Journal of Pharmacy Practice http://jpp.sagepub.com/
Drug Interaction Between Phenytoin and Valproic Acid in a Child With Refractory Epilepsy: A Case Report Indira Valadê Carvalho, Renata Cavalcanti Carnevale, Marília Berlofa Visacri, Priscila Gava Mazzola, Rosiane de Fátima Lopes Ambrósio, Marcelo Conrado dos Reis, Rachel Alvarenga de Queiroz and Patricia Moriel Journal of Pharmacy Practice published online 30 December 2013 DOI: 10.1177/0897190013515708 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2013/12/30/0897190013515708 A more recent version of this article was published on - Mar 19, 2014
Published by: http://www.sagepublications.com
On behalf of:
New York State Council of Health-system Pharmacists
Additional services and information for Journal of Pharmacy Practice can be found at: Email Alerts: http://jpp.sagepub.com/cgi/alerts Subscriptions: http://jpp.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
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Original Article
Drug Interaction Between Phenytoin and Valproic Acid in a Child With Refractory Epilepsy: A Case Report
Journal of Pharmacy Practice 201X, Vol XX(X) 1-3 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013515708 jpp.sagepub.com
Indira Valadeˆ Carvalho, MSc1, Renata Cavalcanti Carnevale, MSc1, Mar´ılia Berlofa Visacri, MSc1, Priscila Gava Mazzola, PhD1, Rosiane de F´atima Lopes Ambro´sio2, Marcelo Conrado dos Reis, MD3, Rachel Alvarenga de Queiroz, MD3, and Patricia Moriel, PhD1
Abstract Introduction: There are no published reports on pediatric phenytoin toxicity, resulting from the drug interaction between phenytoin and valproic acid. Case description: A 12-year-old patient with refractory epilepsy syndrome presented with phenytoin toxicity, following a concomitant treatment with phenytoin, valproic acid, and lamotrigine. The phenytoin concentration detected in the capsules used by the patient was in accordance with the prescribed dose and was appropriate for the age and weight of the patient. However, a supratherapeutic phenytoin serum concentration was observed (21.92 mg phenytoin/mL of blood). Consequently, the phenytoin dose was reduced, and the patient was monitored; 24 hours later the patient did not present with any signs/symptoms of toxicity. Discussion: Despite the appropriate phenytoin concentration in the capsules, the patient presented with phenytoin toxicity. This toxicity likely resulted from the drug interaction between phenytoin and valproic acid that leads to phenytoin displacement from plasmatic proteins and inhibits phenytoin metabolism, thereby increasing the concentration of free drug in the serum. Keywords phenytoin, valproic acid, pediatrics
Introduction Refractory epilepsy is a frequently encountered condition in neurology. It is believed that approximately 30% of patients with any type of epilepsy will continue to have seizures despite drug therapy.1 Patients who were treated with antiepileptic drug at appropriate doses as monotherapy or polytherapy, but are not free of seizures, are considered to be refractory to therapy.1 In recent studies involving children and adults with refractory epilepsy, 64% had polytherapy with 2 or more antiepileptic drugs, and 35% adults had comorbidities related to the central nervous system, resulting in a considerable risk of drug interactions.2,3 Phenytoin, valproic acid, and lamotrigine are important antiepileptic drugs that can be used as monotherapy or polytherapy in epilepsy treatment. Antiepileptic drugs are known to be potentially dangerous because of their high susceptibility to drug interactions.4 There are drug interactions between all 3 of these antiepileptic medications. The interaction of phenytoin with valproic acid results in increased phenytoin toxicity because it displaces plasmatic proteins and inhibits phenytoin metabolism, thereby increasing the concentration of free drug in the serum.5,6 This interaction results in reduced serum levels of valproic acid because of increased metabolism following
cytochrome P450 induction.7-9 The interaction between lamotrigine and valproic acid leads to increased serum levels of lamotrigine and a risk of rash development because valproic acid is capable of competitively inhibiting the glucuronidation system.8,9 The interaction of phenytoin with lamotrigine reduces lamotrigine concentration because of increased clearance following the induction of lamotrigine glucuronidation in the liver, resulting in increased metabolism and reducing the half-life of the drug by 50%.8,9 In the present report, we present a case of phenytoin toxicity resulting from the drug interaction between phenytoin
1 Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil 2 Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil 3 Pediatric Emergency Unit, Clinical Hospital, University of Campinas, Campinas, Brazil
Corresponding Author: Priscila Gava Mazzola, Faculty of Medical Sciences, Rua: Tess´alia Vieira de Camargo, 126, Campinas, 13083-887, Brazil Email: [email protected]
Downloaded from jpp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 8, 2014
2
Journal of Pharmacy Practice XX(X)
and valproic acid, when used in the treatment of a child with refractory epilepsy. Our literature review did not present any published reports on this drug interaction–induced toxicity in pediatric patients. The person responsible for the patient has signed a permission document, allowing the publication of this report.
