A study on the relevance and the need of transmural medication surveillance in ambulatory cancer patients undergoing an intravenous oncolytic regimen is presented
Brigit van Oijen MSc
Carlota Mestres Gonzalvo MSc
Department of Clinical Pharmacy and Toxicology, Orbis Medical Centre, Sittard,
Frans Erdkamp MD
Department of Haematology and Oncology, Orbis Medical Centre, Sittard, The Netherlands
Susanne de Vaal MSc
Polyclinical Transmural Pharmacy, Orbis Medical Centre, Sittard, The Netherlands
Bjorn Winkens PhD
Department of Methodology and Statistics, School for Public Health and Primary Care (CAPHRI), Maastricht University, The Netherlands
Harry Schouten MD PhD
Department of Internal Medicine,
University Hospital Maastricht, The Netherlands
Rob Janknegt PharmD PhD
Paul-Hugo van der Kuy PharmD PhD
Department of Clinical Pharmacy and Toxicology, Orbis Medical Centre, Sittard,
In addition to chemotherapy, cancer patients often take a range of drugs to treat therapy-induced symptoms (for example, antiemetics). Due to the use of co-medication, the risk of interactions and the occurrence of adverse drug reactions (ADRs) are increased.(1–4) An example is the interaction between aprepitant (an antiemetic agent) and irinothecan.
The occurrence of ADRs might cause a negative effect on patients’ quality of life while the primary goal of the treatment is to improve it.(1) In some patients, this negative effect might even lead to discontinuation of chemotherapy.(5,6) It is suggested that the occurrence of drug-related interactions (that is, antithrombotic agents) might even be the cause of death in approximately 4% of cancer patients undergoing chemotherapy.(7)
Because of the narrow therapeutic range of oncolytic drugs, even a small increase or decrease in the activity of the drug due to an interaction may have serious consequences. Therefore, medication surveillance in cancer patients becomes even more important.(4,8)
Prevalence of interactions
The prevalence of potential oncolytic drug-related interactions in cancer patients has been demonstrated in only a few recent studies.(3,9–11) However, there are some differences, depending on the study design. For cancer patients treated only with oral oncolytic drugs, 46% had a potential drug interaction, compared to approximately 5% in cancer patients only treated with intravenous chemotherapy.(9,11) This discrepancy could be explained by the software used to identify the potential drug–drug interactions.
The need to improve medication surveillance for ambulatory cancer patients receiving intravenous oncolytic drugs is increased due to the changing demands concerning the medication surveillance on the one hand, and the high doses of oncolytic drugs in combination with the increasing age of cancer patients on the other. In a previous retrospective study, the frequency and relevance of oncolytic drug-related interactions among ambulatory cancer patients was evaluated. The outcome of this study demonstrated 11 interactions per 100 ambulatory cancer patients, of which one was considered clinically relevant.(11)
The aim of this study was to discuss the relevance and the need of (transmural) medication surveillance in ambulatory cancer patients undergoing an intravenous oncolytic regimen.
Study design and setting
The study was a prospective study performed at the Orbis Medical Center (OMC) in Sittard, The Netherlands. The OMC is a general hospital with approximately 440 beds and in which around 200 (ambulatory) cancer patients are treated weekly. At the OMC, all oncolytic regimens are predefined and prescribed electronically by the oncologist.
There are two computer systems used to prescribe medication:
- The electronic prescribing system (EPS) is used, through which all medications (except oncolytics) are prescribed by physicians, both for ambulatory and hospitalised patients. The EPS also provides an overview of all prescribed medication. In addition, it is possible to collect all medication records prescribed outside the hospital by using an open care information system (OZIS, Open Zorg Informatie Systeem). By using OZIS, it is possible to exchange prescription data from primary care electronically, provided both pharmacists are working in the same region (Westelijke Mijnstreek, a region in the South-east of The Netherlands).
- The electronic patient record (EPR) or hospital information system is used in the daily monitoring of hospitalised patients and also contains a module to prescribe predefined oncolytic regimens. Oncolytic drugs are prescribed in the EPR, because all data concerning the oncolytic regimen are registered in one system.
