Clinical rule on safe methotrexate prescribing and dispensing in The Netherlands

Published in: Volume 7 / Year 2013 / Issue 1
Category: Cover Story
Page: 8-10
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A national clinical rule for proper handling of methotrexate was developed and implemented in The Netherlands in 2010 following a number of fatal incidents. The aim was to increase patient safety by preventing dispensing errors. Interventions implemented and results obtained in two hospitals are discussed.


When prescribing medicines, physicians must be aware that medications can cause considerable harm as well as yield many benefits. Physicians must continuously consider many drug- and patient-specific characteristics during treatment. Appropriate use of information technology, especially the introduction of clinical decision support systems, can substantially reduce medication error rates and improve patient safety [1-3].

In The Netherlands, the occurrence of a number of fatal incidents in the administration of methotrexate prompted the development and implementation of a national rule in 2010 to ensure proper handling of methotrexate in pharmacies. The clinical rule aimed to increase the safety of patients by preventing dispensing errors. Most hospital and community pharmacies implemented this clinical rule. In this paper, we share our daily practice in the Divisions of Clinical Pharmacy, Onze Lieve Vrouwe Gasthuis, Amsterdam, and in the St Elisabeth Ziekenhuis, Tilburg, The Netherlands.

What is a clinical rule

Computerized physician order entry (CPOE) with clinical decision support has been promoted as an effective strategy to prevent the development of a drug injury, defined as an adverse drug event [4]. The clinical pharmacist will define rules to increase medication safety by combining patient-specific medication data with clinical chemistry parameters, and the subsequent application of medication rules. After entering medication orders into the database, a signal or alert arises from the clinical decision support system. Thus, a clinical rule is an algorithm in which patient characteristics are linked, with the aim of generating patient-specific reviews or advice to improve patient safety. The system gives the pharmacist a list of patients at risk, with applicable directives, rather than having to search for these patients by hand. By using clinical rules, the pharmacist can specifically focus on patients at risk and, therefore, save time.

We are particularly interested in clinical rules that contribute to medication safety and that prohibit the occurrence of toxicity and adverse effects. In the field of oncology pharmacy, prevention of medication errors is also especially relevant. Medication errors related to chemotherapy are among the most deleterious. Therefore, pharmacists as members of the oncological team should actively participate in quality management outside the pharmacy and conduct their efforts to reduce medication errors within the pharmacy by implementing clinical rules and records.

Why a clinical rule for methotrexate

Methotrexate is a drug with different indications and strongly different dosage regimens. In oncology, administration occurs often on a daily basis, depending on the chemotherapy scheme (up to several grams per day); however, in rheumatology and gastroenterology, the drug is given in weekly regimens (5–30 mg). Some fatal incidents occurred in The Netherlands when methotrexate was taken daily instead of weekly by rheumatology patients. In some clinical cases, methotrexate was given to the patient for several consecutive days before the mistake was realised. Methotrexate was stored on the ward, making this possible.

These incidents were recorded in the Centrale Medicatiefouten Registratie (CMR), a central medication incidents registration system. The system was developed in The Netherlands in 2006 as a nationwide incident reporting system and web-based application for reporting medication- related incidents [5]. Medication error reports from participating hospitals are collected and stored in the CMR database. This is especially helpful for serious medication errors. In these cases, special ‘alerts’ are sent to all participating hospitals, together with recommendations to prevent the same error happening again. One example was an alert for once-weekly methotrexate dosing. This regimen was switched inadvertently to once-daily dosing a number of times in The Netherlands, and in other countries, sometimes with fatal consequences. For this reason, CMR alerts were sent to all hospital pharmacies, and warning letters issued by the Dutch Healthcare Inspectorate. The CMR also issued a set of recommendations [6]. Analysis of the incidents and recommendations about methotrexate prompted the Dutch Association of Hospital Pharmacists to draw up national guidelines for prescribing and dispensing methotrexate to ensure proper handling of this drug, visit Pharmacists were asked to pay special attention to these patients and to take precautions.

Recommendations from the CMR

The CMR’s main recommendations reflect the events that are most error prone in the distribution chain: 1) every prescription for methotrexate should be checked for indication—which would demonstrate whether a weekly dosage regimen is appropriate—and dosage; methotrexate should only be prescribed by physicians experienced in prescribing and monitoring methotrexate; 2) the pharmacy computer or the CPOE can be set to give an alert for each dose of methotrexate, whether it is correct or not, to facilitate the checking process stated above; 3) methotrexate should only be stored in the hospital pharmacy and not on the wards; 4) each methotrexate weekly prescription should be dispensed for a maximum of one week; this should be recorded per patient with the date of dispensing, in order to prevent another employee from dispensing the methotrexate again the next day; 5) in the hospital pharmacy store, a message should be displayed in the methotrexate area reminding everyone not to dispense for more than one week; and 6) physicians, nurses and pharmacy technicians should be trained about methotrexate [6].


