YEBEH-05476; No of Pages 6 Epilepsy & Behavior xxx (2017) xxx–xxx

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Brief Communication

Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort Reinaldo Uribe-San-Martín a,b,⁎, Ethel Ciampi a,b, Wilhelm Uslar a, Silvana Villagra c, Jaime Godoy a, Patricio Mellado a a b c

Neurology Department, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile Neurology Service, “Dr. Sotero del Río” Hospital, Santiago, Chile Pharmacy Department, School of Medicine, Pontifical Catholic University of Chile, Santiago, Chile

a r t i c l e

i n f o

Article history: Received 11 July 2017 Revised 20 August 2017 Accepted 24 August 2017 Available online xxxx Keywords: Phenytoin Antiepileptic drug Adverse drug reaction Drug monitoring Pharmacovigilance

a b s t r a c t Introduction: Phenytoin (PHT) is an effective and inexpensive antiepileptic drug (AED). However, its use has been limited for fear of adverse drug reactions (ADRs) and is being replaced by newer AED, increasing the costs and causing major budget problems, particularly for developing countries. Objective: The objective of this study was to determine ADR frequency, explore, and establish related risk factors. Methods: Prospective data were collected from a cohort of inpatients using PHT for the first time. Pharmacovigilance was performed during hospitalization and after one month from the discharge. Clinical variables, plasma levels, and concomitant medications were collected and their association with the occurrence of different ADRs was explored. Results: One hundred patients were included: 59 were women, and mean age was 59 ± 21 years. Thirty-three patients presented ADR, all moderate and idiosyncratic. The most frequent were rash (17%), fever (10%), and elevated transaminases (10%). Female gender (85% vs 52%, p = 0.029), younger age (mean age: 49 vs 62 years, p = 0.032), and higher PHT plasmatic levels after IV-PO load (mean plasmatic levels: 18.6 vs 13.9 μg/mL, p = 0.040) were found to be associated with rash. A higher number of concomitant medications were also found to be associated with the risk for developing any ADR. The multivariate analysis revealed an association between rash and younger age (cut-off: 35 years old; relative risk (RR) = 11.7; p = 0.026), and higher PHT plasmatic levels (cut-off: 16 μg/mL; RR = 12.5; p = 0.021); and increased risk of elevated transaminases with use of PHT inductors (RR = 18; p = 0.006). A longer hospital stay was found in patients who developed fever (mean: 43 days, p b 0.0001) and elevated transaminases (mean: 26 days, p = 0.041) compared with patients without ADR (mean: 17 days). Conclusions: Phenytoin is a widely used AED associated with easily detectable ADR through structured pharmacovigilance. The development of ADR is associated with longer hospital stays. Recognition of local risk factors may lead to ADR prevention in a near future. Larger studies are needed to better define PHT-related ADR risk profile and to individualize treatment regimens. © 2017 Elsevier Inc. All rights reserved.

1. Introduction Phenytoin (PHT) is a well-known, inexpensive, and very versatile antiepileptic drug (AED), given its different administration routes and proven efficacy in a variety of epileptic syndromes, seizure prophylaxis, and status epilepticus, which has been compared with other AED, such as carbamazepine, valproic acid, or levetiracetam [1]. However, its usage as first-line treatment has been dramatically reduced, mainly because of fear of developing adverse drug reactions (ADRs). This has led to the prescription of newer AED, increasing health costs [2,3], especially problematic in developing countries [4]. ⁎ Corresponding author at: Neurology Department, Pontifical Catholic University of Chile, Marcoleta 350, 2° floor, Neurology Laboratory, Santiago, Chile. E-mail address: [email protected] (R. Uribe-San-Martín).

Therefore, a more structured way for selecting and using AED should be recognizing their potential risk factors for developing ADR, avoiding their presentation or reducing their severity through pharmacovigilance [5]. The most described risk factors for developing ADR include female gender, administration route, polypharmacy, comorbidities such as infectious (e.g., HIV, herpes virus) or immunologic disorders (e.g., systemic lupus erythematous), organ failure (e.g., renal, hepatic), and genetic polymorphisms. Nonetheless, all of these factors may vary among different populations, warranting their identification in local studies [6]. Antiepileptic drugs like PHT, have specific drug hypersensitivity syndromes caused by non-IgE immune mechanisms, including rash, fever, hepatitis, and lymphadenopathy, among others. These ADRs can be clinically monitored, and their early recognition through pharmacovigilance will lead to prompt suspension avoiding unwanted and severe consequences [7].

http://dx.doi.org/10.1016/j.yebeh.2017.08.032 1525-5050/© 2017 Elsevier Inc. All rights reserved.