The oncologist prescribes the intravenous oncolytic drug(s) as a predefined regimen in the EPR. The hospital pharmacist performs a dose control and authorises the regimen in order to be prepared by pharmacy technicians. Subsequently, the hospital pharmacist enters the oncolytic regimen into the EPS. Next, the hospital pharmacist collects the active medication of the patient in the EPS. Once the oncolytic regimen and the active medication of the patient have been entered into the EPS, the hospital pharmacist performs the medication surveillance electronically by using the G-standard. The G-standard is the national Dutch drug database and is the only source of information used in this study. It classifies all potential interactions by the level of significance and the level of relevance.(12,13) An overview is shown in Table 1.
Medication surveillance is performed by the hospital pharmacist at the start of an oncolytic regimen and, once the medication surveillance is performed, the oncolytic regimen is sent to the patient’s local pharmacy electronically. The prescription contains the composition and the duration of the oncolytic regimen. The pharmacist then adds the oncolytic regimen to its pharmacy information system, and takes over the medication surveillance for the remaining duration of the regimen. This way, interactions with co-medication prescribed in a community setting can be monitored. If an interaction signal is generated during this surveillance, the community pharmacist informs the hospital pharmacist.
All cancer patients starting an intravenous oncolytic regimen in the period between April 2010 and December 2012 were enrolled in the study. Both oncolytic and haemato-oncolytic regimens were included.
Patients were excluded if they were not living in the region around the OMC (Westelijke Mijnstreek), because it would not be possible to import or export their medication records using OZIS. Patients starting experimental therapy were excluded as well, as little is known about drug–drug interactions in trial medication.
Descriptive statistics (means, standard deviation) were applied to analyse patient characteristics.
In total, 703 cancer patients living in the region Westelijke Mijnstreek were included in this study. The mean age of the included patients was 62.7 years and 390 (55.5%) were female.
The patients in whom an interaction sign was registered were on average 64.8 years of age and ten (32.3%) were female. The baseline characteristics are listed in Table 2.
A total of 51 clinically relevant drug-related interactions was found in 31 of the included patients (4.4%). Table 3 shows these interactions and their level of significance and relevance, which are explained in Table 1. The interaction between acenocoumarol and carboplatin occurred most frequently (11 interaction signs; 21.6%), but the levels of clinical significance and relevance are low (1/B).
Interactions with valproic acid (three interaction signs with cyclophosphamide, doxorubicin and etoposide; 5.9%) occur less frequently, but this interaction is clinically more significant and relevant (2/D). An interaction between metronidazole and fluorouracil was found in one patient (2.0%) (3/D). In Table 3, the level of significance and relevance of all the reported interactions is also shown.
In patients in whom an interaction between the intravenous oncolytic drug and the acenocoumarol was found, the International Normalised Ratio (INR) was monitored more frequently. No major differences were found in INR values due to chemotherapy.
An interaction between the intravenous oncolytic drug(s) and an antiepileptic drug that the patient was already using occurred in two patients. These patients were monitored during the oncolytic regimen and a blood sample was taken once at the start of every cycle to monitor the level of the antiepileptic drug. The hospital pharmacist initiated the monitoring of the blood sample and discussed the results with the physician. No major differences were found in blood levels of the antiepileptic drugs during the oncolytic regimen.
The interaction between furosemide and cisplatin was reported by the community pharmacist of an ambulatory cancer patient. The patient was monitored during the oncolytic regimen but no dose adjustments (furosemide) were necessary. The combination of cisplatin and furosemide might lead to an increased risk for nephrotoxicity because of dehydration.
Another interaction sign reported by a community pharmacist was the interaction between metronidazole and fluorouracil. Metronidazole might decrease the clearance of fluorouracil, causing symptoms of toxicity. The local pharmacist contacted the prescriber of metronidazole.
