Issue 21 / 6 June 2016

RESEARCHERS are calling for new initiatives to reduce the incidence of accidental daily dosing of methotrexate after they identified continuing harm, including deaths, from dosing errors.

Writing in the MJA today, researchers reported that eight deaths had been linked to methotrexate dosing errors between 2000 and 2015. The researchers reviewed coronial cases in the National Coronial Information System (NCIS), reports to the Therapeutic Goods Association Database of Adverse Event Notifications (TGA DAEN) and to Australian Poisons Information Centres (PICs).

In the NCIS, the researchers identified 22 deaths linked to methotrexate, including seven cases in which accidental daily dosing was documented. A further 10 cases of methotrexate medication error were listed in the TGA DAEN, with two cases resulting in death (one of which was also listed in the NCIS). A review of PICs data uncovered 92 cases of methotrexate medication error, including a spike in 2014–2015, with 16 and 13 cases reported respectively.

The authors noted that the use of methotrexate – which is prescribed in low, weekly doses for rheumatoid arthritis, psoriasis and inflammatory bowel disease – was likely to continue to increase in line with Australia’s ageing population.

Lead author Dr Rose Cairns, of the NSW Poisons Information Centre, told MJA InSight that previous measures – like the “name the day” recommendation and the introduction of the 15-tablet pack – had not been sufficient.

“It doesn’t seem likely that these events are going to stop happening without some changes,” she said.

“Most newer medicines are provided in packs with 1 month’s supply only; if this was done for methotrexate, this could be really helpful in reducing the chances of error.

“As mentioned in the article, packaging methotrexate with folic acid would be ideal.”

However, she said, packaging changes would require action from the TGA and manufacturers, and there was limited incentive for manufacturers to invest in repackaging this inexpensive drug.

A spokesperson for the TGA said that the organisation would review the information in the MJA research to see if any further action was required.

“The issue of confusing daily with weekly dosing raised in the article relates to rheumatoid arthritis and psoriasis as these have weekly dosing instructions. The product information document currently includes extensive warnings on this issue with a boxed warning, precaution and dosage section discussing it,” the spokesperson said.

In addition to packaging changes, the MJA authors suggested other measures, such as reformulating methotrexate as a distinctly coloured tablet to avoid confusion with folate, as both are currently small yellow tablets; including warnings in prescribing and dispensing software and boosting education initiatives for pharmacists, pharmacy assistants and patients.

Professor Sepehr Shakib, Director of the Department of Clinical Pharmacology at the Royal Adelaide Hospital, said a multifaceted approach was required to address methotrexate dosing errors.

“What we know about medication safety measures is that no one thing is a magic cure for trying to solve medication safety problems. Often they tend to be multifaceted and so a multifaceted intervention is required,” he said.

“There are a number of reasons why these errors are occurring and it certainly seems that putting a number of measures in place would help to reduce the risk.”

He said that providing only a 1-month supply would be particularly helpful in preventing dosing errors.

“It is difficult to have a five-times overdose of methotrexate when you only have four tablets in a month.”

Professor Shakib added that the study also highlighted flaws in Australia’s medication safety reporting system. He said that the researchers had to draw on various databases – each one receiving only voluntary reports of adverse events – to establish the incidence of methotrexate toxicity in Australia.

“Our current systems don’t allow us to readily be able to say how commonly something like this occurs and [the authors acknowledge] that there is probably under-reporting, despite the fact that they went to multiple different sources,” he said.

Daniel Lalor, Deputy Director of Pharmacy (Quality Use of Medicines, Research and Education) at the Canberra Hospitals and Health Services, said that financial disincentives had worked against the 2008 attempts to curb the risks associated with methotrexate.

“The uptake of the smaller pack size hasn’t been significant, and … upwards of 70% of the 10 mg tablets are still supplied in 50-packs. We know that [buying the larger pack] makes economic sense for a concession card holder, so there are financial disincentives for it to work,” Mr Lalor told MJA InSight.

“Additional efforts certainly need to be put in place. These are simple errors that could be prevented.”

Mr Lalor said that several incidents were a result of errors in Webster-paks, and this was “troubling”.

“We know [from the literature] that pharmacists can make mistakes when they pack Webster-paks and really the solution there is to use automation,” said Mr Lalor, adding that robotised packaging of dose administration aids was used in some places in Australia.

Dr Cairns said that health professionals should take the time to ensure that patients understood the unique dosing schedule of methotrexate and to provide clear written and verbal information.

“It is really important to move forward with changes since these errors are preventable,” she said.