Please cite this article as: Uribe-San-Martín R, et al, Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.032

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We conducted a prospective study in a cohort of consecutively recruited inpatients who started PHT therapy for the first time throughout the course of a year. We registered the occurrence of different ADRs, and explored possible risk factors for their development. 2. Methods 2.1. Patients' characteristics We collected prospective data during a period of 12 months from patients consecutively hospitalized in the Neurology Service including basic and critical patient units at the Clinical Hospital of the Pontifical Catholic University of Chile. The protocol was approved by the local Ethics Committee, and a signed informed consent was obtained from patients or their authorized caregivers. Inclusion criteria were as follows: (1) age ≥ 15 years old, (2) diagnosis of an acute brain or systemic illness, and (3) PHT prescription by the treating neurologist. Exclusion criteria comprise patients who were previously exposed to PHT, patients with previous ADR history to other medications, and patients with prescription of PHT without neurologic consultation. Demographics data included gender, age, comorbidities, concomitant medications (number, type, PHT interaction classified in inductors, inhibitors, and neutral or variable effect on enzymatic metabolism, and PHT plasmatic levels), PHT administration route, season, and days of hospitalization. Three administration protocols were identified: intravenous (IV) load, peroral (PO) load, and initial maintenance dose (MD). Loading doses were calculated using 15–20 mg/kg; IV load was administered in 1 h with a mean rate of 10–20 mg/min, PO was administered 1/3 of the dose every 1 h for three times, and MD was usually 300 mg/day administered every 12 h (e.g., 100 mg a.m. and 200 mg p.m.). Phenytoin plasmatic levels, adjusted by albumin, were monitored 1 h after IV load, 6 h after PO load, and at 5–7 days after PHT initiation in MD patients. 2.2. Adverse drug reaction assessment Daily pharmacotherapeutic evaluation was performed in order to monitor drug reactions. We registered infusion-related reactions (bradycardia, phlebitis), presence of cutaneous signs (maculopapular rash, erythroderma, exfoliative dermatitis, fixed drug reactions) not attributed to infusion of other medications or contact with substances, fever (axillary body temperature N 37 °C) not explained by an infection (determined jointly with an infectology consultation), elevated transaminases (mild: b5× normal value, moderate: 5–15×, severe: N 15×), performed as needed, or every 2 weeks during hospitalization and 1 month after discharge. Other ADRs referred by the patient or the treating physician considered to be related to PHT were also recorded. Data were obtained from clinical registries during hospital stay (intrahospital) and until one month after being discharged (ambulatory), supplemented with information provided by the treating physician. An ad hoc pharmacotherapeutic questionnaire was designed using the Dader method, based on patient-oriented health and pharmacotherapeutic problems, and by the establishment of health state evaluation guidelines [8]. Treating physician was informed of any unnoticed ADR for the assessment of an eventual PHT suspension. The drug reaction frequencies were calculated in each group, and a Probability of Causality analysis was applied using both the Naranjo [9] and the WHO (WHO Collaborating Centre for International Drug Monitoring) algorithms [10]. 2.3. Statistical analysis Two groups were compared according to ADR occurrence: (1) ADR group (rash, fever, elevated transaminases, and any adverse effect) and (2) group without any ADR. Differences in qualitative variables between

