Farmacoriflessioni
Cure palliative pediatriche e uso di farmaci off-label
Paediatric palliative care and off-label drug use
Lucia De Zen1, Federico Marchetti2, Egidio Barbi3, Franca Benini4
1SSD Assistenza Domiciliare, Terapia del Dolore e Cure Palliative Pediatriche, AAS5 - Friuli Occidentale Pordenone
2UOC di Pediatria e Neonatologia, Ospedale di Ravenna, AUSL della Romagna
3Università di Trieste; IRCCS Materno-Infantile “Burlo Garofolo”, Trieste
4Centro Regionale Veneto di Terapia del Dolore e Cure Palliative Pediatriche, Università di Padova
Febbraio 2019 - pagg. 97 -102
Abstract
Paediatric palliative care (PPC) aims to ensure the control of symptoms and the best
possible quality of life for patients whose underlying disease, characterised by an unstoppable
evolution and negative prognosis, no longer responds to specific treatments. The
Italian Medicines Agency (Agenzia Italiana del Farmaco - AIFA) and the Italian Society
of Palliative Care (Società Italiana di Cure Palliative - SICP), within a dedicated working
group, wrote a document that collects the scientific evidence available to support the offlabel
drugs that are more frequently used in adult and PPC. The goal is to certify the consolidated
off-label use of these drugs (under the Law 648/96), in the absence of data
from its pivotal clinical trials. The paper reports the conditions for this important work and
presents the 10 drugs that are usually used off-label in PPC and in pain therapy. At present
they are included in Law 648/96 and deemed essential to resolve, at least in part, the
unavailability of medicines approved for use in this specific setting.
Suggerite dall'AI
Classificazione MeSH
Bibliografia
1. European Union. Regulation (EC) N°
1901/2006 on Medicinal Products for Paediatric
Use and Amending Regulation (EEC) N°
1768/92, Directive 2001/20/EC, Directive
2001/83/EC and Regulation (EC) N°
726/2004.
2. European Medicines Agency. Updated priority
list (revised) for studies into off-patent
paediatric medicinal products. Doc. Ref.
EMA/197972/2007. London: EMA, 2007.
3. Pandolfini C, Bonati M. A literature review
on off-label drug use in children. Eur J Pediatr.
2005;164(9):552-8
4. Cuzzolin L, Atzei A, Fanos V. Off-label and
unlicensed prescribing for newborns and children
in different settings: a review of the literature
and a consideration about drug safety.
Expert Opin Drug Saf 2006;5(5):703-718. 2.
5. Gore R, Chugh PK, Tripathi CD, Lhamo Y,
Gautam S. Pediatric off-label and unlicensed
drug use and its implications. Curr Clin Pharmacol
2017;12(1):18-25
6. Barker CIS, Standing JF, Kelly LE, et al
Pharmacokinetic studies in children: recommendations
for practice and research. Arch
Dis Child. 2018;103(7):695-702
7. Steinbrook R. Testing medications in children.
N Engl J Med. 2002;347(18):1462–1470
8. American Academy of Pediatrics Committee
on Drugs. Uses of drugs not described in
the package insert (off-label uses). Pediatrics
2002;110(1 pt 1):181-3.
9. Rocchi F, Paolucci P, Ceci A, Rossi P. The
European paediatric legislation: benefits and
perspectives. Ital J Pediatr. 2010;36:56.
10. Rossi F, Marchetti F. Il regolamento pediatrico
Europeo sui farmaci. Medico e Bambino
2013;32:519-524
11. Tomasi PA, Egger GF, Pallidis C, Saint-
Raymond A. Enabling Development of Paediatric
Medicines in Europe: 10 Years of the EU
Paediatric Regulation. Paediatr Drugs 2017;
19(6):505-13.
12. Frattarelli DA, Galinkin JL, Green TP, et
al; American Academy of Pediatrics Committee
on Drugs. Off-Label Use of Drugs in Children.
Pediatrics 2014;133(3):563-7.
13. Marchetti F, Bua J, Ventura A, et al. The
awareness among paediatricians of off-label
prescribing in children: a survey of Italian hospitals.
Eur J Clin Pharmacol 2007;63(1): 81-5.
14. Bonati M, Jacqz-Aigrain E, Choonara I. Licensed
medicines, off-label use or evidencebased.
Which is most important? Arch Dis
Child 2017;102(1):53-4.
15. Marchetti F. Bambini e farmaci: da un uso
off-label a un uso consapevole e informativo.
Medico e Bambino 2014;33(7):415-6.
16. Luedtke KE, Buck ML. Evaluation of offlabel
prescribing at a children’s rehabilitation
center. J Pediatr Pharmacol Ther 2014;19(4):
296-301.
17. Kwon JH, Kim MJ, Bruera S, Park M,
Bruera E, Hui D. Off-Label Medication Use in
the Inpatient Palliative Care Unit. J Pain
Symptom Manage 2017;54(1):46-54.
