The use of simvastatin 40 mg with various interacting medicines may lead to an increased risk of myopathy. We examined the extent to which hospital inpatients were prescribed simvastatin 40 mg with amiodarone, amlodipine, diltiazem, or verapamil, and assessed if any action was taken by prescribers or the pharmacy team to avoid this interaction. We found 56 patients on a combination of interest during their stay. Of the 20 (36%) patients not discharged on the combination, in six instances this was due to pharmacy intervention, while the remaining instances when simvastatin 40 mg or the interacting drug was amended or ceased were due to other clinical reasons. There is a need among clinicians and pharmacy teams within the hospital for recognition and management of these particular interactions.
Introduction
A drug–drug interaction (DDI) is a pharmacokinetic (PKI) or pharmacological influence of one medicine on another that differs from the known or anticipated effects of each agent alone. A DDI may result in a change in either drug efficacy or drug toxicity for one or both of the interacting medicines. PKI interactions occur when one medicine alters the absorption, distribution, metabolism, or excretion of another, thus, increasing or decreasing the amount of medicine available to produce its pharmacological effects. Such PKI interactions occurring with one medicine do not necessarily occur uniformly across a group of related medicines.1
Although considered relatively safe, statins are associated with adverse drug reactions including statin-induced myopathy. A known risk factor with some of the statins is a combination of medicines that increase the statin plasma level, including some antibiotics and some calcium-channel blockers.2 The various statins have different DDI potentials due to different PKI properties.3 Simvastatin, lovastatin and atorvastatin are all metabolised by cytochrome P450 3A4 (CYP3A4), whereas pravastatin and fluvastatin mainly have other eliminating pathways.4 Many medicines are inhibitors or inducers of CYP3A4, and the general interaction potential of simvastatin, lovastatin and atorvastatin is, therefore, higher than for other statins. The maximum recommended daily dose for simvastatin in conjunction with one of the CYP3A4 inhibitors amiodarone, amlodipine, diltiazem, or verapamil is 20 mg.5
Studies from over 10 years ago have examined concomitant prescribing of simvastatin and CYP3A4 inhibitors in different countries, including the UK.6–9 An unpublished trainee pharmacist project, from a previous year in a primary care setting in Cornwall, identified 42 (14%) of 305 patients prescribed simvastatin and a CYP3A4 inhibitor were receiving the unlicensed dose of simvastatin 40 mg. Hence, we wanted to investigate if there were similar concerns for hospital inpatients.
Aims and objectives
The main aim of this study was to evaluate the extent of prescribing of the combination of simvastatin 40 mg and several predefined high-risk interacting medicines within a hospital setting.
Method
This was a descriptive, retrospective study in a 750-bed acute hospital in the southwest of England serving a population of 450,000. A search was undertaken of adult patients prescribed simvastatin 40 mg with amiodarone, amlodipine, diltiazem, or verapamil using the electronic prescribing system (EPS) (Careflow Medicines Management) between January 2022 to October 2022. Relevant data (medicines, patient demographics) were extracted from the EPS. The EPS and discharge summaries were also searched for any additional information, in particular, for any notes made by the prescriber or pharmacy team signifying that they had recognised and acted on this combination. EPS was also used to identify the total number of patients prescribed simvastatin 40 mg during that time. Any such identified patients who did not have the opportunity during the admission for interacting medicines to be modified (e.g. died in hospital) were excluded. Data were entered into Microsoft Excel for analysis.
Results
Box 1. Notes made by pharmacists about the interaction for six patients
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| Key: LDL-C = low-density lipoprotein cholesterol; od = once daily |
There were 571 patients prescribed simvastatin 40 mg during their hospital admission. Of these, 56 (10%) patients (mean age 78, range 59–94 years, 50% female) were prescribed a combination of interest during their stay. A further 13 who died in hospital were excluded. Thirty (54%) patients were admitted on the combination. Simvastatin 40 mg appeared with amlodipine in 43 (77%) of instances, diltiazem in six (11%), amiodarone in six (11%), and verapamil in one (2%). Thirty (54%) of 56 patients were discharged on this combination, and six had no information on discharge medicines on the EPS available to check. Of those 19 (34%) patients not discharged on the combination, in six instances this was due to pharmacy intervention (box 1). For the remaining instances when simvastatin 40 mg or the interacting drug was amended or ceased, this was due to other clinical reasons, such as amlodipine stopped due to postural hypotension, or simvastatin changed to a higher-intensity statin (atorvastatin).
For one of the 56 patients, the pharmacist had recognised the potential interaction. Rather than make changes to the medicines during the hospital admission, there was a communication to the GP in the discharge summary that simvastatin 20 mg was the maximum dose with concomitant diltiazem.
