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ACSOM meeting statement, Meeting 23, 11 July 2014

Advisory Committee on the Safety of Medicines

5 March 2015

Role of the Advisory Committee on the Safety of Medicines (ACSOM) in the TGA's regulatory decision making process

The ACSOM is a statutory advisory committee established by the Therapeutic Goods Regulations 1990.

The TGA currently has nine statutory advisory committees from which it can obtain independent expert advice on specific scientific and technical matters to aid the TGA's regulatory decision making and other regulatory processes. The ACSOM provides advice to the TGA on, amongst other things, matters relating to the safety, risk assessment, risk management and other matters related to pharmacovigilance of medicines.

How this statement should be read

The advice provided by the ACSOM is an important element in the undertaking of the regulatory functions of the TGA. However, it forms only one part of the total body of information that is available to, for instance, a TGA delegate making a regulatory decision under the Therapeutic Goods Act 1989 ("the Act"). Therefore, while appropriate consideration will be given to such advice, it is important to note that neither the TGA nor a TGA delegate is obliged to follow it.

It should also be noted that details of the committee's advice may not become publicly available for some time after the committee has provided that advice. The purpose of this Meeting Statement is to describe in general terms the matters considered by the committee at each meeting and for it to be available as soon as reasonably practical after the relevant meeting.

Additionally, following publication of this statement, it is most likely that further work will be undertaken by the TGA to investigate, monitor and / or evaluate the medicines considered by the ACSOM; and this will continue for some time into the future. It is therefore possible that further information about the medicines will become publicly available at a later time and this will be pursuant to a regulatory decision under the Act being made and following further consultation with the medicine's sponsor and / or manufacturer.

Overview of the safety reviews and therapeutic goods referred for advice

The TGA continually monitors therapeutic goods supplied in Australia to ensure their ongoing safety, efficacy and quality. As part of this process, the TGA routinely undertakes safety reviews of therapeutic goods.

At this meeting, the committee's advice was sought on the following safety review.

Andrographis paniculata and anaphylactic/allergic reactions

ACSOM noted that a number of allergic-anaphylactic adverse drug reactions (ADRs) have been reported for products included in the Australian Register of Therapeutic Goods (ARTG) that contain the herbal ingredient Andrographis paniculata (A.paniculata). As listed medicines, the indications for each of these particular products have not been evaluated for efficacy and vary widely. A typical example of the indications includes:

  • 'Andrographis supports healthy immune function and is used traditionally to support healthy intestinal function';
  • 'Andrographis has been used traditionally for relief of influenza, cough and sore throat, to relieve fever, to help maintain appetite and digestion and as a liver tonic'; and
  • 'Andrographis extracts standardised for andrographolides may relieve the symptoms of uncomplicated upper respiratory tract infection'.

The Committee noted that in 2008, the TGA investigated the association of anaphylaxis with a range of products containing A.paniculata and that these products were subsequently cancelled from the Australian Register of Therapeutic Goods (ARTG). However, ongoing monitoring of products containing A.paniculata identified that while there had been an initial decline in reports, ADRs of this type continued to be reported and therefore the TGA has undertaken a safety review of A.paniculata and anaphylactic/ allergic reactions.

The committee was advised of the safety review's conclusions, as follows:

  • the reviewed information suggests an association between allergic/anaphylactic reactions and the herbal ingredient A.paniculata;
  • a particular type of extract or solvent cannot be conclusively identified as causative;
  • a precautionary approach appears warranted to include all products that contain A.paniculata in any proposed action;
  • the number of allergic/anaphylactic ADRs reported and the severity of the ADRs suggest that the ingredient A.paniculata presents a potential risk sufficient to warrant further action;
  • the most appropriate action would be one that ensures the risk is communicated to the public; such as, via warning statements on either the TGA website or product labels; and
  • the ADRs reported for these products should be monitored to assess the effectiveness of the risk mitigation strategy.

ACSOM considered whether there was sufficient evidence to confirm an association between anaphylactic/allergic reactions and A.paniculata and if so, whether there is a safety concern to warrant the adoption of risk mitigation strategies (and what strategies may be considered appropriate). ACSOM also considered whether further review of the use of this herb during pregnancy and lactation was warranted.

