Spontaneous Reporting of Adverse Drug Reactions in a Pediatric Population in a Tertiary Hospital
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Setting and Design
2.2. Participants
2.3. Variables
Variable Definitions and Classifications
2.4. ADR Causality Assessment
2.5. Statistical Analysis
3. Results
3.1. Characteristics of ADRs
3.2. Characteristics of Suspected Drugs
3.3. Comparison of ADRs between Age Groups
4. Discussion
Strengths and Limitations
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- World Health Organization Technical Report Series (1972, No 498). International Drug Monitoring. The Role of the National Centres. Report of a WHO Meeting. Geneva, Switzerland. Available online: http://apps.who.int/iris/bitstream/10665/40968/1/WHO_TRS_498.pdf (accessed on 23 September 2021).
- Commission Directive 2010/84/EU of the European Parliament and the Council of 15 December 2010 Amending as Regards Pharmacovigilance, Directive 2001/83/EC on the Community Code Relating to Medicinal Products for Human Use. Official Journal of the European Union 31.12.2010: L348/74-L348/99. Available online: https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32010L0084 (accessed on 23 September 2021).
- Lexchin, J. Adverse Drug Reactions: Review of the Canadian Literature. Can. Fam. Physician 1991, 37, 109–118. [Google Scholar] [PubMed]
- Pirmohamed, M.; Breckenridge, A.M.; Kitteringham, N.R.; Park, B.K. Adverse drug reactions. BMJ 1998, 316, 1295–1298. [Google Scholar] [CrossRef] [PubMed]
- Taché, S.V.; Sönnichsen, A.; Ashcroft, D.M. Prevalence of adverse drug events in ambulatory care: A systematic review. Ann. Pharmacother. 2011, 45, 977–989. [Google Scholar] [CrossRef] [PubMed]
- Strengthening Pharmacovigilance to Reduce Adverse Effects of Medicines. MEMO/08/782. Bruselas. December–November 2008. Available online: http://europa.eu/rapid/press-release MEMO-08-782en.htm (accessed on 23 September 2021).
- Conroy, S.; Choonara, I.; Impicciatore, P.; Mohn, A.; Arnell, H.; Rane, A.; Knoeppel, C.; Seyberth, H.; Pandolfini, C.; Raffaelli, M.P.; et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. BMJ 2000, 320, 79–82. [Google Scholar] [CrossRef] [Green Version]
- Elzagallaai, A.A.; Greff, M.J.E.; Rieder, M.J. Adverse Drug Reactions in Children: The double-edged sword of therapeutics. Clin. Pharmacol. Ther. 2017, 101, 725–735. [Google Scholar] [CrossRef]
- Impicciatore, P.; Choonara, I.; Clarkson, A.; Provasi, D.; Pandolfini, C.; Bonati, M. Incidence of adverse drug reactions in paediatric in/out-patients: A systematic review and meta-analysis of prospective studies. Br. J. Clin. Pharmacol. 2001, 52, 77–83. [Google Scholar] [CrossRef] [Green Version]
- Clavenna, A.; Bonati, M. Adverse drug reactions in childhood: A review of prospective studies and safety alerts. Arch. Dis. Child. 2009, 94, 724–728. [Google Scholar] [CrossRef] [Green Version]
- Aagaard, L.; Christensen, A.; Hansen, E.H. Information about adverse drug reactions reported in children: A qualitative review of empirical studies. Br. J. Clin. Pharmacol. 2010, 70, 481–491. [Google Scholar] [CrossRef]
- Patton, K.; Borshoff, D.C. Adverse drug reactions. Anaesthesia 2018, 73, 76–84. [Google Scholar] [CrossRef] [Green Version]
- Pal, S.N.; Duncombe, C.; Falzon, D.; Olsson, S. WHO strategy for collecting safety data in public health programmes: Complementing spontaneous reporting systems. Drug Saf. 2013, 36, 75–81. [Google Scholar] [CrossRef] [Green Version]
- Hazell, L.; Shakir, S.A. Under-reporting of adverse drug reactions: A systematic review. Drug Saf. 2006, 29, 385–396. [Google Scholar] [CrossRef] [PubMed]
- Guidelines for Detecting & Reporting Adverse Drug Reactions. Individual Case Safety Reports for Healthcare Professionals. Available online: https://www.who-umc.org/media/1079/jordan.pdf (accessed on 23 September 2021).
