Medications: New and  What s on the Horizon

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Anti-Epileptic Drugs Carbamazepine/Tegretol Phenytoin/Dilantin Phenobarbital Valproate/Depakote. . ANTI-EPILEPTIC DRUGS. Carbamazepine (Tegretol, Carbatrol)Phenytoin (Dilantin)Valproate (Depakote)Phenobarbital. Felbamate (Felbatol)Gabapentin (Neurontin)Lacosamide (Vimpat)La

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Medications: New and What s on the Horizon

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1. Medications: New and What’s on the Horizon

2. Anti-Epileptic Drugs Carbamazepine/Tegretol Phenytoin/Dilantin Phenobarbital Valproate/Depakote

3. ANTI-EPILEPTIC DRUGS Carbamazepine (Tegretol, Carbatrol) Phenytoin (Dilantin) Valproate (Depakote) Phenobarbital Felbamate (Felbatol) Gabapentin (Neurontin) Lacosamide (Vimpat) Lamotrigine (Lamictal,LamictalXR Levetiracetam (Keppra,KeppraXR) Oxcarbazepine (Trileptal) Pregabalin (Lyrica) Rufinamide (Banzel) Tiagabine (Gabatril) Topiramate (Topamax) Vigabatrin (Sabril) Zonisamide (Zonegran)

4. Why do we need new drugs?

5. No seizures and no side effects!

6. Newer AEDs May Be More Appropriate for Many Patients Older AEDs may be associated with complications over time Weight gain – Drug interactions Gum hyperplasia – Bone health issues Skin rash – Reproductive dysfunction Changes in facial features, – Polycystic ovarian hair, and skin dysfunction Newer AEDs may provide advantages over the long term Favorable pharmacokinetics – Primarily renally excreted Low potential for drug interactions – Low protein binding – Weight neutral Over time, the older generation AEDs may be associated with complications ranging from weight gain and gum hyperplasia to reproductive dysfunction. Newer AEDs have a reduced potential for adverse effects over time for a number of reasons, as shown on this slide. References: 1. Asconape JJ. Some common issues in the use of antiepileptic drugs. Semin Neurol. 2002;22:27-39; 2. Willmore LJ, Pickens A, Pellock JM. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2006:735-745; 3. Bourgeois BFD. Pharmacokinetics and pharmacodynamics of antiepileptic drugs. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2006:655-664.Over time, the older generation AEDs may be associated with complications ranging from weight gain and gum hyperplasia to reproductive dysfunction. Newer AEDs have a reduced potential for adverse effects over time for a number of reasons, as shown on this slide. References: 1. Asconape JJ. Some common issues in the use of antiepileptic drugs. Semin Neurol. 2002;22:27-39; 2. Willmore LJ, Pickens A, Pellock JM. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2006:735-745; 3. Bourgeois BFD. Pharmacokinetics and pharmacodynamics of antiepileptic drugs. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2006:655-664.

7. New and Improved Antiepileptic Drugs Lacosamide - Vimpat Pregabalin – Lyrica Rufinamide – Banzel Vigabatrin-Sabril KeppraXR LamictalXR

8. Coming Attractions Brivaracetam Eslicarbazepine Ezogabine

9. Seizures

10. Seizures vs. Epilepsy

11. Prevalence and Incidence 2.5 million Americans with epilepsy; 60,000 Minnesotans 70,000 to 128,000 new cases annually Cumulative adjusted lifetime risk 1.3-3.1% 1 in every 60 children has epilepsy Single seizure occurs in 6-9%

12. International Classification of Seizures Partial Seizures Generalized Seizures Unclassified Epileptic Seizures Status Epilepticus

13. Generalized Seizures Absence Tonic-Clonic Clonic-Tonic-Clonic Clonic Myoclonic Atonic (drop attack) Tonic

14. PARTIAL SEIZURES Simple Partial (focal) : retained awareness/consciousness Complex Partial (psychomotor, temporal lobe) : Altered awareness/consciousness Secondarily Generalized Tonic-Clonic (Grand Mal, Convulsive): simple or complex spreading to bilateral involvement

