Drug Monograph-Oxcarbazepine

Transcription

1 Drug Monograph Generic name: Oxcarbazepine Brand name: Trileptal Manufacturer: Norvatis ( Classification: Anti-epileptic drug Similar agents: Carbamazepine Summary Oxcarbazepine is a new class of anticonvulsant derived from carbamazepine. Like carbamazepine, Oxcarbazepine can be used in the treatment of partial seizures in adults with epilepsy and as adjunctive therapy in the treatment of partial seizure in children. In general, Oxcarbazepine is as efficacious as carbamazepine with no significant difference in seizure frequency reduction. However, Oxcarbazepine has been shown to produce less severe adverse effects with carbamazepine, which enhances optimal seizure control. The most commonly adverse effects of Oxcarbazepine are fatigue, N&V, abdominal pain, headache, dizziness, somnolence, diplopia, ataxia, abnormal vision, tremor, dyspepsia, nystagmus, rash, confusion and elevated liver transminases. More severe adverse effects include hyponatremia and is contraindicated in pregnancy. Moreover, cross-sensitivity occurs between Oxcarbazepine and carbamazepine. Although the cost of Oxcarbazepine is much higher than that of carbamazepine, Oxcarbazepine has higher tolerability than carbamazepine in treating seizure. Recommendations It is recommended that Oxycarbazepine be added to the drug formulary for use restricted to those who cannot tolerate carbamazepine due to the development of severe side effects. Oxycarbazepine can be considered to be a valuable alternative to carbamazepine for optimal seizure control. Pharmacologic Data The primary pharmacologic activity of Oxcarbazepine is attributed to the 10-monohydroxy metabolite (MHD) of Oxcarbazepine because of the rapid Clinical Clerkship Group 2 1

2 systemic metabolism of the parent compound. Like most anticonvulsants, the exact mechanism of action is unknown; however, in vitro electrophysiological studies indicate that voltage-sensitive sodium channels are blocked thereby stabilizing hyper-excited neural membranes, inhibiting repetitive neuronal firing, and diminishing propagation of synaptic impulse. These actions are thought to be important in the prevention of seizure spread in the intact brain. Modulation of potassium and calcium channels may also be involved, contributing to the anticonvulsant effects of the drug. No significant interactions of Oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites like GABA receptors have been demonstrated. Therapeutic Indications 6,7,8,9 Indications Oxcarbazepine is FDA approved for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults with epilepsy and as adjunctive therapy in the treatment of partial seizure in children ages 4-16 with epilepsy. 1 Evidence-Based Clinical Guidelines According to the guidelines of the American Academy of Neurology and the American Epilepsy Society, patients with newly diagnosed epilepsy who require treatment can be initiated on standard AEDs such as carbamazepine or on the new AEDs including Oxcarbazepine, and choice of AED will depend on individual patient characteristics. 2 It is appropriate to use Oxcarbazepine as add-on therapy in patients with refractory epilepsy, as monotherapy in patients with refractory partial epilepsy, and as adjunctive treatment of children with refractory partial seizures. 3 Clinical Studies Dam M et. al. conducted a double-blind study to compare Oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. 4 Two hundred and thirty-five patients suffering from newly diagnosed epilepsy were randomly allocated to treatment with either Oxcarbazepine or carbamazepine in a double-blind multi-centre study. After a titration phase (between 4 and 8 weeks), the optimal individual dose of trial medication was determined and treatment with that dose was continued for another 48 weeks. The criteria for assessment were: efficacy--seizure frequency, EEG tracings, global evaluation; tolerability--side effects observed by the patient or the Clinical Clerkship Group 2 2