- Blake, K.V.; Zaccaria, C.; Domergue, F.; La Mache, E.; Saint-Raymond, A.; Hidalgo-Simon, A. Comparison between paediatric and adult suspected adverse drug reactions reported to the European medicines agency: Implications for pharmacovigilance. Paediatr. Drugs 2014, 16, 309–319. [Google Scholar] [CrossRef] [PubMed]
- Aldea, A.; García Sánchez-Colomer, M.; Fernández Quintana, E.; García Sáiz, M. Paediatric adverse drug reactions reported to the Spanish Pharmacovigilance System from 2004 to 2009. Eur. J. Clin. Pharmacol. 2012, 68, 1329–1338. [Google Scholar] [CrossRef]
- Vandenbroucke, J.P.; von Elm, E.; Altman, D.G.; Gøtzsche, P.C.; Mulrow, C.D.; Pocock, S.J.; Poole, C.; Scglesselman, J.J.; Egger, M.; STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): Explanation and elaboration. PLoS Med. 2007, 4, 1628–1654. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- MedDRA Maintenance and Support Services Organization. Introductory Guide MedDRA Version 24.0. March 2021. Available online: https://admin.new.meddra.org/sites/default/files/guidance/file/intguide_%2024_0_English.pdf (accessed on 23 September 2021).
- Montané, E.; Santesmases, J. Adverse drug reactions. Med. Clínica 2020, 154, 178–184. [Google Scholar] [CrossRef]
- European Medicines Agency. ICH Topic E 11. Clinical Investigation of Medicinal Products in the Paediatric Population. CPMP/ICH/2711/99; 2001. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-1.pdf (accessed on 23 September 2021).
- WHO Collaborating Centre for Drug Statistics Methodology. Guidelines for ATC Classification and DDD Assignment 2019. Oslo, Norway. 2018. Available online: http://www.whocc.no (accessed on 23 September 2021).
- Cascorbi, I. Drug interactions—principles, examples and clinical consequences. Dtsch. Ärzteblatt Int. 2012, 109, 546–555. [Google Scholar] [CrossRef]
- Notas Informativas Medicamentos De Uso Humano. Agencia Española De Medicamentos Y Productos Sanitarios (AEMPS). Available online: https://www.aemps.gob.es/acciones-informativas/notas-informativas-medicamentos-de-uso-humano/?cat=266&tag=seguridad-8 (accessed on 23 September 2021).
- European Medicines Agency (EMA). Medicines under Additional Monitoring. Available online: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/medicines-under-additional-monitoring (accessed on 23 September 2021).
- European Medicines Agency (EMA). List of Medicines under Additional Monitoring. Available online: https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/medicines-under-additional-monitoring/list-medicines-under-additional-monitoring (accessed on 23 September 2021).
- Meyers, R.S.; Thackray, J.; Matson, K.L.; McPherson, C.; Lubsch, L.; Hellinga, R.C.; Hoff, D.S. Key potentially inappropriate drugs in pediatrics: The KIDs list. J. Pediatric Pharmacol. Ther. 2020, 25, 175–191. [Google Scholar] [CrossRef] [Green Version]
- Rawlins, M.D.; Thompson, J.W. Mechanisms of Adverse Drug Reactions. In Textbook of Adverse Drug Reactions; Davies, D.M., Ed.; Oxford University Press: Oxford, UK, 1991; pp. 18–45. [Google Scholar]
- National Coordinating Council for Medication Error Reporting and Prevention. About Medication Errors. Available online: https://www.nccmerp.org/about-medication-errors (accessed on 23 September 2021).
