High Risk Medicines

By KnowledgeDose

7th December 2023

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This is a guide on high risk medicines, also known as high alert medications.

Table of Contents:

1. What are high risk medicines?
2. Lists of high risk medicines
3. How to prevent medication errors with high risk medicines
4. Examples of some high risk medicines, along with their possible risks and harm to the patient and what strategies to take to reduce risk

What are high risk medicines?

Medicines with a high potential for causing patient injury or harm due to misuse or error are defined as high-risk medicines (in the USA and some other countries, these are known as high alert medications).

When high risk medicines are used in error or administered incorrectly (as compared to other medicines), there is an increased likelihood of causing severe harm/serious side effects to the patient.

Lists of high risk medicines

Various organisations and institutions worldwide have compiled their classifications or lists of high risk medicines. These can vary depending on the healthcare sector or setting.

Below are two lists showing examples of high risk medicines.

Sources: References 1-5

How to prevent medication errors with high risk medicines

As a doctor, pharmacist or nurse, there are certain precautions you can take when prescribing, dispensing, or administering high-risk medications to avoid medication errors and prevent harm to the patient.

• Follow clinical guidelines, the drug formulary, drug protocols and safety protocols
• Know the monitoring requirements for the high risk medicine
• Know what adverse effects to look out for
• Know when a high risk medicine should be stopped. Also, ensure all team members looking after the patient are aware of what adverse effects to look out for.
• Make sure the instructions on how to take the medicine on the dispensing label are clear and can be understood by the patient
• Handwriting should be legible on handwritten prescriptions
• Check potential drug interactions
• Obtain a full medicine history before prescribing or dispensing a high risk medicine
• Provide the patient with safety netting advice that is individualised to that patient
• Check MHRA safety warnings, FDA-boxed warnings (black box warning) or any other drug safety warnings associated with the medicine
• Take extra care and precautions when prescribing or dispensing look-alike sound-alike medicines
• At the point of handing out a prescription to the patient, always check that that the medicine you have given is what they are expecting, provide patient counselling advice, state the dose to be taken and check with the patient if the doctor is monitoring them
• Always ensure that you are using the right patient parameters to calculate a patient’s dose according to their renal function (e.g. know for what drugs to use eGFR vs. CrCl [Cockcroft-Gault equation]), weight (when to use the adjusted body weight, ideal body weight or actual body weight in calculating a dose) and body surface area (BSA)
• For drugs that have a narrow therapeutic window, ensure that you carry out therapeutic drug monitoring at the recommended frequency and tailor the monitoring frequency according to each patient
• Check the summary of product characteristics (SmPC) when prescribing a high risk medicine such as special precautions for its use

Individual examples of high risk medicines / high alert medications along with their potential for causing harm to the patient and strategies to mitigate these risks

Aminoglycosides

e.g. gentamicin, amikacin

Possible risks and harm to the patient

• Nephrotoxicity
• Ototoxicity (vestibular and auditory toxicity)
• Neuromuscular blockade

Possible strategies to take to reduce risk and harm to the patient

• Avoid concurrent administration of other nephrotoxic drugs (e.g. amphotericin B, NSAIDs, ciclosporin, ACE inhibitors and diuretics), ototoxic drugs (e.g. cisplatin, loop diuretics), or drugs that have neuromuscular blocking effects with an aminoglycoside⁶
• Ensure the patient is hydrated
• Check for drug interactions
• Take care when calculating the aminoglycoside dose for the patient
• Monitor serum aminoglycoside concentration levels during treatment to ensure levels are within therapeutic range. Aminoglycosides have a narrow therapeutic window. Carrying out monitoring of serum aminoglycoside concentration levels avoids toxicity such as nephrotoxicity and ototoxicity and also ensures that concentration levels are not sub-therapeutic.
• Monitor renal function during treatment and compare it with baseline renal function before treatment. If there are any changes, review treatment.
• Monitor auditory and vestibular function during treatment⁶
• Staff education on recognising signs of gentamicin toxicity/adverse effects
• Educate the patient on the signs and symptoms of adverse effects such as allergic reactions, passing less urine than usual, breathlessness, fluid retention, hearing loss, dizziness and poor/loss of balance
• Before prescribing the aminoglycoside, carry out checks to determine the risk of renal toxicity and ototoxicity to the patient and take the necessary steps to avoid this from happening e.g. reduce dose and/or increase dose interval in a person with impaired renal function⁶
• Review the prescription frequently
• Indicate the planned duration of treatment on the prescription
• Follow local guidelines for the use of aminoglycosides

