High-risk medications: a guide for pharmacy professionals

Medications are the mainstay of treatment for a range of conditions, yet it is widely recognised that medication errors are one of the leading causes of patient harm, with 1 in 20 patients exposed to preventable harm^​1​. It could be argued that all medication is high-risk, given the correct conditions. Research has identified that, particularly within acute hospitals, it is the cumulative effect of moderate-harm medication incidents, rather than single catastrophic errors, that usually result in preventable deaths^​2​. 

However, the potential for significant harm or death from medication errors is greatly increased when certain ‘high-risk’ medications are involved^​3,4​. High-risk medications have the potential to cause significant patient harm, even when used as intended, posing challenges for pharmacists and other healthcare professionals^​2,5​. 

Researchers have struggled to establish the prevalence of prescribing errors of high-risk medications. One systematic review, published in 2016, reported error rates ranging from 0.24 to 89.6 per 100 medication orders^​6​. The Institute for Safe Medication Practices (ISMP) has said that, although incident rates for high-risk medicines are not necessarily higher than with other medicines, the consequences are more likely to be significant when incidents do occur^​7​. This article explores the factors that classify a medication as ‘high-risk’ and some of the important considerations surrounding these medications, providing insights into their use, monitoring and prevention of potential complications.

What makes a medication high-risk?

The World Health Organization (WHO) cites high-risk medications as one of the main factors associated with significant patient harm, alongside:

• Healthcare professionals (e.g. poor prescribing practices, human factors);
• Complex patients (e.g. renal/liver impairment, allergies, extreme body weight) and vulnerable patients (e.g. children, older people, people with learning disabilities);
• Work environment (e.g. high-risk settings: perioperative, neonatal, emergency care) and transitions between care settings^​2,4​.

Medications can be deemed high-risk for various reasons. In addition, specific medications may differ in risk between different healthcare sectors and countries^​8​. Owing to the high costs and increased mortality associated with high-risk medications, medication safety organisations have attempted to establish definitions and lists to raise awareness for healthcare professionals^​6​. For example, in 2024, the The Institute for Safe Medication Practices (ISMP) published a ‘List of high-alert medications in acute care settings’, containing 13 specific medications, including insulin U-500 and oral methotrexate, and 21 medication classes, including antithrombotic agents, insulin and opioids^​7​. Some of the medications listed, such as chemotherapy, parenteral therapies and anaesthetic agents, are specific to highly specialised areas and therefore fall outside the scope of this article. However, several of the medications are widely recognised as high-risk and are relevant to all healthcare sectors and will be covered in detail.

A medication can be considered high-risk when its use carries a higher probability of causing severe harm or adverse effects to a patient^​8​. Potential contributing factors are often overlapping; therefore, most high-risk medications may fall into more than one category:

• Narrow therapeutic range;
• Serious adverse effects;
• Monitoring requirements;
• Interactions;
• Withdrawal effects;
• Time critical; 
• Complex or unusual dosing.

Medications with narrow therapeutic range

One class of medications highlighted as high-risk by the WHO includes drugs with a narrow therapeutic range, where the drug concentration needed to produce a therapeutic effect is close to that which produces adverse effects^​8,9​. These medications often require therapeutic drug monitoring to guide prescribing decisions around dosing. Patient harm arises when the process for therapeutic drug monitoring is not followed correctly, leading to toxicity or sub-optimal dosing^​9​. In addition, these drugs are more likely to be susceptible to drug interactions or physiological changes, leading to severe adverse effects. Two common medications in this class are digoxin and lithium. Other drugs that require therapeutic drug monitoring include theophylline, phenytoin, carbamazepine, warfarin, ciclosporin, tacrolimus, gentamicin and vancomycin^​10​.

Medications with serious adverse effects

A medication may be classed as high-risk when it has the known potential for a serious adverse drug reaction. This could be despite correct use or owing to use outside of the marketing authorisation (e.g. medication errors, overdose or misuse)^​19​. Drug reactions can be augmented or ‘type A’ reactions: where the adverse effect is an exaggeration of the drug’s usual action (e.g. bleeding with an anticoagulant or hypoglycaemia with insulin). On the other hand, drug reactions can be bizarre or ‘type B’ reactions: where the reaction is not expected based on the drug’s mode of action (e.g. anaphylaxis with penicillin)^​19​. 