- Day, R. Off-label prescribing. Aust. Prescr. 2013, 36, 182–183. [Google Scholar] [CrossRef]
- Bjerrum, L.; Rosholm, J.U.; Hallas, J.; Kragstrup, J. Methods for estimating the occurrence of polypharmacy by means of a prescription database. Eur. J. Clin. Pharmacol. 1997, 53, 7–11. [Google Scholar] [CrossRef]
- European Medicines Agency. ICH Topic E 2 D. Post Approval Safety Data Management. CPMP/ICH/3945/03; 2004. Available online: https://www.ema.europa.eu/en/documents/scientific-guideline/international-conference-harmonisation-technical-requirements-registration-pharmaceuticals-human-use_en-12.pdf (accessed on 23 September 2021).
- Centro De Información Online De Medicamentos (CIMA). Agencia Española De Medicamentos Y Productos Sanitarios (AEMPS). Available online: https://cima.aemps.es/cima/publico/home.html (accessed on 23 September 2021).
- Aguirre, C.; García, M. Causality assessment in reports on adverse drug reactions. Algorithm of Spanish pharmacovigilance system. Med. Clínica 2016, 147, 461–464. (In Spanish) [Google Scholar] [CrossRef]
- Paracetamol De Administración Intravenosa (IV): Casos De Errores De Dosificación. Agencia Española De Medicamentos Y Productos Sanitarios (AEMPS). March 2012. Available online: https://www.aemps.gob.es/informa/ni-muh_05-2012/ (accessed on 23 September 2021).
- Vitamina D: Casos Graves Dde Hipercalcemia Por Sobredosificación En Pacientes Adultos Y En Pediatria. Agencia Española De Medicamentos Y Productos Sanitarios (AEMPS). March 2019. Available online: https://www.aemps.gob.es/informa/notasinformativas/medicamentosusohumano-3/seguridad-1/vitamina-d-casos-graves-de-hipercalcemia-por-sobredosificacion-en-pacientes-adultos-y-en-pediatria/ (accessed on 23 September 2021).
- Retinoides (Acitretina, Alitretinoína, Isotretinoína): Actualización De Las Medidas Para Evitar La Exposición Durante El EmBarazo Y De Las Advertencias Sobre Efectos Neuropsiquiátricos. Agencia Española De Medicamentos Y Productos Sanitarios (AEMPS). March 2018. Available online: https://www.aemps.gob.es/informa/notasinformativas/medicamentosusohumano-3/seguridad-1/2018/ni-muh_fv_06-retinoides/ (accessed on 23 September 2021).
- Star, K.; Norén, G.N.; Nordin, K.; Edwards, I.R. Suspected adverse drug reactions reported for children worldwide: An exploratory study using vigibase. Drug Saf. 2011, 34, 415–428. [Google Scholar] [CrossRef]
- Lexchin, J. Is there still a role for spontaneous reporting of adverse drug reactions? Can. Med. Assoc. J. 2006, 174, 191–192. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Naranjo, C.A.; Busto, U.; Sellers, E.M.; Sandor, P.; Ruiz, I.; Roberts, E.A.; Janecek, E.; Domecq, C.; Greenblatt, D.J. A method for estimating the probability of adverse drug reactions. Clin. Pharmacol. Ther. 1981, 30, 239–245. [Google Scholar] [CrossRef] [PubMed]
- World Health Organization; Uppsala: The Uppsala Monitoring Centre. The Use of the WHO-UMC System for Standardized Case Causality Assessment. Available online: http://who-umc.org/Graphics/24734.pdf (accessed on 13 November 2021).
- Azar, C.; Allué, D.; Valnet-Rabier, M.B.; Chouchana, L.; Rocher, F.; Durand, D.; Grené-Lerouge, N.; Saleh, N.; Maison, P. Patterns of medication errors involving pediatric population reported to the French Medication Error Guichet. Pharm. Pract. 2021, 19, 2360. [Google Scholar] [CrossRef] [PubMed]
- European Medicines Agency. European Medicines Agency Pre-Authorisation Evaluation of Medicines for Human Use. Evidence of Harm from Off-Label or Unlicensed Medicines in Children. EMEA/126327/2004; 2004. Available online: http://www.ema.europa.eu/docs/en_GB/document_library/Other/2009/10/WC500004021.pdf (accessed on 23 September 2021).
