High risk medicines

Clinical of hospitalisations associated with a medicine, as well as the consequences of missing doses or overdosing. In this article, we will look at a number of medicines that are not listed in PSNC’s high risk medicines MUR group. These include methotrexate, lithium, theophylline and digoxin.

Module 1821

High risk medicines

Methotrexate

From this module, you will learn: • Which medicines are classed as high risk • The consequences of prescribing these medicines • The role of the pharmacist and pharmacy staff in preventing adverse drug reactions caused by these medications

PHILIP CRILLY Pharmacy teaching fellow No medicine is entirely risk-free, but some medicines are more risky than others. If asked to identify a high risk medicine, many community pharmacists and their teams would look at the list of medicines detailed in the medicines use review (MUR) high risk target group (see tinyurl.com/hrmpsnc). This list is limited, however, and there are a number of medicines that many of us would classify as high risk that are not included. When the Pharmaceutical Services Negotiating Committee’s (PSNC) high risk medicines group met to discuss which drugs to include, they focused “on medicines where an MUR could improve patient safety”, bearing in mind that “the purpose of an MUR was not to address problems associated with dosage, but with medicines use”. For this reason, many medicines we would class as high risk did not make the cut.

criteria are generally used: • Has a narrow therapeutic index, and • Poses a high risk of causing a patient significant harm or death when used in error. Classifications have also looked at the number

What do we mean by a high risk medicine? A single definition for ‘high risk’ appears to be lacking. But when attempts have been made to classify these medicines in the past, the following

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Methotrexate is an immunosuppressant. It works by interfering with the growth of certain cells in the body – especially those that reproduce quickly. It is used in the treatment of rheumatoid arthritis, Crohn’s disease and many cancers. As is highlighted in the British National Formulary (BNF), methotrexate is to be taken as a weekly dose. Pharmacists and their teams must be alert to prescription dosage directions that stray from this (see A pre-reg experience, right). It is important to remember that GPs are human and can make mistakes when writing prescriptions. As part of the counselling process for patients on methotrexate, it is always advisable to discuss

medicines High risk ate - Methotrex - Lithium ine - Theophyll - Digoxin

A pre-reg experience I remember an occasion when my preregistration tutor highlighted that a patient’s methotrexate prescription had been written as a daily dose. This was the first time that the patient had been prescribed methotrexate, so they themselves would have been unaware that the dosing frequency was incorrect. Had we not been vigilant and instead dispensed the methotrexate as written on the prescription, the patient would most likely have taken it as directed. It scares me to think what the consequences may have been. This experience taught me to never become complacent and to always be on alert – particularly when dealing with prescriptions for high risk medications.

how they are finding the treatment and to emphasise the importance of dosage instructions. This is also a good opportunity to ensure they understand the importance of blood monitoring requirements for methotrexate. Both you and your customer-facing staff need to be particularly vigilant when responding to requests from patients on methotrexate for remedies for cold symptoms – particularly sore throats – as well as those presenting with: • mouth ulcers • nausea • vomiting • dark-coloured urine • shortness of breath. These can be signs of blood disorders, liver toxicity, or respiratory effects caused by methotrexate toxicity, and the patient must be referred to A&E immediately. You and your staff should also be conscious that non-steroidal antiinflammatory drugs (NSAIDs), such as over-thecounter aspirin and ibuprofen, can increase the risk of methotrexate toxicity and so should be avoided by these patients. If you are conducting an MUR for a patient taking methotrexate, and you find they are not

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prescribed folic acid, you should recommend to their GP to add this treatment to their prescription – to be taken on a different day from the methotrexate – as this may help prevent complications.

Lithium Lithium salts are used in the prophylaxis and treatment of mania, as well as in the prophylaxis of bipolar disorder and recurrent depression. Due to its narrow therapeutic index, lithium should only be prescribed if it will be possible to monitor serum-lithium levels. The BNF provides guidance on target serumlithium concentrations during treatment. Monitoring of serum-lithium levels should happen on a weekly basis following initiation of lithium treatment, as well as after each dose change, and then every three months once the dosage has been stabilised. If a patient has serum-lithium levels above the

therapeutic range, they will suffer from lithium toxicity. Signs of this include: • visual disturbances • nausea and vomiting • confusion • drowsiness • polyuria. Any of these symptoms will warrant immediately referring the patient to A&E for treatment. When taking lithium, it is important that the patient maintains adequate fluid intake and avoids dietary changes that reduce or increase sodium intake. Sodium is competitively reabsorbed in the kidneys and so if quantities are changed, it can have an effect on plasma-lithium levels. This effect is more likely to occur during the summer months or when people go on holiday to a location where temperatures are hotter than normal, as they will be more prone to becoming dehydrated.

Quitting smoking may result in plasma-theophylline levels above the therapeutic range – leading to side effects.


Patients should be advised not to abruptly stop taking their lithium, due to the risk of relapse back to a manic state. If they tell you they want to stop taking their medication, advise them to see their doctor before doing so. The doctor may switch them to an atypical antipsychotic or valproate, to reduce any risks associated with abrupt withdrawal. For those working over the counter, it is important to be aware that there is an interaction between lithium and NSAIDs – which increases the risk of toxicity. You should advise these patients to avoid over-the-counter herbal diuretics, which may affect the excretion of lithium.

