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Aconitum alkaloids in listed medicines

26 August 2021

Background

Aconitum is a genus of flowering plants, with some species used in Ayurveda and Traditional Chinese Medicines. Most members of the genus Aconitum contain substantial amounts of the highly toxic aconitine and related norditerpenoid alkaloids. Aconitine is a potent neurotoxin and cardiotoxin, and entry into the body may lead to diarrhoea, convulsions, ventricular arrhythmia and death.

When present, Aconitum spp are generally included in listed medicines at very low concentrations due to their toxicity, and although manufacturing controls should be in place to ensure the concentration is below scheduled quantities, the TGA has undertaken testing to monitor the safety of these products in the marketplace.

The TGA has previously (in 2013 and 2014) tested individual products in response to adverse events or reports, and detected Aconitum alkaloids at Schedulable levels. The project described in this report was conducted to determine the levels of Aconitum alkaloids in all listed herbal medicines containing Aconitum spp, with testing performed by the TGA Laboratories Branch (LB) over 2018-19.

A total of 19 medicines containing an Aconitum spp. ingredient and listed on the Australian Register of Therapeutic Goods (ARTG) were tested by TGA. These samples covered 18 different products and 7 different types of oral or topical dosage forms.

Testing

Aconitum alkaloids by LC/MS

Each of the samples was screened for the presence of the three Aconitum alkaloids aconitine (AC), hypaconitine (HA) and mesaconitine (MA) using TGA's in-house Liquid Chromatography-Mass Spectrometry (LC/MS) test method.

Aconitum alkaloids were below the limits of detection for 18 of the 19 samples.

In the sample of Jin Gui Shen Qi Wan (AUST L 217716) sponsored by Shen Neng Herbal Medicines Group Pty Ltd, Aconitum alkaloids aconitine, hypaconitine and mesaconitine were detected above the schedulable level. The amounts of the three alkaloids in the sample were determined by LC/MS to be 0.5, 6.1 and 1.6 µg/g, respectively. The total level of alkaloids detected was determined to be 0.3 mg/pack, a level that places the product in Schedule 4 of the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP).

Shen Neng Herbal Medicines Group Pty Ltd was notified of these results and the product was recalled to a consumer level on 30 August 2019.

The information provided by the sponsor in the Australian Register of Therapeutic Goods (ARTG) for Jin Gui Shen Qi Wan states that the declared amount of equivalent alkaloids is 1 µg per pill. With a pack containing 200 pills, the declared amount of total Aconitum alkaloids per pack would be 200 µg, (or 0.2 mg) which places the product in Schedule 4.

A review of the ARTG entry for Jin Gui Shen Qi Wan (AUST L 217716) has led to the product being cancelled from the register on 16 January 2020.

Aconitum alkaloids were not detected in the remaining 18 samples tested, and therefore no further actions were required in response to the LC/MS testing.

Labelling indicating use in children

A requirement for exemption from Schedule 4 of the SUSMP requires labelling of products containing Aconitum spp. to be restricted to use in adults. Failure to do so places the product in Schedule 4 by default if the labelled amount of Aconitum spp is greater than 10 µg/g.

The majority (14/18) of products tested contained information on the labels for use by children, a further 2 products contained directions that did not restrict the medicine's use to adults while the remaining 2 products, both patches, had no age specific information on the label. Seven of the 18 products contained Aconitum spp. at or above concentrations of 10 µg/g or 10 µg/mL. This would place these products into schedule 4 of the SUSMP.

A review of these 7 products by the TGA has resulted in 3 of the 7 products changing the label to include a warning statement for use in adults only, 3 of the 7 products being cancelled from the register and the sponsor of one product amending the register entry so there is no longer a discrepancy between the label, formulation and ARTG entry.

Appendix A: Aconitum scheduling.