The recommendations and national guidelines were implemented in the Onze Lieve Vrouwe Gasthuis, Amsterdam, and in the St Elisabeth Ziekenhuis, Tilburg, The Netherlands, as a clinical rule for physicians, nurses, pharmacists and pharmacy technicians. Results of the implementation of a clinical rule for methotrexate used in patients after three months are listed below:

  • No storage of methotrexate on wards
  • Dosage control in the pharmacy for all prescriptions
  • 100% alert in CPOE
  • Dispensing only after authorization by a pharmacist
  • Dispensing the medication needed for only one cycle
  • Date of delivery recorded
  • Medication review carried out for each patient on methotrexate for rheumatology, gastroenterology or oncology, with emphasis on drug–drug interactions and renal function
  • Enquiries made to prescribing physicians about whether drugs should be taken or omitted during hospital admission
  • Interview with patients about exact use of methotrexate, e.g. indication, dosage, day of administration, and use of folic acid
  • Use of tablet strengths of 2.5 mg only
  • Tablets, syringes, or IV infusions delivered by the pharmacy; use of patient’s own medications not permitted to prevent errors

Pharmacists and pharmacy technicians were asked to follow a flow diagram and a standard operating procedure, entitled ‘Methotrexate: prescription order entry, medication surveillance and logistics’. The purpose of this standard operating procedure was to describe the additional precautions taken in processing a methotrexate medication order for a clinical patient. The procedure described in this document is applicable to all methotrexate medication orders, injections and tablets, for patients admitted to the hospital. Communications to physicians and nurses about additional precautions in processing a methotrexate medication order for a clinical patient were made through various communication channels, e.g. hospital pharmacy websites, various newsletters, and CPOE classes. Key points are as follows: 1) all methotrexate products are at product level in the CPOE (Theriak and Navision Pharma), flagged as consultation medicine to ensure that medication orders for these products are always caught in the buffer zone. This means that every methotrexate medication order is reviewed by a pharmacy technician and a hospital pharmacist before being dispensed; 2) orders for methotrexate solution for injection or infusion, methotrexate tablet, or liquid preparation for clinical patients, are entered into the CPOE by the physician or nurse, or submitted as a medication order to the distribution department of the hospital pharmacy. In the latter case, the pharmacy technician of the distribution department enters the order in the CPOE; 3) on entering methotrexate into the CPOE, the medication order is transferred to the medication alert buffer of the pharmacy technician and the hospital pharmacist on duty; 4) every day, a distribution pharmacy technician has ‘methotrexate duty’ to coordinate orders and dispensing, and to communicate with the preparations department about methotrexate injections, infusions and methotrexate liquid preparation, and the logistics department about methotrexate tablets; 5) the preparations department dispenses methotrexate for injection (on indication of psoriasis, rheumatism or Crohn’s disease) or infusion (oncological indications); methotrexate liquid preparation for paediatric oncology can only be dispensed on the basis of a medication order authorized by a hospital pharmacist; the logistics department dispenses methotrexate tablets; and 6) the labels of the methotrexate syringes for indication of psoriasis, rheumatism or Crohn’s disease, and the labels of methotrexate IV solutions, are provided with a bar code for administration recording purposes.

In both hospitals, we see between three and five patients a week, and screening takes about 10 minutes by pharmacy technician and five minutes by the pharmacist. Patients understand why we do this and are cooperative with the pharmacovigilance and medication surveillance.


With our practice, we contribute to increased patient safety. The interventions can be implemented in a short period of time and do not demand much time from pharmacy technicians and pharmacists in our hospitals. This type of practice could be an important innovation for the pharmaceutical patient care on the wards in Europe. It can, however, be carried out in general practice, so both inpatients and out patients can benefit.


Kathleen Simons-Sanders, PharmD
Hospital Pharmacist
Division of Clinical Pharmacy
St Elisabeth Ziekenhuis
60 Hilvarenbeekse Weg
NL-5022 GC Tilburg, The Netherlands

Mirjam Crul, PharmD, PhD
Hospital Pharmacist
Division of Clinical Pharmacy
Onze Lieve Vrouwe Gasthuis
9 Oosterpark
NL-1090 HM Amsterdam, The Netherlands


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3. Wessels-Basten SJW, Hoeks AMJW, Grouls RJE, et al. Development strategy and potential impact on medication safety for clinical rules: the lithium case. Br J Clin Pharmacol. 2007 April;63(4):507-8.
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