- Choonara, I.; Conroy, S. Unlicensed and off-label drug use in children: Implications for safety. Drug Saf. 2002, 25, 1–5. [Google Scholar] [CrossRef] [PubMed]
- Batchelor, H.K.; Marriott, J.F. Paediatric pharmacokinetics: Key considerations. Br. J. Clin. Pharmacol. 2015, 79, 395–404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Abu Esba, L.C.; Al Mardawi, G.; AlJasser, M.I.; Aljohani, B.; Abu Alburak, A. Adverse Drug Reactions Spontaneously Reported at a Tertiary Care Hospital and Preventable Measures Implemented. J. Clin. Pharmacol. Ther. 2021, 46, 460–469. [Google Scholar] [CrossRef]
- Vallano, A.; Cereza, G.; Pedròs, C.; Agustí, A.; Danés, I.; Aguilera, C.; Arnau, J.M. Obstacles and solutions for spontaneous reporting of adverse drug reactions in the hospital. Br. J. Clin. Pharmacol. 2005, 60, 653–658. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Goldman, S.A. Limitations and strengths of spontaneous reports data. Clin. Ther. 1998, 20, C40–C444. [Google Scholar] [CrossRef]
- Begaud, B.; Moride, Y.; Tubert-Bitter, P.; Chaslerie, A.; Haramburu, F. False-positives in spontaneous reporting: Should we worry about them? Br. J. Clin. Pharmacol. 1994, 38, 401–404. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lopez-Gonzalez, E.; Herdeiro, M.T.; Figueiras, A. Determinants of under-reporting of adverse drug reactions: A systematic review. Drug Saf. 2009, 32, 19–31. [Google Scholar] [CrossRef] [PubMed]
Organ and Systems Classification (SOC): N (%) | Seriousness: N (%) |
---|---|
Nervous system disorders: 14 (13.5) Seizure (4), dystonia (2), somnolence (2), encephalopathy (2), addiction (1), headache (1), hypotonia (1), optic neuritis (1) | 12 (86) |
Immune system disorders: 12 (11.7) Infusion reaction (7), anaphylactic shock (2), urticaria (2), erythema (1) | 6 (50) |
Skin and subcutaneous tissue disorders: 12 (11.7) Erythema or skin rash (9), angioedema (2), psoriasis (1) | 0 (0) |
Blood and lymphatic system disorders: 9 (8.7) Thrombocytopenia (3), neutropenia (3), haemorrhage (2), bone marrow aplasia (1) | 6 (66.7) |
Infections and infestations: 9 (8.7) Cellulitis (3), respiratory infection (2), herpes infection (1), otitis (1), hordeolum (1), subcutaneous infection (1) | 5 (55.5) |
Cardiac disorders: 8 (7.8) Arrhythmias (6), cardiac arrest (1), myocardiotoxicity (1) | 5 (62.5) |
Metabolic and nutritional disorders: 8 (7.8) Hypokalaemia (4), acidosis (1), alkalosis (1), hyperglycaemia (1), hypoglycaemia (1) | 6 (75) |
Gastrointestinal disorders: 7 (6.8) Pancreatitis (3), dysphagia (2), mucositis (1), perforated duodenal ulcus (1) | 6 (85.7) |
Psychiatric disorders: 4 (3.9) Agitation or irritability (2), anxiety (1), sleep disturbances (1) | 1 (25) |
Hepatobiliary disorders: 3 (2.9) Liver enzyme increases (3) | 1 (33.3) |
Renal and urinary disorders: 3 (2.9) Acute renal failure (2), nephrotic syndrome (1) | 3 (100) |
Traumatic injuries, intoxications and complications of therapeutic procedures: 3 (2.9) Intoxication (3) | 3 (100) |
General disorders and alterations at site of administration: 2 (1.9) Fever (1), fainting (1) | 0 (0) |
