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Although there has been a significant increase in the availability and use of oral chemotherapeutic agents, the guidelines around their safe handling are still evolving. Although oral chemotherapy is associated with ease of administration, it has the same exposure risks to health care practitioners, patients, and their caregivers as intravenous formulations, and because it is administered in the home, to the families of patients. However, the general misconception appears to be that exposure risk is low and therefore oral chemotherapeutic agents present little risk and are safer to handle. In a series of three roundtable meetings, a team of international pharmacists from North America and Europe reviewed existing guidelines and identified gaps in recommendations that we believe are important for safe handling. The present article is a compilation of these gaps, especially applicable to manufacturers and distributors, storage and handling, and patient education regarding safe handling. These recommendations, on the basis of our experience and of best practices, provide an international perspective and can be adapted by institutions and practices for development of standardized procedures specific to their needs for the safe handling of oral chemotherapeutic agents.
Traditionally, chemotherapy has been administered by intravenous infusion in an oncology inpatient unit or clinic or a physician's office. Over the past decade, however, self-administration of oral chemotherapy has increased because of the availability of novel therapeutic agents.1–3 Numerous advantages to the use of oral chemotherapy have been described, including increased control and convenience for the patient, potential increase in the quality of life, sustained medication exposure, and potential reduction in travel costs and use of health care resources.1,2,4 Despite these advantages, it is imperative to note that multiple factors associated with oral chemotherapy can compromise patient safety and contribute to medication errors, contamination, and inadvertent exposure to other individuals.5,6
Chemotherapy, because of its relatively narrow therapeutic index, is often associated with a greater risk of adverse events (AEs) than other medications, and when used in combination, may result in an even greater incidence of AEs.5,6 In contrast to administration in the institutional setting, where the prescribed medication, dose, regimen, and response to therapy are subject to several levels of assessment, patient or caregiver (defined as family members or friends who assist the patient) administration of oral chemotherapy is more likely to be susceptible to errors, nonadherence, and increased AEs as a result of a lack of coordinated care. Although there are no publications comparing chemotherapy errors that occur with oral versus intravenous administration, known issues with oral administration include incorrect dosing and limited monitoring, which can lead to underdosing or overdosing, serious toxicity, morbidity, and mortality.5–8 In addition, patient nonadherence to oral chemotherapy is a significant problem, which is less of a concern with parenteral therapy given in an institutional setting under the supervision of health care professionals.9,10 Finally, AEs may be difficult to monitor with the personal administration of oral chemotherapy if fewer clinic visits are needed for drug administration purposes; thus, it is crucial to inform the patient of the known AE profile associated with the medication.11
Accidental exposure to oral chemotherapeutic agents can occur at various stages during handling (ie, transport, unpacking, storage, handling, administration, and disposal).12–14 Thus, guidelines for safe and appropriate handling across the health care continuum are imperative. Some of the existing recommendations to ensure the safe storage, prescribing, dispensing, administration, and disposal of cytotoxic oral chemotherapy drugs are listed in the Appendix (online only).2,7,12,15–31 However, the recommendations have not been universally accepted or incorporated into practice. Recent surveys of health care practitioners as well as patients found that the perception of oral chemotherapy being safer than intravenous chemotherapy was prevalent.32,33 In addition, a survey of pharmacy directors of National Cancer Institute–designated cancer centers published in 2007 identified gaps in pharmacy practices, safety assessments, and prescribing methods and demonstrated the need for safe practice guidelines.34
During our review of existing guidelines, we found that none of the guidelines addressed all areas the panel deemed critical for the safe handling of oral chemotherapeutic agents. The purpose of the present article is to provide an outline of recommendations made by an international panel of pharmacists to address these critical areas that could serve as a starting point to build a framework for the safe storage, handling, administration, and disposal of oral chemotherapeutic agents for manufacturers and distributors, health care workers, and patients or their caregivers. We believe that these recommendations can be adapted by institutions and practices for development of standardized procedures specific to their needs regarding the safe handling of oral chemotherapeutic agents. We have focused on recommendations for oral chemotherapeutic agents; however, they may be applicable to all oral agents utilized in the treatment of cancer.
