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Clinical Pharmacology and Toxicology (U.W., C.M.M.), Inselspital Bern, SwitzerlandGraduate School for Health Sciences (U.W.), University of Bern, Switzerland
Clinical Pharmacology and Toxicology (U.W., C.M.M.), Inselspital Bern, SwitzerlandInstitute of Primary Health Care BIHAM (F.D., C.M.M.), University of Bern, Switzerland
Subcutaneous drug administration is an interesting approach for symptom control in hospice and palliative care. However, most drugs have no marketing authorization for subcutaneous administration and are therefore used off-label. In order to meet the requirements of a safe and effective drug therapy, especially in highly vulnerable patients, it is essential to investigate the scope of evidence of these common practices.
Objectives
The purpose of this scoping review was to provide an overview of available data on the tolerability and/or effectiveness of subcutaneously administered and off-label used drugs.
Method
We performed a scoping review according to the PRISMA extension to identify data available on the tolerability and/or effectiveness of 17 predefined drugs that are commonly administered subcutaneously in Swiss hospices and hospice-like institutions and that have no marketing authorization (off-label use).
Results
The scoping review identified 57 studies with most data available on their tolerability (68% local, 54% systemic), clinical effects (82%), details on dosage (96%) and routes of application (100%). Information on pharmacokinetic properties was mostly missing and only available for fentanyl, levetiracetam, midazolam, and ondansetron. For seven drugs, less than five articles were identified and no studies on codeine or clonazepam were available.
Conclusion
This work provides an overview of current evidence on subcutaneous and off-label used drugs in hospice and palliative care. Although both are common practices, evidence on tolerability and effectiveness, particularly pharmacokinetic data, is limited and the identified information gaps need to be closed. This work establishes a basis for further research in this area.
This scoping review summarizes clinical aspects of 17 drugs that are commonly administered subcutaneously in hospice and palliative care despite not holding a marketing authorization for this route of administration (off-label use). The identified lack of structured practice guidelines and pharmacokinetic data indicate a need for further research.
Introduction
Subcutaneous (SC) drug administration offers a minimal invasive alternative to oral drug administration for symptom control, preferably when oral intake of drugs is severely limited (e.g., due to dysphagia, vomiting or impaired consciousness).
which complies with the comfort-oriented considerations of hospice and palliative care, provided only drugs well-tolerable for SC administration with measurable effect are applied.
A decline in patients’ cognition may lead to a shift in preferences between routes of administration, from mainly oral medication towards parenteral medication. Therefore, the SC administration route becomes increasingly important.
Effectiveness of pharmacist-led medication reconciliation programmes on clinical outcomes at hospital transitions: a systematic review and meta-analysis.
Parenteral drugs can be administered as bolus injection or via infusion. Continuous SC infusions deliver drugs individually or in some cases as a mixture, usually over a period of 24 hours, using a syringe pump.
Even though off-label use is a common practice in palliative care, precise requirements and structured practice guidelines for SC drug administration are lacking.
In Switzerland, the term off-label use is not regulated by law. The Swiss Academy of Medical Sciences (SAMW) defines off-label use as «the use of readily available drugs with marketing authorization in Switzerland that deviate from the purpose approved by Swissmedic
The definition thus includes administration of a drug that deviates from its registered and approved indication, dosage, route of application, duration of therapy, and administration in specific patient groups (e.g., children). Off-label use is permissible provided that due diligence is done and there is compliance with established best practice guidelines.
The responsibility for the off-label use rests solely with the prescribing physician. To be able to justify off-label uses within the meaning of federal requirements, the physician must demonstrate that the decision is evidence-based or based on solid recommendations (i.e., guidelines of professional associations), and the benefit must clearly exceed any risk. Affected patients must be adequately informed and consent to the treatment must be obtained.
As cost coverage of off-label prescriptions is limited, off-label use requires prior approval by the individual's health insurance provider according to the Swiss Health Insurance Ordinance.
