Background
On 30 August 2019, the TGA sought comments on proposed changes to the permissible ingredients Boron, Withania somnifera, Vitex agnus-castus (VAC), Hydroxyisohexyl-3-cyclohexene carboxaldehyde ('HICC') as well as a number of permissible ingredients relating to Ispaghula, Plantago, Psyllium, Cymbopogon and Malus species.
Public consultation
A total of 4 consultation submissions were received in response from:
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- Accord Australasia ('Accord') (pdf,85kb)
- Complementary Medicines Australia ('CMA') (pdf,501kb)*
- Consumer Healthcare Products Australia ('CHP Australia') (pdf,150kb)
- Naturopaths and Herbalists Association of Australia ('NHAA') (pdf,206kb)
Outcome of the public consultation
The TGA thanks all respondents for their comments in response to the consultation.
All comments received for this consultation have now been considered and the proposals have been revised below. These changes will commence on 2 March 2020 (see schedule for low-negligible risk changes for 2019-2020).
General comments that were not directly related to the ingredient specific issues put forward in the consultation are noted.
Boron
Based on findings reported by the European Medicines Agency[1] ('EMA'), the following new warning statements for products containing boron were proposed in the consultation:
- Do not give to a child less than 12 years old as this medicine contains boron and may impair fertility in the future.
- Do not give to a child less than 2 years old as this medicine contains boron and may impair fertility in the future.
- For external use on unbroken skin only.
Summary of consultation received
Submissions received for Boron did not oppose the introduction of additional warning statements in principle. Respondents generally expressed concern regarding the length of the proposed warning statements and that they may cause undue distress for consumers. Respondents also highlighted that the proposed warning statements may not be appropriate for medicines intended only for adults and the risk of boron exposure to children from listed medicines is low.
TGA response
Listed medicines are only permitted to contain unscheduled low-risk ingredients, usually with a long history of safe use. These ingredients are assessed by the TGA for safety and quality. The TGA may require amongst other things, warning statements, or restrictions to dosage or population, to ensure listed medicines remain safe for consumers and only contain low-risk ingredients. The TGA notes the concerns regarding the proposals and has revised the length and wording of the warning statements to ensure boron remains available for use as a low risk ingredient in listed medicines.
The words 'as this medicine contains boron' have been removed where boron or boron containing compounds are already required to be stated on the label as an active ingredient. However, where boron is not identifiable on the label (such as when used as an excipient), an additional warning statement has been included for these situations to alert consumers to the presence of boron at amounts greater than 1 mg per maximum recommended daily dose.
The TGA notes that some boron-containing medicines may only be indicated for use by adults only and warning statements relating to children may not be necessary. As such, the warning 'Adults only' is now available as an option. This measure will ensure medicines containing boron remain low-risk, are used in an appropriate population, and allows sponsors more flexibility to label medicines in line with their intended use. The statement 'or words to the effect' has also been added to allow sponsors flexibility to include a statement with the same intent and meaning on product labels.
Final decisions to amend the Permissible Ingredients - March 2020
The following ingredients will be amended within the Permissible Ingredients Determination commencing on 2 March 2020, in line with the table below. Sponsors will be provided a 12-month transition period from this time to bring existing listed medicines into compliance.
Following a request for clarification from industry stakeholders, the requirements for boron below have been amended to specify that medicines with a maximum recommended daily dose, which provide up to and including 3mg of boron, will also be required to include the additional warning statements.