An expert panel comprising pharmacists from Austria, Canada, France, Germany, Spain, the United Kingdom, and the United States, representing hospital, community, ambulatory care, and specialty pharmacy, convened for a series of three roundtable meetings. Although the panel represented only one discipline, each pharmacist on the panel was chosen to represent a unique patient care setting. The participants were selected by the lead author on the basis of their active participation in international pharmacy societies as well as country-specific societies with a focus on oncology.
Before the meetings, representatives from each country provided any currently available recommendations for handling oral chemotherapy from their respective country, including guideline documents and institutional or country policies. In addition, a literature review was performed through PubMed to search for relevant publications and existing guidelines through January 2010. All the guidelines reviewed at the meetings are listed in the Appendix. In addition to existing guidelines, the panel also drew on best practices that were based on the professional experience of the panel members.
At the initial meeting, the panel formed subgroups. Each subgroup reviewed currently available guidelines for manufacturers, distributors, health care providers, and other individuals or groups involved in the handling of oral chemotherapeutic agents at various stages (stakeholders); identified the gaps in these existing guidelines; identified current best practices; and formulated recommendations for handling of oral chemotherapy drugs. The findings of each subgroup were presented to and commented on by the entire team. A working draft of recommendations for the safe handling of oral chemotherapeutic agents was developed and then discussed for consensus at subsequent meetings. Although no formal process was used to reach a consensus, discussion on each point was continued until consensus was reached, and in a few cases, until it was clear that no consensus would be reached. A flowchart of the methodology is shown in Figure A1 (online only). The goal was to develop a framework of recommendations that can be included in guidelines specific to individual institutions and practices.
A number of stakeholders are involved in handling oral chemotherapeutic agents at various stages. Recommendations for safe handling by these stakeholders are outlined in the following sections.
There are well-defined regulations for manufacturers and distributors to ensure safe transport and handling of chemotherapy drugs. Although the initial step for safe handling of oral chemotherapy agents begins with the manufacturer, recommendations for manufacturers and distributors are not included in currently published safe handling guidelines (see Appendix for the list of guidelines), but the panel believes they play a pivotal role. Appropriate packaging could minimize the handling of chemotherapy drugs by health care providers and patients, thus contributing to safer handling. This includes clear labeling on the outside of the package indicating that the agent is cytotoxic. In addition, manufacturers should package only the amount of tablets or capsules needed for one cycle of therapy. Because new regimens are constantly being developed and approved, another approach for manufacturers is to use unit-of-use packaging, thereby reducing the need for packaging based on a cycle of therapy. Each of these steps will ensure limited handling of these agents. Finally, manufacturers are encouraged to develop a liquid formulation or provide information on compounding a liquid formation of their product. Additional recommendations for manufacturers and distributors are listed in Table 1. Health care professionals are encouraged to reinforce the importance of these points to stakeholders and regulatory agencies whenever possible.
Health care providers have a major responsibility in ensuring safe handling of oral chemotherapeutic agents. Because of the significance of this responsibility, health care providers should be appropriately trained, ensure that their knowledge is current with developments in the field, and follow all applicable discipline-specific guidelines when handling oral chemotherapeutic agents. Because this panel consisted exclusively of pharmacists, our recommendations are focused on the roles typically undertaken by pharmacists, but they can be adapted to other health care professionals who perform similar roles, on the basis of systems existing in individual practice settings or medical centers.
