Therapieempfehlungen zum Off-Label-Use palliativmedizinisch relevanter Arzneistoffe: alternative Applikationsarten – Konsentierung durch Delphi-Verfahren

Zusammenfassung

Der Off-Label-Use (OLU) von Arzneimitteln gehört zum Alltag in der Palliativversorgung. Neben abweichenden Indikationen betrifft dies auch alternative Applikationswege. Die Arzneimitteltherapiesicherheit ist neben Aufklärung und Haftung zu berücksichtigen. Im Alltag fehlen häufig Zeit und Ressourcen für Literaturrecherche und Evidenzbewertung.
Ziel ist die Erstellung und Konsentierung von Therapieempfehlungen zum OLU von Arzneimitteln in der Palliativversorgung sowie deren Veröffentlichung auf der Webseite „pall-OLU.de“.
Nach einem systematischen Vorgehen wurden relevante Wirkstoffe und OLU-Applikationen ausgewählt und Empfehlungen auf Basis der bestverfügbaren Evidenz erarbeitet. Eine Runde aus 60–76 Expert:innen bewertete diese in vier Online-Delphi-Verfahren.
45 der konsentierten Therapieempfehlungen betrafen die Applikationsart als OLU von 21 Wirkstoffen.
Mit Veröffentlichung der Therapieempfehlungen auf pall-OLU.de steht Fachkräften erstmals eine Datenbank mit Informationen zum OLU von Arzneimitteln in der Palliativversorgung zur Verfügung.

Abstract

Off-Label-Use (OLU) of drugs is part of everyday practice in palliative care. In addition to deviating indications, this also applies to alternative routes of administration. Patient information, liability and safety of drug therapy must be considered. There is often a lack of time and resources for literature research and evaluation of evidence in clinical practice.
The aim of this project is to develop and rate agreement on treatment recommendations for the OLU of drugs in palliative care and their publication on the website “pall-OLU.de”.
By a systematic approach, relevant drugs and OLU applications were selected and recommendations were developed based on the best available evidence. An expert panel consisting of 60–76 experts evaluated these recommendations in four Delphi studies.
45 treatment recommendations concerned the route of administration as OLU of 21 substances.
With publication of the treatment recommendations on pall-OLU.de, a database with information regarding OLU of drugs in palliative care is available to healthcare professionals for the first time.

Schlüsselwörter

Off-Label-Use - Palliativversorgung - Delphi-Verfahren - Arzneimitteltherapiesicherheit - Applikationsarten

Keywords

off-label-use - palliative care - Delphi technique - drug safety - drug application