Case Description A 12-year-old white, female patient of Brazilian descent, with history of seizures since 7 years, with approximately 70 seizures a day, was diagnosed with refractory epilepsy syndrome and treated at the Clinic of Child Neurology, Clinical Hospital at Sa˜o Paulo/Brazil, for 9 months. She presented with a fixed gaze, unresponsiveness, confusion, and upward eye movements due to dystonia and generalized tonic–clonic movements, with or without drooling and sphincter release. The patient visited the pediatric emergency unit of the Clinical Hospital because of suspected phenytoin toxicity. The patient was being administered lamotrigine (100 mg, 12/12 hours) and valproic acid (300 mg in the morning and 900 mg at night) for 9 months, and phenytoin (compounded capsules and oral administration, 2 capsules of 100 mg, 12/ 12 hours) for 1 month; therefore, she was at an increased risk of drug interactions. The patient presented with difficulty in walking, nausea, and vomiting since the beginning of phenytoin therapy. Based on a medical examination performed in pediatric emergency unit, she was also diagnosed with dysmetria, ataxia, horizontal diplopia, gaze nystagmus, and a moderate slow diffuse disorder of cerebral activity. The vital signs were also measured and there were no apparent alterations: weight, 35 kg; heart rate, 86 bpm; respiratory rate, 22 bpm; afebrile. The patient’s blood glucose was found to be normal, 78 mg/dL. A peripheral venous blood sample was collected from the patient at pediatric emergency unit in a blood collection tube free of additives. The sample did not require any preparation. Phenytoin blood concentration was obtained using the particleenhanced turbidimetric inhibition immunoassay test (Flex1 reagent cartridge, Dade Behring, Newark, Delaware), demonstrating a supratherapeutic concentration of 21.92 mg of total phenytoin per mL of blood (therapeutic level ¼ 10-20 mg/mL; toxic level ¼ >20 mg/mL). Blood was withdrawn 17 hours after the last phenytoin administration. Therefore, it may be inferred that phenytoin concentration would have reached its peak plasmatic levels. Besides the one performed at pediatric emergency unit, the patient did not undergo any additional blood phenytoin analysis. However, it is important to note that the patient had normal renal function (serum creatinine and urea 3 months before the incident were at 0.67 mg/dL and 25.00 mg/dL, respectively; normal values for the patient age group: serum creatinine
Drug Interaction Between Phenytoin and Valproic Acid in a Child With Refractory Epilepsy: A Case Report Indira Valadê Carvalho, Renata Cavalcanti Carnevale, Marília Berlofa Visacri, Priscila Gava Mazzola, Rosiane de Fátima Lopes Ambrósio, Marcelo Conrado dos Reis, Rachel Alvarenga de Queiroz and Patricia Moriel Journal of Pharmacy Practice published online 30 December 2013 DOI: 10.1177/0897190013515708 The online version of this article can be found at: http://jpp.sagepub.com/content/early/2013/12/30/0897190013515708 A more recent version of this article was published on - Mar 19, 2014
Published by: http://www.sagepublications.com
On behalf of:
New York State Council of Health-system Pharmacists
Additional services and information for Journal of Pharmacy Practice can be found at: Email Alerts: http://jpp.sagepub.com/cgi/alerts Subscriptions: http://jpp.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
Version of Record - Mar 19, 2014 >> OnlineFirst Version of Record - Dec 30, 2013 What is This?
Downloaded from jpp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 8, 2014
Original Article
Drug Interaction Between Phenytoin and Valproic Acid in a Child With Refractory Epilepsy: A Case Report
Journal of Pharmacy Practice 201X, Vol XX(X) 1-3 ª The Author(s) 2013 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0897190013515708 jpp.sagepub.com
Indira Valadeˆ Carvalho, MSc1, Renata Cavalcanti Carnevale, MSc1, Mar´ılia Berlofa Visacri, MSc1, Priscila Gava Mazzola, PhD1, Rosiane de F´atima Lopes Ambro´sio2, Marcelo Conrado dos Reis, MD3, Rachel Alvarenga de Queiroz, MD3, and Patricia Moriel, PhD1
Abstract Introduction: There are no published reports on pediatric phenytoin toxicity, resulting from the drug interaction between phenytoin and valproic acid. Case description: A 12-year-old patient with refractory epilepsy syndrome presented with phenytoin toxicity, following a concomitant treatment with phenytoin, valproic acid, and lamotrigine. The phenytoin concentration detected in the capsules used by the patient was in accordance with the prescribed dose and was appropriate for the age and weight of the patient. However, a supratherapeutic phenytoin serum concentration was observed (21.92 mg phenytoin/mL of blood). Consequently, the phenytoin dose was reduced, and the patient was monitored; 24 hours later the patient did not present with any signs/symptoms of toxicity. Discussion: Despite the appropriate phenytoin concentration in the capsules, the patient presented with phenytoin toxicity. This toxicity likely resulted from the drug interaction between phenytoin and valproic acid that leads to phenytoin displacement from plasmatic proteins and inhibits phenytoin metabolism, thereby increasing the concentration of free drug in the serum. Keywords phenytoin, valproic acid, pediatrics