Oral and parenteral anticoagulants

Oral anticoagulants e.g. warfarin, apixaban, dabigatran, edoxaban, rivaroxaban

Parenteral anticoagulants e.g. heparin, low molecular weight heparins

Possible risks and harm to the patient

• Bleeding
• Thrombosis (due to sub-therapeutic dose/missed doses)
• Prescribers/pharmacists check for potential drug interactions and manage clinically significant drug interactions including herbal products and over-the-counter medicines

Possible strategies to take to reduce risk and harm to the patient

• Taking care when switching anticoagulants or during bridging
• Carry out a regular review of prescription
• Follow anticoagulant guidelines/protocol
• Test for INR in patients taking warfarin and at the appropriate frequency
• Check the APTT ratio in patients on heparin
• Low molecular weight heparins: Treatment dose is dependent on the patient’s weight and renal function. Ensure you are using the most up-to-date weight and renal function of the patient.
• Ensure patients taking warfarin have received an information booklet (e.g. yellow book) and an alert card. Remind the patient to carry their alert card with them at all times. Also, remind them to show this card to healthcare professionals when they need medical/dental treatment.
• Check patients taking direct oral anticoagulants have been given an alert card
• Check for contraindications when prescribing anticoagulants
• Provide patient counselling on the indication and duration of treatment, taking at the same time of the day, alcohol intake and reporting signs of bleeding and thrombosis
• Advise patients to report to their healthcare team any changes that might affect their INR e.g. changes in diet, changes in alcohol intake, illness, starting a new medicine
• Reiterate the importance of not missing doses when it comes to direct oral anticoagulants as the anticoagulant effect is reduced 12-24 hours after the last dose is taken

Antihypertensives

ACE inhibitors e.g. ramipril, perindopril, lisinopril

Angiotensin-II receptor blockers e.g. irbesartan, losartan, candesartan

Possible risks and harm to the patient

• Hypotension
• Falls
• Hyperkalaemia
• Acute kidney injury
• Renal function decline
• Angioedema (can occur first week of treatment or after months/years of treatment)

Possible strategies to take to reduce risk and harm to the patient

• Monitor electrolytes before and during treatment
• Monitor renal function before and during treatment
• Monitor blood pressure
• Avoid postural hypotension by sitting up and standing slowly
• Undertake a risk fall assessment in older people
• To avoid side effects and increase patient compliance, use the lowest effective dose
• Provide clear advice to patients about what to do when they fall sick and when to temporarily stop and restart their ACE inhibitor or angiotensin-II receptor blockers versus providing generic advice on sick day rules
• Prescribers/pharmacists check for potential drug interactions and manage clinically significant drug interactions (e.g. ACE inhibitor/angiotensin-II receptor blocker + diuretic + NSAID)
• Educate the patient on the signs/symptoms of angioedema

Antiplatelets

e.g. aspirin, clopidogrel

Possible risks and harm to the patient

• Bleeding
• Thrombosis (due to sub-therapeutic dose)
• Dual antiplatelet therapy vs antiplatelet monotherapy carries higher bleeding risk

Possible strategies to take to reduce risk and harm to the patient

• Prescribers/pharmacists check for potential drug interactions and manage clinically significant drug interactions including herbal products and over-the-counter medicines
• Regular review of prescription
• Patient counselling on the indication and duration of treatment, signs of bleeding and thrombosis and taking prophylactic gastro-protection
• Before initiating dual antiplatelet therapy in the patient, consider the balance between thrombosis risk and bleeding risk

Benzodiazepines

e.g. diazepam, alprazolam, temazepam, lorazepam

Possible risks and harm to the patient

• Falls
• Confusion
• Over-sedation
• Paradoxical effects e.g. aggressive behaviour, increased anxiety
• Dependence

Possible strategies to take to reduce risk and harm to the patient

• Avoid prescribing long-term
• Avoid use in the elderly where possible
• Sedation score
• Prescription monitoring
• Treating or managing the underlying condition