| Ingredient name | Purpose | Specific requirements |
|---|---|---|
| BORAX | A, E, H | Boron is a mandatory component of borax. The percentage of boron from borax should be calculated based on the molecular weight of borax. The maximum recommended daily dose must not provide more than 6mg of boron. In preparations for dermal use, which are not for paediatric or antifungal use, the concentration of boron in the medicine must be no more than 3500 mg/kg or 3500 mg/L or 0.35%. When the maximum recommended daily dose of the medicine provides more than 3 mg of boron and the medicine is for internal use and/or oral application, one of the following warning statements is required on the label:
When the maximum recommended daily dose of the medicine provides more than 1 mg boron and up to, and including, 3 mg of boron, and the medicine is for internal use and/or oral application, one of the following warning statements is required on the label:
When for excipient use and the maximum recommended daily dose of the medicine provides more than 1 mg of boron and the medicine is for internal use and/or oral application, the following warning statement is required on the label:
When the medicine is for topical use for dermal application, the following warning statement is required on the label:
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| BORAX PENTAHYDRATE | A, E | Boron is a mandatory component of borax pentahydrate. The percentage of boron from borax pentahydrate should be calculated based on the molecular weight of borax pentahydrate. The maximum recommended daily dose must provide no more than 6mg of boron from borax pentahydrate. In preparations for dermal use, which are not for paediatric or antifungal use, the concentration of boron in the medicine must be no more than 3500 mg/kg or 3500 g/L or 0.35%. When the maximum recommended daily dose of the medicine provides more than 3 mg of boron and the medicine is for internal use and/or oral application, one of the following warning statement is required on the label:
When the maximum recommended daily dose of the medicine provides more than 1 mg boron and up to, and including, 3 mg of boron, and the medicine is for internal use and/or oral application, one of the following warning statements is required on the label:
When used as an excipient and the maximum recommended daily dose of the medicine provides more than 1 mg and the medicine is for internal use and/or oral application, the following warning statement is required on the label:
When the medicine is for topical use for dermal application, the following warning statement is required on the label:
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| BORIC ACID | A, H | Boron is a mandatory component of boric acid. The percentage of boron from boric acid should be calculated based on the molecular weight of boric acid. The maximum recommended daily dose must provide no more than 6mg of boron. In preparations for dermal use, which are not for paediatric or antifungal use, the concentration of boron in the medicine must be no more than 3500 mg/kg or 3500 mg/L or 0.35%. When the maximum recommended daily dose of the medicine provides more than 3 mg of boron and the medicine is for internal use and/or oral application, one of the following warning statement is required on the label:
When the maximum recommended daily dose of the medicine provides more than 1 mg of boron but less than 3 mg of boron and the medicine is for internal use and/or oral application, the following warning statement is required on the label:
When the maximum recommended daily dose of the medicine provides more than 1 mg of boron and the medicine is for internal use and/or oral application, the following warning statement is required on the label:
When the medicine is for topical use for dermal application, the following warning statement is required on the label:
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| SODIUM PERBORATE | A, H | Boron is a mandatory component of sodium perborate. When for internal use, the maximum recommended daily dose must not provide more than 6 mg of boron. When used in preparations for dermal use, which are not for paediatric or antifungal use, the concentration of boron from all ingredients in the product must not exceed 3500 mg/kg or 3500 mg/L or 0.35%. When for oral or sublingual use and the total amount of sodium from all ingredients in the maximum daily dose is more than 120 mg, the medicine requires the following warning statement on the label:
When the maximum recommended daily dose of the medicine provides more than 3 mg of boron and the medicine is for internal use and/or oral application, one of the following warning statement is required on the label:
When the maximum recommended daily dose of the medicine provides more than 1 mg boron and up to, and including, 3 mg of boron, and the medicine is for internal use and/or oral application, one of the following warning statements is required on the label:
When the maximum recommended daily dose of the medicine provides more than 1 mg of boron and the medicine is for internal use and/or oral application, the following warning statement is required on the label:
When the medicine is for topical use for dermal application, the following warning statement is required on the label:
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References
| [1] | European Medicines Agency (2017) Questions and answers on boric acid and borates used as excipients in medicinal products for human use, EMA/CHMP/619104/2013, Retrieved from https://www.ema.europa.eu/en/boric-acid-borates |
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Withania somnifera
Based on international monographs and evidence of traditional use of Withania somnifera to induce abortion[1-2] a cautionary warning statement was proposed in the consultation to advise consumers to consult a health professional prior to taking Withania somnifera if they are pregnant or breastfeeding.
Summary of consultation received
There were differences of opinion regarding the inclusion of a warning statement for Withania somnifera. Respondents proposed adding 'or words to that effect' and reducing the length of the warning statement. Others noted that Withania somnifera exhibits adverse events at high doses and provided additional toxicological data[3] for consideration. Respondents requested revising the term 'prior to' to avoid causing unwarranted distress if a woman becomes unexpectedly pregnant. Respondents also noted that the ingredient has been used by herbalists for women for a long time and that there is a lack of reported adverse events concerning women and babies during lactation.
