- Email: [email protected]
Characteristics of Pediatric Exposures to Antidementia Drugs Reported to a Poison Control System
Characteristics of Pediatric Exposures to Antidementia Drugs Reported to a Poison Control System Stephen L. Thornton, MD1,2, Julia L. Pchelnikova, PharmD3, and F. Lee Cantrell, PharmD4 Objective To characterize pediatric exposures to the antidementia drugs donepezil, memantine, rivastigmine, and galantamine by reviewing a poison control system’s database.
Study design A retrospective review of a statewide poison control system’s database identified cases of pediatric (less than 19 years of age) exposures to antidementia drugs over an 11-year period. Data collected included age, sex, drug(s) involved, route of exposure, reason for exposure, symptoms, and interventions. Results There were 189 cases identified (53% male, median age: 2.3 years, 99% unintentional exposures). Donepezil was the most commonly reported exposure (106 cases), followed by memantine (57), galantamine (18), oral rivastigmine (16), and transdermal rivastigmine (3). Coingestants were reported in 68 (36%) cases. Symptoms were reported in 38 (20%) cases. Gastrointestinal symptoms were most common (n = 21) followed by central nervous system depression (n = 15). Oral rivastigmine was associated with higher rates of symptoms. No bradycardia, seizures, or fasciculations were reported. Eighty-nine cases (47%) were evaluated at a health care facility, and 13 (7%) were admitted to a hospital. Oral rivastigmine exposures were associated with increased rate of health care facility evaluation. Activated charcoal was administered in 28 cases. Atropine was given only once, for drooling. There were no serious outcomes or deaths in this series. Conclusions Reported pediatric exposures to antidementia drugs resulted in minimal morbidity and no mortality. Oral rivastigmine exposures were found to be associated with more symptoms and health care facility evaluations. (J Pediatr 2016;-:---).
N
early 5 million people in the US have Alzheimer dementia, and the prevalence continues to rise.1 Not surprisingly, there has been a concomitant increase in the use of antidementia drugs.2 Currently, donepezil, memantine, rivastigmine, and galantamine are approved by the Food and Drug Administration (FDA) to treat dementia, primarily of the Alzheimer type. Although not approved for use in children, pediatric exposures to these agents may occur in children because of the increased presence of these agents. There is a paucity of literature regarding the characteristics and outcomes associated with pediatric exposures to antidementia agents. We sought to characterize further such exposures by reviewing a statewide poison control system’s database.
Methods The University of California-San Diego Institutional Review Board approved this retrospective observational case series. A chart review of the California Poison Control System (CPCS) electronic database (Visual Dotlab, Madera, California) was performed to identify all cases of antidementia drug exposures from January 1, 2001, until December 31, 2011. The CPCS electronic database contains records from all four California Poison Control centers. Cases were then selected only if they involved pediatric patients (defined as less than 19 years old), and the reported exposure involved an antidementia drug(s). Age, patient weight (kg), drug name, dose (either exact or maximum) (mg), route of exposure, presence of coingestants, reason for exposure, symptoms, interventions, length of hospital stay, and outcomes were collected. Exact or maximum dose was used to calculate a dose per kg for each drug type exposure, when possible. For the purposes of this study, intentional ingestions were defined as deliberate ingestions with intent for self-harm. Unintentional ingestions were defined as ingestions of the patient’s or another person’s medications without therapeutic intent. Therapeutic errors were defined as purposeful but incorrect dosage(s) of the patient’s prescribed medications. All cases were redacted by a single author (J.P.) and then reviewed by the primary author (S.T.) for accuracy. From the 1Department of Emergency Medicine, 2Poison Control Center, University of Kansas Hospital, Kansas City, KS; 3Skaggs School of Pharmacy, University of California-San Diego; and 4California Poison Control System, San Diego Division, San Diego, CA
