High Risk Medications
High alert medicines — prescribing safety, monitoring and clinical essentials for prescribing candidates
High risk medications — also known as high alert medicines — are drugs that carry a disproportionately high risk of serious patient harm or death when used incorrectly. Identified by the NPSA (National Patient Safety Agency) and underpinned by NICE guidelines, these medicines require enhanced prescribing vigilance, structured monitoring and clear patient counselling. The ability to identify high risk medicines, articulate their risks, monitoring requirements and red flags is a core prescribing competency.
What are high risk medications?
High risk medications are defined as medicines that have a heightened risk of causing significant patient harm when used in error — even when the error itself might appear minor (such as a wrong dose or wrong frequency). The term 'high alert medicine' was coined by the Institute for Safe Medication Practices (ISMP) and adopted in the UK by the NPSA. The key characteristic is not that errors are more frequent with these drugs, but that the consequences of any error are more severe. Examples include anticoagulants, insulin, opioids, methotrexate, lithium, digoxin, immunosuppressants, chemotherapy agents, and concentrated electrolytes. NICE Medicines Optimisation guidance (NG5, 2015) emphasises that all healthcare professionals involved in prescribing must be able to identify high risk medicines and apply appropriate safety checks at every stage of the medicines pathway.
Anticoagulants: warfarin, DOACs and heparin
Anticoagulants are among the most commonly implicated medicines in preventable harm. Warfarin requires regular INR monitoring (target 2.0–3.0 for most indications; 2.5–3.5 for mechanical heart valves) and is highly susceptible to drug interactions — antibiotics, NSAIDs and amiodarone all enhance its effect. An INR above 5.0 requires the drug to be withheld and expert advice sought immediately. Direct oral anticoagulants (DOACs — apixaban, rivaroxaban, dabigatran, edoxaban) do not require routine INR monitoring but renal function must be checked before prescribing and at least annually thereafter. Dabigatran is contraindicated if eGFR falls below 30; all DOACs are contraindicated below eGFR 15. Heparin (both unfractionated and low-molecular-weight) carries risk of heparin-induced thrombocytopaenia (HIT) — if platelets fall by more than 50% within 5–10 days of starting, all heparin must be stopped immediately. Prescribing red flags: any active or unexplained bleeding, eGFR below threshold for chosen anticoagulant, concurrent NSAIDs or aspirin without clear indication.
Insulin and antidiabetic medicines
Insulin errors are a leading cause of preventable medication-related harm in hospital and community settings. Insulin must always be prescribed by brand name — never as generic 'insulin' — because different preparations (rapid-acting, long-acting, mixed) are not interchangeable. Device type (pen versus syringe) and concentration (100 units/mL vs 500 units/mL for some preparations) must be confirmed. Hypoglycaemia is the primary acute risk: mild cases are treated with 15–20 g of fast-acting carbohydrate; severe cases (loss of consciousness) require glucagon 1 mg intramuscularly or 10% glucose intravenously. Metformin must be withheld if eGFR falls below 30, and also held in acute illness, before contrast imaging, and perioperatively (sick day rules). SGLT2 inhibitors (empagliflozin, dapagliflozin) must be held if eGFR <45, during acute illness, or around surgery due to euglycaemic diabetic ketoacidosis risk. Prescribing red flags: incorrect insulin brand, failure to co-prescribe hypo treatment, metformin in eGFR <30.
Opioids and strong analgesics
Opioids cause dose-dependent respiratory depression, which can be fatal — making correct dose selection and equianalgesic conversion critical. When switching between opioids or routes of administration, a BNF conversion table must be used to calculate the equivalent dose. Fentanyl patches must never be prescribed without first calculating the total 24-hour oral morphine equivalent. A laxative (not PRN — regularly scheduled) must always be co-prescribed with any opioid, as constipation is universal. In renal impairment, morphine accumulates (its active metabolite M6G causes prolonged sedation and respiratory depression) — fentanyl, alfentanil or carefully dose-adjusted oxycodone are safer alternatives. Naloxone 400 micrograms IV or IM, titrated, reverses opioid-induced respiratory depression. Prescribing red flags: respiratory rate below 8 per minute, excessive sedation, opioid without laxative, morphine prescribed in eGFR <30.
Methotrexate — the weekly drug that must never be taken daily
Methotrexate is the drug most associated with fatal prescribing errors in non-oncological use in the UK. It is prescribed once weekly for conditions such as rheumatoid arthritis and psoriasis — NOT daily. Multiple patient deaths have followed daily prescribing errors (NPSA/2006/RRR008). Every prescription must state the dose followed by 'once weekly on [named day]'. Folic acid 5 mg once weekly, taken on a different day to methotrexate, must always be co-prescribed to reduce toxicity. Monitoring requires FBC, U&E and LFTs every two weeks until stable for six months, then every twelve weeks. Methotrexate is renally cleared and must not be used in significant renal impairment. It is also hepatotoxic, teratogenic and causes severe immunosuppression. NSAIDs must be avoided as they reduce renal clearance of methotrexate, increasing toxicity. Prescribing red flags: methotrexate without stated day of the week, missing folic acid co-prescription, no monitoring in place, NSAIDs co-prescribed, female patient of childbearing age without confirmed contraception.