TGA response
The TGA has considered the additional information provided and amended the warning statement. The warning statement will apply to listed medicines containing Withania somnifera, unless:
- the plant part used is root;
- the plant preparation is an extract;
- extraction solvents are only water, ethanol or methanol; and
- the maximum recommended daily dose contains no more than the equivalent of 12 g dry root.
These exceptions are in-line with the reproductive and developmental toxicology study on rats by Prabu and Panchapakesan[3]. This study did not observe effects when Withania somnifera was extracted from the root using a hydroalcoholic solvent, and when administered to rats up to 2000 mg/kg bodyweight/day. The maximum daily dose specified in this study has been adapted to consider appropriate use for human populations, assuming a bodyweight of 60kg, in accordance with international OECD guidelines[4].
The warning statement has also been revised to only relate to pregnancy as there is a lack of information relating to established safety risks during lactation. The warning statement wording now aligns with similar existing pregnancy warning statements for other permissible ingredients. The statement 'or words to the effect' has also been added to allow sponsors more flexibility to include the warning statement with the same intent and meaning on product labels.
The responses highlight that products containing Withania somnifera are recommended for use during pregnancy and breastfeeding by herbal practitioners. Sponsors of medicines are reminded of their responsibilities to collect, record and follow-up on all reports of exposure during pregnancy and breastfeeding. Any abnormal pregnancy outcome or serious adverse reaction in the mother or child must be reported to the TGA within 15 calendar days, in accordance with the Pharmacovigilance Responsibilities of Medicine Sponsors.
Outcome
Withania somnifera will be amended as specified in the table below within the Permissible Ingredients Determination commencing on 2 March 2020. Sponsors will be provided a 12-month transition period from this time to bring existing listed medicines into compliance.
Following a request for clarification by industry stakeholders, the requirements for Withania somnifera below have been amended to better align with the parameters specified in the study by Prabu & Panchapakesan[3] by stating the equivalent quantity of dry root, rather than the mass of the extract used in the study.
| Ingredient name | Purpose | Specific requirements |
|---|---|---|
| WITHANIA SOMNIFERA | A, E, H | The medicine requires the following warning statement on the label: - (WITHANIA) 'If you are pregnant, or considering becoming pregnant, do not take without consulting a health professional' (or words to that effect) unless:
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References
| [1] | Health Canada (2019) Monograph: Ashwagandha, Retrieved from http://webprod.hc-sc.gc.ca/nhpid-bdipsn/monoReq.do?id=35 |
|---|---|
| [2] | World Health Organization (2009) WHO Monographs on Selected Medicinal Plants - Volume 4 (pp. 388), Retrieved from https://apps.who.int/medicinedocs/en/m/abstract/Js16713e/ |
| [3] | P. C. Prabu & S. Panchapakesan (2015) Prenatal developmental toxicity evaluation of Withania somnifera root extract in Wistar rats, Drug and Chemical Toxicology, 38:1, 50-56, DOI: 10.3109/01480545.2014.900073 |
| [4] | OECD (2014) Guidance Document 116 on the Conduct and Design of Chronic Toxicity and Carcinogenicity Studies, Supporting Test Guidelines 451, 452 and 453: Second edition, OECD Series on Testing and Assessment, doi: 10.1787/9789264221475-en |
Vitex agnus-castus
Following a recent TGA safety alert and in-line with international monographs[1-4], a new warning statement was proposed in the consultation for medicines containing Vitex agnus-castus (VAC), advising consumers of the potential interaction with medicines such as the oral contraceptive pill (OCP).
Stakeholder comment
Respondents requested that the TGA consider reducing the length of the warning statement and to add 'or words to that effect'. One respondent expressed concern that the warning statement appears to be based on limited and theoretical supporting evidence. The respondent also provided a systematic review of VAC related adverse events[5] and highlighted that it did not find any reports of unplanned pregnancies or interactions with OCP.
TGA response
The TGA notes that VAC is traditionally used for its effects on hormones. Despite the absence of a definitive mechanism of action there is scientific evidence[5] to suggest VAC competitively binds to oestrogen receptors which may affect the way hormone-related medicines work.