CNS CPCS FDA
Central nervous system California Poison Control System Food and Drug Administration
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.01.056
1
THE JOURNAL OF PEDIATRICS
Volume -
www.jpeds.com
Results During the study period, 189 pediatric exposures to antidementia agents were reported to the CPCS. The number of cases reported increased from 4 in 2001 to 33 in the last year of the study. One hundred (53%) were male. The median age was 2.3 years (range 8 months to 12 years). One hundred fifty-two (80%) of the exposures were in patients 2 years of age or younger. Weight was available in 108 (57%), and the mean weight was 13.9 kg (range 7-61). One hundred eighty-seven (99%) exposures were unintentional. There was 1 intentional exposure reported: a 12-yearold reportedly ingested 25.5 mg of rivastigmine in a suicide attempt. She developed diaphoresis, gastrointestinal distress, and mild hypotension but recovered fully within 24 hours. There was also 1 therapeutic error reported: a 2-year-old was reported to have been given a double dose of his 2.75 mg galantamine, which had been prescribed to him for autism. He had no symptoms reported. One hundred eighty-seven (99%) of the exposures were oral. There were 2 cases in which children reportedly placed used rivastigmine transdermal patches on themselves. No symptoms were reported in either case. Donepezil was the most common drug involved in exposures (n = 106) followed by memantine (n = 57). One hundred eighteen (62%) cases involved exposure to a single antidementia drug. Eleven (6%) cases involved more than 1 antidementia drug. Seven of these 11 cases involved both donepezil and memantine. Sixty-eight (36%) cases involved exposures to coingestants. On average there were 2.3 coingestants recorded (range 1-10). Actual dose taken was available in 30 (15%) cases, and maximum possible dose was available in 162 (86%) cases. The largest doses reported involved a 2-year-old male who may have ingested a maximum of 60 mg of donepezil and 120 mg of memantine and had mild central nervous system (CNS) depression, which resolved without intervention following observation in an emergency department. The Table details further the number of cases, drug involved, patient weights, and doses. Symptoms were reported in 38 (20%) of all cases and in 23 (20%) of single agent exposures. Gastrointestinal symptoms (nausea, vomiting, diarrhea) were most commonly reported (n = 21) followed by CNS depression (n = 15). The Table
details number of cases with symptoms reported, and the Figure shows type of symptoms reported by drug type. No bradycardia, seizures, or fasciculations were reported. One child was noted to have respiratory difficulty prior to the prehospital setting after ingesting possibly 3 mg of rivastigmine, but this resolved spontaneously on arrival to the emergency department. No other respiratory symptoms were reported. One hundred (53%) cases were managed at home. Of the 89 (47%) cases evaluated at a health care facility, no treatment or intervention except for observation was performed in 62 (33%) of the cases. Twenty-five (13%) patients were given activated charcoal. Atropine was given in 1 case: a 2year-old boy had significant drooling after possibly ingesting up to 36 mg of rivastigmine. This resolved with 0.25 mg of intravenous atropine. Thirteen (7%) were admitted to a hospital, and in all cases were discharged within 1 day. No deaths were reported in this study. By c2 analysis, oral rivastigmine exposures were found to be associated with significantly more symptoms and health care facility evaluations when compared with the other 3 drugs (P < .05). Memantine was found to be associated with significantly more asymptomatic exposures (P < .05).
