Revised: 12 March 2014

Committees

Medsafe Advice on MCC Recommendation on Ibuprofen

Background

The safety and efficacy of ibuprofen as a general sales medicine had already been reviewed on two occasions in 2003 by the Australian National Drugs and Poisons Scheduling Committee (NDPSC) before the New Zealand MCC reviewed the Boots Healthcare application in November of last year. On both occasions, the NDPSC concluded that preparations containing 200mg or less of ibuprofen per dosage unit in packs containing 25 or less dosage units, labelled with a recommended daily dose of 1200mg of ibuprofen met the criteria for general sales medicines as:

• The proposed indication and the product are suitable for self-identification and self-treatment without professional advice;
• The safety profile of low dose ibuprofen in the OTC setting is good;
• A comparison with similar unscheduled analgesic products (aspirin and paracetamol in small pack sizes) indicated that the short term intermittent use of low dose ibuprofen had a relatively good safety profile;
• Ibuprofen administered orally has been demonstrated to have a wide therapeutic index and the risk of masking serious disease is very low; ibuprofen has a very low to absent potential for abuse;
• There is considerable OTC marketing experience in Australia as well as considerable international marketing experience with prescription, pharmacy and general sales.
• The spontaneous reporting rates of adverse events in Australia and overseas has been low.

The conclusions stated above indicate that the data presented are sufficient to meet the criteria set out in the handbooks of the NDPSC (and the MCC) for reclassification to general sales medicine status.

In reaching these conclusions, the NDPSC examined essentially the same information as the MCC, including adverse reaction reporting data from New Zealand. Yet despite the similarity of the evaluation process for reclassification, the two committees have reached differing conclusions. The MCC did not support reclassification as:

1. there was no need for ibuprofen in the general sales market;
2. the availability of aspirin as a general sales product was insufficient justification for allowing another non-steroidal agent such as ibuprofen to enter the market at this level;
3. adverse reactions reporting are an unreliable source of safety data for OTC medicines;
4. safety concerns associated with the use of ibuprofen, especially in the elderly and patients taking other medications, required professional pharmacist advice to be available at the point of sale;
5. product labelling could not resolve the potential safety issues; and
6. it would need either an impact assessment study of the implementation of reclassification in an appropriate market, or a "real" world study based on patient self-selection of ibuprofen i.e. without exclusion criteria for entry into the study other than those obtained on the product label when read by the patient, before it would consider reclassification of ibuprofen.

It is Medsafe's contention that in reaching its conclusions the committee merely restated its position on non-steroidal medicines first developed in 1996 and it did not give appropriate weight to the long history of general sales use in the UK and USA, the overall safety data presented in the meta-analyses of safety of ibuprofen, the data presented by the sponsor relating to consumer testing of the readability and understandability of the label, and the safety data in the PAIN study. In Medsafe's opinion the data presented in the application refute the MCC arguments for declining reclassification of ibuprofen. A copy of the NDPSC Records of Reasons is attached as they provide a further semi-independent evaluation that also refutes many of the claims made by the MCC.

Data supporting general sales classification

The application for reclassification included safety data from spontaneous adverse reaction programmes in markets such as Australia and New Zealand, where ibuprofen has been available for several years for patient self-selection in pharmacies, and from the UK and USA where the product has been available General Sale from supermarkets for a number of years. Trends analysis over time did not reveal increased reporting rates of adverse reactions following reclassification. While spontaneous reports of ADRs are poor indicators of product safety for OTC medicines, the good safety profile for low dose intermittent use of ibuprofen has also been demonstrated in a number of meta-analyses and clinical studies in the medical literature and provided by the sponsor.

The PAIN study described in the application was one example of a study demonstrating the comparative overall safety of ibuprofen. The PAIN study used GPs to identify and enrol patients with painful conditions for allocation to treatment with either: aspirin, paracetamol or low dose ibuprofen. Patients with a past history of ulcer, asthma or renal disease or other contraindication to the study medications were excluded from entry. As the exclusion criteria were based on the warning statements normally included on the products, the study attempted to ensure that the enrolled patient group mimicked real world use, (based on the assumption that real world patients would not take treatment if the warning statements on the product instructed them not to). The study demonstrated that the safety profile for all products was excellent and that amongst those patients without a past history of ulcer disease, low dose ibuprofen was less likely to cause a stomach problem than either aspirin or paracetamol.

In addition to safety data, the sponsor presented data consumer testing the labelling of the proposed product. These data demonstrated that a majority of patients read the label of OTC products when first using the product and that the warning statements proposed for the product were both readable and understandable by more than 80% of a representative sample of potential users of the product. These data support the NDPSC conclusion that the various safety concerns raised by objectors to the proposal to reclassify ibuprofen, many of which were similar to the objections raised by MCC, could be more than adequately resolved by appropriate labelling. Interestingly elsewhere in the MCC Minutes, the committee actually cite the Ibuprofen consumer testing data in support of reclassification of another product. As the proposed NZ label for low dose ibuprofen advises patients with a past history of stomach problems such as ulcer, renal disease or those taking any other medications to seek medical advice before starting treatment, Medsafe concurs with the NDPSC that the safety concerns raised by the MCC, are more than adequately addressed by the labelling proposed by the sponsor.

Medsafe does not support the claim that access to professional advice is essential for ibuprofen. Currently ibuprofen is available for self-selection by patients in a pharmacy. During the several years that it has been available at this level of classification, no data demonstrating that significant safety concerns have arisen has been presented. Pharmacists are not routinely involved in sale of pharmacy-only medicines and what studies that have been conducted within pharmacy, largely "mystery shopper" studies examining whether pharmacists comply with the legislation when supplying Restricted (Pharmacist-only) Medicines, demonstrate that pharmacist intervention in the sale of more restrictively classified medicines is not commonplace. Over the past 15 years, ibuprofen has gradually moved from prescription medicine to lower levels of classification, including general sales status, there is no evidence to suggest that increased consumer access has led either an increased need for pharmacist involvement or the emergence of consumer safety issues.

Lastly, the MCC considered that as there were a number of alternative aspirin and paracetamol containing products already available as general sales products, there was no need for general sale ibuprofen. While it is appropriate for the MCC to scan the market for available alternatives to a product being considered for reclassification, it is not within the terms of reference of the committee to determine whether there is a need for a product. The Committee are asked to consider whether the product meets the required safety criteria for a particular level of classification. In Medsafe's analysis the data provided indicates that low dose ibuprofen in limited pack sizes meets the MCC requirements for a general sales medicine. If the Minister's delegate accepts the case put by Medsafe, reclassification of ibuprofen to general sales category will place New Zealand in the company of the United Kingdom, the United States of America and Australia.