SAMW Swiss Academy of Medical Sciences and FMH Swiss Medical Association, [Legal principles in everyday medical practice: a guide for practitioners]. 2020.
Off-label use should not be confused with unlicensed use, which alludes to drugs for which no marketing authorization for any indication has been granted by the relevant licensing authority (i.e., Swissmedic). Examples are the import from countries where the drug is licensed by authorities with comparable regulatory drug control or pharmaceutical modifications to registered and approved drugs (e.g., crushing tablets to prepare a solution) and dispensing it in a different form.
To meet the requirements of a safe and effective drug therapy, especially in highly vulnerable patients, it is essential to investigate the scope of evidence of these common practices. The purpose of this scoping review was to obtain a scope of evidence from the literature on the tolerability and/or effectiveness of drugs that are administered subcutaneously and off-label in Swiss hospices and hospice-like institutions.
Method
A protocol was used to document the process of the scoping review that was performed and documented according to the PRISMA extension.
The protocol was not previously published. Based on a previous survey study performed in Swiss hospices and hospice-like institutions, we identified 14 drugs that are used subcutaneously and off-label.
Additionally, three representatives of the therapeutic drug group of PPIs (esomeprazole, omeprazole, pantoprazole) were included in the scoping review, as a particular request for information on this drug group emerged from the survey (see Table 1).
Table 1Drugs That Were Identified to Be Used Subcutaneously and Off-label in Swiss Hospices and Hospice-like Institutions
Drugs Used Subcutaneously and Off-Label in Switzerland (n = 17)
We performed a scoping review searching in PubMed, Embase, and CINAHL databases. The search string was designed using two topic blocks “Palliative Care Setting” and “Subcutaneous Drug Administration,” using MeSH terms and keywords. It was initially developed in PubMed and then translated for use in Embase (using Emtrees) and CINAHL (using Subject Headings). The full electronic search strategy from the search in PubMed is available as a Supplemental file. No filters were applied. If a full text article was not available online, employees of the university's library were contacted for procurement.
Selection Sources of Evidence
The final search was performed on April 6, 2021. After removing duplicates, title-abstract screening was performed according to the eligibility criteria (see Eligibility criteria,Table 2) by two independent reviewers (F. D., U. W.); any discrepancies were resolved through discussion until consensus was reached. In reviews that were excluded according to the predefined eligibility criteria, “backward citation chasing” was applied to identify potentially missed studies. Full text screening was performed by one reviewer (F. D. ) and discussed with two additional reviewers (U. W. , C. M. M.).
Table 2Eligibility Criteria for Inclusion and Exclusion of Studies in Scoping Review
Eligibility Criteria IN
Eligibility Criteria OUT
•
Primary literature (intervention and observational studies including case reports and case series)
•
Nonprimary literature (e.g., reviews), editorials, conference abstracts, expert opinions
•
Studies reporting local and/or systemic tolerability and/or effectiveness (clinical effect, blood plasma levels) of n = 17 predefined drugs
•
Reports of drugs that are not among the predefined drugs
•
Drug administration and investigation in patients ≥18 years that receive palliative care
•
Drug administration and investigation in patients <18 years, nonpalliative, or healthy study subjects
•
Referral of reported tolerability and/or effectiveness (clinical effect, blood plasma levels) to a specific drug or a mixture of active substances that contains at least one of the n=17 drugs of interest, must be feasible
Eligibility criteria are listed in Table 2. Included were all publications reporting tolerability and/or effectiveness (clinical effect, blood plasma or serum levels) of the 17 predefined drugs of interest (SC administration and off-label use). No restrictions for time of publication were defined. Hypodermoclysis (i.e., SC fluid infusions) was excluded as this scoping review aimed at putting an emphasis on the administration of drugs only.
Data Charting Process and Data Items
A detailed table was created for data extraction (i.e., study type, drug, number of patients, tolerability, clinical effect, details on drug administration, and references) with one row for each included publication. The detailed table is provided by the authors upon special request. The charted data was transferred to another, less detailed table (see Synthesis of results).