Discussion Alzheimer dementia is a growing health care problem associated with significant morbidity and mortality.3 Currently, there are 4 FDA-approved drugs to treat Alzheimer dementia. Donepezil, rivastigmine, and galantamine are centrally acting reversible acetylcholinesterase inhibitors that are hypothesized to help with Alzheimer dementia by addressing a purported deficiency in cholinergic neurotransmission.4 Memantine is a N-methyl-aspartate receptor antagonist, which is thought to have benefit via inhibition of excitatory neurotoxicity and expression of tau proteins.5 These drugs are all oral agents, though rivastigmine is also available as a transdermal patch.6 Over the last decade, there has been an increase in the use of these drugs and this study demonstrates a rise in reported exposures over that time frame.2 These medications have also been studied for the treatment of autism, attention deficit hyperactivity disorder, and other psychiatric conditions.7,8 There is no literature on how frequently antidementia drugs
Table. Results by drug type Antidementia drugs Donepezil Memantine Rivastigmine Rivastigmine transdermal Galantamine 2
Number of cases
Mean weight (kg) [range]
Mean actual or maximum dose (mg/kg) [range]
Number of cases with symptoms reported
Number evaluated at health care facility
Number admitted to health care facility
108 57 16 3
14.0 [7-61] 13.0 [8.6-17.3] 15.0 [10.9-20.5] No weights obtained
0.78 [0.14-4.32] 0.75 [0.18-2.32] 0.73 [0.27-1.17] Unable to calculate
21 4 10 0
51 23 14 0
8 0 4 0
18
13.5 [11.4-15.9]
0.63 [0.31-1.05]
4
9
1
Thornton, Pchelnikova, and Cantrell
- 2016
ORIGINAL ARTICLES
Figure. Type of symptoms reported by drug type.
are used for these non-FDA-approved indications. Although serious adverse effects are rarely reported in these typically small studies, these off-label uses may increase further the risk of unintentional pediatric exposures, similar to trends seen with attention deficit hyperactivity disorder medications.9 Available pediatric literature regarding the toxicity from exposures to antidementia agents is sparse. There is concern that ingestions of acetylcholinesterase inhibitor drugs could result in cholinergic excess similar to that seen with carbamate insecticides and cause increased secretions (eg, drooling, diarrhea, or bronchorrhea), CNS toxicity, and muscle fasciculation and weakness.10 Pediatric donepezil ingestions have previously been associated with encephalopathy and bradycardia.11,12 In both cases, laboratory confirmed unintentional exposures to donepezil resulted in significant CNS depression and hospitalization. Donepezil was the most frequently reported exposure in this study. Although CNS depression was seen, gastrointestinal symptoms predominated. No bradycardia or other cholinergic symptoms were seen with donepezil exposures. Reports of pediatric toxicity from rivastigmine exposures are limited to 2 case reports in the medical literature. One describes a 3-year-old girl who developed altered mental status and dysrhythmias after ingesting between 4.5 and 9 mg of rivastigmine.13 She was treated with atropine and recovered fully. Another case detailed significant muscle weakness in an 11-month-old that resolved in 48 hours with supportive care.14 Adult case reports report significant morbidity and death from rivastigmine exposure.15-17 Our findings of higher rates of reported symptoms and health care facility evaluations with rivastigmine exposures are consistent with the increased morbidity seen in these prior case reports,
and merit attention to more exposures from this drug in the years ahead. There are several prior reports of toxicity from rivastigmine patches in adults but none in pediatric patients.16,18 Theoretically, these patches could pose a risk similar to those described with transdermal fentanyl or clonidine.19,20 However, only 3 cases were reported in our study, and none reported any symptoms. Two involved children placing a used patch on themselves, and the other case involved licking the patch. As far as other agents, there are no prior reports of pediatric or adult exposures to galantamine. Our study found that galantamine exposures were not associated with serious symptoms but did result in health care evaluation in 50% of cases. There is limited experience with pediatric exposures to memantine. The only published pediatric case report detailed prolonged