High Risk Medications

“Methotrexate is a high-alert drug, requiring extra safeguards at every stage—prescription, dispensation, and administration.”

Case Scenario 

A patient diagnosed with Systemic Lupus Erythematosus 17 years back was placed on Hydroxychloroquine tablets.  The antimalarial drugs Chloroquine and hydroxychloroquine are approved for the treatment of SLE and have been shown to reduce the frequency of disease flares (particularly of lupus nephritis). They contribute to the maintenance of remission, prolong the onset of disease and reduce the risk of complications. In this case the patient failed to respond to Hydroxychloroquine so she was switched to the new drug Methotrexate. However, while switching to the new drug, communication with the patient was not clear and although it was indicated on the prescription that the medicine ought to be taken on a weekly basis and even the day Saturday was marked on the prescription. The patient, having developed the habit of taking the earlier drug Hydroxychloroquine on a daily basis, went on to take the medicine Methotrexate on a daily basis. While doing so she started developing oral candidiasis and painful swallowing for which she went on to see her consultant for SLE and they identified the culprit as Methotrexate. It was the sixth day of her taking Methotrexate that the drug was stopped and treatment was started for her weakened immune system. Had she not developed Oral candidiasis and painful swallowing, the problem could have been even more sinister and caused much more damage. The patient was later discharged from the hospital after 5 days of management. In this case the patient got lucky that she developed oral candidiasis and dysphagia for which she soon went on to see her consultant itself. Had she not developed the problem or had she approached a different healthcare professional for her oral candidiasis without giving proper medication history, her case could have escalated to a much worse condition. The drug under consideration here is Methotrexate, though this drug is frequently prescribed for autoimmune diseases and even comes as a first line drug in rheumatoid arthritis, this is considered a high risk medicine. In 2004, ISMP published a study of methotrexate errors over a four-year period that resulted in 25 deaths and 48 serious outcomes, many due to daily dosing. 1

“The patient’s adverse outcome underscores the critical importance of precise dosing instructions and thorough patient education for high-risk medications.”

High Risk Medicines 

High risk medicines (HRMs) are medications that have an increased risk of causing significant patient harm or death if they are misused or used in error. Institute of Safe Medication Practices (ISMP) uses the term High Alert Medication. ISMP has identified methotrexate as a high-alert medication in both hospital and community settings, even when used for non-oncological purposes, such as RA. Since 2014, a bundle of three strategies to help prevent these types of errors has been highly promoted as one of the ISMP Targeted Medication Safety Best Practices for Hospitals—

1. Using a weekly dosage regimen default when oral methotrexate orders are entered,
2. Requiring a hard stop verification of an appropriate oncological reason for all daily oral methotrexate orders, and
3. Educating patients and/or family members prior to discharge.

“Healthcare providers are urged to adopt recommended system safeguards to enhance the safety of Methotrexate therapy.”

High risk medicines include:

Medicines with a narrow therapeutic index

Medicines that present a high risk when

     Administered via the wrong route or

     Other medication management system errors occur.

“While severe harm has occurred during hospitalization, many adverse outcomes have taken place post-discharge, highlighting the need for ongoing monitoring.”

Errors with these medicines are not necessarily more common than with other medicines. As they have a very narrow margin of safety, the consequences of errors with these medicines can be more devastating. There is no standard list of high risk medicines followed worldwide. Lists of HRMs have been created largely based on incident reporting systems in different health services, jurisdictions and countries. In the USA and Canada, HRMs are known as ‘high-alert medications’.

High risk medicines may vary between hospitals and other health care settings depending on the types of medicines used and patients treated. In the acute sector in Australia, the ‘APINCH’ acronym and classification is widely used to assist clinicians focus on a group of medicines known to be associated with high potential for medication-related harm.

The ‘APINCH’ classification is not an exhaustive list. Other medicines or classes of medicines may also present a high risk. Examples include neuromuscular blocking agents, digoxin, antipsychotics and oral hypoglycemics.

Recommendations for Methotrexate 

The following measures are suggested to reduce the possibility of inadvertent medication incidents associated with weekly oral methotrexate therapy.

Prescribers:

• Provide clear dosing instructions, avoiding phrases such as “use as directed”. In consultation with the patient, choose a particular day of the week when the medication is to be taken, and specify this day on the prescription. However, avoid choosing Monday as the designated day, as this word has reportedly been misinterpreted as “morning”.
• Consider including the indication for methotrexate use on prescriptions, as helpful information for other health care providers (e.g., pharmacists and nurses).
• When possible, for patients living in the community, consider limiting quantities to be dispensed to a one month supply at a time.

“Clear communication and stringent safety protocols are essential to prevent severe adverse effects with high-risk medicines like Methotrexate.”

Nurses and pharmacists:

• If methotrexate is ordered with a dosing frequency more often than weekly, and the indication is unclear, contact the prescriber to verify the appropriateness of the dosing schedule.