18. Pellegatta F, De Zen L, Lazzarin P, et al.
La definizione della eleggibilità alle cure palliative
pediatriche. Medico e Bambino 2016;
35(9):573-8.
19. Benini F, Orzalesi M, de Santi A, et al. Barriers
to the development of pediatric palliative
care in Italy. Ann Ist Super Sanita 2016;52
(4):558-564.
20. Jamieson L, Wong IC, Craig F, et al. Palliative
medicines for children - a new frontier in
paediatric research. J Pharm Pharmacol 2017;
69(4):377-383
21. AIFA. Legge 648/96. http://www.agenziafarmaco.
gov.it/content/legge-64896
22. Working Group Pediatrico dell’AIFA. La
prima lista dei farmaci cardiovascolari autorizzati
per un uso pediatrico. Medico e Bambino
2010;29:172-6.
23. Salvo I, Landoni G, Mucchetti M, Cabrini
L, Pani L. Use and reimbursement of off-label
drugs in pediatric anesthesia: the Italian experience.
Pediatric Anesthesia 2014;24:625-31.
24. Benini F, De Zen L, Marchetti F, Barbi E;
Società Italiana di Cure Palliative (SICP);
Agenzia Italiana del Farmaco (AIFA). Farmaci
off-label in cure palliative (CP) per la popolazione
pediatrica. 2018.
25. Gazzetta Ufficiale. Inserimento nuovo
elenco per uso consolidato relativo ai farmaci
per le cure palliative in Pediatria erogabili a
totale carico del Servizio Sanitario Nazionale.
(Determina n. 128842/2018). 3-12-2018, Anno
159° - Numero 281.
26. De Zen L, Marchetti F, Barbi E, Benini F.
Off-label drugs use in pediatric palliative care.
Ital J Pediatr 2018;44(1):144.
27. Cozzi G, Norbedo S, Barbi E. Intranasal
Dexmedetomidine for procedural sedation in
children, a suitable alternative to chloral hydrate.
Paediatr Drugs 2017;19(2):107-11.
28. Goldman A, Hain R, Liben S. Oxford Textbook
of Palliative Care for Children. 2nd edition.
New York: Oxford University Press Inc
2012.
29. Wolfe J, Hinds PS, Sourkes BM. Textbook
of Interdisciplinary Pediatric Palliative Care.
Philadelphia: Elsevier Saunders; 2011.
30. Zernikow B, Michel E, Craig F, Anderson
BJ. Pediatric palliative care: use of opioids for
the management of pain. Paediatr Drugs
2009;11(2):129-51.
31. Poonai N, Canton K, Ali S, Hendrikx S, et
al. Intranasal ketamine for procedural sedation
and analgesia in children: a systematic review.
PLoS One 2017;12(3):e0173253.
32. Mehran M, Tavassoli-Hojjati S, Ameli N, et
al. Effect of Intranasal Sedation Using Ketamine
and Midazolam on Behavior of 3-6 Year-Old
Uncooperative Children in Dental Office: A
Clinical Trial. J Dent (Tehran) 2017;14(1):1-6
33. Scheier E, Siman A, Balla U. Intranasal ketamine
proved feasible for pain control in paediatric
care and parental support was high.
Acta Paediatr 2017;106(10):1702.
34. Carr DB, Goudas LC, Denman WT, et al.
Safety and efficacy of intranasal ketamine for
the treatment of breakthrough pain in patients
with chronic pain: a randomized, doubleblind,
placebo-controlled, crossover study.
Pain 2004;108(1-2):17-27.
35. Neri E, Maestro A, Minen F, et al. Sublingual
ketorolac versus sublingual tramadol for
moderate to severe post-traumatic bone pain
in children: a double-blind, randomised, controlled
trial. Arch Dis Child 2013;98:721-4.
36. Molassiotis A, Smith JA, Mazzone P, et al.
Symptomatic treatment of cough among adult
patients with lung Cancer: CHEST guideline
and expert panel report. Chest 2017;151(4):
861-74.
37. Kajiume T, Sera Y, Nakanuno R, et al.
Continuous intravenous infusion of ketamine
and lidocaine as adjuvant analgesics in a 5-
year-old patient with neuropathic cancer pain.
J Palliat Med 2012;15(6):719-22.
38. Stokland E, Andréasson S, Jacobsson B,
Jodal U, Ljung B. Sedation with midazolam for
voiding cystourethrography in children: a randomised
double-blind study. Pediatr Radiol
2003;33(4):247-9
39. Chiaretti A, Barone G, Rigante D, et al.
Intranasal lidocaine and midazolam for procedural
sedation in children. Arch Dis Child.
2011;96(2):160-3.
40. Jitpakdee T, Mandee S. Strategies for preventing
side effects of systemic opioid in postoperative
pediatric patients. Paediatr Anaesth
2014;24(6):561-8.
Corrispondenza: federico.marchetti@auslromagna.it