Lithium, digoxin and narrow therapeutic index drugs
Lithium has one of the narrowest therapeutic windows in clinical practice. The target serum range is 0.6–1.0 mmol/L for maintenance, measured as a trough level taken 12 hours after the last dose. Levels above 1.5 mmol/L are toxic; above 2.0 mmol/L, severe toxicity with neurological damage can occur. Dehydration — from vomiting, diarrhoea, hot weather — rapidly raises lithium levels. NSAIDs, ACE inhibitors and thiazide diuretics all substantially increase lithium levels. All patients on lithium must carry a lithium treatment card. Thyroid function and renal function must be checked every six months as lithium causes hypothyroidism and nephrotoxicity over time. Digoxin similarly has a narrow therapeutic index (1.0–2.0 nanograms/mL); toxicity causes nausea, characteristic yellow-green visual disturbances (xanthopsia), bradycardia and potentially fatal arrhythmias. Amiodarone doubles digoxin levels — the digoxin dose must be halved when amiodarone is started. Hypokalaemia potentiates digoxin toxicity; potassium must be maintained above 4.0 mmol/L. Prescribing red flags for lithium: level not checked in 3+ months, NSAIDs co-prescribed, dehydration risk not addressed. Red flags for digoxin: amiodarone co-prescribed without dose reduction, hypokalaemia, level above 2.0 nanograms/mL.
Immunosuppressants and chemotherapy
Azathioprine requires TPMT (thiopurine methyltransferase) enzyme testing before initiation — patients with absent TPMT activity are at risk of fatal myelosuppression at standard doses and require dose reduction or alternative therapy. The combination of azathioprine with allopurinol is potentially fatal due to a fourfold increase in azathioprine toxicity — if this combination is unavoidable, azathioprine must be reduced to 25% of its dose with intensive FBC monitoring. Ciclosporin must always be prescribed by brand name (Neoral and Sandimmun have different bioavailability and cannot be substituted). It is nephrotoxic and extensively metabolised by CYP3A4 — levels are affected by a wide range of drugs including azole antifungals, macrolide antibiotics, rifampicin, and even grapefruit juice. NSAIDs are contraindicated with ciclosporin. Chemotherapy agents are specialist-only prescriptions requiring two-person independent checking at all stages. Neutropenic fever (temperature ≥38°C with ANC <0.5 × 10⁹/L) is an oncological emergency requiring IV antibiotics within one hour (NICE NG143). Prescribing red flags: azathioprine without TPMT testing, azathioprine + allopurinol without dose adjustment, switching ciclosporin brand.
Concentrated electrolytes and NSAIDs in high-risk groups
Concentrated potassium chloride (IV KCl) is designated a NEVER EVENT if administered as an undiluted bolus — it causes immediate cardiac arrest. All IV KCl must be diluted (maximum 40 mmol/L peripherally, administered at no more than 10 mmol/hour via peripheral access; central line access allows up to 20 mmol/hour with continuous cardiac monitoring). Commercially prepared pre-mixed bags should be used wherever possible. Hypertonic saline (1.8–3% NaCl) is reserved for specialist management of symptomatic severe hyponatraemia. Rapid correction of chronic hyponatraemia causes osmotic demyelination syndrome (central pontine myelinolysis) — an irreversible neurological catastrophe. Correction must not exceed 10–12 mmol/L per 24 hours in chronic cases. NSAIDs carry significant risks in vulnerable patients: they are contraindicated or must be used with extreme caution in CKD (eGFR <30), heart failure, peptic ulcer disease, elderly frail patients, and those on anticoagulants or corticosteroids. The 'triple whammy' combination of an NSAID, an ACE inhibitor/ARB and a diuretic carries a high risk of acute kidney injury. NSAIDs also raise lithium and methotrexate levels — these combinations must generally be avoided. A proton pump inhibitor should always be co-prescribed if an NSAID is used in a high-risk GI patient. Prescribing red flags: IV KCl without stated dilution and rate; NSAIDs co-prescribed with lithium, methotrexate, or warfarin without explicit review; NSAIDs in a patient with eGFR <30.
Clinical essentials: what prescribing candidates must demonstrate
In prescribing assessments, candidates are expected to demonstrate the following for any high-risk medicine: (1) Recognise the drug as high risk and state why. (2) Confirm the indication is appropriate and the dose is correct for this individual patient, accounting for renal and hepatic function. (3) Identify contraindications and relevant drug interactions. (4) State the monitoring plan — which test, target range, how frequently, and who is responsible. (5) Describe what action to take if monitoring results are abnormal or toxicity is suspected. (6) Outline the key counselling points the patient must receive. (7) Know and apply relevant NPSA safety alerts (methotrexate weekly dosing, IV KCl dilution, ciclosporin brand prescribing). Failure to demonstrate these steps for a high-risk medicine in a prescribing assessment is likely to result in a fail outcome for that station. Sources: NICE NG5 (Medicines Optimisation, 2015), NPSA/2007/RRR014, individual NICE condition guidelines, and BNF 2024. All clinical information reflects current national guidance.