3 investigator, laboratory tests; other assessments--blood pressure and heart rate, carbamazepine and 10,11-dihydro-10-hydroxycarbamazepine trough serum levels. The results of the study showed the following: no significant difference in seizure frequency between Oxcarbazepine and carbamazepine; no correlation between the therapeutic effect and the EEG findings in either treatment group; Oxcarbazepine caused significantly fewer (P = 0.04) 'severe' side effects than carbamazepine; global evaluation of tolerability demonstrated a trend towards the better tolerability of Oxcarbazepine; no correlation was observed between either efficacy or tolerability and the actual serum trough levels of antiepileptic drugs; clinically relevant abnormal laboratory test findings were observed in 2 patients, both on carbamazepine. The authors consider Oxcarbazepine to be a valuable alternative to carbamazepine, particularly in patients who develop side effects which prevent optimal seizure control. Glauser TA et. al. conducted a multicentered, randomized controlled trial to evaluate the safety and efficacy of Oxcarbazepine (OXC) as adjunctive therapy in children with inadequately controlled partial seizures on one or two concomitant antiepileptic drugs (AEDs). 5 A total of 267 patients were evaluated in a multicenter, randomized, placebo-controlled trial consisting of three phases: 1) a 56-day baseline phase (patients maintained on their current AEDs); 2) a 112-day double-blind treatment phase (patients received either OXC mg/kg/day orally or placebo); and 3) an open-label extension phase. Data are reported only from the double-blind treatment phase; the open-label extension phase is ongoing. Children (3 to 17 years old) with inadequately controlled partial seizures (simple, complex, and partial seizures evolving to secondarily generalized seizures) were enrolled. The results showed that Patients treated with OXC experienced a significantly greater median percent reduction from baseline in partial seizure frequency than patients treated with placebo (p = ; 35% versus 9%, respectively). Forty-one percent of patients treated with OXC experienced a > or =50% reduction from baseline in partial seizure frequency per 28 days compared with 22% of patients treated with placebo (p = ). Ninety-one percent of the group treated with OXC and 82% of the group treated with placebo reported > or =1 adverse event; vomiting, somnolence, dizziness, and nausea occurred more frequently (twofold or greater) in the group treated with OXC. The authors concluded that OXC adjunctive therapy administered in a dose range Clinical Clerkship Group 2 3

4 of 6 to 51 mg/kg/day (median 31.4 mg/kg/day) is safe, effective, and well tolerated in children with partial seizures. Bioavailability/Pharmacokinetics Absorption Oxcarbazepine is completely absorbed following oral administration. Food has no effect on the rate and extent of absorption of Oxcarbazepine. Bioavailability is decreased in children less than 8 years and increased in elderly over 60 years. Distribution The apparent volume of distribution of Oxcarbazepine s 10-monohydroxy metabolite (MHD) is 49L. Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein. Metabolism Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD). The pharmacokinetics and metabolism of Oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900 mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of Oxcarbazepine and MHD. No dose adjustment is recommended in patients with mild-to-moderate hepatic impairment. The pharmacokinetics of Oxcarbazepine and MHD have not been evaluated in severe hepatic impairment. Elimination The half-life of the parent drug Oxcarbazepine is about 2 hours, while the half-life of MHD is about 9 hours Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged Oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the Clinical Clerkship Group 2 4

5 dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and Oxcarbazepine account for 13% of the dose. There is a linear correlation between creatinine clearance and the renal clearance of MHD. When Oxcarbazepine is administered as a single 300 mg dose in renally impaired patients (creatinine clearance <30 ml/min), the elimination half-life of MHD is prolonged to 19 hours, with a two-fold increase in AUC. Dose adjustment is recommended in these patients Dosage Forms Film-coated tablet, 150mg, 300mg, 600mg Oral suspension, sugar-free, 300 mg/5 ml (i.e. 60mg/ml) Dosage Range Adult Initially 300mg twice daily increased according to response in steps of up to 600mg daily at weekly intervals. Usual dose range is g in divided doses. Children Over 6yo, 8 10 mg/kg daily in 2 divided doses increased according to response in steps of up to 10 mg/kg daily at weekly intervals (in adjunctive therapy, maintenance dose approx. 30 mg/kg daily); max. 46 mg/kg daily in divided doses Note. In adjunctive therapy, patients may require dose reduction of concomitant antiepileptics when using high doses of Oxcarbazepine. Adverse Events The most commonly experienced adverse events of Oxcarbazepine are fatigue, N&V, abdominal pain, headache, dizziness, somnolence, diplopia, ataxia, abnormal vision, tremor, dyspepsia, nystagmus, rash, confusion and elevated liver transminases. The following table summarized the adverse events experienced when Oxcarbazepine is used as an adjunctive therapy in adults. Clinical Clerkship Group 2 5

6 Oxcarbazepine Dosage (mg/day) OXC 600 OXC 1200 OXC 2400 Placebo Body System/ N=163 N=171 N=126 N=166 Adverse Event % % % % Body as a Whole Fatigue Asthenia Digestive System Nausea Vomiting Pain Abdominal Diarrhea Dyspepsia Constipation Metabolic and Nutritional Disorders Hyponatremia Nervous System Headache Dizziness Somnolence Ataxia Nystagmus Gait Abnormal Insomnia Tremor Respiratory System Rhinitis Special Senses Diplopia Vertigo Vision Abnormal Clinical Clerkship Group 2 6

