Executive summary 5
TGA recommendations 6
1 Introduction 7
2 Background 7
2.1 Mechanism of action 7
2.2 Dosage forms 7
Table : Dosage forms available in Australia for the investigated non-aspirin NSAIDs. 7
2.3 Indications for use 8
2.4 Scheduling status 9
2.5 Specific conditions of use 9
2.6 Regulatory and Pharmaceutical Benefit Scheme (PBS) funding status 9
2.7 Related products 9
3 The safety concern 9
4 Product Information and Labelling 10
4.1 Product Information 10
4.2 Required Advisory Statements for Medicine Labels (RASML) 11
Table : Required advisory statements relating to pregnancy for different non-aspirin NSAIDs and conditions 11
Table : Required advisory statements relating to pregnancy for the different conditions of aspirin 14
5 Literature 16
5.1 Literature provided with premarket application 16
Table : Prescription of NSAIDs among women recorded as having a miscarriage in their 1st pregnancy compared with women who had a live birth* 17
*Reproduced from p 268 of Nielsen et al (2001) 17
Table : Prenatal use of NSAIDs by pregnant women and risk of miscarriage* 18
*Reproduced from p 3 of Li et al (2003) 18
Table : Prenatal use of aspirin by pregnant women and risk of miscarriage* 19
*Reproduced from p 3 of Li et al (2003) 19
Table : Association between the use and the percent maximum daily doses of different non-aspirin NSAIDs and risk of having a spontaneous abortion* 20
*Reproduced from p 3 of Nakhai-Pour et al (2011) 20
5.2 Literature search 20
5.2.1 Non-aspirin NSAIDs 20
5.2.2 Published guidelines 23
Australian Medicines Handbook (AMH) 23
Therapeutic Guidelines 23
Australian Rheumatology Association 23
Australian Prescriber 24
5.2.3 Aspirin 24
Table : Association of aspirin use by lunar month with miscarriage* 26
6 Adverse Drug Reaction System (ADRS) data 26
Table : ADR case details for aspirin and spontaneous abortion 27
7 Discussion 27
TGA recommendations 28
This issue arose from a pre-market review of the ‘Use in pregnancy’ section of the Product Information (PI) document for a naproxen-containing medicine. The review identified differences between the PIs of naproxen-containing medicines in regard to information about the potential risk of miscarriage after nonsteroidal anti-inflammatory drug (NSAID) exposure in early pregnancy. This observed discrepancy prompted an evaluation to determine whether this safety issue pertained to all NSAIDs, including aspirin.
The evaluation included comparisons of Australian and international product information documents across the range of NSAIDs; a review of mandated warnings, published literature and therapeutic guidelines; and an analysis of case reports from the TGA Adverse Drug Reactions System (ADRS) database.
NSAIDs are indicated for the treatment of pain, inflammation and fever. Aspirin is also indicated for the treatment of acute coronary syndrome and for the inhibition of platelet aggregation. NSAIDs are available in a variety of doses and formulations for a range of administration routes, including oral, rectal, parenteral, and topical. They are also available in combination products. Under the Poisons Standard February 2016, NSAIDs are classified as unscheduled or schedule 2, 3, or 4 medicines, depending on dose, dosage form and pack size.
A review of Australian and international NSAID product information documents demonstrated that the risk of spontaneous abortion is inconsistently included in Australian PIs across the different non-aspirin NSAIDs. At present, the Australian PIs for only five non-aspirin NSAIDs include a statement warning of the increased risk of miscarriage. The majority of non-aspirin NSAIDs which do not include a warning in their Australian PI have a statement in at least one international product reference document. Australian product information for aspirin alone is not available which is also the situation in the US and New Zealand. Neither the EU Summary of Product Characteristics (SmPC) nor the Canadian Product Monograph for aspirin documents an increased risk of spontaneous abortion.
NSAIDs that are not scheduled as an S4 are required to have various advisory statements on their medicine labels. The following advisory statement is used for NSAIDs in relation to the risk of use in pregnancy:
‘Do not use [this product/insert name of product] during the first 6 months of pregnancy, except on doctor’s advice. Do not use at all during the last 3 months of pregnancy.’
This advisory statement does not address the use in women who have just conceived and are therefore unlikely to be aware that they are pregnant. This is of relevance as the data to support the increased risk of miscarriage with non-aspirin NSAID use suggests that the risk is greatest when the non-aspirin NSAID is taken at the time of conception.
Diclofenac when indicated for children, non-aspirin NSAID preparations for dermal or external use and those which are indicated exclusively for dysmenorrhoea are not required to include this statement. The latter is of concern since treatment guidelines recommend pre-emptive treatment of dysmenorrhoea with non-aspirin NSAIDs and an implantation bleed can mimic the commencement of menstruation, with the potential for women who have conceived but are not yet aware, to self-treat for dysmenorrhoea. Additionally, given the increasing consumer awareness of over-the-counter (OTC) medicine marketing strategies, consumers may realise that NSAIDs indicated exclusively for dysmenorrhoea have the same active ingredient as NSAIDs not indicated exclusively for dysmenorrhoea despite the former being labelled specifically for “period pain”. Thus consumers may use non-aspirin NSAIDs that are indicated exclusively for dysmenorrhoea for other indications without being cautioned against the use whilst pregnant.
A review of the medical literature relating to NSAIDs and spontaneous abortion determined that on balance, the epidemiological data supports 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. The association between non-aspirin NSAID use and increased risk of miscarriage is widely accepted by professional medical organisations. Australian adverse event data was minimal for this association and provides limited support for a causal association. The association is biologically plausible and is supported by animal studies.
In regard to aspirin, there is at present insufficient evidence to support a causal association between aspirin use and an increased risk of miscarriage.
Harmonise the warnings in the product information for systemic and ophthalmic non-aspirin NSAIDs in regard to the increased risk of spontaneous abortion when NSAIDs are taken around the time of conception.
Require all OTC non-aspirin NSAIDs, including those exclusively indicated for dysmenorrhoea, to include an advisory statement on their packaging which appropriately addresses the risk of spontaneous abortion.
Communicate the risk to health professionals and consumers.