the groups were established using Fisher exact test. For quantitative variables, Mann–Whitney U test was used, because of the nonnormal distribution of the data, and for significant differences, a Receiver Operating Characteristic (ROC) curve was created to calculate the cut-off values according to Youden's J index. Further, relative risk (RR) and 95% confidence interval (95% CI) were obtained using a univariate and multivariate analysis with binomial logistic regression. The results were reported using mean ± standard deviation, median, range, and percentages. Differences were considered significant at p b 0.05. For statistical analysis IBM SPSS Statistics 21 was used. 3. Results 3.1. Clinical characteristics One hundred patients were included in the study. Mean age was 59 ± 21 years and females represented the 59%. Fifty-one different comorbidities were registered in previous medical history, or were newly diagnosed during the hospital stay (supplementary table 1). The most common was epilepsy (45%), arterial hypertension (26%), brain tumor (18%), status epilepticus (17%), and hemorrhagic stroke (16%). From the 17 patients that were hospitalized with status epilepticus, one had previous diagnosis of epilepsy, and the other 16 patients were newly diagnosed. Mean hospital stay was 20 ± 24 days (Table 1). Patients received a mean of 8 ± 5 (range: 0–25) concomitant medications from a list of 116 drugs, divided in inductors or capable of decreasing PHT plasmatic levels (n = 4), inhibitory or that increased PHT plasmatic levels (n = 15), and with variable or neutral effects (n = 97) (supplementary table 2). 3.2. Phenytoin treatment regimen Forty-four patients received IV load, 35 PO load, and 21 MD. Phenytoin loading (IV or PO) was used as treatment of recent seizure or status epilepticus in 47 patients (59.5%) and as prophylaxis in 32 patients (40.5%). Seasons of PHT onset were autumn (36 patients), winter (33), spring (18), and summer (13). Mean plasmatic levels achieved from IV/PO load was 14.4 ± 7.0 and 14.6 ± 7.4 in MD patients. Overdose (plasmatic levels: N20 μg/mL) occurred in 23% (18/79) and 24% (5/21) of the patients with IV-PO load and MD respectively (Table 1). 3.3. Phenytoin ADRs A total of 33 patients developed ADR to PHT. These appeared in mean 12 ± 9 days (median: 10 days) after the initiation of PHT (range: 1–30 days). The most frequent were mild skin rash (n = 15), transient fever (n = 4), and mild–moderate elevated transaminases (n = 4). Seven patients developed 2 simultaneous ADRs: association of fever/elevated transaminases (n = 5), rash/elevated transaminases (n = 1), and fever/rash (n = 1). Infusion-related ADR was only present in 1 patient (mild bradycardia), and no phlebitis were observed. Other ADRs reported were: 1 patient with confusion and 1 with walking instability (Table 1). 3.4. Risk factors for developing ADR When creating groups according to ADR occurrence, the univariate analysis for developing rash found a greater proportion of females (85% vs 52%, p = 0.029), younger age (mean age: 49 vs 62 years, p = 0.032), higher PHT plasmatic levels after IV-PO load (mean plasmatic levels: 18.6 vs 13.9 μg/mL, p = 0.040), and higher number of concomitant medications (mean: 10 vs 7, p = 0.043) (Table 2). Every comorbidity and comedication that was statistically significant more frequent in patients who developed rash is described in supplementary tables 3 and 4. The RR and 95% CI obtained from univariate analysis are showed

Please cite this article as: Uribe-San-Martín R, et al, Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.032

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Table 1 Characteristics of included patients. Gender (n) Female Male

Seizure, status, and epilepsy (n) Acute symptomatic seizure Status epilepticus Epilepsy Previously dx Newly dx Comorbidities (n) Arterial hypertension Brain tumor Hemorrhagic stroke Ischemic stroke Administration route PHT (n) IV load PO load MD Adverse drug reactions (n) Rash Fever Elevated transaminases Other Patients with 1 ADR Patients with ≥2 ADRs Plasmatic level (IV-PO load/MD) Mean Median SD Range IV-PO load Range MD According to value (n) Overdose IV-PO load (N20 μg/mL) Overdose MD (N20 μg/mL)

59 41

1 17 45 9 36

Age Mean Median SD Range Hospital stay Mean Median SD Range

59.1 63.0 21.3 15–98 19.8 13.5 23.8 1–171

26 18 16 12 44 35 21

17 10 10 3 26 7 14.4/14.6 14.3/14.0 7.0/7.4 0.9–33.6 2.1–24.9 18/79 5/21

Seasons of PHT onset (n) Summer Autumn Winter Spring Days with PHT until ADR Mean Median SD Range Intrahospital suspension (n) Ambulatory suspension (n) Concomitant medications (used during follow-up) Mean Median SD Range According to type (X + SD) Decreases PHT levels Increases PHT levels Neutral effects

13 36 33 18 12.3 10.0 8.9 1–30 27 6 7.9 7.0 5.0 0–25 0.1 ± 0.3 1.7 ± 1.2 6.2 ± 4.2

n: number = percentage; dx: diagnosis; PHT: phenytoin; IV: intravenous; PO: peroral; MD: maintenance dose; ADR: adverse drug reaction. SD: standard deviation.