encephalopathy in a 2-year-old from a laboratory confirmed ingestion of memantine.11 This case was complicated by coingestion of donepezil. Memantine exposures in this study were associated with a low rate of reported symptoms. Of note, no gastrointestinal symptoms were seen with possible memantine exposures. Our study has several limitations. It is a retrospective review of a poison control system’s data and is subject to reporting bias. The poison control system was possibly not contacted for all cases, including those considered trivial or those of severely poisoned patients. Another important limitation is the possibility of incomplete data collection by the poison control system’s staff. Exact dosages, weights, and other information may not have been available, or callers were not being able to relay all pertinent information. Finally, this study provides reported exposures, but the actual ingestions of these agents were not confirmed. It is
Characteristics of Pediatric Exposures to Antidementia Drugs Reported to a Poison Control System
3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
possible that in many cases, there was no actual ingestion. This could explain in part the low number of symptoms reported in this study. Any interpretation of dose and effect must be made with caution. Although our data suggest that unintentional pediatric exposures to this class of medications are relatively safe, additional studies are warranted to confirm these findings. n Submitted for publication Nov 9, 2015; accepted Jan 20, 2016. Reprint requests: Stephen L. Thornton, MD, Department of Emergency Medicine, Poison Control Center, University of Kansas Hospital, 3901 Rainbow Blvd, 4045 Delp, Kansas City, KS 66160. E-mail: [email protected]
References 1. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 2013;80:1778-83. 2. Fowler NR, Chen YF, Thurton CA, Men A, Rodriguez EG, Donohue JM. The impact of Medicare prescription drug coverage on the use of antidementia drugs. BMC Geriatr 2013;13:37. 3. Weuve J, Hebert LE, Scherr PA, Evans DA. Deaths in the United States among persons with Alzheimer’s disease (2010-2050). Alzheimers Dement 2014;10:e40-6. 4. Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging 2004; 21:453-78. 5. Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev 2003; 9:275-308. 6. A rivastigmine patch for dementia. Med Lett Drugs Ther 2008;50:21-2.
4
Volume 7. Hosenbocus S, Chahal R. Memantine: a review of possible uses in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 2013;22: 166-71. 8. Rossignol DA, Frye RE. The use of medications approved for Alzheimer’s disease in autism spectrum disorder: a systematic review. Front Pediatr 2014;2:87. 9. Foley R, Mrvos R, Krenzelok EP. A profile of methylphenidate exposures. J Toxicol Clin Toxicol 2000;38:625-30. 10. Zwiener RJ, Ginsburg CM. Organophosphate and carbamate poisoning in infants and children. Pediatrics 1988;81:121-6. 11. Thornton SL, Clark RF. Encephalopathy from unintentional donepezil and memantine ingestion. Pediatr Emerg Care 2014;30:649-50. 12. Garlich FM, Balakrishnan K, Shah SK, Howland MA, Fong J, Nelson LS. Prolonged altered mental status and bradycardia following pediatric donepezil ingestion. Clin Toxicol (Phila) 2014;52:291-4. 13. Raucci U, Vanacore N, Cecchetti C, Russo MS, Rossi R, Pirozzi N. Transient cardiac effects in a child with acute cholinergic syndrome due to rivastigmine poisoning. J Emerg Med 2014;47:21-5. 14. Lai MW, Moen M, Ewald MB. Pesticide-like poisoning from a prescription drug. N Engl J Med 2005;353:317-8. 15. Hoffman RS, Manini AF, Russell-Haders AL, Felberbaum M, MercurioZappala M. Use of pralidoxime without atropine in rivastigmine (carbamate) toxicity. Hum Exp Toxicol 2009;28:599-602. 16. L€ ovborg H, J€ onsson AK, H€agg S. A fatal outcome after unintentional overdosing of rivastigmine patches. Curr Drug Saf 2012;7:30-2. 17. Sener S, Ozsarac M. Case of the month: rivastigmine (Exelon) toxicity with evidence of respiratory depression. Emerg Med J 2006;23:82-5. 18. Lee DH, Choi YH, Cho KH, Yun SY, Lee HM. A case of rivastigmine toxicity caused by transdermal patch. Am J Emerg Med 2011;29:695. e1-2. 19. Hardwick WE Jr, King WD, Palmisano PA. Respiratory depression in a child unintentionally exposed to transdermal fentanyl patch. South Med J 1997;90:962-4. 20. Caravati EM, Bennett DL. Clonidine transdermal patch poisoning. Ann Emerg Med 1988;17:175-6.