• Literatur

• 1 Hagemann V, Bausewein C, Rémi C. Off-label-prescriptions in daily clinical practice – a cross-sectional national survey of palliative medicine physicians. Progress in Palliative Care 2019; 27: 154-159
• 2 García-López I, Cuervas-Mons Vendrell M, Martín I Romero. et al. Off-Label and unlicensed drugs in pediatric palliative care: a prospective observational study. J Pain Symptom Manage 2020; 60: 923-932
• 3 Kwon JH, Kim MJ, Bruera S. et al. Off-Label medication use in the inpatient palliative care unit. J Pain Symptom Manage 2017; 54: 46-54
• 4 Hagemann V, Bausewein C, Remi C. Off-label use in adult palliative care – more common than expected. A retrospective chart review. European Journal of Hospital Pharmacy 2021; ejhpharm-2020- 2020;
• 5 Eguale T, Buckeridge DL, Verma A. et al. Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. JAMA internal medicine 2016; 176: 55-63
• 6 Dickman A, Schneider J. The Syringe Driver: Continuous Subcutaneous Infusions in Palliative Care. 4. Oxford: Oxford University Press; 2016
• 7 Wernli U, Dürr F, Jean-Petit-Matile S. et al. Subcutaneous Drugs and Off-label Use in Hospice and Palliative Care: A Scoping Review. J Pain Symptom Manage 2022; 64: e250-e259
• 8 Rémi C, Bausewein C. Zum Umgang mit Off-Label-Use in der Palliativmedizin: Deutsche Gesellschaft für Palliativmedizin. 2. Auflage. 2020 https://www.dgpalliativmedizin.de/images/RZ_200219_Offlabel_DS_ONLINE_aktuell_v2.pdf
• 9 Remi C, Weingärtner K, Hagemann V. et al. Off-label drugs in palliative care: a group delphi treatment recommendation process. BMJ supportive & palliative care 2021; 11: 180-187
• 10 Hui D, Arthur J, Dalal S. et al. Quality of the supportive and palliative oncology literature: a focused analysis on randomized controlled trials. Support Care Cancer 2012; 20: 1779-1785
• 11 Hui D, Parsons HA, Damani S. et al. Quantity, design, and scope of the palliative oncology literature. Oncologist 2011; 16: 694-703
• 12 Surges SM, Brunsch H, Jaspers B. et al. Revised European Association for Palliative Care (EAPC) recommended framework on palliative sedation: An international Delphi study. Palliative Medicine 2024; 38: 213-228
• 13 Payne S, Harding A, Williams T. et al. Revised recommendations on standards and norms for palliative care in Europe from the European Association for Palliative Care (EAPC): A Delphi study. Palliative Medicine 2022; 36: 680-697
• 14 Jünger S, Payne SA, Brine J. et al. Guidance on Conducting and REporting DElphi Studies (CREDES) in palliative care: recommendations based on a methodological systematic review. Palliative Medicine 2017; 31: 684-706
• 15 Pügge S, Dukic-Ott A, Baumgärtel J. et al. Off-label drug use in palliative medicine: Delphi study for the consensus of evidence-based treatment recommendations. Palliat Med 2025; 39: 530-542
• 16 AWMF online. Formulierung und Graduierung von Empfehlungen. 2023 https://www.awmf.org/regelwerk/formulierung-und-graduierung-von-empfehlungen
• 17 Iqbal S, Pipon-Young L. The delphi method. The Psychologist 2009; 22: 598-601
• 18 Deutsche Gesellschaft für Palliativmedizin. Guide to hospices and palliative care (Wegweiser Hospiz- und Palliativversorgung). https://www.wegweiser-hospiz-palliativmedizin.de/en
• 19 Limesurvey GmbH. LimeSurvey: An Open Source survey tool. Hamburg, Germany: LimeSurvey GmbH;
• 20 Hjermstad MJ, Kaasa S. Research in palliative care. In: Cherny NI, Fallon MT, Kaasa S. et al. , Hrsg. Oxford Textbook of Palliative Medicine. Oxford University Press; 2021.
• 21 Mann N-K, Mathes T, Sönnichsen A. et al. Potenziell inadäquate Medikation für ältere Menschen: PRISCUS 2.0. Dtsch Arztebl International 2023; 120: 3-10
• 22 Pazan F, Weiss C, Wehling M. et al. The EURO-FORTA (Fit fOR The Aged) List Version 2: Consensus validation of a clinical tool for improved pharmacotherapy in older adults. Drugs & Aging 2023; 40: 417-426
• 23 Schol J, Wauters L, Dickman R. et al. United European Gastroenterology (UEG) and European Society for Neurogastroenterology and Motility (ESNM) consensus on gastroparesis. United European Gastroenterology Journal 2021; 9: 287-306
• 24 Fachinformation. MSI 10/20/100/200 mg Mundipharma® 2024/03. https://www.fachinfo.de/fi/detail/004645/msi-10-mg-20-mg-100-mg-200-mg-mundipharma-r
• 25 Fachinformation. Palladon® injekt 2 mg/10 mg/100 mg 2024/07. https://www.fachinfo.de/fi/detail/010084/palladon-r-injekt-2-mg-10-mg-100-mg
• 26 Fachinformation. Tramal® 50 mg/100 mg Injektionslösung 2024/07. https://www.fachinfo.de/fi/detail/012320/tramal-r-50-mg-100-mg-injektionsloesung
• 27 Good PD, Schneider JJ, Ravenscroft PJ. The Compatibility and Stability of Midazolam and Dexamethason in Infusion Solutions. Journal of Pain and Symptom Management 2004; 27: 471-475
• 28 Matoses Chirivella C, Rodriguez Lucena FJ, Sanz Tamargo G. et al. Subcutaneous drug administration in palliative care. Farmacia hospitalaria: organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria 2015; 39: 71-79
• 29 Jensen JJ, Sjøgren P. Administration of label and off-label drugs by the subcutaneous route in palliative care: an observational cohort study. BMJ supportive & palliative care 2022; 12: e723-e729
• 30 Herndon CM, Fike DS. Continuous subcutaneous infusion practices of United States hospices. J Pain Symptom Manage 2001; 22: 1027-1034
