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ACSOM meeting statement, Meeting 30, 20 November 2015

Advisory Committee on the Safety of Medicines

11 October 2016

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 ten 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.

Non-steroidal anti-inflammatory drugs (NSAIDs) and Spontaneous Abortion

This safety review relates to non-steroidal anti-inflammatory drugs (NSAIDs)[1] registered on the Australian Register of Therapeutic Goods (ARTG) for use in Australia. As at October 2015, there were 652 registered, NSAID-containing medicines intended for oral, rectal or parenteral administration; and sponsored by 52 companies.

All strengths and combination products of these formulations are relevant to this review and many of these medicines are available over-the-counter (OTC) in pharmacies or from supermarkets and other retailers. Consumers are able to purchase such medications with little or no verbal advice or counselling.

Generally, non-aspirin NSAIDs are indicated for pain due to rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, gout, ankylosing spondylitis, psoriatic arthritis and Reiter's syndrome; pain, especially due to inflammation and tissue injury (e.g. dysmenorrhoea, pericarditis, bone metastases, renal colic, headache, migraine, postoperative pain); fever.

Aspirin is indicated for inhibition of platelet aggregation; acute coronary syndrome; relief of pain, inflammation and fever.

A pre-market review of the 'Use in pregnancy' section of the Product Information (PI) document for a particular naproxen-containing medicine identified differences between the PIs of naproxen-containing medicines in regard to information about the potential risk of miscarriage after NSAID exposure in early pregnancy.

At present, the Australian PIs for only five non-aspirin NSAIDs (ibuprofen, mefenamic acid, piroxicam, celecoxib and parecoxib) mention the increased risk of miscarriage. Internationally, the risk is documented inconsistently across the different non-aspirin NSAIDs.

The TGA undertook a safety review to address this matter and the review included comparisons of PIs across the range of NSAIDs; a review of mandated warnings, published literature and therapeutic guidelines; and analysis of case reports from the TGA Adverse Drug Reactions System (ADRS) database.

On balance, the TGA found that the epidemiological data support an association between non-aspirin NSAID use in pregnancy and the risk of spontaneous abortion, particularly when the non-aspirin NSAID is taken close to the time of conception. TGA ADR data are minimal for this association but do provide some support for it. The association between NSAID use and increased risk of miscarriage is widely accepted by professional medical organisations. The TGA also concluded that in regard to aspirin there is at present insufficient evidence to support a causal association between aspirin use and an increased risk of miscarriage.

The draft TGA safety review made several recommendations and ACSOM firstly provided advice on the strength of the evidence for the association, the nature of the risk itself, and the presently inconsistent documentation of the risk for prescription and OTC NSAIDs, as follows:

  • Strength of evidence: all studies identified in the safety review have issues with methods and generalisability. Overall, the strength of the evidence is weak but the most robust study did suggest an increased risk associated with timing of exposure.
  • Nature of risk: given the potential for large numbers of women to be exposed to these medicines, particularly those available OTC, any small risk is likely to be of public health significance.
  • Inconsistent documentation in PIs: the evidence suggests that the risk is consistent across products (where the product is known), therefore documentation of risk should be consistent across products. It was noted that all medicines which do not have a statement in their Australian PI have a statement in at least one other country.

The committee provided advice in relation to the adequacy of the presently required advisory statements in mitigating the risk identified in the review for OTC non-aspirin NSAIDs indicated exclusively and not exclusively for dysmenorrhoea.

In noting the lower bioavailability of eye drops, the committee also provided advice on the appropriateness of eye drops being included in the recommendations of the safety review. In considering this, the committee noted the theoretical risk of systemic adverse reactions following ophthalmic administration of medicines. The committee also noted that the PIs for diclofenac and ketorolac eye drops report clinical data showing nil or negligible systemic exposure after ocular administration.

Overall, in the absence of data on the extent of systemic exposure following ophthalmic administration of all NSAID ophthalmic formulations, the committee could neither confirm nor exclude that there is a risk of spontaneous abortion following the use of NSAID eye drops.

ACSOM was also asked to provide advice on the evidence for the association between aspirin and spontaneous abortion. From the studies considered, the committee advised that overall, the evidence is weak for a positive association between aspirin use and spontaneous abortion, and the evidence is insufficient to change the current advisory statements for aspirin.

The committee was also asked to provide advice on any other risk mitigation strategies that could be further considered. ACSOM advised that any warning statements should be specific about the nature of the risk and the timing of the risk (i.e. at or before conception), that targeted advice be provided to consumers and pharmacists, that advice for consumers would need to make clear that paracetamol is not subject to the advisory statements and education for pharmacists regarding pharmacy-only OTC NSAIDs should include medicines exclusively indicated for dysmenorrhoea.

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 eight RMPs for medicines with proposed indications relating to:

  • a fluid and electrolyte disorder
  • respiratory disorders
  • a cardiac disorder
  • vascular disorders
  • a lipid disorder
  • a musculoskeletal disorder.

For these medicines, the committee was asked to provide advice on matters including:

  • the adequacy and completeness of proposed safety concern lists and if considered incomplete, what additional safety concerns should be included. This included consideration of whether the proposed safety concern lists reflected both the new chemical entity and a previously-approved chemical entity in fixed-dose combination medicines
  • whether concomitant use with strong CYP3A inhibitors / inducers, and concomitant use with CYP3A substrates with a narrow therapeutic index, should be listed as potential risks rather than identified risks
  • if any further ongoing safety concerns are considered necessary, what pharmacovigilance and risk minimisation activities may be proposed for these new concerns
  • the adequacy of the proposed routine and additional risk minimisation plans to mitigate all the safety concerns (including the adequacy of managing specified missing information) and if not considered to be adequate, what other additional risk minimisation activities might be required. This included consideration of the risk minimisation plan for Australia which did not contain the same activities (e.g. prescriber checklists) as required in other countries
  • the adequacy of the proposed routine and additional pharmacovigilance plans (including proposed Post Authorisation Safety Studies) to monitor all safety concerns (including use in specific patient groups) and if not considered to be adequate, what other additional pharmacovigilance activities might be required
  • the potential for off-label use of the medicine in Australia and if this potential is considered to be significant, how this risk could best be minimised
  • the adequacy of the draft Product Information / Consumer Medicines Information documents to inform healthcare professionals and consumers about the risks associated with the medicines and how to minimise these risks, including coverage of unusual scenarios where the medicine may be used.

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.


At this meeting, the committee's advice was also sought on whether the lack of a scoreline on a specific tablet raises safety concerns and if so, is it possible that these could be mitigated via risk minimisation measures.

Further information

Meeting statements are made publicly available after each meeting.

For further information on the ACSOM, please visit: the ACSOM web page or email:


  1. NSAIDs include aspirin, diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, mefenamic acid, naproxen, piroxicam, sulindac, celecoxib, etoricoxib, meloxicam and parecoxib.