The systematic review[6] provided to the TGA also states that the action of VAC on the pituitary gland could interfere with endocrine therapy such as oral contraceptives. This reference was published in 2005 and does not include the most recent adverse event data. Recently, the TGA has received one report of an unintended pregnancy following concurrent use of VAC and a progesterone-only oral contraceptive pill. One other similar case has also been reported internationally.
The TGA is unable to establish that VAC will not affect hormone-related medicines and a cautionary approach is warranted considering there is common use of prescription hormone related medications such as the OCP and evidence to suggest a plausible interaction. International regulators consider similar evidence sufficient to warrant a caution for VAC and concurrent hormone-medication use. As such, a warning statement to advise consumers to exercise caution and make health professionals aware of the potential interaction is warranted to ensure listed medicines only contain low-risk ingredients.
The statement 'or words to the effect' has also been added to allow sponsors more flexibility to include the warning statement with the same intent and meaning on product labels. The length of the warning statement has also been reduced to be more succinct.
Outcome
Vitex agnus-castus will be amended as specified in the table below within the Permissible Ingredients Determination commencing on 2 March 2020. Sponsors will be provided a 12-month transition period from this time to bring existing listed medicines into compliance.
| Ingredient name | Purpose | Specific requirements |
|---|---|---|
| VITEX AGNUS-CASTUS | A, E, H | When for internal use, the medicine requires the following warning statement on the label:
|
References
| [1] | Health Canada (2018) Chaste tree - Vitex agnus-castus, Retrieved from http://webprod.hc-sc.gc.ca/nhpid-bdipsn/atReq.do?atid=chaste.tree.vitex&lang=eng |
|---|---|
| [2] | European Medicines Agency (2018) European Union herbal monograph on Vitex agnus-castus L. fructus, EMA/HMPC/606742/2017, Retrieved from https://www.ema.europa.eu/en/documents/herbal-monograph/final-european-union-herbal-monograph-vitex-agnus-castus-l-fructus-revision-1_en.pdf (pdf,146kb) |
| [3] | World Health Organization (2009) WHO Monographs on Selected Medicinal Plants - Volume 4 (pp. 24), Retrieved from https://apps.who.int/medicinedocs/en/m/abstract/Js16713e |
| [4] | National Center for Complementary and Integrative Health (2016) Chasteberry, Retrieved from https://nccih.nih.gov/health/chasteberry |
| [5] | Liu, J., Burdette, J. E., Xu, H., Gu, C., van Breemen, R. B., Bhat, K. P. L., Booth, N., Constantinou, A. I., Pezzuto, J. M., Fong, H. H. S., Farnsworth, N. R., Bolton, J. L. (2001) Evaluation of Estrogenic Activity of Plant Extracts for the Potential Treatment of Menopausal Symptoms, Journal of Agricultural and Food Chemistry, 49:5, 2472-2479, doi: 10.1021/jf0014157 |
| [6] | Daniele, C., Coon, J.T., Pittler, M.H., Ernst, E. (2005) Vitex agnus castus: A Systematic Review of Adverse Events, Drug Safety, 28:4, 319-332, doi: 10.2165/00002018-200528040-00004 |
Hydroxyisohexyl-3-cyclohexene carboxaldehyde ('HICC')
Based on skin sensitisation and contact allergy concerns established by the National Industrial Chemicals Notification and Assessment Scheme[1] and the Scientific Committee on Consumer Safety[2], the consultation proposed removal of HICC from the Therapeutic Goods (Permissible Ingredients) Determination ('the Determination').
Stakeholder comment
Respondents were supportive of the removal of HICC from the Determination. One respondent suggested the transition period should be extended to 24-months.
TGA response
Due to the safety concerns associated with the use of HICC, further delay in the removal of this ingredient from listed medicines is not appropriate. All low-negligible risk changes afford sponsors with a standard 12 months transition period to bring their medicines into compliance, including a 3 months prior notification of any changes.
Outcome
HICC will be removed from the Determination commencing on 2 March 2020. New products which contain HICC will not be available for listing in the Register. Sponsors of existing listed medicines will have until the end of the 12 month transition period to remove the ingredient from their medicines.