7 The following table summarized the adverse events experienced when Oxcarbazepine is used as a monotherapy in adults. Oxcarbazepine Dosage (mg/day) Body System/ Adverse Event Body as a Whole 2400 N=86 % 300 N=86 % Fatigue 21 5 Allergy 2 0 Digestive System Nausea 22 7 Vomiting 15 5 Diarrhea 7 5 Dyspepsia 6 1 Anorexia 5 3 Pain Abdominal 5 3 Mouth Dry 3 0 Hemorrhage Rectum 2 0 Toothache 2 1 Infections and Infestations Infection Viral 7 5 Infection 2 0 Metabolic and Nutritional Disorders Hyponatremia 5 0 Nervous System Headache Dizziness 28 8 Somnolence 19 5 Anxiety 7 5 Ataxia 7 1 Confusion 7 0 Nervousness 7 0 Clinical Clerkship Group 2 7

8 Insomnia 6 3 Tremor 6 3 Amnesia 5 1 Convulsions Aggravated 5 2 Respiratory System Upper Respiratory Tract Infection 10 5 Coughing 5 0 Special Senses Vision Abnormal 14 2 Diplopia 12 1 Taste Perversion 5 0 Urogenital and Reproductive System Urinary Tract Infection 5 1 Safety A number of safety issues have to be considered before prescribing the drug. Hyponatremia Clinically significant hyponatremia (sodium <125 mmol/l) can develop during Oxcarbazepine use. Clinically significant hyponatremia generally occurred during the first 3 months of treatment with Oxcarbazepine, although there were patients who first developed a serum sodium <125 mmol/l more than 1 year after initiation of therapy. In clinical trials, patients whose treatment with Oxcarbazepine was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment. Measurement of serum sodium levels should be considered for patients during maintenance treatment with Oxcarbazepine, particularly if the patient is receiving other medications known to decrease serum sodium levels or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity). Clinical Clerkship Group 2 8

9 Withdrawal of AEDs As with all antiepileptic drugs, Oxcarbazepine should be withdrawn gradually to minimize the potential of increased seizure frequency. Pregnancy and Lactation Issue Oxcarbazepine is considered Pregnancy Category C. Tests in pregnant animals have shown adverse effects. There are no adequate and well-controlled clinical studies of Oxcarbazepine in pregnant women; however, Oxcarbazepine is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Given this fact, and the results of the animal studies, it is likely that Oxcarbazepine is a human teratogen. Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to Oxcarbazepine in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother. Overall, when considering use in pregnant or lactating women, the physician must consider if the potential benefit can justify the potential risks. Female patients of childbearing age should be warned that the concurrent use of Oxcarbazepine with hormonal contraceptives may render this method of contraception less effective (Please refer to the Drug Interaction Section). Additional non-hormonal forms of contraception, such as condoms, are recommended when using Oxcarbazepine. Overdose Isolated cases of overdose with Oxcarbazepine have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment. There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered. Contraindications Oxcarbazepine should not be used in patients with a known hypersensitivity to Oxcarbazepine or to any of its components. Patients who have had hypersensitivity reactions to carbamazepine should be Clinical Clerkship Group 2 9

10 informed that approximately 25%-30% of them will experience hypersensitivity reactions with Oxcarbazepine. For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with Oxcarbazepine only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, Oxcarbazepine should be discontinued immediately. Drug Interactions Antidepressants-Anticonvulsant effect of antiepileptics antagonized by SSRIs and tricyclics, as well as possibly antagonized by MAOIs and tricyclic-related antidepressants, due to the decreased convulsive threshold. Antiepileptics-Oxcarbazepine sometimes reduces plasma concentration of carbazepine and also plasma concentration of an active metabolite of Oxcarbazepine is often reduced. Oxcarbazepine increases plasma concentration of phenytoin and also plasma concentration of an active metabolite of Oxcarbazepine is often reduced. Oxcarbazepine increases plasma concentration of an active metabolite of primidone and also plasma concentration of an active metabolite of Oxcarbazepine is reduced. The plasma concentration of an active metabolite of Oxcarbazepine is sometimes reduced by valproate. Antimalarials-There is possible increased risk of convulsions when antiepileptics are used with chloroquine and hydrochloroquine. Anticonvulsant effect of antiepileptics can be antagonized by mefloquine. Antipsychotics-Anticonvulsant effect of Oxcarbamazepine can be antagonized by antipsychotics as the convulsive threshold is lowered. Barbiturates-Oxcarbazepine increases plasma concentration of phenobarbital and also the plasma concentration of an active metabolite of Oxcarbazepine is reduced. Oestrogens & Progestogens-Oxcarbazepine accelerates metabolism of oestrogens and progestogens due to its hepatic enzyme inducing activity. Therefore, the effectiveness of both combined and progestogen-only oral Clinical Clerkship Group 2 10