in Table 3 and multivariate analysis with binomial logistic regression model revealed an association between rash and two of the variables mentioned above: younger age (cut-off: 35 years old; RR = 11.7; p = 0.026) and higher PHT plasmatic levels (cut-off: 16 μg/mL; RR = 12.5; p = 0.021). Higher number of concomitant medications was also found in patient with fever and elevated transaminases compared with patients without any ADR (Table 2). Comorbidities and comedications that were statistically significant more frequent in patients with fever and elevated transaminases compared with patients without ADR are described in supplementary tables 3 and 4. In particular, omeprazole was the most frequent comedication used in our cohort (supplementary table 2) and was associated with development of fever in doses of 40 mg (p = 0.018, supplementary table 4 and 5). The multivariate analysis showed an increased risk of elevated transaminases with the use of PHT inductors (RR = 18; p = 0.006) (Table 3). Longer hospital stays were found in patients who developed fever (mean: 43 ± 30 days, p b 0.0001) and elevated transaminases (mean: 26 ± 18 days, p = 0.041) compared with patients without any ADR (mean: 17 ± 24 days, Table 2).

3.5. Probability of causality Using the Naranjo and WHO algorithm criteria, most ADRs were categorized as probable (73% with Naranjo and 82% with WHO criteria), and the rest were categorized as possible. Regarding severity, all 33 ADRs were categorized as moderate (WHO criteria). No severe events were observed. Most ADRs were classified as Type B nondose-dependent or idiosyncratic (94%).

4. Discussion We found that 33% of ADRs are associated with PHT use. Polypharmacy was the common risk factor among all ADRs studied. Female gender, younger age, and higher PHT plasmatic levels after loading doses were found to be risk factors for the developing rash. As a consequence, longer hospital stays were observed in patients who developed any ADR. From a pathophysiological stand of view, a sensitization period of 7–10 days is required in patients with ADR [11], which is supported by our median time for developing any ADR of 10 days. Previous reviews have reported similar prevalence of ADR with PHT, ranging from 27 to 43% [12]. Cutaneous ADR (mainly maculopapular rash) is usually the most common presentation, and our incidence (17%) was on the higher side of the range previously described (5 to 17%) [11,12]. Extreme ages (b 12 or N64 years), comorbidities, and polypharmacy have also been associated with an increased risk for developing ADR [11,13]. In our study, a higher number of concomitant medications were observed in every type of ADR compared with those patients without any ADR. The analysis of every subtype of medications and comorbidities, and their interactions with PHT metabolism is very complex. In the case of omeprazole, commonly associated with PHT-induced ADR, given it can inhibit CYP 2C19 and reduce PHT clearance [14], we found that doses of 40 mg per day, but not doses of 20 mg per day were associated with the development of fever. In this cohort, it was the most frequently used comedication because of an internal protocol for prevention of gastroduodenal ulcers in hospitalized patients. However, although we were able to find some comedications and comorbidities that were more frequent in each ADR group, a causal

Please cite this article as: Uribe-San-Martín R, et al, Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.032

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Table 2 Phenytoin ADRs and associations with clinical variables.

Gender (n) Female Male Age Mean Median SD Range Comorbidities Mean Median SD Range Administration route PHT (n) IV load PO load MD Seasons of PHT onset (n) Summer Autumn Winter Spring Plasmatic levels (IV-PO load/MD) Mean Median SD Range IV-PO load Range MD According to value (n) Overdose IV-PO load (N20 μg/mL) Overdose MD (N20 μg/mL) Bolus dose (n) b1 g ≥1 g Days with PHT until ADR Mean Median SD Range Intrahospital suspension (n) Ambulatory suspension (n) Concomitant medications (used during follow-up) Mean Median SD Range According to type Decreases PHT levels Mean Median SD Range Increases PHT levels Mean Median SD Range Neutral effects Mean Median SD Range Hospital stay Mean Median SD Range

Rash (n = 17)

Fever (n = 10)

ET (n = 10)

Any ADR (n = 33)

No ADR (n = 67)