Diuretics

e.g. loop diuretics, thiazides

Possible risks and harm to the patient

• Hypotension
• Falls
• Hyponatraemia
• Hypokalaemia
• Dehydration

Possible strategies to take to reduce risk and harm to the patient

• Prescribers/pharmacists check for potential drug interactions and manage clinically significant drug interactions (e.g. ACE inhibitor/angiotensin-II receptor blocker + diuretic + NSAID)
• Laboratory monitoring of electrolyte imbalances and creatinine
• Monitor blood pressure
• Avoid postural hypotension–sit up and stand slowly
• Fall prevention strategies
• Timing of dose to avoid interference with sleep
• Reviewing the prescription regularly
• Using the lowest effective dose
• Adequate fluid intake

NSAIDs

e.g. ibuprofen, indometacin, ketoprofen

Possible risks and harm to the patient

• Peptic ulcers
• Gastrointestinal bleeding
• Renal toxicity
• Exacerbation of asthma
• NSAIDs can increase the risk of cardiovascular adverse events

Possible strategies to take to reduce risk and harm to the patient

• Prescribers/pharmacists check for potential drug interactions and manage clinically significant drug interactions
• Take with meals
• Consider prophylactic gastro-protection
• Patient counselling on recognising signs of bleeding, using the lowest effective dose for the shortest time possible to avoid adverse events/effects and avoiding over-the-counter NSAIDs
• Review the prescription regularly

Insulin and oral hypoglycaemic drugs

e.g. sulfonylureas, metformin, pioglitazone, acarbose, repaglinide, DPP-4 inhibitors, SGLT2 inhibitors, GLP-1 receptor agonists, insulin and their analogues

Possible risks and harm to the patient

• Hypoglycaemia
• Hyperglycaemia
• Metformin can cause lactic acidosis (risk factors for metformin-associated lactic acidosis include renal impairment, hepatic insufficiency and excessive alcohol intake)
• Rare cases of diabetic ketoacidosis (DKA) including life-threatening and fatal cases have been reported with SGLT2 inhibitors⁷
• Post-marketing cases of cardiac failure have been reported when pioglitazone was used in combination with insulin or in patients with a history of cardiac failure^8,9
• Serious and life-threatening cases of DKA have been reported in association with exenatide, liraglutide, and dulaglutide, particularly after discontinuation or reduction of concomitant insulin¹⁰

Possible strategies to take to reduce risk and harm to the patient

• Educating patient on recognising signs/symptoms and the prevention and management of hypoglycaemia/hyperglycaemia
• Monitor blood glucose at the correct frequency
• Show dispensed insulin to the patient to confirm the correct insulin has been given
• Patient counselling on the proper administration of insulin, sick day rules, storage of insulin and lifestyle advice
• When prescribing insulin, write units in words
• Prescribe insulin by brand name
• Provide/check that a person has an insulin passport
• Educate/train prescribers and nurses on the types of insulin products available and the safe use of insulin
• Educate patients on the symptoms of lactic acidosis e.g. nausea, vomiting, fatigue, rapid breathing
• Pioglitazone and insulin combination: monitor patient for signs and symptoms of heart failure, oedema and weight gain. Pioglitazone should be stopped if there is any deterioration in cardiac status.⁹
• SGLT2 inhibitors: patient counselling on how to recognise the symptoms of DKA and to seek immediate medical attention if DKA is suspected
• Advise the patient to monitor their blood glucose when adjusting the dose of insulin, particularly when GLP-1 receptor agonist therapy is initiated and insulin is reduced¹⁰

Lithium

Possible risks and harm to the patient

• Toxicity

Possible strategies to take to reduce risk and harm to the patient

• Counsel patients to recognise signs and symptoms of lithium toxicity, side effects, the importance of maintaining adequate fluid intake, avoiding dietary changes that may increase or decrease sodium intake and discontinuing lithium abruptly
• Maintain the patient on the same brand name
• Monitor serum lithium concentration (lithium has a narrow therapeutic window), thyroid function, renal function and electrolytes
• Ensure patients taking lithium have received a purple lithium treatment pack (information booklet, record booklet and an alert card). Remind the patient to carry their alert card with them at all times. Also, remind them to show this card to healthcare professionals when they need medical/dental treatment.