As recommended in most safe handling guidelines, health care professionals should attend orientation programs and routine training courses specific to their roles. They should also complete competencies associated with these training programs, along with an accompanying assessment for licensing qualification if applicable. The training programs should be approved by an oncology organization or appropriate local organizations.35,36 In addition, within a health care institution, a primary educator should be established as a source of referral and continued education for training health care professionals on oral chemotherapy. This would ensure that patients receive consistent education, training, and monitoring across the multidisciplinary team.8,37
Health care workers should be trained and competent to treat individuals accidently exposed to chemotherapeutic agents and on the disposal of cytotoxic medications. All clinical staff who are likely to come in contact with oral chemotherapeutic agents or with waste from patients who have received these agents (eg, clerks, hygiene workers, and sanitation workers) should undergo appropriate training. The latter point of training non–health care professional staff was important to the panel because this recommendation is not included in the any guidelines. With the changing paradigm of oral chemotherapy, these individuals should be appropriately trained because the traditional systems of handling chemotherapy, and those involved, are more diverse with oral chemotherapy. A list of training recommendations for health care providers is shown in Table 2.
When handling oral chemotherapeutic agents, health care providers must adhere to good practice as defined by local standard operating procedures and national guidelines. Key recommendations are outlined in Table 2, many of which are targeted to retail pharmacies, particularly in the United States, because the panel felt there was a gap in practice in this setting.
Handling of oral chemotherapy by pregnant staff members initiated a broad discussion by the panel, and no consensus was reached regarding a recommendation. All members of the panel agreed the goal was to minimize or eliminate any role of pregnant staff in handling chemotherapy agents, oral or intravenous; however, this may not be feasible in all practice settings. Many panel members argued against a recommendation as long as appropriate protection (eg, gown, gloves) were used by pregnant staff.
Another issue for handling that generated a significant discussion was the cleaning of nondisposable materials exposed to chemotherapy drugs. This includes counting trays, tools, and surfaces. When intravenous chemotherapy drugs are mixed in a biologic safety cabinet, all the guidelines recommend terminal cleaning or cleaning with each shift. With the increase in the prescribing of oral chemotherapy, more pharmacies will be involved in fulfilling the prescription. Cleaning of the tools and surfaces exposed to these agents has been limited to washing the items and area thoroughly with soap and water, 70% alcohol, or sodium hypochlorite; in some settings, no cleaning occurs. The risk for contamination of other medications and patient exposure could be significant. Currently, there are limited options for cleaning of these surfaces, although in some European countries, limited data support the use of cleaning agents that have been validated for the removal of cytotoxic agents.38 The panel agreed further research is urgently needed to develop a valid, readily available, and affordable decontamination agent for use in the health care setting and the patient home.
Health care professionals should provide patients and caregivers with education and training to ensure their understanding of safe handling procedures as well as thorough knowledge of proper administration of all medications. Patient literature and other educational materials should be monitored and evaluated to ensure that current and accurate information is being delivered.
Patient consent for oral chemotherapy should be obtained. Patients should be consulted and assessed for their ability to take oral therapy and to comply with their treatment plan. Tools are available to assist with this evaluation.39 Patients should also be advised on all matters related to safe handling.
All current medications should be reviewed with the patient or caregiver to identify potential medication interactions or interference with dietary requirements, and clear dosing instructions should be provided, including what to do when a dose is skipped or when vomiting of a dose (spillage) occurs. During refill of prescriptions, any potential medication and food interactions must be reassessed and discussed with the patient or caregiver. The patient should be made aware of the required monitoring arrangements by being provided with access to the written protocol and treatment plan from the institution where the treatment was initiated. Patients who are pregnant or breast-feeding should be counseled on recommended medications and their risk-benefit profiles.
Recommendations for patients and caregivers are included in some guidelines but are limited in details, so the panel focused on these responsibilities and created a summary of dos and don'ts for patients that could be put into practice and provided to all patients (Table 3). Caregivers should understand all information given to patients, including the transport, storage, dispensing, and disposal requirements to ensure safe handling. They must work with the patient and health care provider to ensure appropriate dosing for patients in their care and report any treatment-related adverse effects. Caregivers who are pregnant, breast-feeding, or children should not handle any chemotherapy medications or waste products. Finally, to further ensure the safety of these individuals and others in the patient's home, guidelines from Australia and Canada recommend that patient's clothes and bed linen be handled with gloves and washed separately from other items and that toilets be double-flushed after use, during and 4 to 7 days after discontinuing chemotherapy.12,18 These recommendations are supported by a recent publication involving cyclophosphamide exposure that showed significant contamination on and around the toilet and that the use of gloves reduced personal contamination from changing bed linens one- to six-fold.40 Because drugs may be eliminated from the body as active or inactive metabolites in sweat, saliva, urine, or stool for five to seven half-lives, the panel agreed that these recommendations were important and should be implemented.
