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Outcomes: Low-negligible risk changes to Permissible Ingredients - 2020-2021

16 September 2021

Background

On 25 August 2020, the TGA published a consultation on low-negligible risk changes to permissible ingredients for 2020-21 regarding:

  • Easily-dissociable magnesium salts and laxative effects
  • Andrographis paniculata and taste disturbance

Public consultation

A total of 5 consultation submissions were received in response. All submissions that gave permission to be published on the TGA website are now available below in PDF format.

A further submission from an industry sponsor was received with claims of confidentiality or privacy that prevent the publication of the submissions and the identities of those individuals providing submissions.

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 1 March 2021 (see schedule for low-negligible risk changes for 2020-2021).

General comments that were not directly related to the ingredient specific issues put forward in the consultation are noted.

In consideration of assessments of magnesium salts by the National Health and Medical Research Council[1] (NHMRC), the Institute of Medicine (US) Standing Committee[2], the European Food Safety Authority[3], and the Norwegian Scientific Committee for Food Safety (VKM)[4], the TGA proposed that listed medicines not indicated as laxatives containing easily-dissociable magnesium salts carry warning statements alerting consumers to the risk of diarrhoea.

Summary of consultation submissions

Two submissions either agreed or did not oppose the proposals, with one suggesting minor wording amendments.

Three submissions suggested that the proposed recommended daily dose requirement for individuals over the age of 9 should be aligned with the upper limit from the NHMRC[5].

One submission suggested that requiring warning statements below the Recommended Dietary Intake (RDI) specified by the NHMRC was excessively restrictive.

Two submissions suggested that this warning statement should be applied to inorganic magnesium salts only, in lieu of the proposal for easily-dissociable magnesium salts, as the bioavailability (and therefore the risk of diarrhoea) of inorganic magnesium salts is less than that of organic magnesium salts.

One submission suggested the warning statement regarding the risk of laxative effect be shortened by removing the words 'this product', as the risk of diarrhoea should refer to magnesium (rather than the product). The submission suggested this would improve consumer understanding and would be aligned with similar warning statements (e.g. sugar alcohols in the Therapeutic Goods Order No. 92).

Two submissions considered that TGA's proposal to address the risk of diarrhoea to infants under 12 months is not appropriate. One submission suggested that that listed medicines for magnesium supplementation will not be used in this age group other than part of infant formula (food) and proposed, instead of a warning statement, a requirement that sponsors do not include directions for use for infants under 12 months. It was suggested that almost all, if not all, magnesium supplements would already be in compliance with this. Another submission suggested that magnesium supplementation in this age group is appropriate based on NHMRC comments which has recommended intake levels; and a warning statement may signal to consumers that magnesium is harmful. A third submission suggested that when a medicine is not intended for use in children, that the warning statement 'Adults only' should be specified as an alternative.

TGA response

In consideration of the response regarding the maximum dose for adults and children over 9 years of age, the TGA reviewed the available studies discussed by the VKM[6]. The TGA notes that the incidence of diarrhoea was infrequent at doses of 365 mg per day or less, and the severity of diarrhoea at these doses were mild, and reversible within a short time. As such, the risk of diarrhoea from doses of magnesium between 250 mg and 350 mg is lower than for higher doses. The proposed changes will be amended to reflect that the warning statement will be required on medicine labels when a medicine delivers 350 mg or more elemental magnesium per day for adults and children aged 9 years and over.

Consultation feedback provided evidence suggesting that the risk of diarrhoea may be more accurately associated with inorganic magnesium salts, rather than easily-dissociable magnesium salts. Due to the increased bioavailability of the organic magnesium salts, the risk of diarrhoea appears to be less than that for inorganic magnesium salts. The proposed changes have been amended to apply specifically to inorganic magnesium salts.

The NHMRC considered that magnesium is widely distributed in the food supply, and that diarrhoea has been observed from magnesium containing medicinal products at doses lower than the RDI. The specification of upper limits for magnesium supplementation by the NHMRC are lower than the RDI. The TGA considers that the NHMRC upper limits are appropriate thresholds for warning statements regarding the risk of diarrhoea from consumption of listed medicines containing inorganic magnesium salts, and rejects the suggestion that these thresholds are excessive.