Oral methotrexate

Possible risks and harm to the patient

• Bone marrow suppression
• Liver toxicity
• Pulmonary toxicity

Possible strategies to take to reduce risk and harm to the patient

• State the methotrexate strength to dispense, the dose and directions on the prescription
• Communicate the dosing schedule to the patient including when to take folic acid
• Exercise caution when performing the clinical check and dispensing methotrexate
• Monitor full blood count, renal function and liver function
• Patient counselling on methotrexate toxicity (e.g. fever, sore throat, mouth ulcers, abdominal pain, dyspnoea, chest pain) and using effective contraception
• Prescribers/pharmacists check and manage potential drug interactions with methotrexate and advise the patient to avoid over-the-counter NSAIDs
• Ensure patients taking methotrexate have received an information booklet and a patient card. Remind patients to carry their patient cards with them at all times. Also, remind them to show this card to healthcare professionals when they need medical/dental treatment.

Opioids

e.g. morphine, fentanyl, oxycodone, buprenorphine, tramadol, codeine

Possible risks and harm to the patient

• Respiratory depression
• Dependence
• Overdose
• Sedation
• Confusion
• Constipation
• Nausea and vomiting

Possible strategies to take to reduce risk and harm to the patient

• Use the lowest effective dose
• Assessment of pain relief
• Discuss the risks and benefits of opioids with the patient
• Follow up and evaluate the need for opioids frequently with the patient
• Measure pain
• When re-prescribing/dispensing opioids, always check with the patient that tolerance to the opioid has not been lost or reduced
• Counsel patient on the cautions for use and how to apply an opioid transdermal patch (e.g. buprenorphine, fentanyl)
• Follow prescribing guidelines
• Undertaking medicines reconciliation
• Referral to the pain team
• Prescribe the smallest quantity

Azathioprine

Possible risks and harm to the patient

• Toxicity

Possible strategies to take to reduce risk and harm to the patient

• Ongoing monitoring of the patient for toxicity during treatment
• Counsel patient to report any signs and symptoms of bone marrow suppression e.g. unexplained bleeding, bruising and infection
• Routinely carry out liver function tests and full blood counts

Tacrolimus

Possible risks and harm to the patient

• Toxicity and graft rejection

Possible strategies to take to reduce risk and harm to the patient

• Prescribe and dispense by brand name only¹¹
• Monitor blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes, liver function, renal function, haematology parameters, coagulation values and plasma protein determinations¹²
• Narrow therapeutic index window–monitor whole blood-tacrolimus trough concentration¹²
• Make patients aware that grapefruit juice can increase tacrolimus blood levels and to avoid it¹²

Ciclosporin

Possible risks and harm to the patient

• Toxicity
• Nephrotoxicity
• Hypertension
• Neurotoxicity
• Hyperlipidaemia

Possible strategies to take to reduce risk and harm to the patient

• Prescribe and dispense by brand name only
• Carry out regular therapeutic drug monitoring
• Carry out regular blood pressure monitoring
• Monitor urea and electrolytes, full blood count, liver function, renal function and lipids¹³

Vancomycin

Possible risks and harm to the patient

• Nephrotoxicity
• Agranulocytosis or neutropenia
• Tinnitus
• Ototoxicity
• Red man’s syndrome
• Severe cutaneous adverse reaction (SCAR)

Possible strategies to take to reduce risk and harm to the patient

• Monitor auditory and vestibular function during treatment. Avoid concurrent administration or sequential use of other ototoxic drugs with vancomycin.¹⁴
• Carry out full blood count, liver function test, urinalysis and renal function test¹⁴
• Monitor vancomycin serum concentration. The frequency should be individualised.
• Administer vancomycin intravenous infusion at the correct rate
• Monitor patients for skin reactions and counsel patients to report symptoms of SCARs immediately¹⁴

Colchicine

Possible risks and harm to the patient

• Toxicity
• Bone marrow depression

Possible strategies to take to reduce risk and harm to the patient

• Colchicine has a narrow therapeutic window. Monitor the patient for signs/symptoms of colchicine toxicity. Advise patients to stop taking colchicine if they develop nausea, vomiting, abdominal pain or diarrhoea.¹⁵
• Patient counselling on how to take colchicine including the maximum dose
• Advise patients to stop taking colchicine and seek immediate medical attention if they develop signs or symptoms that could indicate a blood cell dyscrasia, such as fever, stomatitis, sore throat, prolonged bleeding, bruising or skin disorders¹⁵

