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Outcomes: Changes to permissible ingredients - Low-negligible risk

2 December 2019

Background

On 30 August 2019, the TGA sought comments on proposed changes to the permissible ingredients 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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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.

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. Sponsors will be provided a 12-month transition period from this time to bring existing listed medicines into compliance.

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 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, the following warning statement is required on the label:

  • (NOTUND12) 'Not to be taken by children under 12 years old' (or words to that effect); or
  • (ADULT) 'Adults only' (or words to that effect).

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:

  • (NOTUND2) 'Not to be taken by children under 2 years old' (or words to that effect); or
  • (ADULT) 'Adults only' (or words to that effect).

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:

  • (BORON) 'Contains boron' (or words to that effect).

When the medicine is for topical use for dermal application, the following warning statement is required on the label:

  • (BROKEN) 'Use on unbroken skin only' (or words to that effect).
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, the following warning statement is required on the label:

  • (NOTUND12) 'Not to be taken by children under 12 years old' (or words to that effect); or
  • (ADULT) 'Adults only' (or words to that effect).

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:

  • (NOTUND2) 'Not to be taken by children under 2 years old' (or words to that effect); or
  • (ADULT) 'Adults only' (or words to that effect).

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:

  • (BORON) 'Contains boron' (or words to that effect).

When the medicine is for topical use for dermal application, the following warning statement is required on the label:

  • (BROKEN) 'Use on unbroken skin only' (or words to that effect).
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, the following warning statement is required on the label:

  • (NOTUND12) 'Not to be taken by children under 12 years old' (or words to that effect); or
  • (ADULT) 'Adults only' (or words to that effect).

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:

  • (NOTUND2) 'Not to be taken by children under 2 years old' (or words to that effect); or
  • (ADULT) 'Adults only' (or words to that effect).

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 label of the medicine, the following warning statement is required on the label:

  • (BORON) 'Contains boron' (or words to that effect).

When the medicine is for topical use for dermal application, the following warning statement is required on the label:

  • (BROKEN) 'Use on unbroken skin only' (or words to that effect).
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 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 medicine label:

  • (SODIUM) 'The recommended daily dose of this medicine contains [state quantity and units] of sodium (or words to that effect).'

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, the following warning statement is required on the label:

  • (NOTUND12) 'Not to be taken by children under 12 years old' (or words to that effect); or
  • (ADULT) 'Adults only' (or words to that effect).

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:

  • (NOTUND2) 'Not to be taken by children under 2 years old' (or words to that effect); or
  • (ADULT) 'Adults only' (or words to that effect).

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:

  • (BORON) 'Contains boron' (or words to that effect).

When the medicine is for topical use for dermal application, the following warning statement is required on the label:

  • (BROKEN) 'Use on unbroken skin only' (or words to that effect).

References

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 to only apply to listed medicines which contain Withania somnifera when:

  • the plant part used is not limited to root; or
  • any extraction solvents are not alcoholic or aqueous; or
  • the maximum recommended daily dose is more than 1,200 mg.

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.

Ingredient name Purpose Specific requirements
WITHANIA SOMNIFERA A, E, H

When the maximum recommended daily dose of the medicine contains more than 1200 mg of Withania somnifera; or the plant part is other than root; or any extraction solvents used are not water, ethanol or methanol; the medicine requires the following warning statement on the label:

'If you are pregnant, or considering becoming pregnant, do not take without consulting a health professional' (or words to that effect).

References

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:

  • (VAC) 'Vitex agnus-castus may affect hormones and medicines such as oral contraceptives. Consult your health professional before use' (or words to that effect).

References

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

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:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
ISPAGHULA HUSK POWDER

When a dose for children is stated, the medicine requires the following warning statement on the medicine label:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
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:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
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:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
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:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
PLANTAGO LANCEOLATA

The medicine requires the following warning statement on the medicine label:

  • (CHILD5) 'Use in children under 3 years is not recommended'

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:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
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:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
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:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
PLANTAGO SEED DRY

When a dose for children is stated, the medicine requires the following warning statement on the medicine label:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
PSYLLIUM HUSK DRY

When a dose for children is stated, the medicine requires the following warning statement on the medicine label:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
PSYLLIUM HUSK POWDER

When a dose for children is stated, the medicine requires the following warning statement on the medicine label:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
PSYLLIUM SEED DRY

When a dose for children is stated, the medicine requires the following warning statement on the medicine label:

  • (PSYLL) 'Should only be used for children on medical advice' (or words to that effect).
CYMBOPOGON FLEXUOSUS

When for topical use:

  • Aldehydes calculated as citral is a mandatory component of Cymbopogon flexuosus;
  • the concentration of Aldehydes calculated as citral in the medicine must not be more than 5%.
CYMBOPOGON MARTINI

When for topical use:

  • Aldehydes calculated as citral is a mandatory component of Cymbopogon martini;
  • the concentration of Aldehydes calculated as citral in the medicine must not be more than 5%.
CYMBOPOGON NARDUS

When for topical use:

  • Aldehydes calculated as citral is a mandatory component of Cymbopogon nardus;
  • the concentration of Aldehydes calculated as citral in the medicine must not be more than 5%.
CYMBOPOGON SCHOENANTHUS

When for topical use:

  • Aldehydes calculated as citral is a mandatory component of Cymbopogon schoenanthus
  • the concentration of Aldehydes calculated as citral in the medicine must not be more than 5%.
MALUS PUMILA

Ingredient to be removed from the Determination.