14* 3

6 4

5 5

24 9

35* 32

48.9* 54.0* 23.2 17–87

59.9 67.0 27.9 15–98

56.8 56.5 18.8 24–85

53.8 56.5 23.4 15–98

62.1* 67.0* 19.2 16–92

2.9 3.0 1.5 1–6

2.5 2.0 1.8 1–5

2.4 1.5 2.1 1–7

2.6 2.0 1.7 1–7

2.6 2.0 1.3 1–6

8 3 6

7 2 1

5 4 1

16 9 8

28 26 13

4 8 3 2

2 2 3 3

0 3 5 2

7 13 8 5

6 23 25 13

18.6*/14. 19.9*/13.3 6.5/7.5 4.5-27.1 4.4-24.9

13.3/12.8 14.7/– 7.3/– 1.5–24.9 –

15.2/14.5 12.2/– 8.5/– 6.6–33.6 –

15.3/14.5 16.1/13.3 7.4/6.8 1.5–33.6 4.4–24.9

13.9*/14.8 14.2*/17.4 6.6/8.7 0.9–24.3 2.1–24.3

5/10 1/6

1/9 0/1

2/8 0/1

8/30 1/8

11/53 4/13

8 9

6 4

6 4

17 16

37 28

13.8 10.0 10.7 1–30 13 4

9.4 9.5 5.3 2–20 10 0

11.8 9.5 7.5 2–23 10 0

12.1 10.0 8.6 1–30 34 6

– – – – – –

10.2* 10.0* 5.8 3–25

10.3# 10.5# 4.3 5–18

11.6& 6.8& 6.4 2–25

10.0□ 9.5□ 5.7 1–25

7.1*#&□ 6.0*#&□ 4.7 0–18

0.1 0 0.3 0–1

0.2# 0# 0.4 0–1

0.4& 0& 0.5 0–1

0.2□ 0□ 0.4 0–1

0.1#&□ 0#&□ 0.2 0–1

2.1 2.0 1.4 0–5

2.1 2.0 1.4 0–4

2.2 2.0 1.6 0–5

2.1 2.0 1.3 0–5

1.6 1.0 1.2 0–5

7.9 8.0 4.8 2–19

8.0# 8.0# 3.4 3–14

9.0& 8.0& 4.8 3–19

7.7 8.0 4.6 0–19

5.6#& 5.0#& 4.0 1–16

19.7 16.0 16.0 3–66

43.3# 36.5# 29.8 10–112

26.2& 22.5& 18.2 4–65

26.0□ 22.0□ 22.8 2–112

17.1#&□ 10.0#&□ 23.7 1–171

ET: elevated transaminases; ADR: adverse drug reaction; n: number = percentage; SD: standard deviation; PHT: phenytoin; IV: intravenous; PO: peroral; MD: maintenance dose. Statistically significant result: For rash: Gender*: p = 0.029 (Fisher exact test); Age*: p = 0.032 (Mann–Whitney U test); Plasmatic levels*: p = 0.040 (Mann–Whitney U test); Concomitant medications*: p = 0.043 (Mann–Whitney U test). For fever: Concomitant medications#: p = 0.039 (Mann–Whitney U test); Comedications inductors#: p = 0.025 (Mann–Whitney U test); Comedications with neutral effects#: p = 0.048 (Mann–Whitney U test); Hospital stay#: p b 0.0001 (Mann–Whitney U test). For elevated transaminases: Concomitant medications&: p = 0.024 (Mann–Whitney U test); Comedications inductors&: p b 0.0001 (Mann–Whitney U test); Comedications with neutral effects&: p = 0.025 (Mann–Whitney U test); Hospital stay&: p = 0.041 (Mann–Whitney U test). For any ADR: Concomitant medications□: p = 0.036 (Mann–Whitney U test); Comedications inductors□: p = 0.026 (Mann–Whitney U test); Hospital stay□: p = 0.014 (Mann–Whitney U test). Bold values are statistically significant values.