7 thoughts on “Preventable methotrexate errors need a fix

  1. dr gary champion says:

    So here we have a study by Pharmacists – why has not the Australasian Rheumatology Association been contacted for comment? There would be more deaths per year from NSAIDS but a very few said to be associated with MTX is highlighted. In my over 30 years of Rheumatology I have never had a death from MTX usage. MTX has been one of the greatest drugs of the late 20th & early 21st centuries fo RA, PsA & Ps. Now would the authors like to handle all the queries that will flood my rooms, & also deal with the flare in inflammatory disease that will occur when patients abandon treatment as this article has been reported in the popular press.

  2. Greg Luke says:

    Notwithstanding excellent counselling at the supply level, MTX continues to be a problem.

    In conducting HMR’s I have noticed  that many people DO NOT READ THE LABEL.

    Monthly su[pplies of this type of medication would probably eliminate misadventures

  3. Steve Flecknoe-Brown says:

    For nearly a decade now we have had safe, effective disease-modifying agents active in all of the conditions for which low-dose methotrexate is prescribed, yet the PBS insists on methotrexate being used first.  How many deaths and the processes which follow will it take for the PBAC to reduce the restrictions and burdensome paperwork which limits the use of these costly but safe medications?

  4. Glenn Rosendahl says:

    We have the precedent of ‘the pill’ where a daily pill is dispensed, even through a third of them are sugar pills, in some circumstances with three different strengths of active agents in the other pills.  Think of how many unexpected, undesired pregnancies would have occurred if the regimens had not been provided in this manner.   There is no reason why methotrexate could not be dispensed in a similar manner, once a week, with a supply of folic acd in the daily pills.

  5. Mark Arnold says:

    I would concur with the “senior rheumatologist”. As is often the case, this is a complex matter for which a single beaurocatically-imposed solution will not be appropriate.

    I my experince these errors were more common 20 yars ago and now are rare, though clearly avoidable. Patient education at the time of writing the intial prescription and checking that the weekly dosage regimen is adhered to at each followup is mandatory.

    It is more common for toxcity to occur when it is not appreciated that the dose of methorexate needs to be reduced in the context of renal imprment, and that persons treated with methotrexate should have their renal function monitored for this poential pitfall.

    The probem of weekly dosing regimens when the 2.5 mg and 10mg tablets are used together is also problematic.

    Finally, it should  also be appreciated that weekly sc or im injections are often better tolerated and can offer superior efficacy. Overseas, pre-packaged injectable preparations are used regularly. In Australia there are unjustifiable and illogical fears expressed about adminstering parenteral methotexate. These fears equate methotrexate to vesicant chemotherapeutic agents, and are often unhelpfully expressed by other healh care professionals without reference to the presciber.

    I disagree that the extent of the problem can justify the imposition of a very restrctive dispensing policy on the many thousands of patients safely treated over many years by providing only one months’ supply of medication at a time. 

  6. Dr Duncan Carradice says:

    Whilst I concur with “Mark Arnold” that this is a complex problem which will likely be “overtreated” by a rigid system, I disagree with the comments regarding the administration of parenteral methotrexate.

    Whilst each state may have different legislation, the preparation of cytotoxic drugs (of which methotrexate is one) is covered in Victoria by OHS legislation and DHS guidelines (…)

    Due to the non-availabilty of pre-packaged parenteral methotrexate in Australia, all parenteral methotrexate has to be prepared for injection. It is no longer acceptable for this to happen anywhere outside of a designated, approved cytotoxic preparation facility (not at the point of administration). This unfortunately severely limits the ability to administer parenteral methotrexate outside of a hospital setting in most instances, due to these requirements and the requirements for staff to have cytotoxic administration training, wear cytotoxic specific PPE and abide by cytotoxic waste disposal requirements. 

    Whilst this may seem excessive for low-dose parenteral methotrexate, the reason for this is to appropriately protect healthcare staff from accidental exposure to cytotoxic drugs. The safe exposure level to methotrexate is not known and therefore exposure has to be minimised.



  7. David Liew says:

    Pre-packaged low-dose methotrexate injections intended for subcutaneous administration are commercially available in Australia but are not PBS subsidised. This mode of administration has significant potential benefits given increased bioavailability and tolerability leading to improved drug survival, which has significant implications for patient outcomes and utilisation of more expensive alternatives (such as biological DMARDs). Greater emphasis should be put on the PBS price negotiation process for this product or, in the alternative, tertiary hospitals should be financial enabled to pre-package this (as some already do).

    On this article, naturally I agree with “senior rheumatologist”. The popular media sometimes forgets its own strength (see statins, bisphosphonates etc).

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