11 contraceptives may be reduced. Patient Monitoring Guidelines Monitor effectiveness Monitor patient for objective evidence of effectiveness including the number of episode of partial seizure reported by the patient. Dosage adjustment Dose adjustment for Oxcarbazepine is recommended in renal impaired patients and the elderly. In renally-impaired patients (creatinine clearance <30 ml/min), the elimination half-life of MHD is prolonged with a corresponding increase in AUC. Oxcarbazepine therapy should be initiated at one-half the usual starting dose and increased, if necessary, at a slower than usual rate until the desired clinical response is achieved. Patient Information Patient should be reminded of the following information when they are prescribed for Oxcarbazepine: Oxcarbazepine is a drug that affects the nerves and brain. Do not stop taking Oxcarbazepine without first talking to their doctor, even if they feel better. It is important to continue taking Oxcarbazepine to prevent the seizures from recurring. Stopping Oxcarbazepine suddenly may result in increased seizure frequency. If the medication needs to be stopped, their doctor may need to lower the dosage gradually. Do not drink alcohol while taking Oxcarbazepine. Alcohol may increase drowsiness or dizziness caused by Oxcarbazepine. Alcohol may also increase the risk of seizures. Oxcarbazepine may cause drowsiness, dizziness, blurred vision, or poor coordination. Do not drive, operate dangerous machinery, or perform other hazardous activities until they know how Oxcarbazepine affects them. If they experience drowsiness, dizziness, blurred vision, or poor coordination, avoid these activities. Do not take this medication without first talking to their doctor if they are pregnant or could become pregnant during treatment. Moreover, Oxcarbazepine may decrease the effectiveness of birth control pills. Use a second method of birth control while taking Oxcarbazepine to ensure protection from unintended pregnancy. Oxcarbazepine passes into breast milk and may be harmful to a nursing infant. Do not breast-feeding a baby if they Clinical Clerkship Group 2 11

12 are taking this medicine If they experience any of the following serious side effects, seek emergency medical attention or consult their doctor immediately: an allergic reaction (difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; or hives); symptoms of low blood sodium (nausea, general discomfort, headache, extreme drowsiness, or confusion); central nervous system effects (difficulty with concentration, speech, or language; excessive sleepiness or fatigue; a loss of coordination or trouble walking); double vision, nystagmus (back-and-forth movements of the eyes), blurred vision, or other visual disturbances; or increasing frequency or worsening of seizures. If they are over 60 years of age, they may be more likely to experience side effects from Oxcarbazepine. Their doctor may prescribe a lower dose or special monitoring during treatment. Carry or wear a medical identification tag to let others know that they are taking this medicine in the case of an emergency. Store Oxcarbazepine at room temperature away from moisture and heat. The suspension should be used within 7 weeks of first opening the bottle. If they missed a dose, take the missed dose as soon as they remember. However, if it is almost time for the next dose, skip the missed dose and take only the next regularly scheduled dose. Do not take a double dose of this medication. If they are overdosed, seek emergency treatment. Cost comparison Drug Oxcarbazepine Tablet <TRILEPTAL> 150MG Oxcarbazepine Tablet <TRILEPTAL> 300MG Oxcarbazepine Tablet <TRILEPTAL> 600MG Oxcarbazepine Oral Suspension <TRILEPTAL> 300MG/5ML Acetazolamide Tablet <DIAMOX> 250MG Unit Cost / Recommended Unit Adult Usual Dose Daily cost ($) Tablet Tablet g-2.4 g daily in Tablet divided doses ML g daily in Tablet divided doses Clinical Clerkship Group 2 12