In consideration of the feedback regarding the wording of the proposed requirements concerning the risk of diarrhoea/laxation, the proposed changes have been amended to clarify the requirements by correcting a typographical error, removing reference to 'this product' in the warning statement and replacing with 'contains magnesium'. The TGA notes that this wording may also improve consumer awareness about the laxative effects of magnesium, rather than referring to the effects of a specific product. The updated wording will also better align with existing warnings in the Therapeutic Goods Order No. 92 for example the laxative warning for sugar alcohols.

In consideration of the feedback regarding the warning statement for use in infants under 12 months of age, the TGA considers that the risk of diarrhoea from magnesium in infants must be appropriately addressed. A risk assessment of diarrhoea in infants from magnesium supplementation was not available. Rather than a warning statement, the risk is appropriately mitigated by a requirement that the medicine must not be directed for use in infants under 12 months. The proposed changes have been amended to this effect, in place of the warning statement.

Final decision to amend the Permissible Ingredients Determination - March 2021

The following 19 ingredients, being inorganic magnesium salts, will be amended within the Permissible Ingredients Determination commencing on 1 March 2021 to include the following requirements. Sponsors will be provided a 12 month transition period from this time to bring existing listed medicines into compliance.

Ingredients

MAGNESIUM AMINO ACID CHELATE had incorrectly been included as an inorganic magnesium salt. The below requirements, which had been specified for MAGNESIUM AMINO ACID CHELATE, were removed in the Therapeutic Goods (Permissible Ingredients) Determination (No. 2) 2021.

  • ALUMINIUM MAGNESIUM SILICATE
  • BITTERN
  • DIBASIC MAGNESIUM PHOSPHATE TRIHYDRATE
  • DRIED MAGNESIUM SULFATE
  • HEAVY MAGNESIUM OXIDE
  • LIGHT MAGNESIUM OXIDE
  • MAGNESIUM CHLORIDE 4.5-HYDRATE
  • MAGNESIUM CHLORIDE HEXAHYDRATE
  • MAGNESIUM HYDROGEN PHOSPHATE
  • MAGNESIUM HYDROXIDE
  • MAGNESIUM OXIDE
  • MAGNESIUM PHOSPHATE PENTAHYDRATE
  • MAGNESIUM PHOSPHATE TRIBASIC
  • MAGNESIUM SULFATE DIHYDRATE
  • MAGNESIUM SULFATE HEPTAHYDRATE
  • MAGNESIUM SULFATE MONOHYDRATE
  • MAGNESIUM SULFATE TRIHYDRATE
  • MAGNESIUM TRISILICATE
New requirements

Magnesium is a mandatory component of this ingredient.

When used in a medicine:

  1. with an oral route of administration;
  2. not indicated for laxative (or related) use; and
  3. where the maximum recommended daily dose for:
    1. children aged between 1 and 3 years (inclusive) provides 65 mg or more total magnesium from inorganic magnesium salts;
    2. children aged between 4 and 8 years (inclusive) provides 110 mg or more total magnesium from inorganic magnesium salts; or
    3. individuals aged 9 years or older provides 350 mg or more total magnesium from inorganic magnesium salts;

the following warning statement is required on the medicine label:

  • 'Contains magnesium, which may have a laxative effect or cause diarrhoea' (or words to that effect).

When the route of administration is oral, the medicine must not be directed for use in infants younger than 12 months of age.


References

Following reports of loss of taste or taste disturbance associated with listed medicines containing Andrographis paniculata, the TGA proposed that such products should alert consumers to this risk.

Summary of consultation submissions

Two submissions agreed with or did not oppose the proposed requirements concerning Andrographis paniculata and taste disturbance.

Two submissions suggested that the concern of taste disturbance might be linked to the andrographolide component of the Andrographis paniculata ingredient. They also suggested that Andrographis paniculata extracts that use hydroalcoholic solvents may have higher andrographolide content than extracts that use water based solvents and that medicines that contain water based extracts would be likely to result in fewer taste-related adverse event reports.