Please cite this article as: Uribe-San-Martín R, et al, Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.032

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Table 3 Risk factors for ADRs. Univariate analysis Rash Gender Age (b35 y.o) Plasmatic levels (N16 μg/mL) Comedications (N5) Fever Comedications (N5) Comedications Decreases PHT levels (≥1) Comedications Neutral effects (N6) ET Comedications (N5) Comedications Decreases PHT levels (≥1) Comedications Neutral effects (N4)

Multivariate analysis

RR: 4.3 RR: 5.2

95% CI: 1.1–16 95% CI: 1.5–17

p: 0.033 p: 0.008

RR: 4.2 RR: 11.7

95% CI: 0.56–32 95% CI: 1.3–102

p: 0.161 p: 0.026

RR: 6.1

95% CI: 1.2–32

p: 0.031

RR: 12.5

95% CI: 1.5–107

p: 0.021

RR: 4.2

95% CI: 1.1–16

p: 0.036

RR: 13.5

95% CI: 0.98–186

p: 0.052

RR: 8.7

95% CI: 1.1–73

p: 0.045

RR: 5.8

95% CI: 0.47–71

p: 0.172

RR: 8.1

95% CI: 1.0–66

p: 0.050

RR: 6.3

95% CI: 0.61–64

p: 0.122

RR: 5.1

95% CI: 1.2–22

p: 0.027

RR: 1.7

95% CI: 0.29–9.9

p: 0.564

RR: 8.7

95% CI: 1.1–73

p: 0.045

RR: 2.9

95% CI: 0.07–120

p: 0.568

RR: 22

95% CI: 3.3–144

p: 0.001

RR: 18

95% CI: 2.3–134

p: 0.006

RR: 8.7

95% CI: 1.1–73

p: 0.045

RR: 2.9

95% CI: 0.07–120

p: 0.568

y.o: years old; Comedications: concomitant medications; PHT: phenytoin; ET: elevated transaminases; RR: relative risk; ADR: adverse drug reaction; RR: relative risk; 95% CI: 95% confidence interval. p value obtained using a univariate and multivariate analysis with binomial logistic regression.

relationship is difficult to establish with this small sample size and multiple comparisons assessed. We found that patients who developed fever and elevated transaminases were using a higher number of PHT inductors and medications with a neutral effect, perhaps showing an idiosyncratic nonplasmaticlevel-dependent ADR. Female gender predisposition has also been previously described with a 1.5 to 1.7 fold increase risk in women [15]. Possible explanations include differences in pharmacokinetic, immunologic, and hormonal mechanisms. Women have less lean body mass, reduced hepatic depuration, and different cytochrome P450 activity. As seen in our cohort, most ADRs found in women were the cutaneous reactions, which are primarily immunogenic [16]. Some authors have described a seasonal predisposition of developing cutaneous reactions, unrelated to plasma levels of PHT with a higher incidence in patients treated during summer [17]. We observed a trend for developing rash during summer (RR = 3.1, 95% CI = 0.77–13, p = 0.110). Although previous studies have associated the IV load with an increased ADR risk, especially rash [18–20], interestingly, no association between administration route and risk for developing ADR was found in our study. This finding has also been reported in different cohorts [17], which seem to support the safety of any of these administration protocols when a prompt therapeutic response is needed. Recently, other risk factors have been associated with the development of ADR including infectious diseases such as Human Herpes Virus 6, and genetic factors such as the CYP2C variants, mainly CYP2C9*3, and the HLA-B*1502 associated with severe cutaneous adverse reactions [21] in Asian population, and the HLA-A*3101 allele in European and North Asian populations [11]. Limitations of our study include small sample size, and the lack of understanding of the in-vivo pharmacokinetic interactions between PHT and concomitant medications in each particular patient. 5. Conclusion Phenytoin is a widely used AED associated with easily detectable ADR using structured pharmacovigilance. The latter is of great importance in the early detection and prevention of severe reactions, such a fulminant hepatic failure or Steven Johnson's Syndrome [22]. The development of ADR is associated with longer hospital stays and increasing healthcare

costs [23]. Recognizing the local risk factors may lead to ADR prevention in a near future. Newer AEDs possibly have less adverse events, but they are more expensive and less available than PHT in developing countries, so larger studies are needed to better define PHT-related ADR risk profile and to individualize treatment regimens. Disclosure of conflict of interest None of the authors has any conflict of interest to disclose.