Pharmacists:

• Ensure that a pharmacist reviews every methotrexate order before the medication is dispensed.
• Include explicit dosing instructions for methotrexate administration, such as the day of the week, on pharmacy-generated medication labels, medication administration records, and other forms.
• Ensure that written information provided to the patient about the use of methotrexate in the treatment of autoimmune disorders contains only the information applicable to such treatment.

In addition, in community pharmacies:

• Implement a system that requires pharmacist counseling for all methotrexate prescriptions, including refills, to ensure that patients are reminded of once-weekly dosing.
• Encourage patients to keep track of the day when they take each dose of methotrexate, e.g., by marking off the date on a calendar.
• When possible, dispense only one month’s supply of methotrexate at a time to prompt a review and follow-up if the patient makes a refill request sooner than anticipated.

In general:

• Ensure that all practitioners involved in the care of patients receiving methotrexate for autoimmune disorders are aware of the high-alert nature of this medication and the potential for harm if it is administered incorrectly.
• Encourage patients to become active participants in their own care. During counseling sessions, ensure that patients understand the information provided, for example, by asking them to describe their understanding of the information provided. (Notably, a study about lack of patient understanding has suggested the need to reinforce key messages related to methotrexate therapy.)
• Build alerts in electronic prescribing systems and pharmacy information systems prompting practitioners to review the indication and dosing frequency for methotrexate orders.
• As illustrated by the cases described above, weekly dosing schedules can easily be misinterpreted by prescribers, pharmacists, nurses, patients and patient caregivers. It is hoped that sharing information about reported cases will raise awareness and lead to system enhancements to ensure the safe use of oral methotrexate.

Key points to consider:

Medication Errors with High-Risk Medicines:

High-risk medicines, such as Methotrexate, have a narrow therapeutic index, making errors potentially devastating.

Methotrexate, although effective for autoimmune diseases, can cause significant harm if not used correctly. Here the patient’s experience of oral candidiasis and painful swallowing was a direct consequence of incorrect daily dosing.

Importance of Clear Communication:

The patient’s habit of daily medication intake and unclear communication led to a serious medication error. The prescription indicated weekly dosing, but this critical detail was not effectively communicated or reinforced.

Ensuring patients understand their dosing schedule is vital, especially when switching medications.

Safety Protocols and Best Practices:

The Institute of Safe Medication Practices (ISMP) has recommended several strategies to prevent such errors:

• Using weekly dosage regimen defaults for Methotrexate orders.
• Implementing hard stop verifications for daily orders without an oncological reason.
• Providing thorough patient and family education before discharge.

Other best practices include marking the specific day of the week for dosing on prescriptions, avoiding ambiguous terms like “use as directed,” and limiting the dispensing quantity of the medicine to one month to ensure regular review.

System Enhancements and Patient Involvement:

Electronic prescribing systems and pharmacy information systems should include alerts for Methotrexate dosing to prompt verification of the indication and dosing frequency.

Encouraging patients to actively participate in their care by understanding their medication regimen and maintaining a record of their dosing can further reduce the risk of errors.

Pharmacists and nurses play a critical role in verifying dosing instructions and ensuring patient comprehension.

Conclusion: 

This article underscores the critical need for clear communication and stringent safety protocols when managing high-risk medicines, particularly Methotrexate. The presented case highlights the potential for severe adverse effects due to dosing errors, emphasizing the importance of precise dosing instructions and patient education. Methotrexate is a high-alert drug, requiring extra safeguards at every stage—prescription, dispensation, and administration—regardless of the setting, dose, or indication for use. The patient’s adverse outcome could have been mitigated with better communication and understanding of the dosing regimen.

Outpatient pharmacists play a crucial role in ensuring that Methotrexate prescription labels have accurate instructions and that patients are properly counseled to understand the directions for use. Healthcare providers are urged to adopt recommended system safeguards, such as using weekly dosage defaults, hard stop verifications, and patient education, to enhance the safety of Methotrexate therapy. Implementing these measures can significantly reduce the risk of medication errors and improve patient outcomes in the management of autoimmune disorders with Methotrexate.

 

Reference:

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871236/
2. https://www.ncbi.nlm.nih.gov/books/NBK585602/table/ch31.Tab2/

Sanjaya Mani Dixit 

Sanjaya Mani Dixit is a pharmacist, pharmacologist, and medical journalist who currently serves as an Assistant Professor of Pharmacology at Kathmandu Medical College. With extensive experience in teaching MBBS, BDS, Pharmacy, Nursing, and physiotherapy students, he possesses a deep knowledge of pharmacology and drugs. Sanjaya has expertise in various aspects of the pharmaceutical field and medicine, both domestically and internationally, having completed his bachelor’s and master’s studies in Pakistan and China respectively. As the editor of MedicosNext magazine, he is dedicated to curating relevant articles on medicine that address the unique challenges and needs of the Nepali context. Additionally, Sanjaya is a passionate advocate for medication safety and patient safety, striving to raise awareness and improve standards in Nepal.