Theophylline

Possible risks and harm to the patient

• Toxicity

Possible strategies to take to reduce risk and harm to the patient

• Theophylline has a narrow therapeutic window. Carry out therapeutic drug monitoring.
• Smoking and alcohol consumption can increase the clearance of theophylline. Before prescribing theophylline, check smoking and alcohol consumption with the patient. For those patients prescribed theophylline, advise the patient to report changes to smoking and alcohol consumption as the dose may need to be adjusted.¹⁶
• Prescribe and dispense by brand name only

References:

1. Australian Commission on Safety and Quality in Health Care. APINCHS classification of high risk medicines. Available at: https://www.safetyandquality.gov.au/our-work/medication-safety/high-risk-medicines/apinchs-classification-high-risk-medicines [Accessed on 27/11/2023].
2. General Pharmaceutical Council. Registration assessment framework for sittings in 2023. Available at: https://www.pharmacyregulation.org/sites/default/files/document/registration_assessment_framework_for_sittings_in_2023.pdf [Accessed on: 31/10/2023].
3. Institute for Safe Medication Practices (ISMP). ISMP List of High-Alert Medications in Community/Ambulatory Care Settings. ISMP; 2021. Available at: https://www.ismp.org/recommendations/high-alert-medications-community-ambulatory-list [Accessed on: 27/11/2023].
4. Institute for Safe Medication Practices (ISMP). ISMP List of High-Alert Medications in Long-Term Care (LTC) Settings. ISMP; 2021. Available at: https://www.ismp.org/recommendations/high-alert-medications-long-term-care-list [Accessed on: 27/11/2023].
5. Institute for Safe Medication Practices (ISMP). ISMP List of High-Alert Medications in Acute Care Settings. ISMP; 2018. Available at: https://www.ismp.org/recommendations/high-alert-medications-acute-list [Accessed on: 27/11/2023].
6. B.Braun Medical. Gentamicin 1 mg/ml solution for infusion – Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/15144/smpc [Accessed on 15/11/2023].
7. Medicines and Healthcare products Regulatory Agency. SGLT2 inhibitors: updated advice on the risk of diabetic ketoacidosis. Drug Safety Update volume 9 issue 9 April 2016: 1. Available via https://www.gov.uk/drug-safety-update/sglt2-inhibitors-updated-advice-on-the-risk-of-diabetic-ketoacidosis [Accessed on: 27/11/2023].
8. Medicines and Healthcare products Regulatory Agency. Insulin combined with pioglitazone: risk of cardiac failure. Drug Safety Update Jan 2011, volume 4 issue 6: A2. Available via https://www.gov.uk/drug-safety-update/insulin-combined-with-pioglitazone-risk-of-cardiac-failure [Accessed on: 27/11/2023].
9. Sandoz Limited. Pioglitazone 15 mg Tablets – Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/7407/smpc [Accessed on 27/11/2023].
10. Medicines and Healthcare products Regulatory Agency. GLP-1 receptor agonists: reports of diabetic ketoacidosis when concomitant insulin was rapidly reduced or discontinued. Drug Safety Update volume 12, issue 11: June 2019: 2. Available via https://www.gov.uk/drug-safety-update/glp-1-receptor-agonists-reports-of-diabetic-ketoacidosis-when-concomitant-insulin-was-rapidly-reduced-or-discontinued [Accessed on: 27/11/2023].
11. Medicines and Healthcare products Regulatory Agency. Oral tacrolimus products: prescribe and dispense by brand name only, to minimise the risk of inadvertent switching between products, which has been associated with reports of toxicity and graft rejection. Drug Safety Update June 2012, volume 5 issue 11: A1. Available via https://www.gov.uk/drug-safety-update/sglt2-inhibitors-updated-advice-on-the-risk-of-diabetic-ketoacidosis [Accessed on: 27/11/2023].
12. Sandoz Limited. Adoport 0.5 mg Hard Capsules – Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/585/smpc [Accessed on 15/11/2023].
13. Mylan. Capimune 25 mg soft capsules – Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/693/smpc [Accessed on 15/11/2023].
14. Flynn Pharma Ltd. Vancocin Powder for Solution – Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/6407/smpc [Accessed on 15/11/2023].
15. Strides Pharma UK Ltd. Colchicine 500 mcg Tablets – Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/14362/smpc [Accessed on 15/11/2023].
16. Ennogen Healthcare Ltd. Uniphyllin Continus 300mg prolonged-release tablets – Summary of Product Characteristics. Available at: https://www.medicines.org.uk/emc/product/14510/smpc [Accessed on 15/11/2023].

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