The committee discussed the mode of action of A.paniculata in relation to allergy. While there was evidence to show various immunomodulation and cytokine effects in vitro and in animal studies, there was no available evidence which explained a mechanism of action for inducing anaphylaxis. Therefore, in determining whether there was an association between anaphylactic /allergic reactions and A.paniculata, the committee advised that this will be dependent on the review of case reports and consensus opinions.

The committee considered the current international consensus and various case reports entered in the TGA's Adverse Drug Reactions System (ADRS) database which included reports of both anaphylaxis and allergic-type reactions associated with products that contain A.paniculata. The committee also noted that it was possible that these reports were more likely to be for products where methanol extraction was used and / or which included a higher concentration of plant extract.

In assessing these safety concerns, the committee further discussed the dose, concentration and extraction methods used for A.paniculata. In particular, the committee discussed whether the method of extraction was likely to be the cause of anaphylactic or allergic-type reactions. It was noted that in the more traditional uses of A.paniculata (such as in teas and tinctures), the extract is used in lower concentrations and such products have not been implicated in ADRs.

The review noted that the majority of products in the ARTG contain highly concentrated extracts of A.paniculata, which may be a contributing factor to the higher number of ADRs for these products. The review further noted that the extreme bitterness of A.paniculata is a likely deterrent for its use in more traditional oral liquid preparations, possibly contributing to the lack of ADRs for these types of preparations. Considering the absence of data on dose, duration and general use, the review concluded that a correlation between ADRs and dose/ concentration could not be conclusively established.

The committee advised that while further statistical analysis would be beneficial, taking account of the heterogeneity of the products and preparation methods, there was still sufficient information currently available to confirm an association between anaphylactic / allergic reactions and A.paniculata; and that from the data presented was more likely in products with higher concentrations of plant extract obtained using the methanol extraction method.

In view of this advice and in noting that products containing A.paniculata are available over-the-counter, the committee agreed there is a safety concern sufficient to warrant the adoption of risk mitigation strategies. ACSOM advised that it would be appropriate for the TGA to:

  • give consideration to ensuring information was provided to the public. Options could include the addition of warning statements to labels of products containing A.paniculata and to the development of education or awareness raising program for General Practitioners (GPs) and complementary medicine practitioners;
  • continue to monitor and review ADR case reports; and
  • given the apparent knowledge gap in relation to products being supplied in Australia and the extraction method, consider requesting sponsors to define the method of extraction as part of the application process for listing in the ARTG.

The committee also advised, that based on the currently available international data, further investigation around the use of A.paniculata in pregnancy and lactation is warranted in the Australian context.  The committee advised that since this issue was not within the scope of the current review, the TGA should undertake a new safety review on the effects of A.paniculata on pregnancy and lactation, and when completed, seek further advice about the need for a specific warning about this issue.

Risk management plans

A Risk Management Plan (RMP) is a set of pharmacovigilance activities and interventions designed to identify, characterise and manage risks relating to a medicine. At this meeting, the committee's advice was sought on four RMPs for medicines with proposed indications relating to the:

  • reduction of alcohol consumption in a specified patient group with alcohol dependence;
  • improvement of glycaemic control in specified patients with type 2 diabetes mellitus;
  • treatment for specified patients with Gaucher disease type 1; and
  • treatment of type 1 and type 2 diabetes mellitus in specified patients.

The committee was asked to provide advice regarding the adequacy of the RMPs to monitor, characterise and/or mitigate the risks for each medicine.  Specifically, the committee provided advice on the completeness of the ongoing safety concerns listed in the RMPs and the strength of the evidence to support the inclusion of additional safety concerns. ACSOM also provided advice on the suitability of proposed pharmacovigilance and risk minimisation activities to ensure risks associated with the medicines are adequately mitigated in the Australian context.

Additionally, ACSOM provided advice on the adequacy of proposed educational materials, the Product Information, Consumer Medicine Information, and various programmes intended to minimise the risks associated with the medicines.

The committee's advice will shortly be provided to the TGA for consideration as part of the TGA's regulatory decision making processes.

Following complete assessment of the application, information on the RMP evaluation will be included in the Australian Public Assessment Reports (AusPAR), which is published on the TGA website once it is finalised.

Further information

Meeting statements are made publicly available after each meeting.

For further information on the ACSOM, please visit: the ACSOM webpage or contact the ACSOM Secretary: Mr Craig Davies on 02 6232 8641 or via email: acsom@tga.gov.au.