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CMEC Meeting 27, 14-15 June 2001

Complementary Medicines Evaluation Committee

14 June 2001

Extracted ratified minutes

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CMEC Meeting 27 extracted ratified minutes (pdf,67kb)

Public recommendation summary

This summary has been posted immediately after the CMEC meeting to give quick advice of the recommendations made by CMEC to the TGA. This summary does not represent the decisions of TGA. Reasons underlying these recommendations will be available after Members ratify the Minutes at the next CMEC meeting.

Item 2 Minutes of CMEC's 26th meeting

Recommendation 27.1

CMEC confirms that the draft Minutes of its previous meeting (CMEC 26, 23 March 2001), as amended, are a true and accurate record of that previous meeting.

Item 3 Guidelines on levels and kinds of evidence to support claims for therapeutic goods ('Guidelines')

Recommendation 27.2

CMEC endorsed the revised Guidelines (May 2001 version) and recommended some minor revisions. Members supported the Guidelines being placed on the TGA website.

Item 4 Draft stakeholder consultation paper: Review of the regulation of herbal medicinal substances

Recommendation 27.3

CMEC agreed that the draft consultation paper could be released for stakeholder comment, subject to minor revisions. The consultation paper will be examined with a view to formulating an overview document relevant to consumers, to assist with consumer consultation on this matter.

Item 5.1.1 (S)-S-Adenosylmethionine ('SAMe') - report on claims SAMe can produce a 'legal high'

Recommendation 27.4

CMEC recommends to the TGA, based on an extensive literature and electronic media review, that the recent media promotions of SAMe as a 'legal high' appear to be without foundation and do not preclude the use of SAMe as an active ingredient in listable therapeutic goods. However CMEC recommends that all therapeutic goods containing SAMe should carry the following label statement:

"Individuals who are using prescription anti-depressants or suffer from bipolar depression should not use this product unless under the supervision of a health practitioner" (or words to that effect).

CMEC also recommends that the TGA should advise relevant health practitioner organisations of the potential for 'switching' from depressive to manic states, where SAMe is taken by people with bipolar disorder.

Note: Further information on the listable forms of SAMe and the Australian Approved Names for these forms is found at the end of this document. A draft compositional guideline is also attached.

Item 6.2 Tall oil phytosterols

Recommendation 27.6

CMEC recommends to the TGA that the substance 'tall oil phytosterols' is suitable for use as an active ingredient in listable therapeutic goods.

Note: an Australian Approved Name is yet to be approved for this substance and the final name approved may vary from the name used in this summary.

Item 6.3 Azadirachta indica ('neem') cold-pressed seed oil

Recommendation 27.7

CMEC recommends to the TGA that cold-pressed neem (Azadirachta indica) seed oil is suitable for use in listable therapeutic goods, provided it is restricted to topical application on the skin only and that the following conditions are met:

  • therapeutic goods containing the substance are supplied with label warnings that these goods are for external use only and should be kept out of the reach of children; and
  • the containers of therapeutic goods containing this substance are fitted with child-resistant closures.

Item 6.4 Black boned chicken

Recommendation 27.8

CMEC recommends to the TGA that black boned chicken (a variety of Gallus gallus domesticus Brisson) is suitable for use as an active ingredient in listable therapeutic goods, subject to inclusion of appropriate limits for antibiotic residues and hormones in the compositional guideline for this substance.

Note: an Australian Approved Name is yet to be approved for this substance and the final name approved may vary from the name used in this summary.

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Item 7.2 Tricosanthes kirilowii

Recommendation 27.10

CMEC recommends to the TGA that Tricosanthes kirilowii should be maintained as a listable active substance and considers that, based on available evidence, no substance-specific restrictions should be placed on its use at this time.

Item 8 Registration applications

CMEC made recommendations to the TGA in relation to two matters under this agenda item.

Item 9 Registration variations

CMEC made a recommendation to the TGA in relation to a matter under this agenda item.

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(S)-S-Adenosylmethionine - naming and compositional issues

(S)-S-Adenosylmethionine ('SAMe') is available commercially in a number of different chemical forms. The CMEC has previously recommended that sulfates, tosylates and mixed sulfates/tosylates are suitable for use in listable therapeutic goods. Australian Approved Names (AANs) have been developed for a number of these commercially available forms. The TGA proposes to require the use of label AANs for the listable forms of SAMe. Label AANs must be used within product labels, including in the label statement of active ingredients, but regular AANs must be used in the listing application.

The following table identifies AANs and label AANs that have been assigned for SAMe sources.