Appendix A. Supplementary data Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.yebeh.2017.08.032. References [1] Alvarez V, Januel JM, Burnand B, Rossetti AO. Second-line status epilepticus treatment: comparison of phenytoin, valproate, and levetiracetam. Epilepsia 2011; 52:1292–6. [2] Beghi E, Atzeni L, Garattini L. Economic analysis of newer antiepileptic drugs. CNS Drugs 2008;22:861–75. [3] Strzelczyk A, Haag A, Reese JP, Nickolay T, Oertel WH, Dodel R, et al. Trends in resource utilization and prescription of anticonvulsants for patients with active epilepsy in Germany. Epilepsy Behav 2013;27:433–8. [4] Mesa T, Mesa JT, Guarda J, Mahaluf F, Pauchard F, Undurraga F, et al. The direct costs of epilepsy in a Chilean population. Rev Neurol 2007;16–30(44):710–4. [5] Gupta A, Yek C, Hendler RS. Phenytoin toxicity. JAMA 2017;317:2445–6. [6] Riedl MA, Casillas AM. Adverse drug reactions: types and treatment options. Am Fam Physician 2003;68:1781–90. [7] Bohan KH, Mansuri TF, Wilson NM. Anticonvulsant hypersensitivity syndrome: implications for pharmaceutical care. Pharmacotherapy 2007;27:1425–39. [8] Silva-Castro MM, Tuneu I, Valls L, Faus MJ. Systematic review of the implementation and evaluation of pharmaceutical care in hospitalised patients (pharmaceutical care implementation in hospitalised patients. Systematic review). Farm Hosp 2010;34: 106–24. [9] Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30: 239–45. [10] WHO. The Uppsala Monitoring Centre, Collaborating Centre for International Drug Monitoring. Guidelines for setting up and running a pharmacovigilance Centre. Available from: http://www.who-umc.org/DynPage.aspx?id=105828&mn1= 7347&mn2=7259&mn3=7297&mn4=7496. [11] Ye YM, Thong BY, Park HS. Hypersensitivity to antiepileptic drugs. Immunol Allergy Clin North Am 2014;34:633–43.

Please cite this article as: Uribe-San-Martín R, et al, Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.032

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[12] Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol 2012;11: 792–802. [13] Berthoux É, Dufour C, Raharisondraibe E, Bonnefoy M. Preventable drug events in acute geriatric unit. Geriatr Psychol Neuropsychiatr Vieil 2013;11:15–20. [14] Yampayon K, Sukasem C, Limwongse C, Chinvarun Y, Tempark T, Rerkpattanapipat T, et al. Influence of genetic and non-genetic factors on phenytoin-induced severe cutaneous adverse drug reactions. Eur J Clin Pharmacol 2017;73:855–65. [15] Rademaker M. Do women have more adverse drug reactions? Am J Clin Dermatol 2001;2:349–51. [16] Zopf Y, Rabe C, Neubert A, Gassmann KG, Rascher W, Hahn EG, et al. Women encounter ADRs more often than do men. Eur J Clin Pharmacol 2008;64:999–1004. [17] Leppik IE, Lapora J, Loewenson R. Seasonal incidence of phenytoin allergy unrelated to plasma levels. Arch Neurol 1985;42:120–2. [18] Collins M, Gidal BE, Garnett WR, Reinfeldt G, Tusch GM. Potential underreporting of intravenous phenytoin adverse events. Ann Pharmacother 1999;33:111–2.

[19] Trumic E, Pranjic N, Begic L, Becic F, Asceric M. Idiosyncratic adverse reactions of most frequent drug combinations longterm use among hospitalized patients with polypharmacy. Med Arh 2012;66:243–8. [20] Osborn HH, Zisfein J, Sparano R. Single-dose oral phenytoin loading. Ann Emerg Med 1987;16:407–12. [21] Chung WH, Chang WC, Lee YS, Wu YY, Yang CH, Ho HC, et al. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA 2014 Aug 6;312:525–34. [22] Zaccara G, Franciotta D, Perucca E. Idiosyncratic adverse reactions to antiepileptic drugs. Epilepsia 2007;48:1223–44. [23] Vargas E, Terleira A, Hernando F, Perez E, Cordón C, Moreno A, et al. Effect of adverse drug reactions on length of stay in surgical intensive care units. Crit Care Med 2003; 31:694–8.

Please cite this article as: Uribe-San-Martín R, et al, Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort, Epilepsy Behav (2017), http://dx.doi.org/10.1016/j.yebeh.2017.08.032

Risk factors of early adverse drug reactions with phenytoin: A prospective inpatient cohort.

Phenytoin (PHT) is an effective and inexpensive antiepileptic drug (AED). However, its use has been limited for fear of adverse drug reactions (ADRs) ...
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