Discussion
Official warning about these interactions is at least 10 years old, and appears in readily available prescribing resources.5,10,11 In addition, for primary care this is an area of prescribing that the Care Quality Commission may review when inspecting general practices.12 However, we observed a distinct lack of attention to, or possible lack of knowledge of, these potentially hazardous interactions with simvastatin 40 mg. We had patients admitted on a combination of interest, some inpatients commenced on a combination, and just over half of the cohort discharged on such a combination. Such in-hospital prescribing of interacting drugs and lack of pharmacy team clinical check could be due to unawareness of the Medicines and Healthcare products Regulatory Agency (MHRA) alert.5 In addition, though our EPS has the functionality of triggering alerts to notify prescribers of interactions, only level 4 warnings (contraindicated combinations) are flagged, and the combination interactions of interest are dose-dependent, so at level 3 warning, which remains suppressed and not easily visible to the prescriber. It is possible that our prescribers believe that by prescribing electronically there is an element of clinical support that flags important interactions. They may not know of the distinction on our EPS between level 4 and level 3 warnings. Furthermore, there are recognised barriers (such as false positive alerts and alert fatigue) to the use of DDI clinical decision support systems (CDSS).13 Interestingly, statin interactions were overridden in between 80 and 90% of DDI alerts in an evaluation of CDSS.13
Five of the six patients with evidence of pharmacist intervention on in-hospital prescribing were from the cardiology pharmacist reviewing these patients on cardiology wards; the remaining note was from a pharmacist covering an acute medical ward. This latter pharmacist was also responsible for spotting the interaction and communicating to the GP in the discharge summary.
A study in Norway from 2004/05 concluded that Norwegian physicians generally do not recognise the drug interaction risk associated with co-administration of CYP3A4 inhibitors and simvastatin or atorvastatin, despite warnings in the prescribing information of these drugs.14 In this primary care study, trained community pharmacists alerted the prescribing physician about the co-prescription in approximately two-thirds of cases. This study utilised a simple computer program in the pharmacy that automatically produced a message on the computer screen when a CYP3A4 inhibitor was dispensed.14 As mentioned above, our hospital EPS does not have this alerting functionality. This Norway study also occurred in a time period when there was perhaps more attention directed at statin interactions. Likewise, a study in the USA from 2006 suggests that there is insufficient consideration of risk by physicians of DDIs due to co-prescribing of CYP3A4-metabolised statins with CYP3A4 inhibitors.15
Clinical reasons, rather than recognition of the interaction, for changing patients from simvastatin 40 mg to a different statin included when a higher-intensity statin was required. National guidance recommends use of atorvastatin 10 mg in primary prevention and higher doses in secondary prevention.16 Any use of simvastatin 40 mg should, therefore, be prompting a review of the lipid management, regardless of any concomitant interacting medicine.17 Results of this review of simvastatin and its implications are to be shared with hospital and primary care clinicians and pharmacy teams.
Strengths and limitations
This is a cross-sectional study that collected data on all patients prescribed simvastatin 40 mg in combination with pre-defined target medicines over a 10-month period. There are recognised limitations of this single-centre, retrospective study. We did not look at interactions between simvastatin and other medicines, including more potent CYP3A4 inhibitors, such as macrolide and azole antifungals, nor interactions with other statins. We did not investigate whether these patients were suffering from muscle-related adverse events. We also note that three patients were not seen by the pharmacy team during their very short hospital admission, and so there was no opportunity for pharmacy intervention.
Conclusion
Despite, or perhaps due to, over a decade having passed since warnings emerged about the interaction between simvastatin 40 mg and interacting medicines, we found that concomitant prescribing still occurs. The absence of an alert on the prescribing system in a hospital setting, and the fact that prescribers may be unaware that the system does not trigger an alert, may contribute to this problem.
Key messages
- Simvastatin at a dose of 40 mg daily has a number of important pharmacokinetic interactions, which may increase the risk of myopathy
- We assessed whether simvastatin 40 mg was co-prescribed with amiodarone, amlodipine, diltiazem, or verapamil for hospital inpatients
- Over 10 months, 56 patients were prescribed a combination of interest during their admission. There was little evidence of proactive intervention to avoid the interaction
- Our study provides further evidence that more attention is needed from clinicians and the pharmacy team to this interaction
Conflicts of interest
None declared.
Funding
None.
Study approval
This study was categorised as a service evaluation, not requiring NHS Research Ethics Committee approval. This study was approved locally as a Clinical Effectiveness Project. As data collection occurred within standard clinical care, routinely provided at the study site, patient consent was neither sought nor required. Patient data were used in accordance with local NHS Trust Policy and in line with general data protection regulations.
References
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