Thornton, Pchelnikova, and Cantrell
Study design A retrospective review of a statewide poison control system’s database identified cases of pediatric (less than 19 years of age) exposures to antidementia drugs over an 11-year period. Data collected included age, sex, drug(s) involved, route of exposure, reason for exposure, symptoms, and interventions. Results There were 189 cases identified (53% male, median age: 2.3 years, 99% unintentional exposures). Donepezil was the most commonly reported exposure (106 cases), followed by memantine (57), galantamine (18), oral rivastigmine (16), and transdermal rivastigmine (3). Coingestants were reported in 68 (36%) cases. Symptoms were reported in 38 (20%) cases. Gastrointestinal symptoms were most common (n = 21) followed by central nervous system depression (n = 15). Oral rivastigmine was associated with higher rates of symptoms. No bradycardia, seizures, or fasciculations were reported. Eighty-nine cases (47%) were evaluated at a health care facility, and 13 (7%) were admitted to a hospital. Oral rivastigmine exposures were associated with increased rate of health care facility evaluation. Activated charcoal was administered in 28 cases. Atropine was given only once, for drooling. There were no serious outcomes or deaths in this series. Conclusions Reported pediatric exposures to antidementia drugs resulted in minimal morbidity and no mortality. Oral rivastigmine exposures were found to be associated with more symptoms and health care facility evaluations. (J Pediatr 2016;-:---).
N
early 5 million people in the US have Alzheimer dementia, and the prevalence continues to rise.1 Not surprisingly, there has been a concomitant increase in the use of antidementia drugs.2 Currently, donepezil, memantine, rivastigmine, and galantamine are approved by the Food and Drug Administration (FDA) to treat dementia, primarily of the Alzheimer type. Although not approved for use in children, pediatric exposures to these agents may occur in children because of the increased presence of these agents. There is a paucity of literature regarding the characteristics and outcomes associated with pediatric exposures to antidementia agents. We sought to characterize further such exposures by reviewing a statewide poison control system’s database.
Methods The University of California-San Diego Institutional Review Board approved this retrospective observational case series. A chart review of the California Poison Control System (CPCS) electronic database (Visual Dotlab, Madera, California) was performed to identify all cases of antidementia drug exposures from January 1, 2001, until December 31, 2011. The CPCS electronic database contains records from all four California Poison Control centers. Cases were then selected only if they involved pediatric patients (defined as less than 19 years old), and the reported exposure involved an antidementia drug(s). Age, patient weight (kg), drug name, dose (either exact or maximum) (mg), route of exposure, presence of coingestants, reason for exposure, symptoms, interventions, length of hospital stay, and outcomes were collected. Exact or maximum dose was used to calculate a dose per kg for each drug type exposure, when possible. For the purposes of this study, intentional ingestions were defined as deliberate ingestions with intent for self-harm. Unintentional ingestions were defined as ingestions of the patient’s or another person’s medications without therapeutic intent. Therapeutic errors were defined as purposeful but incorrect dosage(s) of the patient’s prescribed medications. All cases were redacted by a single author (J.P.) and then reviewed by the primary author (S.T.) for accuracy. From the 1Department of Emergency Medicine, 2Poison Control Center, University of Kansas Hospital, Kansas City, KS; 3Skaggs School of Pharmacy, University of California-San Diego; and 4California Poison Control System, San Diego Division, San Diego, CA
CNS CPCS FDA
Central nervous system California Poison Control System Food and Drug Administration
The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2016.01.056
1
THE JOURNAL OF PEDIATRICS
Volume -
www.jpeds.com