• 31 Leitlinienprogramm Onkologie. Erweiterte S3-Leitlinie Palliativmedizin für Patienten mit einer nicht-heilbaren Krebserkrankung Langversion 2.2 – September 2020 AWMF- Registernummer: 128/001OL. 2020 https://www.dgpalliativmedizin.de/images/stories/pdf/LL_Palliativmedizin_Langversion_2.2.pdf
• 32 Schlunk T. Parenterale Schmerztherapie. In: Zenz M, Donner B. , Hrsg. Schmerz bei Tumorerkrankungen. Stuttgart: Wissenschaftliche Verlagsgesellschaft mbH; 2002: 117-123
• 33 Rémi C, Büsel S, Volk M. et al. Subkutane Arzneimittelanwendung in der Palliativmedizin. Zeitschrift für Palliativmedizin 2021; 22: 255-264
• 34 Kriel RL, Birnbaum AK, Cloyd JC. et al. Failure of Absorption of Gabapentin After Rectal Administration. Epilepsia 1997; 38: 1242-1244
• 35 Bockbrader HN, Wesche D, Miller R. et al. A Comparison of the Pharmacokinetics and Pharmacodynamics of Pregabalin and Gabapentin. Clinical Pharmacokinetics 2010; 49: 661-669
• 36 Doddrell C, Tripathi SS. Successful use of pregabalin by the rectal route to treat chronic neuropathic pain in a patient with complete intestinal failure. BMJ Case Reports 2015; 29: 29
• 37 Roch C, Para S, Brandhofer C. et al. Successful use of Rectal Pregabalin for the Treatment of Chemotherapy-Induced Neuropathic Pain – a Case Report. Journal of Palliative Care 2023; 38: 412-415
• 38 Kram S, Tatum M, Iboaya E. et al. 882: NONENTERAL ADMINISTRATION OF PREGABALIN FOR WITHDRAWAL IN A SURGICAL CRITICALLY ILL PATIENT. Critical Care Medicine 2020; 48: 420
• 39 Yajima R, Matsumoto K, Yokono K. et al. Pharmacokinetic and pharmacodynamic studies of pregabalin suppositories based on pharmacological research. Journal of Pharmacy & Pharmacology 2019; 71: 746-752
• 40 Stockis A, Sargentini-Maier ML, Otoul C. et al. Assessment of levetiracetam bioavailability from targeted sites in the human intestine using remotely activated capsules and gamma scintigraphy: Open-label, single-dose, randomized, four-way crossover study in healthy male volunteers. Clinical Therapeutics 2010; 32: 1813-1821
• 41 Dunteman E. Cancer pain: palliative care. The Journal of Pain 2004; 5: S50
• 42 Slikkerveer M, Van Rossum L, Krings AWH. Pharmacokinetics of levetiracetam after rectal administration in healthy volunteers. Pharmaceutisch Weekblad 2010; 145: 151-153
• 43 Selge C, Bausewein C, Remi C. Rectal Administration of Baclofen at the End of Life. J Pain Symptom Manage 2018; 56: e1-e3
• 44 Eschbach T, Grüneck S. SOP intranasale Applikation von Medikamenten im Notfall. Notfallmedizin up2date 2020; 15: 120-124
• 45 Wermeling DP. Intranasal delivery of antiepileptic medications for treatment of seizures. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 2009; 6: 352-358
• 46 Knoester PD, Jonker DM, Van Der Hoeven RTM. et al. Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers. British Journal of Clinical Pharmacology 2002; 53: 501-507
• 47 Miller JL, Ashford JW, Archer SM. et al. Comparison of intranasal administration of haloperidol with intravenous and intramuscular administration: a pilot pharmacokinetic study. Pharmacotherapy 2008; 28: 875-882
• 48 Duñó Ambròs R, Oliva Morera JC, Iglesias-Lepine ML. et al. Efficacy and safety of intranasal haloperidol in an acute Psychiatry Unit: a pilot study on schizophrenic patients with mild-modedate agitation. Actas espanolas de psiquiatria 2021; 49: 205-209
• 49 Hanning SM, Orlu Gul M, Toni I. et al. A mini-review of non-parenteral clonidine preparations for paediatric sedation. Journal of Pharmacy and Pharmacology 2017; 69: 398-405
• 50 Almenrader N, Larsson P, Passariello M. et al. Absorption pharmacokinetics of clonidine nasal drops in children. Pediatric Anesthesia 2009; 19: 257-261
• 51 Almenrader N, Passariello M, Coccetti B. et al. Steal-induction after clonidine premedication: a comparison of the oral and nasal route. Pediatric Anesthesia 2007; 17: 230-234
• 52 Mukherjee S, Ray M, Ray A. et al. Clonidine premedication for paediatric patients: A comparison of the oral & nasal route. Journal of Anaesthesiology Clinical Pharmacology 2010; 26: 319-322
• 53 Larsson P, Eksborg S, Lönnqvist P-A. Onset time for pharmacologic premedication with clonidine as a nasal aerosol: a double-blind, placebo-controlled, randomized trial. Pediatric Anesthesia 2012; 22: 877-883
• 54 Hankerson MJ, Raffetto B, Mallon WK. et al. Nebulized Tranexamic Acid as a Noninvasive Therapy for Cancer-Related Hemoptysis. J Palliat Med 2015; 18: 1060-1062
• 55 Davies AN, Singer J. A comparison of artificial saliva and pilocarpine in radiation induced xerostomia. The Journal of Laryngology & Otology 1994; 108: 663-665
• 56 Hamlar DD, Schuller DE, Gahbauer RA. et al. Determination of the efficacy of topical oral pilocarpine for postirradiation xerostomia in patients with head and neck carcinoma. Laryngoscope 1996; 106: 972-976
• 57 Frydrych AM, Davies GR, Slack-Smith LM. et al. An investigation into the use of pilocarpine as a sialagogue in patients with radiation induced xerostomia. Aust Dent J 2002; 47: 249-253
• 58 Mercadante S. Pilocarpine as an adjuvant to morphine therapy. Lancet 1998; 351: 338-339
• 59 Mercadante S, Calderone L, Villari P. et al. The use of pilocarpine in opioid-induced xerostomia. Palliat Med 2000; 14: 529-531