Skip to main content
SpringerLink
Log in

Off-Label Prescribing of Antiepileptic Drugs in Pharmacoresistant Epilepsy: A Cross-Sectional Drug Utilization Study of Tertiary Care Centers in Italy

  • Original Research Article
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Purpose

To assess the extent of off-label prescribing of antiepileptic drugs (AEDs) and associated variables in a large population of patients with pharmacoresistant epilepsy.

Methods

Descriptive analysis of data recorded from consecutively enrolled patients with pharmacoresistant epilepsy attending 11 tertiary referral centers in Italy. Off-label use was stratified by therapeutic indication, dose, and age. Multivariate logistic regression was used to identify variables associated with off-label prescription.

Results

Of a total of 1,124 patients enrolled between November 2006 and August 2007, 53 % (101/191) of children and 31 % (287/933) of adults were receiving at least one off-label AED prescription. Among adults, off-label use was related primarily to indication and was highest for clobazam (100 %) and ethosuximide (40 %), followed by lamotrigine (25 %), and vigabatrin (25 %). In children, clobazam (100 %), lamotrigine (79 %), vigabatrin (55 %), ethosuximide (46 %), and levetiracetam (43 %) were most frequently used off-label, with indication or age being the main causes depending on the specific AED. Logistic regression analysis indicated that higher rates of off-label use were associated with a polytherapy regimen (odds ratio [OR] 2.50, 95 % confidence interval [95 % CI], 1.55–4.03), pediatric age (2.49, 1.66–3.76), having failed ≥3 AEDs (2.16, 1.04–4.48), a diagnosis of generalized epilepsy with structural/metabolic or unknown etiology (2.97, 1.25–7.04), and increasing seizure frequency (1.07, 1.01–1.14).

Conclusions

Off-label prescribing of AEDs is common among patients with pharmacoresistant epilepsy and is influenced by demographic and disease-related characteristics. Studies are needed to improve the quality of evidence guiding epilepsy treatment, and to evaluate the risks and benefits of off-label prescribing in epilepsy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Notes

  1. The members of SOPHIE are listed in the "Appendix".

References

  1. Baulac M, Brodie MJ, Patten A, Segieth J, Giorgi L. Efficacy and tolerability of zonisamide versus controlled-release carbamazepine for newly diagnosed partial epilepsy: a phase 3, randomised, double-blind, non-inferiority trial. Lancet Neurol. 2012;11(7):579–88.

    Article  PubMed  CAS  Google Scholar 

  2. Perucca E. Designing clinical trials to assess antiepileptic drugs as monotherapy: difficulties and solutions. CNS Drugs. 2008;22(11):917–38.

    Article  PubMed  CAS  Google Scholar 

  3. French JA, Kanner AM, Bautista J, Abou-Khalil B, Browne T, Harden CL, et al. Efficacy and tolerability of the new antiepileptic drugs. I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 2004;62(8):1252–60.

  4. National Institute for Health and Care Excellence (NICE). The epilepsies: the diagnosis and management of the epilepsies in adults and children in primary and secondary care. NICE Clinical Guideline 137. http://guidance.nice.org.uk/CG137/NICEGuidance/pdf. Accessed 20 March 2014.

  5. Larkin M. Warner–Lambert found guilty of promoting neurontin off label. Lancet Neurol. 2004;3(7):387.

  6. Conroy S, Peden V. Unlicensed and off label analgesic use in paediatric pain management. Pediatr Anesth. 2001;11(4):431–6.

    Article  CAS  Google Scholar 

  7. Jonville-Bera AP, Bera F, Autret-Leca E. Are incorrectly used drugs more frequently involved in adverse drug reactions? A prospective study. Eur J Clin Pharmacol. 2005;61(3):231–6.

    Article  PubMed  CAS  Google Scholar 

  8. Chen H, Deshpande AD, Jiang R, Martin BC. An epidemiological investigation of off-label anticonvulsant drug use in the Georgia Medicaid population. Pharmacoepidemiol Drug Saf. 2005;14(9):629–38.

    Article  PubMed  Google Scholar 

  9. Citrome L, Levine J, Allingham B. Utilization of valproate: extent of inpatient use in the New York State Office of Mental Health. Psychiatr Q. 1998;69(4):283–300 (Epub 1998/10/30).

    Article  PubMed  CAS  Google Scholar 

  10. Eguale T, Buckeridge DL, Winslade NE, Benedetti A, Hanley JA, Tamblyn R. Drug, patient, and physician characteristics associated with off-label prescribing in primary care. Arch Intern Med. 2012;172(10):781–8.