Results During the study period, 189 pediatric exposures to antidementia agents were reported to the CPCS. The number of cases reported increased from 4 in 2001 to 33 in the last year of the study. One hundred (53%) were male. The median age was 2.3 years (range 8 months to 12 years). One hundred fifty-two (80%) of the exposures were in patients 2 years of age or younger. Weight was available in 108 (57%), and the mean weight was 13.9 kg (range 7-61). One hundred eighty-seven (99%) exposures were unintentional. There was 1 intentional exposure reported: a 12-yearold reportedly ingested 25.5 mg of rivastigmine in a suicide attempt. She developed diaphoresis, gastrointestinal distress, and mild hypotension but recovered fully within 24 hours. There was also 1 therapeutic error reported: a 2-year-old was reported to have been given a double dose of his 2.75 mg galantamine, which had been prescribed to him for autism. He had no symptoms reported. One hundred eighty-seven (99%) of the exposures were oral. There were 2 cases in which children reportedly placed used rivastigmine transdermal patches on themselves. No symptoms were reported in either case. Donepezil was the most common drug involved in exposures (n = 106) followed by memantine (n = 57). One hundred eighteen (62%) cases involved exposure to a single antidementia drug. Eleven (6%) cases involved more than 1 antidementia drug. Seven of these 11 cases involved both donepezil and memantine. Sixty-eight (36%) cases involved exposures to coingestants. On average there were 2.3 coingestants recorded (range 1-10). Actual dose taken was available in 30 (15%) cases, and maximum possible dose was available in 162 (86%) cases. The largest doses reported involved a 2-year-old male who may have ingested a maximum of 60 mg of donepezil and 120 mg of memantine and had mild central nervous system (CNS) depression, which resolved without intervention following observation in an emergency department. The Table details further the number of cases, drug involved, patient weights, and doses. Symptoms were reported in 38 (20%) of all cases and in 23 (20%) of single agent exposures. Gastrointestinal symptoms (nausea, vomiting, diarrhea) were most commonly reported (n = 21) followed by CNS depression (n = 15). The Table
details number of cases with symptoms reported, and the Figure shows type of symptoms reported by drug type. No bradycardia, seizures, or fasciculations were reported. One child was noted to have respiratory difficulty prior to the prehospital setting after ingesting possibly 3 mg of rivastigmine, but this resolved spontaneously on arrival to the emergency department. No other respiratory symptoms were reported. One hundred (53%) cases were managed at home. Of the 89 (47%) cases evaluated at a health care facility, no treatment or intervention except for observation was performed in 62 (33%) of the cases. Twenty-five (13%) patients were given activated charcoal. Atropine was given in 1 case: a 2year-old boy had significant drooling after possibly ingesting up to 36 mg of rivastigmine. This resolved with 0.25 mg of intravenous atropine. Thirteen (7%) were admitted to a hospital, and in all cases were discharged within 1 day. No deaths were reported in this study. By c2 analysis, oral rivastigmine exposures were found to be associated with significantly more symptoms and health care facility evaluations when compared with the other 3 drugs (P < .05). Memantine was found to be associated with significantly more asymptomatic exposures (P < .05).
Discussion Alzheimer dementia is a growing health care problem associated with significant morbidity and mortality.3 Currently, there are 4 FDA-approved drugs to treat Alzheimer dementia. Donepezil, rivastigmine, and galantamine are centrally acting reversible acetylcholinesterase inhibitors that are hypothesized to help with Alzheimer dementia by addressing a purported deficiency in cholinergic neurotransmission.4 Memantine is a N-methyl-aspartate receptor antagonist, which is thought to have benefit via inhibition of excitatory neurotoxicity and expression of tau proteins.5 These drugs are all oral agents, though rivastigmine is also available as a transdermal patch.6 Over the last decade, there has been an increase in the use of these drugs and this study demonstrates a rise in reported exposures over that time frame.2 These medications have also been studied for the treatment of autism, attention deficit hyperactivity disorder, and other psychiatric conditions.7,8 There is no literature on how frequently antidementia drugs
Table. Results by drug type Antidementia drugs Donepezil Memantine Rivastigmine Rivastigmine transdermal Galantamine 2
Number of cases
Mean weight (kg) [range]
Mean actual or maximum dose (mg/kg) [range]
Number of cases with symptoms reported
Number evaluated at health care facility
Number admitted to health care facility
108 57 16 3
14.0 [7-61] 13.0 [8.6-17.3] 15.0 [10.9-20.5] No weights obtained
0.78 [0.14-4.32] 0.75 [0.18-2.32] 0.73 [0.27-1.17] Unable to calculate
21 4 10 0
51 23 14 0
8 0 4 0
18
13.5 [11.4-15.9]
0.63 [0.31-1.05]
4
9
1
Thornton, Pchelnikova, and Cantrell
- 2016
ORIGINAL ARTICLES
Figure. Type of symptoms reported by drug type.