Theophylline Theophylline is used to promote bronchodilation in the treatment of asthma and chronic obstructive pulmonary disease (COPD). However, it has a narrow therapeutic index. Patients starting theophylline must have their plasma-theophylline levels monitored five days after starting oral treatment, and at least three days after any dose adjustments. They should be advised to look out for signs of theophylline toxicity, which include vomiting, agitation, restlessness and dilated pupils. In addition, at higher concentrations – serum levels approaching 80mcg/mL – seizures, hypotension, and significant dysrhythmias are observed. Should patients experience symptoms that indicate theophylline toxicity, they should be referred to A&E, where activated charcoal may be used to eliminate theophylline. Smoking decreases plasma-theophylline levels, so quitting smoking may result in plasmatheophylline levels above the therapeutic range – leading to side effects. Anyone working on the healthcare counter or offering a smoking cessation service should therefore be aware of this and take extra care with those taking theophylline. If these patients want to quit smoking, they should be advised to do so while having their plasma-theophylline levels closely

monitored. Alcohol consumption may also affect these levels, so patients should be advised to avoid any drinking binges. During an MUR with a patient taking modifiedrelease theophylline, you should ensure they are using a specific brand. If a prescription does not contain a named brand, then you must speak to the GP and agree on a brand to be prescribed and dispensed in the future. This is because different brands of theophylline are absorbed at different rates, which may affect plasma-theophylline levels.

Digoxin The cardiac glycoside digoxin is used for the treatment of atrial fibrillation, tachycardia and heart failure. As digoxin is primarily eliminated from the body through renal excretion, kidney function is used to determine the dose required. Those with renal impairment should have their dose reduced and their plasma-digoxin levels monitored closely. In addition to kidney function, electrolyte levels should also be monitored – particularly potassium – as hypokalaemia can increase the chances of developing digoxin toxicity. It is recommended to carry out this monitoring at least six hours after a dose has been administered. The toxic effects of elevated digoxin levels include: • nausea and vomiting • visual disturbances • fatigue • delirium. These symptoms are similar to those which also indicate atrial fibrillation deterioration; therefore, it can be difficult to distinguish between the two. Elderly patients are particularly prone to digoxin toxicity, so extra care must be taken with them. Treatment of digoxin toxicity includes digoxin withdrawal, the correction of electrolyte abnormalities, and the use of atropine. In more serious instances, where these initial measures have not been successful, digoxin-specific antibody fragments are required.


Healthcare assistants should be particularly alert to any patients taking digoxin who ask to purchase St John’s wort. This herbal remedy can reduce plasma-digoxin levels, and so should not be taken by these customers. Other interactions that you should be aware of include amiodarone, which can increase the plasma concentration of digoxin, and therefore may require the digoxin dose to be adjusted. In addition, macrolide antibiotics, calcium channel blockers and certain diuretics can also increase the risk of digoxin toxicity.

The pharmacist’s role This article does not contain a definitive list of high risk medicines. It may therefore be useful to draw up your own list of medications that you would class as high risk in your pharmacy – and make your whole team aware of them. It may include enzyme-inducers – such as phenytoin, carbamazepine and St John’s wort – as well as medications that are enzyme inhibitors, such as: • macrolides eg erythromycin • quinolones eg ciprofloxacin • sodium valproate.

For those patients taking a high risk medication on a repeat prescription, it is important to discuss how they are getting on with their medication, so that you are satisfied it is safe to continue with their treatment. You should also highlight the importance of attending regular blood monitoring clinics, if this is required. Should you have a concern that a patient is experiencing the toxic effects of a medication, it is vital you refer them to the most appropriate source of support. In some instances, this will be

their GP, who will review their treatment. But in other situations – as described earlier – they may need to be referred to A&E for immediate medical attention. Pharmacists are uniquely placed to recognise the side effects of high risk medications. Patients may not visit their GP on a regular basis, so you may be the only point of contact they have with a healthcare professional. The role you and your team play in keeping people safe from the adverse effects of high risk medications is therefore essential.

High risk medicines CPD

Take the 5-minute test online

Reflect What criteria defines a high risk medicine? What are the symptoms of methotrexate toxicity? How does smoking affect theophylline blood levels?

1. Not all high risk medicines are included in the PSNC’s high risk medicines MUR target group. True or false?

7. Symptoms of theophylline toxicity include vomiting, agitation, restlessness and dilated pupils. True or false?

2. Methotrexate is usually taken twice weekly. True or false?

8. Smoking increases plasma-theophylline levels, so the dosage for smokers should be reduced to avoid toxicity. True or false?

Plan This article contains information about high risk medicines, including which medicines are classified as high risk, the consequences of prescribing them, and the role of the pharmacist and pharmacy staff in preventing adverse drug reactions caused by these medications. Act Revise your knowledge of methotrexate, lithium, theophylline and digoxin by reading their entries in the BNF. Think about other high risk medicines might you need to revise your knowledge of. Read about how to identify high risk medicines with this systematic review at tinyurl.com/highrisksysreview Read about the cautions and contraindications of digoxin on the BNF website at tinyurl.com/BNFdigoxin

3. NSAIDs can increase the risk of methotrexate toxicity. True or false? 4. Common side effects of methotrexate include visual disturbances, drowsiness and polyuria. True or false?

Identify any patients taking a high risk medicine who might benefit from an MUR or patient consultation

5. Patients taking lithium should maintain adequate fluid intake and avoid dietary changes that reduce or increase sodium intake. True or false?

Evaluate Are you now familiar with the risks associated with methotrexate, lithium, theophylline and digoxin? Could you give advice to patients and carers about recognising side effects and adverse reactions?

6. Over-the-counter herbal diuretics may affect the excretion of lithium. True or false?

Identify any training needs that you or your pharmacy staff may have, and find out about learning courses focusing on high risk medicines


9. Patients with renal impairment should have a reduced dose of digoxin and their plasmadigoxin levels monitored closely. True or false? 10. Plasma-digoxin levels can be decreased by amiodarone. True or false?
