling of sanguinarine including, but not limited to, the impact the scheduling decision may have on herbal products. In particular, the concern that the specific scheduling of sanguinarine may inadvertently capture other plant species that contain this substance. In considering these factors and the advice obtained from the Committee, it is my view that the best way to mitigate these concerns is to limit the sanguinarine content in Sanguinaria canadensis to 0.01 per cent so it is in line with the permitted ingredient determination for homeopathic use, thereby not impacting other ingredients that may contain sanguinarine. I consider that the new scheduling entry for Sanguinaria canadensis will allow for the continued use of this plant in homeopathic products, whilst simultaneously prohibiting its use in black salve preparations.

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