13 Acetazolamide S.R. Capsule <GLAUPAX> 250MG Acetazolamide S.R. Capsule <DIAMOX> 500MG Carbamazepine Tablet <TEGRETOL> 200MG Carbamazepine Suspension <TEGRETOL> 100MG/5ML Carbamazepine CR Tablet <TEGRETOL CR> 200MG Clonazepam Tablet <RIVOTRIL> 0.5MG Clonazepam Tablet <RIVOTRIL> 2MG Ethosuximide Capsule <ZARONTIN> 250MG Garbapentin Capsule <NEURONTIN> 300MG Garbapentin Capsule <NEURONTIN> 400MG Lamotrigine Tablet <LAMICTAL> 50MG Lamotrigine Tablet <LAMICTAL> 100MG Phenobarbitone Sodium Tablet <LUMINAL> 15MG Phenobarbitone Sodium Tablet <LUMINAL> 30MG Phenobarbitone Sodium Tablet <LUMINAL> 60MG Phenobarbitone Sodium ELIXIR 60MG/5ML Phenobarbitone Sodium(ALCOHOL FREE) Syrup 30MG/5ML Phenytoin Syrup <DILANTIN> 125MG/5ML Capsule Capsule Tablet ML 0.8 g-1.2 g daily in divided doses Tablet Tablet mg daily in Tablet divided doses Capsule 1 g-1.5 g daily in divided doses Capsule g-2.4 g daily in divided doses Capsule Tablet mg daily in 1-2 divided Tablet doses Tablet Tablet Tablet mg at night ML ML mg daily ML at divided doses Clinical Clerkship Group 2 13

14 Phenytoin Sodium Tablet <DILANTIN> 100MG Tablet Primidone Tablet g daily in Tablet <MYSOLINE> 250MG divided doses Valproate Sodium Tablet E.C. <EPILIM> 200MG Tablet Valproate Sodium SOLUTION <EPILIM> ML MG/5ML Valproate Sodium C.R. Tablet <EPILIM CHRONO> Tablet g daily in divied MG doses Valproate Sodium C.R. Tablet <EPILIM CHRONO> Tablet MG Valproate Sodium C.R. Tablet <EPILIM CHRONO> Tablet MG Vigabatrin Tablet <SABRIL> 500MG Tablet g daily Remark: Price of TRILEPTAL (Oxcarbazepine) purchased by Hospital Authority is predicted by the price listed in the BNF 48 and comparison with TERGRETOL CR (Carbamazepine), which is another drug of same class produced by same manufacturer (Novartis). This price is only a wild prediction. Final price of offer is determined by local distributor. Formula used: Price = Price of TEGRETOL CR in PWH x Price of TRILEPTAL IN Formulary BNF48 Price of TEGRETOL CR in BNF48 Comparison over current PWH Formulary Drugs 10,11 Efficacy According to a systematic review, Oxcarbazepine as mono drug therapy for childhood and adolescence partial onset seizures[8,51] or generalized tonic-clonic seizures has the similar efficacy as phenytoin in rendering seizure free (both appropriately 60%). The seizure frequency is also not significantly Clinical Clerkship Group 2 14

15 different between Oxcarbazepine and phenytoin groups. In contrast, fewer patients treated with Oxcarbazepine monotherapy than with carbamazepine monotherapy were seizure free in a smaller randomized nonblind trial reported as an abstract (65.4% vs 88.5%) In a Oxcarbazepine-vs-valporate efficacy analyses comprising 212 patients who had at least one seizure assessment during the maintenance period, no statistically significant difference at the 5% level was found between the two treatment groups. Sixty patients (56.6%) in the OXC group and 57 patients (53.8%) in the VPA group were seizure free during maintenance treatment. Safety According to the same review mentioned above, the number of patients prematurely discontinuing treatment due to adverse events (the primary tolerability endpoint) was significantly in favor of Oxcarbazepine relative to phenytoin over a 48-week period in a well designed trial (2.5% vs 18%; p = 0.002). Adverse event occurrence (causally related) was lower in the Oxcarbazepine treatment group than in the phenytoin group. In a small non-blind study Oxcarbazepine mg/day, compared with carbamazepine mg/day, was associated with similar types of adverse events (oversleeping, headache, vomiting, dizziness) but a lower total incidence (31% vs 61%, p = 0.013) in 52 children treated for up to 19 months (abstract only) Reference 1. British National Formulary Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. 7. Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Clinical Clerkship Group 2 15

16 8. Dam M et. al. A double-blind study comparing oxcarbazepine and carbamazepine in patients with newly diagnosed, previously untreated epilepsy. Epilepsy Research. 3(1):70-6, 1989 Jan-Feb. 9. Glauser TA et. al. Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine Pediatric Study Group. Neurology. 54(12): , 2000 Jun LM. Bang and KL. Goa. Oxcarbazepine A Review of its Use in Children with Epilepsy. Pediatr Drugs. Vol. 5(8): pp , W Christe, G Kramer,U Vigonius, H Pohlmann, BJ Steinhoff, MJ Brodie, A Moore. A double-blind controlled clinical trial: Oxcarbazepine versus sodium valproate in adults with newly diagnosed epilepsy. Epilepsy Research. Vol. 26(3)(pp ), Clinical Clerkship Group 2 16