Aconitum spp. has entries in both Schedule 2 and Schedule 4 of the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP). As well as applying to all the plant species in the genera Aconitum, these entries apply to every plant preparation (‘any part of that plant when packed or prepared for therapeutic use') and every alkaloid of the substance. For use in adults the entries are defined in terms of the amount of ‘total alkaloids' per pack of product; between 0.02 and 0.2 mg per pack classifies the product as Schedule 2, and above 0.2 mg, Schedule 4, as follows:

SCHEDULE 2 (Pharmacy Medicine)

Aconitum spp. for therapeutic use in adults:

a) in preparations for oral use in packs each containing 0.2 mg or less of total alkaloids except in packs containing 0.02 mg or less of total alkaloids; or

b) in preparations for dermal use containing 0.02 per cent or less of total alkaloids, in packs each containing 0.2 mg or less of total alkaloids except in packs containing 0.02 mg or less of total alkaloids.

SCHEDULE 4 (Prescription Only Medicine)

Aconitum spp. except:

a) when included in Schedule 2;

b) in preparations for oral use in adults in packs containing 0.02 mg or less of total alkaloids; or

c) in preparations for dermal use in adults containing 0.02 per cent or less of total alkaloids in packs containing 0.02 mg or less of total alkaloids.

For use in children, only Schedule 4 applies with no exemptions.

Appendix B: Details and results of samples analysed
ARTG No Product Name Dosage form Sponsor Batch No Expiry Date Result for Aconitine (AC), Hypaconitine (HA) and Mesaconitine (MA).

127035

Jin Kui Shen Qi Wan

Pill

Beijing Tong Ren Tang Australia Pty Ltd

17031638

02 2022

Not detected

124132

BRAUER DRY COUGH

Oral Liquid

Brauer Natural Medicine Pty Ltd

13715

AUG21

Not detected

132568

BRAUER BABY & CHILD COLD & FLU

Oral Liquid

Brauer Natural Medicine Pty Ltd

13907

JUL21

Not detected

132569

BRAUER BABY & CHILD COUGH

Oral Liquid

Brauer Natural Medicine Pty Ltd

13905

SEP21

Not detected

222226

Brauer Kids Manuka Honey Dry Cough

Oral Liquid

Brauer Natural Medicine Pty Ltd

13959

SEP20

Not detected

222236

Brauer Kids Manuka Honey Cold & Flu

Oral Liquid

Brauer Natural Medicine Pty Ltd

13823

SEP20

Not detected

234882

Brauer Manuka Honey Dry Cough Elixir

Oral Liquid

Brauer Natural Medicine Pty Ltd

13132

JUL20

Not detected

234889

Brauer Manuka Honey Cold & Flu Elixir

Oral Liquid

Brauer Natural Medicine Pty Ltd

13490

JUL20

Not detected

287075

Brauer Head Cold Tablets

Tablet

Brauer Natural Medicine Pty Ltd

11370

JUN20

Not detected

62225

GRIPP-HEEL

Tablet

Brauer Professional Pty Ltd

74485

01.2021

Not detected

82622

TRAUMEEL S

Tablet

Brauer Professional Pty Ltd

78028

11.2021

Not detected

93564

Cerebrum compositum

Tablet

Brauer Professional Pty Ltd

78476

12.2021

Not detected

148695

Traumeel

Cream

Brauer Professional Pty Ltd

82556

11.2020

Not detected

152670

Traumeel Gel

Gel

Brauer Professional Pty Ltd

81135

07.2020

Not detected

99743

COOLING PATCH FOR EXTERNAL PAIN RELIEF

Patch, dermal

Shen Neng Herbal Medicines Group Pty Ltd

BG05

7/07/2021

Not detected

99917

PAINRELIEV COOLING PATCH

Patch, dermal

Shen Neng Herbal Medicines Group Pty Ltd

NAL12

2020.12.27

Not detected

217716

JIN GUI SHEN QI WAN

Pill

Shen Neng Herbal Medicines Group Pty Ltd

20160787-3

15JUL2021

AC 0.5 µg/g

MA 1.6 µg/g

HA 6.1 µg/g

Total AC+MA+HA = 8.2 µg/g

AC+MA+HA/pack = 0.3 mg

68041

Weleda Cold & Flu Pilules

Granules

Weleda Australia Pty Ltd

B8X08

02/23

Not detected

68041

Weleda Cold & Flu Pilules

Granules

Weleda Australia Pty Ltd

E8X04

05/23

Not detected