Introduction Refractory epilepsy is a frequently encountered condition in neurology. It is believed that approximately 30% of patients with any type of epilepsy will continue to have seizures despite drug therapy.1 Patients who were treated with antiepileptic drug at appropriate doses as monotherapy or polytherapy, but are not free of seizures, are considered to be refractory to therapy.1 In recent studies involving children and adults with refractory epilepsy, 64% had polytherapy with 2 or more antiepileptic drugs, and 35% adults had comorbidities related to the central nervous system, resulting in a considerable risk of drug interactions.2,3 Phenytoin, valproic acid, and lamotrigine are important antiepileptic drugs that can be used as monotherapy or polytherapy in epilepsy treatment. Antiepileptic drugs are known to be potentially dangerous because of their high susceptibility to drug interactions.4 There are drug interactions between all 3 of these antiepileptic medications. The interaction of phenytoin with valproic acid results in increased phenytoin toxicity because it displaces plasmatic proteins and inhibits phenytoin metabolism, thereby increasing the concentration of free drug in the serum.5,6 This interaction results in reduced serum levels of valproic acid because of increased metabolism following
cytochrome P450 induction.7-9 The interaction between lamotrigine and valproic acid leads to increased serum levels of lamotrigine and a risk of rash development because valproic acid is capable of competitively inhibiting the glucuronidation system.8,9 The interaction of phenytoin with lamotrigine reduces lamotrigine concentration because of increased clearance following the induction of lamotrigine glucuronidation in the liver, resulting in increased metabolism and reducing the half-life of the drug by 50%.8,9 In the present report, we present a case of phenytoin toxicity resulting from the drug interaction between phenytoin
1 Department of Clinical Pathology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil 2 Department of Pharmacology, Faculty of Medical Sciences, University of Campinas, Campinas, Brazil 3 Pediatric Emergency Unit, Clinical Hospital, University of Campinas, Campinas, Brazil
Corresponding Author: Priscila Gava Mazzola, Faculty of Medical Sciences, Rua: Tess´alia Vieira de Camargo, 126, Campinas, 13083-887, Brazil Email: [email protected]
Downloaded from jpp.sagepub.com at UNIV OF SOUTHERN CALIFORNIA on April 8, 2014
2
Journal of Pharmacy Practice XX(X)
and valproic acid, when used in the treatment of a child with refractory epilepsy. Our literature review did not present any published reports on this drug interaction–induced toxicity in pediatric patients. The person responsible for the patient has signed a permission document, allowing the publication of this report.
Case Description A 12-year-old white, female patient of Brazilian descent, with history of seizures since 7 years, with approximately 70 seizures a day, was diagnosed with refractory epilepsy syndrome and treated at the Clinic of Child Neurology, Clinical Hospital at Sa˜o Paulo/Brazil, for 9 months. She presented with a fixed gaze, unresponsiveness, confusion, and upward eye movements due to dystonia and generalized tonic–clonic movements, with or without drooling and sphincter release. The patient visited the pediatric emergency unit of the Clinical Hospital because of suspected phenytoin toxicity. The patient was being administered lamotrigine (100 mg, 12/12 hours) and valproic acid (300 mg in the morning and 900 mg at night) for 9 months, and phenytoin (compounded capsules and oral administration, 2 capsules of 100 mg, 12/ 12 hours) for 1 month; therefore, she was at an increased risk of drug interactions. The patient presented with difficulty in walking, nausea, and vomiting since the beginning of phenytoin therapy. Based on a medical examination performed in pediatric emergency unit, she was also diagnosed with dysmetria, ataxia, horizontal diplopia, gaze nystagmus, and a moderate slow diffuse disorder of cerebral activity. The vital signs were also measured and there were no apparent alterations: weight, 35 kg; heart rate, 86 bpm; respiratory rate, 22 bpm; afebrile. The patient’s blood glucose was found to be normal, 78 mg/dL. A peripheral venous blood sample was collected from the patient at pediatric emergency unit in a blood collection tube free of additives. The sample did not require any preparation. Phenytoin blood concentration was obtained using the particleenhanced turbidimetric inhibition immunoassay test (Flex1 reagent cartridge, Dade Behring, Newark, Delaware), demonstrating a supratherapeutic concentration of 21.92 mg of total phenytoin per mL of blood (therapeutic level ¼ 10-20 mg/mL; toxic level ¼ >20 mg/mL). Blood was withdrawn 17 hours after the last phenytoin administration. Therefore, it may be inferred that phenytoin concentration would have reached its peak plasmatic levels. Besides the one performed at pediatric emergency unit, the patient did not undergo any additional blood phenytoin analysis. However, it is important to note that the patient had normal renal function (serum creatinine and urea 3 months before the incident were at 0.67 mg/dL and 25.00 mg/dL, respectively; normal values for the patient age group: serum creatinine