References
| [1] | National Industrial Chemicals Notification and Assessment Scheme (2018) HICC: Human health tier II assessment, IMAP Group Assessment Report, Retrieved from https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-group-assessment-report?assessment_id=13315 |
|---|---|
| [2] | Scientific Committee on Consumer Safety (2011) Opinion on Hydroxyisohexyl 3-cyclohexene carboxaldehyde (HICC) (SCCS/1456/11) Retrieved from https://ec.europa.eu/health/scientific_committees/consumer_safety/sccs_09-13/opinions_en |
Minor changes
The consultation proposed minor changes to clarify the existing requirements of permissible ingredients relating to Ispaghula, Plantago, Psyllium, Cymbopogon and Malus species.
Stakeholder comment
Feedback was provided by one respondent and was generally supportive of the proposed amendments. This respondent noted that the proposal regarding the PSYLL warning statement may unnecessarily impact use of Plantago species, and suggested that the specific requirements capture the intended usage and product type. With respect to Cymbopogon species, the respondent suggested limiting the requirements to topical administrations. The respondent suggested that the ingredient database should be updated to reflect Malus pumila as a synonym of Malus domestica.
TGA response
The TGA acknowledges the feedback provided and has made amendments to the proposals.
The TGA notes that the Therapeutic Goods (Permissible Ingredients) Determination (No. 2) 2019 specifies that the PSYLL statement for Plantago species is only required when the plant part is flower, seed or pollen. These requirements were inadvertently omitted from the proposed changes and will not be removed. To address the feedback, only the text of the PSYLL warning statement will be amended (from "On medical advice" to "Should only be used for children on medical advice").
As the current requirements for Cymbopogon species are only specified for topical use, the TGA will specify that the mandatory component requirement will only be specified for topical use.
As requested, the TGA entry for Malus domestica (pdf,41kb) has been amended to include Malus pumila as a synonym.
Outcome
The following ingredients will be amended as specified in the table below within the Permissible Ingredients Determination commencing on 2 March 2020. Sponsors will be provided a 12-month transition period from this time to bring existing listed medicines into compliance.
| Ingredient name | Specific requirements |
|---|---|
| ISPAGHULA HUSK DRY | When a dose for children is stated, the medicine requires the following warning statement on the medicine label:
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| ISPAGHULA HUSK POWDER | When a dose for children is stated, the medicine requires the following warning statement on the medicine label:
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| PLANTAGO AFRA | When a dose for children is stated and the plant part is flower, seed or pollen, the medicine requires the following warning statement on the medicine label:
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| PLANTAGO ARENARIA | When a dose for children is stated and the plant part is flower, seed or pollen, the medicine requires the following warning statement on the medicine label:
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| PLANTAGO ASIATICA | When a dose for children is stated and the plant part is flower, seed or pollen, the medicine requires the following warning statement on the medicine label:
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| PLANTAGO LANCEOLATA | The medicine requires the following warning statement on the medicine label:
When a dose for children is stated and the plant part is flower, seed or pollen, the medicine requires the following warning statement on the medicine label:
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| PLANTAGO MAJOR | When a dose for children is stated and the plant part is flower, seed or pollen, the medicine requires the following warning statement on the medicine label:
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| PLANTAGO OVATA | When a dose for children is stated and the plant part is flower, seed or pollen, the medicine requires the following warning statement on the medicine label:
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| PLANTAGO SEED DRY | When a dose for children is stated, the medicine requires the following warning statement on the medicine label:
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| PSYLLIUM HUSK DRY | When a dose for children is stated, the medicine requires the following warning statement on the medicine label:
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| PSYLLIUM HUSK POWDER | When a dose for children is stated, the medicine requires the following warning statement on the medicine label:
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| PSYLLIUM SEED DRY | When a dose for children is stated, the medicine requires the following warning statement on the medicine label:
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| CYMBOPOGON FLEXUOSUS | When for topical use:
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| CYMBOPOGON MARTINI | When for topical use:
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| CYMBOPOGON NARDUS | When for topical use:
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| CYMBOPOGON SCHOENANTHUS | When for topical use:
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| MALUS PUMILA | Ingredient to be removed from the Determination. |