are used for these non-FDA-approved indications. Although serious adverse effects are rarely reported in these typically small studies, these off-label uses may increase further the risk of unintentional pediatric exposures, similar to trends seen with attention deficit hyperactivity disorder medications.9 Available pediatric literature regarding the toxicity from exposures to antidementia agents is sparse. There is concern that ingestions of acetylcholinesterase inhibitor drugs could result in cholinergic excess similar to that seen with carbamate insecticides and cause increased secretions (eg, drooling, diarrhea, or bronchorrhea), CNS toxicity, and muscle fasciculation and weakness.10 Pediatric donepezil ingestions have previously been associated with encephalopathy and bradycardia.11,12 In both cases, laboratory confirmed unintentional exposures to donepezil resulted in significant CNS depression and hospitalization. Donepezil was the most frequently reported exposure in this study. Although CNS depression was seen, gastrointestinal symptoms predominated. No bradycardia or other cholinergic symptoms were seen with donepezil exposures. Reports of pediatric toxicity from rivastigmine exposures are limited to 2 case reports in the medical literature. One describes a 3-year-old girl who developed altered mental status and dysrhythmias after ingesting between 4.5 and 9 mg of rivastigmine.13 She was treated with atropine and recovered fully. Another case detailed significant muscle weakness in an 11-month-old that resolved in 48 hours with supportive care.14 Adult case reports report significant morbidity and death from rivastigmine exposure.15-17 Our findings of higher rates of reported symptoms and health care facility evaluations with rivastigmine exposures are consistent with the increased morbidity seen in these prior case reports,
and merit attention to more exposures from this drug in the years ahead. There are several prior reports of toxicity from rivastigmine patches in adults but none in pediatric patients.16,18 Theoretically, these patches could pose a risk similar to those described with transdermal fentanyl or clonidine.19,20 However, only 3 cases were reported in our study, and none reported any symptoms. Two involved children placing a used patch on themselves, and the other case involved licking the patch. As far as other agents, there are no prior reports of pediatric or adult exposures to galantamine. Our study found that galantamine exposures were not associated with serious symptoms but did result in health care evaluation in 50% of cases. There is limited experience with pediatric exposures to memantine. The only published pediatric case report detailed prolonged encephalopathy in a 2-year-old from a laboratory confirmed ingestion of memantine.11 This case was complicated by coingestion of donepezil. Memantine exposures in this study were associated with a low rate of reported symptoms. Of note, no gastrointestinal symptoms were seen with possible memantine exposures. Our study has several limitations. It is a retrospective review of a poison control system’s data and is subject to reporting bias. The poison control system was possibly not contacted for all cases, including those considered trivial or those of severely poisoned patients. Another important limitation is the possibility of incomplete data collection by the poison control system’s staff. Exact dosages, weights, and other information may not have been available, or callers were not being able to relay all pertinent information. Finally, this study provides reported exposures, but the actual ingestions of these agents were not confirmed. It is
