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A decade of Australian methotrexate dosing errors

Rose Cairns, Jared A Brown, Ann-Maree Lynch, Jeff Robinson, Carol Wylie and Nicholas A Buckley
Med J Aust 2016; 204 (10): 384. || doi: 10.5694/mja15.01242

Summary

Objective: Accidental daily dosing of methotrexate can result in life-threatening toxicity. We investigated methotrexate dosing errors reported to the National Coronial Information System (NCIS), the Therapeutic Goods Administration Database of Adverse Event Notifications (TGA DAEN) and Australian Poisons Information Centres (PICs).

Design and setting: A retrospective review of coronial cases in the NCIS (2000–2014), and of reports to the TGA DAEN (2004–2014) and Australian PICs (2004–2015). Cases were included if dosing errors were accidental, with evidence of daily dosing on at least 3 consecutive days.

Main outcome measures: Events per year, dose, consecutive days of methotrexate administration, reasons for the error, clinical features.

Results: Twenty-two deaths linked with methotrexate were identified in the NCIS, including seven cases in which erroneous daily dosing was documented. Methotrexate medication error was listed in ten cases in the DAEN, including two deaths. Australian PIC databases contained 92 cases, with a worrying increase seen during 2014–2015. Reasons for the errors included patient misunderstanding and incorrect packaging of dosette packs by pharmacists. The recorded clinical effects of daily dosage were consistent with those previously reported for methotrexate toxicity.

Conclusion: Dosing errors with methotrexate can be lethal and continue to occur despite a number of safety initiatives in the past decade. Further strategies to reduce these preventable harms need to be implemented and evaluated. Recent suggestions include further changes in packet size, mandatory weekly dosing labelling on packaging, improving education, and including alerts in prescribing and dispensing software.

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  • Rose Cairns1,2
  • Jared A Brown1
  • Ann-Maree Lynch3,4
  • Jeff Robinson5
  • Carol Wylie6
  • Nicholas A Buckley1,2

  • 1 NSW Poisons Information Centre, The Children's Hospital at Westmead, Sydney, NSW
  • 2 University of Sydney, Sydney, NSW
  • 3 Western Australian Poisons Information Centre, Sir Charles Gairdner Hospital, Perth, WA
  • 4 University of Western Australia, Perth, WA
  • 5 Victorian Poisons Information Centre, Austin Health, Melbourne, VIC
  • 6 Queensland Poisons Information Centre, Lady Cilento Children's Hospital, Brisbane, QLD


Acknowledgements: 

We thank the staff at the New South Wales, Western Australian, Victorian and Queensland Poisons Information Centres; the Therapeutic Goods Administration; and the National Coronial Information System. We thank Eva Saar (National Coronial Information System) for providing comments on the manuscript. Ongoing toxico-vigilance studies are supported by a National Health and Medical Research Council Program Grant (1055176).

Competing interests:

No relevant disclosures.

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access_time 07:15, 10 June 2016
Betty Shuk Han Chan

Serum Methotrexate concentrations do not correlate with toxicity in chronic poisoning.

We read with interest regarding a study on “A decade of Australian methotrexate medication errors” and noted there were eight deaths identified as medication errors due to daily dosing. In addition, 92 cases of methotrexate (MTX) dosing errors were reported to the 4 Poisons Information Centres in Australia with the concerning rise in 2014-5. The authors found that low dose daily administration for 3-7 days could cause toxicity and even deaths.1 The toxicity of methotrexate is likely to be more dependent on the duration of exposure rather than serum concentration.(2) In a retrospective series of 28 patients pancytopenia (79%) was found to be the most common manifestation of low dose chronic MTX toxicity.(3) In contrast we observed no effects in acute single dose exposures.(4)

We recently performed an audit of calls referred to the clinical toxicologists at the New South Wales Poisons Information Centres (2004-2015). Ethics approval was granted by the Sydney Children’s Hospitals Network HREC (approval number LNR-2011-04-06). There were 21 chronic MTX poisonings, the median age was 62 years (IQR: 52-77), 15 of which were reported to have symptoms indicating toxicity with stomatitis/mucositis (30% 7/21 patients) and neutropenia (30% 7/21 patients) being the most commonly reported symptoms.

Serum MTX concentration (n=20) did not correlate with neutropenia (r=-0.36) or thrombocytopenia (r=0.44).3 There was no difference in MTX concentration between those who died (n=6, 0.05 +/- 0.04 µg/ml) and those that survived (n=14, 0.04 +/- 0.04 µg/ml p=0.45). These concentrations are a many fold lower than those seen with in our audit of asymptomatic acute MTX overdose which had a median concentration of 0.32 +/- 0.08 µg/ml.4 Hence there is no rationale to monitor methotrexate concentrations in chronic methotrexate toxicity; very low concentrations can still be associated with severe or fatal toxicity.

References
1. Cairns R, Brown JA, Lynch AM, Robinson J, Wylie C and Buckley NA. A decade of Australian methotrexate dosing errors. The Medical journal of Australia. 2016;204:384.
2. Goldie JH, Price LA and Harrap KR. Methotrexate toxicity: correlation with duration of administration, plasma levels, dose and excretion pattern. European journal of cancer. 1972;8:409-14.
3. Kivity S, Zafrir Y, Loebstein R, Pauzner R, Mouallem M and Mayan H. Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients. Autoimmunity reviews. 2014;13:1109-13.
4. Chan BS, Dawson A and Buckley NA. What can toxicologists learn from therapeutic studies about the treatment of acute and chronic methotrexate poisoning? Clinical toxicology. 2016;54 S1:479.


Competing Interests: No relevant disclosures

Dr Betty Shuk Han Chan
Prince of Wales Hospital

access_time 12:57, 25 June 2016
Carol Simmons

It is shocking that methotrexate poisoning from inadvertent daily dosing of oral methotrexate intended for weekly dosing is still causing significant numbers of deaths and serious morbidity in Australian patients, as highlighted in this article.
This issue has been recognised for many years now, and numerous measures, such as “naming the day”, have not stopped it.
In 2012, we asked the PBAC to consider restricting the PBS quantities of oral methotrexate for weekly dosing patients (1). The reply we received stated that prescribers are free to prescribe lesser quantities if they wish. Yes, they are, but are unlikely to do so, when a larger pack is available, is potentially more convenient, and the cost per dose to the patient is much less.
Methotrexate supply is clearly a case where medication safety should take priority over economics. Surely it is time to restrict supply of methotrexate to weekly dosing patients to pack sizes consistent with a month’s supply.

(1) Simmons C and Copeland T-S. Your questions to the PBAC. Methotrexate. Aust Prescr 2012;35:46 | 1 April 2012 | http://dx.doi.org/10.18773/austprescr.2012.028

Competing Interests: No relevant disclosures

Ms Carol Simmons
Fremantle Hospital, WA

Responses are now closed for this article.