    Article  PubMed  Google Scholar 

  11. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med. 2006;166(9):1021–6.

    Article  PubMed  Google Scholar 

  12. Alexandre V, Capovilla G, Fattore C, Franco V, Gambardella A, Guerrini R, et al. Characteristics of a large population of patients with refractory epilepsy attending tertiary referral centers in Italy. Epilepsia. 2010;51(5):921–5.

    Article  PubMed  Google Scholar 

  13. Canevini MP, De Sarro G, Galimberti CA, Gatti G, Licchetta L, Malerba A, et al. Relationship between adverse effects of antiepileptic drugs, number of coprescribed drugs, and drug load in a large cohort of consecutive patients with drug-refractory epilepsy. Epilepsia. 2010;51(5):797–804.

    Article  PubMed  CAS  Google Scholar 

  14. Malerba A, Ciampa C, De Fazio S, Fattore C, Frassine B, La Neve A, et al. Patterns of prescription of antiepileptic drugs in patients with refractory epilepsy at tertiary referral centres in Italy. Epilepsy Res. 2010;91(2–3):273–82.

    Article  PubMed  Google Scholar 

  15. Perucca E. Pharmacoresistance in epilepsy. How should it be defined? CNS Drugs. 1998;10(3):171–9.

    Article  Google Scholar 

  16. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia. 1981; 22:489–501.

  17. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia. 1989; 30:389–99.

  18. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia. 2010;51(4):676–85.

  19. Marchetti F, Bua J, Ventura A, Notarangelo LD, Di Maio S, Migliore G, 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.

    Article  PubMed  Google Scholar 

  20. Kwan P, Arzimanoglou A, Berg AT, Brodie MJ, Allen Hauser W, Mathern G, et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc task force of the ILAE Commission on Therapeutic Strategies. Epilepsia. 2010;51(6):1069–77.

  21. Glauser T, Ben-Menachem E, Bourgeois B, Cnaan A, Guerreiro C, Kalviainen R, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551–63 (Epub 2013/01/29).

    Article  PubMed  CAS  Google Scholar 

  22. Perucca E, Dulac O, Shorvon S, Tomson T. Harnessing the clinical potential of antiepileptic drug therapy: dosage optimisation. CNS Drugs. 2001;15(8):609–21.

    Article  PubMed  CAS  Google Scholar 

  23. Choonara I, Conroy S. Unlicensed and off-label drug use in children: implications for safety. Drug Saf. 2002;25(1):1–5.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This study was conducted under the auspices of the Italian League Against Epilepsy (LICE) and the Italian Pharmacological Society (SIF) and was supported by the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) within the independent drug research program, contract no. FARM52K2WM. Valentina Franco was the recipient of a Ph.D. bursary from the University of Pavia. Angela La Neve received funding for travel and speaker honoraria from UCB-Pharma, GSK, Eisai, Inc. and Cyberonics. Carlo Andrea Galimberti received speaker’s fees from UCB, GSK and Eisai and research grants paid to his institution from Eisai, UCB Pharma, GSK, and Bial. Emilio Perucca received speaker and/consultancy fees from Bial, Eisai, GSK, Lundbeck, Medichem, Pfizer, Sun Pharma, Supernus, UCB Pharma, Viropharma, and Vertex. Luigi Maria Specchio received speaker and/consultancy fees from GSK, UCB, and Eisai. Maria Paola Canevini received consultancy and/or research grants and support for congress participation from Cyberonics, UCB, Eisai, and Novartis. Salvatore Striano received speaker and/consultancy fees from Viropharma, Eisai, GSK, UCB, and Janssen-Cilag. Valentina Franco is a former employee of Eisai s.r.l. Italy. Giuseppe Capovilla, Giovambattista De Sarro, Giuliana Gatti, Renzo Guerrini, Eleonora Rosati, and Paolo Tinuper have no conflicts of interest to declare.