One submission suggested that the proposed warning statement should only be applied to medicines that use Andrographis paniculata extracts that use a hydroalcoholic solvent.

One submission cited that the data in the Database of Adverse Event Notifications (DAEN) (from 1 January 1971 to 14 June 2020) identified reports related to taste disturbance for nine products containing Andrographis paniculata. The submission stated that given the time period and number of reports, that it was considered insufficient to warrant an ingredient-based warning. The submission suggested that monitoring for at least another 12 months was necessary to establish trends, such as those relating to different products and extraction solvent, before requiring changes to other products.

TGA Response

The suggestion that andrographolide is the potentially causative component is consistent with evidence from clinical trials considered as part of TGA's investigation, which also suggested the effect may be dose related. However, the evidence was limited and did not establish a dose of andrographolide, or Andrographis paniculata, below which the risk of taste-related adverse effects is no longer a concern. Water-based Andrographis paniculata extracts used in listed medicines are in a concentrated form that is not consistent with dilute water-based traditional preparations, such as infusions or decoctions. The andrographolide content of listed medicines using water-based extracts, where quantified in the Australian Register of Therapeutic Goods (ARTG) entries, is up to 60mg per maximum recommended daily dose. One of the submissions referred to a study that found Andrographis paniculata water extracts contained 25mg/g andrographolide[1]. As such, andrographolide is present in significant concentrations when water is used as a solvent, which may be further increased in highly concentrated extracts.

The TGA recognises that the majority of taste-related reports were associated with medicines that use methanol, or a combination of ethanol and water as the extract solvent. However, the majority of Andrographis paniculata products on the ARTG contain extracts that use these solvent types, which could account for the relatively higher number of reports for these products. The TGA has received a report of taste disturbance associated with the use of a product with water as the only solvent for the Andrographis paniculata extract in the medicine. The available evidence does not support that water-based Andrographis paniculata extracts used in listed medicines are without the potential to cause loss of taste or taste disturbance.

Adverse events reports are publically available on the DAEN ninety days following receipt by the TGA. As previously noted in the TGA's consultation publication (Adverse events subheading), the number of reports associated with products other than ArmaForce does not support that the concern is product specific. As of 3 November 2020, 21 reports of loss of taste or taste disturbance have been received for 10 Andrographis paniculata-containing listed medicines, other than ArmaForce.

Spontaneous adverse events are generally under reported[2] and possibly even more so for adverse events associated with complementary medicines due to the general perception that such medicines are safe and unlikely to cause harm. This became apparent during TGA's investigation, where several consumers reported making the association between the medicine and loss of taste only after reading the TGA safety advisory. Therefore, a lower number of adverse event reports associated with medicines other than ArmaForce or with those that use water based extracts is not considered adequate reassurance of safety or of minimal potential for side effects. Further, the receipt of 21 reports for these other medicines is considered a valid signal for Andrographis paniculata and taste-related adverse events. The TGA does not consider a wait and watch approach is appropriate where a clear adverse event signal is evident, along with clinical trial data.

Therefore the TGA considers that the available evidence establishes a risk of loss of taste or taste disturbance from any listed medicine containing Andrographis paniculata. The risk should be communicated at the time of purchase to ensure consumers can associate adverse events with the product, should they occur.

Final decision to amend the Permissible Ingredients Determination - March 2021

Andrographis paniculata will be amended within the Permissible Ingredients Determination commencing on 1 March 2021 as specified in the table below. Sponsors will be provided a 12 month transition period from this time to bring existing listed medicines into compliance.

Ingredient name Purpose Specific requirements

ANDROGRAPHIS PANICULATA

A, H

The following warning statements are required on the medicine label:

  • (ANDROG) Andrographis may cause allergic reactions in some people. If you have a severe reaction (such as anaphylaxis), stop use and seek immediate medical attention (or words to that effect).
  • (ANDROT) Andrographis may cause taste disturbance including loss of taste. If you develop any adverse symptoms, stop use and seek medical advice (or words to that effect).

References