Australian approved names (AANs) and label Australian approved names from listable forms of (S)-S-Adenosylmethionine
AAN Racemic salt AAN Non-racemic salt Label - AAN
Ademetionine tetratosylate dihydrate (S)-S Adenosylmethionine tetratosylate dihydrate (S)-S Adenosylmethionine (quantity) as tosylate
Ademetionine pentatosylate dihydrate (S)-S Adenosylmethionine pentatosylate dihydrate (S)-S Adenosylmethionine (quantity) as tosylate
Ademetionine hexatosylate dihydrate (S)-S Adenosylmethionine hexatosylate dihydrate (S)-S Adenosylmethionine (quantity) as tosylate
Ademetionine tetrasulfate dihydrate (S)-S Adenosylmethionine tetrasulfate dihydrate (S)-S Adenosylmethionine(quantity) as sulfate
Ademetionine pentasulfate dihydrate (S)-S Adenosylmethionine pentasulfate dihydrate (S)-S Adenosylmethionine (quantity) as sulfate
Ademetionine hexasulfate dihydrate (S)-S Adenosylmethionine hexasulfate dihydrate (S)-S Adenosylmethionine (quantity) as sulfate
Ademetionine disulfate ditosylate dihydrate (S)-S Adenosylmethionine disulfate ditosylate dihydrate (S)-S Adenosylmethionine (quantity) as sulfate/tosylate
Ademetionine disulfate tritosylate dihydrate (S)-S Adenosylmethionine disulfate tritosylate dihydrate (S)-S Adenosylmethionine (quantity) as sulfate/tosylate
Ademetionine trisulfate ditosylate dihydrate (S)-S Adenosylmethionine trisulfate ditosylate dihydrate (S)-S Adenosylmethionine (quantity) as sulfate/tosylate
Ademetionine disulfate tosylate (S)-S Adenosylmethionine disulfate tosylate (S)-S Adenosylmethionine (quantity) as sulfate/tosylate

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Draft compositional guidelines for SAMe (ademetionine)

A draft compositional guideline has been developed for (S)-S-Adenosylmethionine, as follows:

Draft Compositional Guideline for SAMe (ademetionine) (10 May 2001)

DEFINITION

Ademetionine of non-recombinant biological or chemical synthetic origin, intended for use in encapsulated, tabletted or powdered complementary medicines for oral administration, comprises a mixture of the biologically-active (S),S-diastereoisomer and the biologically inactive (R)-S-diastereoisomer of S-adenosylmethionine, also known as SAMe, stabilised as salts with suitable anions. Anions typically include sulfate, tosylate or tosylate/sulfate, but may comprise any anion which confers stability on the SAMe moeity and which is acceptable for use in therapeutic goods in Australia. The SAMe salt may be a lyophilised or spray dried powder or may be stabilised by drying on a suitable inert matrix material such as silicon dioxide, mannitol or lactose.

Picrolonic acid must not be used in the manufacture of ademetionine.

Small amounts of the degradation products adenine, homoserine lactone, S-pentosylmethionine and methylthioadenosine may be present. The product may be microencapsulated to enhance stability and may include free flowing agents.

Test Min Max Typical Method
(S)-Sadenosylmethionine as the free cation 95% of label claim 110% of label claim 10-50% by weight in salt HPLC*§; 1H-NMR*‡; CZE*¶
(R)-Sadenosylmethionine as the free cation NMT 40% of (S)-Sadenosylmethioni ne isomer as the free cation HPLC*§; 1H-NMR*‡; CZE*¶
Identification of (S)-Sadenosylmethionine and (R)-Sadenosylmethionine HPLC* by comparison to a reference standard
Identification of counterions HPLC* by comparison to a reference standard
Moisture - 1% 0.2% Karl Fischer Method or USP<921>
Solvent residues Complies with limits for specific solvents in the ICH topic Q3C. GC
Heavy metals (total) total limit of 10 ppm, determined as lead, according to the BP limit tests.
Microbiological finished products incorporating this substance must be in accordance with AGRD2 specifications**
Adenine - NMT 5% of (S),SSAMe HPLC*§
Methylthioadenosine - NMT 5% of (S),SSAMe HPLC*§
S-adenosylhomocysteine - NMT 2.5% of (S),S-SAMe 1.5% HPLC*§
* Methods must be validated and must be able to separate (S),S-SAMe from potential degradation compounds, counter ions and (R),S-SAMe isomer
§ e.g. Hoffmann, J.L. (1986) Biochemistry 25: 4444-4449.
‡ e.g. Revelle et al. (1995) J. AOAC Intl. 78: 353-358.
¶ e.g. Panak et al. (1997) Electrophoresis 18: 2047-2049
'NMT' means 'not more than'
**AGRD2 = Australian guidelines for the registration of drugs, Volume 2, Non-prescription drugs registered via Compliance Branch
BP = British Pharmacopoeia
CZE = Capillary zone electrophoresis
GC = gas chromatography
HPLC = high performance liquid chromatography
ICH = International Conference on Harmonisation
ICH topic Q3C = Quality Guidelines: Impurities: Residual solvents
SAMe = S-adenosyl-L-methionine
USP = US Pharmacopoeiaa

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