In situations where severe adverse effects can be predicted, proactive steps can be taken to reduce the risk. Life-threatening respiratory depression caused by opioids usually occurs in acute pain management in patients who have not developed opioid tolerance or in persistent pain where there are large dose increases or changes in route or formulation^​20​. Resources, such as the Faculty of Pain Medicine’s ‘Opioids Aware’, raise awareness and provide guidance for healthcare professionals on how to start, titrate, switch and deprescribe opioids safely^​20​. In the case of direct oral anticoagulants, steps can be taken to reduce the risk of bleeding by ensuring that the patient is prescribed an appropriate dose, considering the patient’s age, weight and creatinine clearance^​21​. 

Where adverse drug reactions are unpredictable, monitoring can be employed to detect adverse drug reactions in a timely manner. Azathioprine is a disease-modifying antirheumatic drug (DMARD), with the known and potentially fatal complication of myelosuppression^​22​. Current guidelines require baseline thiopurine methyltransferase (TMPT) levels to be checked so that azathioprine can be avoided in patients with absent TPMT levels (i.e. patients who would be at increased risk of developing severe myelosuppression)^​23​. However, normal TPMT activity doesn’t exclude the risk of myelosuppression, so a full blood count (FBC), alongside other parameters, such as liver function tests (LFTs) and renal function, must be checked at frequent intervals^​24​. Comparable guidelines exist for other DMARDs, with similar risks of serious adverse effects, such methotrexate, mercaptopurine, sulfasalazine and leflunomide.

Patients should be made aware of any potential serious adverse effects and how to identify them early (e.g. tendonitis with fluoroquinolone antibiotics)^​25​. Fluoroquinolones, such as ciprofloxacin, carry a specific Medicines and Healthcare products Regulatory Agency warning that details the patient information that should be provided to every patient^​25​.

Medications with monitoring requirements

Medications with the potential to cause severe adverse effects usually overlap with those that require specific or regular monitoring. Some high-risk medications, such as DMARDs, are managed under shared-care protocols, to enable safe prescribing to continue in primary care once treatment has been initiated by a hospital specialist. Shared-care protocols are essential to support effective prescribing and monitoring, as well as improve patient safety^​26​. However, they are only effective if everyone involved understands and carries out their responsibilities. 

Most high-risk medications have specific monitoring requirements. The Specialist Pharmacy Service (SPS) has produced a quick-reference summary of monitoring requirements for a range of medicines to support healthcare professionals^​27​.

Medications susceptible to interactions

Medications with a narrow therapeutic range are highly susceptible to drug interactions, leading to potential patient harm. Common examples of medications with a narrow therapeutic range include digoxin, theophylline, warfarin and carbamazepine — all of which have many drug interactions listed in the British National Formulary^​30​. These drug interactions include potential toxicity with enzyme inhibitors (e.g. clarithromycin) and potential sub-therapeutic effects with enzyme inducers (e.g. St. John’s Wort, phenytoin)^​30​. An awareness of drug interactions is required to avoid potentially life-threatening consequences of drug interactions with commonly prescribed medicines (e.g. the risk of myelosuppression when trimethoprim is co-prescribed with methotrexate)^​31​. 

Medications may not necessarily be classed as high-risk themselves but can become high-risk when used in combination. The risk of life-threatening Torsades de Pointes is increased when multiple QT-prolonging drugs are given together^​32​. The risk of respiratory depression is increased when multiple central-nervous-system depressants (e.g. opioids, alcohol and gabapentin/pregabalin) are used in combination. 

The impact of smoking or smoking cessation on drug levels is clinically relevant with certain high-risk medications, as toxins released in tobacco smoke are responsible for the induction of certain cytochrome P450 enzymes^​33​. Specific examples of high-risk medications with drug levels that are impacted by smoking or smoking cessation include clozapine, olanzapine and theophylline. Therapeutic drug monitoring is recommended if a patient stops smoking^​33,34​.