Data was charted independently by one reviewer (F. D.) and independently repeated in n = 6 (approximately 10%) randomly selected studies by a second reviewer (U. W.). The charted data was discussed among all three reviewers (F.D., U.W., C.M.M.) to resolve any discrepancies.
Synthesis of Results
To summarize the charted data, a table was created (see Results of individual sources of evidence,Table 3). References investigating the same drug were grouped and shaded to make them more discernible in the table.
Table 3Overview of Extracted Data From N = 57 Articles
and reported the same findings but they were published in different journals at different times. The two articles were combined for data extraction leading to a total of N = 57 included articles (see Fig. 1).
Fig. 1Flowchart of articles identified in scoping review.
Adapted from: Page MJ et al. (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews
Of the included sources, 57.9% (n = 33/57) were of European origin. Almost half and thus the majority of the European sources (48.5%, n = 16/33) originated from the United Kingdom
Morphine, haloperidol and hyoscine N-butyl bromide combined in s.c. infusion solutions: compatibility and stability. Evaluation in terminal oncology patients.
was a collaboration with a palliative care unit in Switzerland. The remaining articles originated from South America (n = 3/57, 5.3%) with one contribution each from Argentina,
Morphine, haloperidol and hyoscine N-butyl bromide combined in s.c. infusion solutions: compatibility and stability. Evaluation in terminal oncology patients.
In Table 3 an overview of the charted data from the literature is presented. The brackets indicate that information presented in the studies was not entirely conclusive or that some of the patients received the reported drug in a drug mixture instead of single drug administrations.
Synthesis of Results
The drugs most commonly investigated in the studies were midazolam (n = 14/57, 24.6%), levetiracetam (n = 8/57, 14.0%), haloperidol (n = 8/57, 14.0%), furosemide (n = 7/57, 12.3%), and ketamine (n = 7/57, 12.3%). Haloperidol was mostly reported as part of a drug mixture. None of the included articles contained studies on subcutaneously administered clonazepam or codeine.
Information on local, systemic and/or general tolerability of the investigated drugs was identified in n = 47/57 (71.9%) articles. Most of the patients tolerated SC drug administration well and there were no or only mild reactions such as redness, induration, pain, or edema at the injection site. In most of the reported cases, the reactions could be avoided by changing injection site or increase dilution of the infusion/injection solution. More severe local side effects were described in a few individual study patients, which in some cases required discontinuation of therapy or initiation of antibiotic treatment. The reactions included painful indurations
Clinical effects were reported in n = 47/57 (82.5%) articles. Most of these effects were reported for midazolam (n = 8), levetiracetam (n = 7), and furosemide and ketamine, both with six studies reporting clinical effects (see Table 3).
Information on PK properties (i.e., plasma levels) was available for fentanyl, levetiracetam, midazolam, and ondansetron. Three articles reported plasma concentrations of SC levetiracetam,
This was the only PK analysis identified among the totally N = 57 included articles.
Discussion
This scoping review provides the first overview on important clinical aspects (i.e., tolerability and effectiveness) of SC drug administration in hospice and palliative care. These clinical aspects need to be considered in order to meet the requirements of safe and effective symptom management, especially if drugs are used off-label. The identified scope of evidence reflects that SC administration is essential for symptom control in hospice and palliative care. If in compliance with best practice guidelines,
off-label use offers treatment options for patients with special symptom control needs for whom conventionally approved routes of administration are inadequate. Hence, in hospice and palliative care, SC drug administration is often associated with off-label use.