The results are comparable with a previous retrospective study conducted at the OMC in which acenocoumarol was also the most frequently involved drug.(11)
In the present study, only the intravenous oncolytic regimens were considered because the community pharmacist is currently responsible for the medication surveillance concerning oral oncolytic drugs.(9,10)
Usually it is not clear for a community pharmacist as to whether or not a patient is on an oncolytic regimen and, if so, which regimen is followed. By contrast, hospital pharmacists have little or no actual information concerning the use of medication in primary care. The fact that the medication surveillance is performed by the hospital pharmacy at the start of a regimen and is continued by the community pharmacy is a major advantage in this study. Medication surveillance of cancer patients is therefore monitored during the entire oncolytic regimen. To improve the quality of life of ambulatory cancer patients, the medication surveillance should be incorporated into the regular procedures concerning pharmacovigilance, and the community pharmacy and hospital pharmacy need to cooperate in order to cover prescriptions of all healthcare professionals involved in the care of ambulatory cancer patients. In addition, medication surveillance should not be bound to a specific region, but it should be made possible to import or export medication records in patients not living in the region as well.
In total, 12 alerts were reported by the community pharmacists to the hospital pharmacists, of which six of the alerts were new. Although these interactions were reported, it is to be expected that not all alerts detected by the community pharmacists were communicated with the hospital pharmacists. This lack of communication might result from the fact that the pharmacovigilance in oncolytic cancer patients is relatively new and the community pharmacists are not yet used to perform medication surveillance for intravenous medication administered in the hospital. It is unclear if the detected alerts are discussed with the ambulatory cancer patient’s general practitioner.
The interactions between intravenous oncolytic drugs and antiepileptic drugs were observed in this study by monitoring the blood levels of the antiepileptic drug. As blood samples were taken at the start of a new cycle in all patients undergoing an oncolytic regimen, it was decided to monitor the antiepileptic drug levels also at the start of the cycle. No differences in level were found when taking a blood sample once every cycle. However, a point of discussion is the fact that the samples were taken at the start of every cycle, just before administering the oncolytic drug. Therefore, it is difficult to interpret these results, as the oncolytic drug is administered later and the effects of the oncolytic drug on the blood level of the valproic acid are not determinable.
Recently, an epilepsy patient who was seizure-free for several years underwent chemotherapy with cisplatin. An interaction was determined between cisplatin and antiepileptic drugs (valproic acid and carbamazepine) and, despite the fact that blood samples at the start of the regimen were within reference range, the patient developed a status epilepticus.
Another point of interest is the fact that over-the-counter (OTC) medication is often not registered in the pharmacy information system, and therefore especially not known to the hospital pharmacist, and so not identified in this study when performing the medication surveillance. Taking into account that many cancer patients are using OTC medication, either to prevent or treat symptoms due to chemotherapy, it is to be expected that the percentage of oncolytic drug-related interactions among ambulatory cancer patients is even higher.
In this study, a total of 51 chemotherapy-related interactions were identified in 31 patients. Obtaining serum levels of antiepileptic drugs and monitoring the INR more frequently during an oncolytic regimen might help in defining the interactions between intravenous oncolytic drugs and antiepileptics or acenocoumarol. It is to be advised to monitor interactions between antiepileptic drugs and intravenous oncolytic drugs more frequently during an oncolytic regimen, not only at the start of the cycle but also after the administration of the intravenous oncolytic drugs.
Taking into account that oncolytic drugs will be prescribed more often and in higher doses, medication surveillance in ambulatory cancer patients will become more important. Therefore, the responsibility concerning medication surveillance in intravenously administered oncolytic drugs needs to be defined and optimised.
- The number of patients requiring chemotherapy continues to increase. This leads to a rise in the incidence of oncolytic drug-related interactions among cancer patients and medication surveillance in ambulatory cancer patients will therefore become more important.
- Medication surveillance in ambulatory cancer patients should be incorporated into the regular procedures concerning pharmacovigilance, and in order to improve the quality of life of ambulatory cancer patients, healthcare professionals need to cooperate.
- Pharmacists can play a key role in implementing this new procedure because they are expert in medication surveillance.
- Frequently monitoring, for example, the serum levels of antiepileptic drugs and the International Normalised Ratio during an oncolytic regimen will help in defining the interactions between (intravenous) oncolytic drugs and other medications.
- The responsibility concerning medication surveillance in ambulatory cancer patients needs to be defined and optimised.
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