Endocrine disorders: 2 (1.9) Syndrome of inappropriate antidiuretic hormone (SIADH) (2) | 2 (100) |
Vascular disorders: 2 (1.9) Arterial hypertension (AHT) (1), cerebral venous thrombosis (1) | 1 (50) |
Congenital, familial and genetic disorders: 2 (1.9) Congenital cardiopulmonary malformation (1), cardiomyopathy (1) | 2 (100) |
Musculoskeletal disorders: 1 (1.0) Systemic lupus erythematosus (SLE) /Pericarditis (1) | 1 (100) |
Respiratory, thoracic and mediastinal disorders: 1 (1.0) Respiratory arrest (1) | 1 (100) |
Total: 103 (100) | 61 (59.2) |
ATC Category | Therapeutic Area | N | % |
---|---|---|---|
L | Antineoplastic and immunomodulating agents: Methotrexate (7), adalimumab (5), azathioprine (5), doxorubicin (4), rituximab (4), vincristine (4), asparaginase (3), cyclophosphamide (3), tocilizumab (3), infliximab (2), antithymocyte immunoglobulin (1), cytarabine (1), PEG-asparaginase (1), siltuximab (1), tacrolimus (1) | 45 | 32.4 |
N | Nervous system: Metamizole (3), oxcarbazepine (3), valproic acid (2), acetaminophen (paracetamol) (1), acetylsalicylic acid (1), methylphenidate (1), bupivacaine (1), caffeine (1), clonazepam (1), dextromethorphan (1), dimemorfan (1), droperidol (1), fentanyl (1), fluoxetine (1), haloperidol (1), lamotrigine (1), lidocaine (1), lorazepam (1), mepivacaine (1), olanzapine (1), petidine (1), quetiapine (1), remifentanil (1), sulpiride (1), ziprasidone (1) | 30 | 21.6 |
J | Anti-infectives for systemic use: Amoxicillin-clavulanate (2), cefazolin (2), meningococcal ACWY vaccine (2), meningococcal B vaccine (2), ceftazidime (1), clindamycin (1), doxycycline (1), DTaP vaccine (1), ganciclovir (1), gentamicin (1), immunoglobulin (1), influenza vaccine (1), isoniazide (1), metronidazole (1), pneumococcal vaccine (1), valganciclovir (1), vancomicin (1), varicella vaccine (1) | 22 | 15.9 |
R | Respiratory system: Salbutamol (5), salmeterol (2), budesonide (1), montelukast (1), vilanterol (1), fluticasone (1), ivy * (1) | 12 | 8.6 |
M | Musculo-skeletal system: Ibuprofen (8), dexketoprofen (1) | 9 | 6.5 |
H | Systemic hormonal preparations, excluding sex-hormones and insulins: Methylprednisolone (4), dexamethasone (2), corticotrophin (1) | 7 | 5.0 |
A | Alimentary tract and metabolism: Ondansetron (3), insulin (1), pyridoxine (1), vitamin D (1) | 6 | 4.3 |
C | Cardiovascular system: Bisoprolol (1), furosemide (1), epinephrine (1) | 3 | 2.15 |
V | Various: Iomeprol (1), sugammadex (1), melissa officinalis * (1) | 3 | 2.15 |
D | Dermatologicals: Isotretinoin (1) | 1 | 0.7 |
S | Sensory organs: Cyclopentolate (1) | 1 | 0.7 |
B | Blood and blood forming organs | 0 | 0 |
G | Genito-urinary system and sex hormones | 0 | 0 |
P | Antiparasitic products, insecticides and repellents | 0 | 0 |
Total | 139 | 100 |
Sex | Age | Drug | ADR | Type of Error | Seriousness |
---|---|---|---|---|---|
Female | 21 days | Vitamin D | Intoxication | Overdose | Serious |
Male | 1 month | Acetaminophen | Hepatitis | Overdose | Serious |
Female | 1 month | Valproic acid | Somnolence | Overdose | Serious |
Female | 4 months | Dextromethorphan | Intoxication | Overdose | Serious |