Summary of Evidence
Information gaps on the tolerability and/or effectiveness (clinical effect, blood plasma or serum levels) of the drugs of interest became evident in the scoping review. Considering the substantial number of drugs of interest, only a rather small number of sources qualified for inclusion and data extraction. For seven drugs (ceftriaxone, esomeprazole, metamizole, olanzapine, omeprazole, ondansetron, pantoprazole), less than five studies were included. Interestingly, all three representatives of the therapeutic group of proton pump inhibitors, that were included in the scoping review upon request, were among these seven drugs. For two drugs (clonazepam, codeine), no studies were identified at all. However, both substances seem to have become less important in hospice and palliative care. The most recent “Model List of Essential Medicines,”
published by the WHO in 2021, lists only codeine tablets for oral administration among the medicines considered essential for hospice and palliative care, clonazepam is not listed at all. Although the evidence remains low, both drugs are still used in Swiss hospices and hospice-like institutions. The lack of identified information in the literature on the SC administration of most included drugs of interest reflects the need for more evidence to support clinical decision-making by hospice and palliative care physicians, as the responsibility for off-label use rests solely with them. Decisions need to be evidence-based or based on solid recommendations, and the benefits must clearly exceed any risk.
It is particularly important to increase medication safety in highly vulnerable patients. Evidence-based structured guidelines can help to improve medication safety in clinical settings. A lack of structured guidelines on SC drug administration and off-label use pertaining to hospice and palliative care was identified in this scoping review. Structured guidelines are desirable to support clinical decision-making, especially when drugs are used off-label. Guidelines are preferably based on evidence from studies that have investigated the safety and/or effectiveness of drug administration, particularly when administered to highly vulnerable patients, in order to prevent adverse drug events that may affect quality of life.
Even though SC drug administration is usually well-tolerated, there are substances among the 17 investigated drugs that are associated with severe adverse drug reactions (e.g., haloperidol) that can be misinterpreted as symptoms (e.g., extrapyramidal movements). Potentially life-threatening adverse drug reactions (e.g., qt-time prolongation) may occur.
More severe local side effects were also described in individual patients where initiation of antibiotic treatment was required, albeit occurring rarely.
A potentially resulting prescribing cascade must be avoided as this is somewhat contradictory to the approach of maintaining quality of life.
The number of randomized double-blind placebo-controlled or cross-over clinical trials, which are considered to provide the highest level of evidence, was scarce. This study design is particularly difficult to perform in patients of hospice and palliative care due to the complexity and high frailty of this patient population.
Randomization into different treatment arms is impractical and blinding is often unethical. Comparison among drugs is nearly impossible due to the high inter-patient variability and required daily doses vary greatly between patients.
Drug therapy regimens are adapted to current requirements in symptom control and thus, can change frequently. This lack of high-level evidence results in a deficit of structured guidelines for evidence-based clinical decision-making. As a result, current recommendations on dosage and route of administration to guide drug choice and/or dose tailoring to individual patients are rarely supported by high-level evidence.
Guidelines may also be based on well-documented clinical experience shared among institutions. In Switzerland, no database to facilitate the exchange of clinical experience pertaining to SC drug administration among institutions is available. As a result, most off-label prescriptions and SC drug administration remain low in evidence and are often limited to clinical experience at an institutional level. Available guidelines (e.g., BIGORIO Best Practice Guidelines) cover only a part of the broad spectrum of safety and effectiveness of drug administrations in palliative care.
The identified information gaps establish a basis for further research to support clinical decision-making. To provide evidence that subcutaneous drug administration, especially used off-label, is safe and effective in hospice and palliative care patients, studies providing pharmacokinetic data are required.
Limitations
The basis for selection of the drugs of interest was a previously performed survey study in Swiss hospices and hospice-like institutions. Hospice and palliative care physicians and nurses were asked to list all drugs that are subcutaneously administered in their institutions. Findings are therefore mainly of interest for institutions that use a similar list of SC drugs in hospice and palliative care patients. The clinical trial register was not searched for ongoing studies; therefore, the low number of intervention studies potentially underrepresents current progress in research on this topic.
Conclusion
To our knowledge, this is the first scoping review that provides an overview of clinical aspects on subcutaneous drug administration and off-label use in hospice and palliative care. Evidence on tolerability and effectiveness is limited, resulting in a lack of structured guidelines. Although both are common practices, in-depth knowledge is deficient, and the scoping review revealed a need to close existing information gaps, especially on pharmacokinetic properties of commonly used drugs.