Characteristics of Pediatric Exposures to Antidementia Drugs Reported to a Poison Control System
3
THE JOURNAL OF PEDIATRICS
www.jpeds.com
possible that in many cases, there was no actual ingestion. This could explain in part the low number of symptoms reported in this study. Any interpretation of dose and effect must be made with caution. Although our data suggest that unintentional pediatric exposures to this class of medications are relatively safe, additional studies are warranted to confirm these findings. n Submitted for publication Nov 9, 2015; accepted Jan 20, 2016. Reprint requests: Stephen L. Thornton, MD, Department of Emergency Medicine, Poison Control Center, University of Kansas Hospital, 3901 Rainbow Blvd, 4045 Delp, Kansas City, KS 66160. E-mail: [email protected]
References 1. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology 2013;80:1778-83. 2. Fowler NR, Chen YF, Thurton CA, Men A, Rodriguez EG, Donohue JM. The impact of Medicare prescription drug coverage on the use of antidementia drugs. BMC Geriatr 2013;13:37. 3. Weuve J, Hebert LE, Scherr PA, Evans DA. Deaths in the United States among persons with Alzheimer’s disease (2010-2050). Alzheimers Dement 2014;10:e40-6. 4. Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging 2004; 21:453-78. 5. Rogawski MA, Wenk GL. The neuropharmacological basis for the use of memantine in the treatment of Alzheimer’s disease. CNS Drug Rev 2003; 9:275-308. 6. A rivastigmine patch for dementia. Med Lett Drugs Ther 2008;50:21-2.
4
Volume 7. Hosenbocus S, Chahal R. Memantine: a review of possible uses in child and adolescent psychiatry. J Can Acad Child Adolesc Psychiatry 2013;22: 166-71. 8. Rossignol DA, Frye RE. The use of medications approved for Alzheimer’s disease in autism spectrum disorder: a systematic review. Front Pediatr 2014;2:87. 9. Foley R, Mrvos R, Krenzelok EP. A profile of methylphenidate exposures. J Toxicol Clin Toxicol 2000;38:625-30. 10. Zwiener RJ, Ginsburg CM. Organophosphate and carbamate poisoning in infants and children. Pediatrics 1988;81:121-6. 11. Thornton SL, Clark RF. Encephalopathy from unintentional donepezil and memantine ingestion. Pediatr Emerg Care 2014;30:649-50. 12. Garlich FM, Balakrishnan K, Shah SK, Howland MA, Fong J, Nelson LS. Prolonged altered mental status and bradycardia following pediatric donepezil ingestion. Clin Toxicol (Phila) 2014;52:291-4. 13. Raucci U, Vanacore N, Cecchetti C, Russo MS, Rossi R, Pirozzi N. Transient cardiac effects in a child with acute cholinergic syndrome due to rivastigmine poisoning. J Emerg Med 2014;47:21-5. 14. Lai MW, Moen M, Ewald MB. Pesticide-like poisoning from a prescription drug. N Engl J Med 2005;353:317-8. 15. Hoffman RS, Manini AF, Russell-Haders AL, Felberbaum M, MercurioZappala M. Use of pralidoxime without atropine in rivastigmine (carbamate) toxicity. Hum Exp Toxicol 2009;28:599-602. 16. L€ ovborg H, J€ onsson AK, H€agg S. A fatal outcome after unintentional overdosing of rivastigmine patches. Curr Drug Saf 2012;7:30-2. 17. Sener S, Ozsarac M. Case of the month: rivastigmine (Exelon) toxicity with evidence of respiratory depression. Emerg Med J 2006;23:82-5. 18. Lee DH, Choi YH, Cho KH, Yun SY, Lee HM. A case of rivastigmine toxicity caused by transdermal patch. Am J Emerg Med 2011;29:695. e1-2. 19. Hardwick WE Jr, King WD, Palmisano PA. Respiratory depression in a child unintentionally exposed to transdermal fentanyl patch. South Med J 1997;90:962-4. 20. Caravati EM, Bennett DL. Clonidine transdermal patch poisoning. Ann Emerg Med 1988;17:175-6.
Thornton, Pchelnikova, and Cantrell