Male | 8 years | Immunoglobulin | Cerebral venous thrombosis | Drug error | Serious |
Female | 10 years | Insulin | Hypoglycaemia | Overdose | Nonserious |
Female | 14 years | Valproic acid | Intoxication | Overdose | Serious |
Female | 17 years | Bisoprolol | AV blocking | Overdose | Nonserious |
Sex | Age | Drug | Indication | ADR | Type of Off-Label | Severity |
---|---|---|---|---|---|---|
Female | 4 months | Dextromethorphan | Cough | Intoxication * | Patient age | Serious |
Male | 8 months | Corticotrophin | Spasms | Hypokalaemia | Indication | Serious |
Male | 5 years | Pyridoxine | Convulsions | Inefficacy | Patient age | Serious |
Male | 5 years | Ondansetron | Nausea and vomiting | Cardiac arrest | Indication | Serious |
Female | 9 years | Ibuprofen | Pain | Infusional reaction | Patient age | Nonserious |
Male | 14 years | Ondansetron | Nausea and vomiting | Erythema | Indication | Nonserious |
Male | 16 years | Olanzapine | Anxiety | Bradycardia and ventricular trigeminy | Patient age Indication | Serious |
Female | 16 years | Sulpiride | Dizziness | Acute dystonia | Patient age Posology | Serious |
Male | 17 years | Siltuximab | Castelman disease | Thrombocytopenia | Patient age | Nonserious |
Female | 17 years | Bisoprolol | Palpitations/ ventricular extrasystoles | AV blocking | Patient age | Nonserious |
ADR Characteristics | ||||
NIT (n = 27) | Child (n = 35) | Adolescent (n = 41) | p | |
Male: n (%) | 17 (63) | 19 (54.3) | 23 (56.1) | 0.774 |
Type A ADR: n (%) | 16 (59.3) | 15 (42.9) | 15 (36.6) | 0.177 |
Serious ADR: n (%) | 26 (96.3) | 16 (45.7) | 19 (46.3) | <0.001 |
Hospital-acquired ADR: n (%) | 14 (51.9) | 15 (42.9) | 13 (31.7) | 0.241 |
Number of involved drugs: median (IQR) | 1 (1–2) | 1 (1–1) | 1 (1–1) | 0.084 |
ADR by SOC category a | Nervous system | Immune system disorders | Skin and subcutaneous tissue disorders | NA |
Involved drugs characteristics | ||||
NIT (n = 38) | Child (n = 47) | Adolescent (n = 54) | p | |
Unlabeled reactions: n (%) | 8 (21.1) | 2 (4.3) | 1 (1.9) | 0.004 |
Drugs by ATC category b | Nervous system (N) | Antineoplastic and immunomodulating agents (L) | Antineoplastic and immunomodulating agents (L) | NA |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
López-Valverde, L.; Domènech, È.; Roguera, M.; Gich, I.; Farré, M.; Rodrigo, C.; Montané, E. Spontaneous Reporting of Adverse Drug Reactions in a Pediatric Population in a Tertiary Hospital. J. Clin. Med. 2021, 10, 5531. https://doi.org/10.3390/jcm10235531
López-Valverde L, Domènech È, Roguera M, Gich I, Farré M, Rodrigo C, Montané E. Spontaneous Reporting of Adverse Drug Reactions in a Pediatric Population in a Tertiary Hospital. Journal of Clinical Medicine. 2021; 10(23):5531. https://doi.org/10.3390/jcm10235531
Chicago/Turabian StyleLópez-Valverde, Laura, Èlia Domènech, Marc Roguera, Ignasi Gich, Magí Farré, Carlos Rodrigo, and Eva Montané. 2021. "Spontaneous Reporting of Adverse Drug Reactions in a Pediatric Population in a Tertiary Hospital" Journal of Clinical Medicine 10, no. 23: 5531. https://doi.org/10.3390/jcm10235531