Disclosures and Acknowledgments
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. We acknowledge the support received from Marc von Gernler, PhD, of the library at University of Bern when planning and performing the literature review. There are no conflicts to disclosure. All authors declare no competing interests nor personal financial interests.
Supplemental file: Search strategy PubMed
((("terminal patient*"[Title/Abstract]) OR ((((((((((Hospice*[Title/Abstract]) OR ("Palliative Care*"[Title/Abstract])) OR ("Palliative Treatment*"[Title/Abstract])) OR ("Palliative Therap*"[Title/Abstract])) OR ("Palliative Nursing* "[Title/Abstract])) OR ("Terminal Care*"[Title/Abstract])) OR ("End of Life Care*"[Title/Abstract])) OR ("End-Of-Life Care*"[Title/Abstract])) OR ("Palliative Supportive Care*"[Title/Abstract])) OR (("terminally ill"[Title/Abstract]) OR ("hospice patient*"[Title/Abstract])))) OR ((terminally ill[MeSH Terms]) OR (((((("Terminal Care"[Mesh:NoExp]) OR (hospices[MeSH Terms])) OR (hospice care[MeSH Terms])) OR (hospice and palliative care nursing[MeSH Terms])) OR (palliative medicine[MeSH Terms])) OR (palliative care[MeSH Terms])))) AND ((("Infusions, Subcutaneous"[Mesh:NoExp]) OR ("Injections, Subcutaneous"[Mesh:NoExp])) OR ((((((((((((((((((((((("subcutaneous administration*"[Title/Abstract]) OR ("s.c. administration*"[Title/Abstract])) OR ("sc administration*"[Title/Abstract])) OR ("Subcutaneous Infusion*"[Title/Abstract])) OR ("s.c. infusion*"[Title/Abstract])) OR ("sc infusion*"[Title/Abstract])) OR ("Continuous subcutaneous infusion*"[Title/Abstract])) OR ("CSCI*"[Title/Abstract])) OR ("Subcutaneous injection*"[Title/Abstract])) OR ("s.c. injection*"[Title/Abstract])) OR ("sc injection*"[Title/Abstract])) OR ("Subcutaneous bolus injection*"[Title/Abstract])) OR ("Subcutaneous application*"[Title/Abstract])) OR ("Subcutaneous Access*"[Title/Abstract])) OR ("Subcutaneous drug*"[Title/Abstract])) OR ("Subcutaneous medic*"[Title/Abstract])) OR ("Subcutaneous route*"[Title/Abstract])) OR ("Subcutaneous deliver*"[Title/Abstract])) OR ("Subcutaneous dosage*"[Title/Abstract])) OR ("Subcutaneous dose*"[Title/Abstract])) OR ("Subcutaneous therap*"[Title/Abstract])) OR ("Syringe pump*"[Title/Abstract])) OR ("Syringe driver*"[Title/Abstract]))).
References
Dickman A
Schneider J
The syringe driver: continuous subcutaneous infusions in palliative care.
Effectiveness of pharmacist-led medication reconciliation programmes on clinical outcomes at hospital transitions: a systematic review and meta-analysis.
SAMW Swiss Academy of Medical Sciences and FMH Swiss Medical Association, [Legal principles in everyday medical practice: a guide for practitioners]. 2020.
Morphine, haloperidol and hyoscine N-butyl bromide combined in s.c. infusion solutions: compatibility and stability. Evaluation in terminal oncology patients.
All authors contributed to the study conception and design. Preparation, data collection and analysis for the scoping review were performed by F.D., C.M.M. and U.W. They were supported by S.J.P.M., who contributed her specialist knowledge from hospice care to this project. F.D. performed the scoping review (support by U.W. and C.M.M.). Title-abstract screening was performed by F.D. and U.W. The first draft of the manuscript was written by U.W. and all authors commented on all versions of the manuscript. All authors read and approved the final manuscript.
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