In this article, our international team of oncology pharmacists identified gaps in existing guidelines for the safe handling of oral chemotherapeutic agents, especially as it applies to manufacturers and distributors, storage and handling, and patient education. Although the limitations of our approach include informal methods of panel selection, the lack of a voting method for consensus agreement, and a nonsystematic literature review, there are significant strengths to the recommendations. First, our recommendations are relevant to multiple stakeholders, beginning with the manufacturer. In addition, although the panel was composed solely of pharmacists, this group has significant experience with safe handling of hazardous agents coupled with managing oral agents for all disease types. On the basis of our international experience and best practices, we compiled key recommendations to fill the gaps of existing guidelines. Therefore, this article, which provides an international perspective, is timely and is ideally suited to be a framework for the development of safe handling guidelines specific to individual institutions and practices.
Oral chemotherapy has distinct advantages and disadvantages compared with intravenous chemotherapy. Although the responsibility for safe handling and administration of oral chemotherapy ultimately lies with the patient or their caregiver, it is the responsibility of all members of the health care team to ensure they are informed regarding the safe and appropriate use of their chemotherapy. All stakeholders should follow established guidelines when handling oral chemotherapeutic agents and continually review and assess their standards and compliance with agreed procedures. In addition, all facilities that handle oral chemotherapy drugs should develop standard operating procedures that are specific to their practice.
This article is a result of roundtable meetings to discuss the safe handling of oral chemotherapeutic agents. Although the meetings were supported by Merck (formerly Schering Corp.), only the authors had control over the content of this article. Medical writing assistance was provided by Philip Reigan, PhD, and Meenakshi P. Subramanian, PhD, Evidence Scientific Solutions, which was supported by Merck.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory Role: Susan Goodin, Merck (C); Niesha Griffith, Merck (C); Karen Chuk, Merck (C); Mikael Daouphars, Merck (C); Christian G. Doreau, Merck, sanofi aventis (C), GlaxoSmithKline (C); Robert Terkola, Merck (C); Barbara Vadnais, Merck (C); Debbie Wright, Merck (C) Stock Ownership: None Honoraria: Beth Chen, Merck; Rinku A. Patel, Merck; Maria José Tamés, Merck; Debbie Wright, Merck Research Funding: None Expert Testimony: None Other Remuneration: Mikael Daouphars, Roche; Christian G. Doreau, LFB, Jannsen-Cilag
Conception and design: Susan Goodin, Niesha Griffith, Mikael Daouphars, Christian G. Doreau, Rinku A. Patel, Rowena Schwartz, María José Tamés, Robert Terkola, Barbara Vadnais, Debbie Wright, Klaus H. Meier
Collection and assembly of data: Susan Goodin, Niesha Griffith, Beth Chen, Karen Chuk, Maria José Tamés, Robert Terkola, Barbara Vadnais
Data analysis and interpretation: Susan Goodin, Beth Chen, Karen Chuk, Christian G. Doreau, Rinku A. Patel, Maria José Tamés, Robert Terkola, Barbara Vadnais
Manuscript writing: Susan Goodin, Niesha Griffith, Karen Chuk, Mikael Daouphars, Rinku A. Patel, María José Tamés, Barbara Vadnais
Final approval of manuscript: Susan Goodin, Niesha Griffith, Beth Chen, Karen Chuk, Mikael Daouphars, Christian G. Doreau, Rinku A. Patel, Rowena Schwartz, María José Tamés, Robert Terkola, Barbara Vadnais, Debbie Wright, and Klaus Meier