Medications with potential to cause dependency or withdrawal symptoms

Medications with the potential to cause dependence or withdrawal symptoms may be considered high-risk because of the need for safe prescribing and withdrawal management^​35​. In some cases, sudden withdrawal can lead to life-threatening situations, such as the risk of adrenal crisis and death when steroids are omitted in patients with adrenal sufficiency. This is a risk for patients with primary adrenal insufficiency, such as Addison’s disease, but also patients on oral, inhaled or topical steroids for other conditions. Patients on long-term steroids may also be at risk of adrenal crisis at times of physiological stress (e.g. acute illness, trauma or surgery), and so increased steroid doses may be required^​36​. A national patient safety alert, published in 2020, promoted the patient-held steroid emergency card to enable ‘at risk’ patients to be identified and managed appropriately^​37​.

Medications used to treat Parkinson’s disease can cause severe harm if withdrawn suddenly, potentially leading to the development of acute akinesia or neuroleptic malignant-like syndrome (i.e. reduced consciousness, fever, marked rigidity and raised creatinine kinase)^​38​. Owing to the nature of Parkinson’s disease, there are several precipitating factors that could lead to sudden drug withdrawal, such as loss of swallow, gastrointestinal problems, onset of confusion or hallucinations, loss of adherence or a need to switch therapy^​39​. As Parkinson’s disease and its medication regimens are complex, it is recommended that the patient’s specialist team are involved in any changes, to reduce the risk of patient harm^​40​. 

Other medications that have potentially serious withdrawal symptoms include opioids, benzodiazepines, antidepressants and antipsychotics. These groups of medicines should be withdrawn gradually, taking a shared-decision-making approach with the patient^​35,41​.

Time-critical medicines

Medicines are classed as time-critical if they need to be given at a certain time to ensure they are safe or work effectively; these include medicines where delayed administration can cause immediate harm (e.g. Parkinson’s disease medications). Medicines deemed to be time-critical according to the Care Quality Commission include those that:

• Should be given at a time related to food intake;
• Contain paracetamol;
• Are prescribed for Parkinson’s disease;
• Should be taken at a certain time to maximise effectiveness^​42​. 

Medications with complex dosing

A final consideration is medication with complex or unusual dosing schedules, which are more susceptible to errors, owing to unfamiliarity of dosing for both patients and healthcare professionals. An example of this is once-weekly methotrexate, which has been linked with serious and fatal overdoses owing to inadvertent once-daily administrations. These incidents led to a number of important prescribing and dispensing recommendations in a patient safety alert published in 2006^​47​. Another example of safety directives being issued to address known risks is insulin^​48​. The frequency and dose are variable depending on the insulin type and a number of patient-specific factors. Other examples include drugs that have loading doses, such as amiodarone, or apixaban for treatment of venous thromboembolism.

Strategies to reduce risk

Although it is tempting to focus safety improvement initiatives solely on specific medications or groups of medicines considered to be high-risk, the most effective safety improvements are those directed at underlying causes^​2​. Research in primary care, published in 2021, concluded that most effective safety improvements could be made through using existing information technology and improving team communication and continuity of care, which are contributory factors in many cases of patient harm^​49​. 

It is also important that we address other contributors to patient harm — for example, by applying the principles of human factors and optimising the interaction between people, systems and environments^​50​. Integrating medication-related improvements into broader healthcare challenges is more likely to be effective. However, a core safety principle is to focus efforts on areas where the risk of severe harm or death is most likely to occur, which often include high-risk medications^​2​.

Conclusion

The safe management of high-risk medicines is a critical responsibility for pharmacists. By staying informed, adhering to evidence-based guidelines and maintaining clear communication with patients and healthcare teams, pharmacists play a vital role in minimising harm and improving outcomes for patients. Vigilance, ongoing education and a proactive approach are essential to ensuring the safe use of high-risk medicines. Thankfully, many high-quality resources are available to support pharmacy professionals in this task.