Author information

Authors and Affiliations

  1. Clinical and Experimental Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Via Ferrata, 9, 27100, Pavia, Italy

    Valentina Franco, Giuliana Gatti & Emilio Perucca

  2. Division of Neurology 2, Department of Health Science Medicine, Surgery, Dentistry, San Paolo Hospital, University of Milan, Milan, Italy

    Maria Paola Canevini

  3. Department of Child Neuropsychiatry, Epilepsy Center, C. Poma Hospital, Mantua, Italy

    Giuseppe Capovilla

  4. Department of Health Science and Pharmacovigilance Centre Calabria Region, University Hospital Mater Domini, University of Catanzaro, Catanzaro, Italy

    Giovambattista De Sarro

  5. C. Mondino National Neurological Institute, Pavia, Italy

    Carlo Andrea Galimberti & Emilio Perucca

  6. Pediatric Neurology Unit and Laboratories, Neuroscience Department, A. Meyer Children’s Hospital, University of Florence, Florence, Italy

    Renzo Guerrini

  7. Clinic for Nervous System Diseases, University of Bari, Bari, Italy

    Angela La Neve

  8. 3rd Neurology Division and Epilepsy Center, Careggi Hospital, Florence, Italy

    Eleonora Rosati

  9. Epilepsy Center, Clinic of Nervous System Diseases, Ospedali Riuniti, University of Foggia, Foggia, Italy

    Luigi Maria Specchio

  10. Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy

    Salvatore Striano

  11. IRCCS Istituto delle Scienze Neurologiche di Bologna and Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy

    Paolo Tinuper

Authors
  1. Valentina Franco
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria Paola Canevini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppe Capovilla
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giovambattista De Sarro
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Carlo Andrea Galimberti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Giuliana Gatti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Renzo Guerrini
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Angela La Neve
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Eleonora Rosati
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luigi Maria Specchio
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Salvatore Striano
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Paolo Tinuper
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Emilio Perucca
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Emilio Perucca.

Appendix: Study of Outcome of Pharmacoresistance in Epilepsy (SOPHIE) collaborators:

Appendix: Study of Outcome of Pharmacoresistance in Epilepsy (SOPHIE) collaborators:

Study coordinator Emilio Peruccaa,b

Steering committee Agostino Baruzzi,c Giovambattista De Sarro,d and Emilio Peruccaa,b

Central coordination and data analysis Erminio Bonizzoni,a Cinzia Fattore,b Valentina Franco,a Giuliana Gatti,a Ambra Malerba,a Mario Marzanatti,a Iolanda Mazzucchellia

Clinical study investigators at enrolling centers Veriano Alexandre Jr,b,e Francesca Beccaria,f Francesca Bisulli,c Sophie Cagdas,f Maria Paola Canevini,g Giuseppe Capovilla,f Clotilde Ciampa,h Salvatore De Fazio,d Giovambattista De Sarro,d Luigi Del Gaudio,h Benedetta Frassine,f,i Carlo Andrea Galimberti,b Antonio Gambardella,d Simone Gana,l Lucio Giordano,i Renzo Guerrini,l,m Angelo Labate,d Francesca La Briola,g Marianna Ladogana,n Paolo Lamberti,n Angela La Neve,n Laura Licchetta,c Giancarlo Muscas,o Anna Maria Papantonio,p Angelo Pascarella,h Simona Pellacani,l Eleonora Rosati,o Lia Santulli,h Luigi Maria Specchio,p Pasquale Striano,q Salvatore Striano,h Alessandra Tiberti,i Paolo Tinuper,c Rossana Tozzi,b Marina Trivisano.p

aClinical and Experimental Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia; bC. Mondino National Neurological Institute, Pavia; cIRCCS Istituto delle Scienze Neurologiche di Bologna and Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna; dMagna Graecia University, Catanzaro; eHospital of Clinics, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto (Brazil); fEpilepsy Center, Department of Child Neuropsychiatry, C. Poma Hospital, Mantova; gDepartment of Medicine, Surgery, Dentistry, University of Milan, Division of Neurology 2, San Paolo Hospital, Milan; hEpilepsy Center, Federico II University, Napoli; iEpilepsy Center, Department of Child and Adolescent Neuropsychiatry, Spedali Civili, Brescia; lPediatric Neurology Unit and Laboratories, Children’s Hospital A. Meyer, University of Florence, Florence; mIRCCS Stella Maris, Pisa; nEpilepsy Center, Neurology Hospital “Amaducci,” University of Bari, Bari; o3rd Neurology Division and Epilepsy Center, Careggi Hospital, Florence (current address Division of Neurology, Prato Hospital, Prato); pEpilepsy Center, Clinic of Nervous System Diseases, Ospedali Riuniti, University of Foggia, Foggia; qPediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, G. Gaslini Institute, Genova.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Franco, V., Canevini, M.P., Capovilla, G. et al. Off-Label Prescribing of Antiepileptic Drugs in Pharmacoresistant Epilepsy: A Cross-Sectional Drug Utilization Study of Tertiary Care Centers in Italy. CNS Drugs 28, 939–949 (2014). https://doi.org/10.1007/s40263-014-0189-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-014-0189-8

Keywords

Search

Navigation