15. Lacosamide / Vimpat

16. VIMPAT / Lacosamide VIMPAT® tablets are indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged =17 years VIMPAT® injection for intravenous use is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy aged =17 years when oral administration is temporarily not feasible Key Point: VIMPAT® tablets are indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy =17 years. VIMPAT® injection for intravenous use is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy =17 years when oral administration is temporarily not feasible. VIMPAT® is a member of a series of functionalized amino acids that were specifically synthesized as AED candidates,1 with a molecular formula of C13H18N2O3 and a molecular weight of 250.3 g/mol. Reference: Beyreuther BK, Freitag J, Heers C, et al. Lacosamide: a review of preclinical properties. CNS Drug Rev. 2007;13:21-42. Key Point: VIMPAT® tablets are indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy =17 years. VIMPAT® injection for intravenous use is indicated as adjunctive therapy in the treatment of partial-onset seizures in patients with epilepsy =17 years when oral administration is temporarily not feasible. VIMPAT® is a member of a series of functionalized amino acids that were specifically synthesized as AED candidates,1 with a molecular formula of C13H18N2O3 and a molecular weight of 250.3 g/mol. Reference: Beyreuther BK, Freitag J, Heers C, et al. Lacosamide: a review of preclinical properties. CNS Drug Rev. 2007;13:21-42.

17. Vimpat/ Lacosamide Generic Name: Lacosamide ((la-COS-a-mide)) Used to Treat: Partial onset seizures No labs, no levels required Low potential for drug interactions Forms of the medicine: Tablets, Injection, Oral Solution

18. Phase II/III Clinical Trials Assessed the Efficacy and Safety of VIMPAT® as Adjunctive Therapy Key Point: The primary evaluation of VIMPAT® for adjunctive therapy in adults with partial-onset seizures is based on 3 phase II/III clinical trials: Study 1 (Phase II, N=415, conducted in the US and Europe), Study 2 (Phase III, N=477, conducted in Europe and Australia), and Study 3 (Phase III, N=402, conducted in the US). (Note: The total number of patients in each study represents the intent-to-treat population, which is defined as patients who received trial medication and had =1 post-Baseline efficacy assessment.)1-3 All 3 trials were powered to be adequate and well-controlled studies to evaluate the efficacy and safety of the oral formulation of VIMPAT® 200, 400, or 600 mg/day vs placebo in patients with refractory partial-onset seizures taking 1 to 3 AEDs, with or without vagus nerve stimulation (VNS). (Note: The 600-mg/day dose was included in the clinical trial designs shown on this slide in the interest of full disclosure. However, because VIMPAT® 600 mg/day is not an approved dose, the efficacy and safety data for this dosage are not included in this presentation.)1-3 Each of the trials used a fixed-dose, forced-titration design and included an 8-week Baseline Phase to evaluate Baseline seizure frequency, a 4- or 6-week Titration Phase, a 12-week Maintenance Phase, and a 2- to 3-week Taper or Transition Phase into open-label extension trials.1-3 The 3 trials were similar in design; all were multicenter, randomized, double-blind, placebo-controlled trials to assess the efficacy and safety of VIMPAT® as adjunctive therapy in adult subjects with partial-onset seizures.1-3 In Study 1, patients were randomized in a 1:1:1:1 ratio to placebo, VIMPAT® 200 mg/day, VIMPAT® 400 mg/day, or VIMPAT® 600 mg/day, and in Study 2, patients were randomized in a 1:1:1 ratio to placebo, VIMPAT® 200 mg/day or VIMPAT® 400 mg/day.1,2 However, in Study 3, patients were randomized in a 1:2:1 ratio to placebo, VIMPAT® 400 mg/day, or VIMPAT® 600 mg/day.3 The dosage of concomitant AEDs was kept constant for =4 weeks prior to entry into the Baseline Phase and throughout the trial. In each trial, patients were enrolled and entered into an 8-week Baseline Phase. Only patients who reported =4 partial-onset seizures per 28 days on the average, with seizure-free period =21 days during the Baseline Phase, were randomized.1-3 After randomization, the patients began double-blind treatment as follows: a 4- (Study 2) or 6-week (Studies 1 and 3) forced titration up to the respective randomized dose of VIMPAT® (200, 400, or 600 mg/day) or placebo (note: a 1-step, back-titration of VIMPAT® 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the Titration Phase); a 12-week Maintenance Phase on the achieved randomized (or back-titrated) dose; and either a 2-week Transition Phase or a 2- (Study 2) or 3-week (Studies 1 and 3) Taper Phase. The 2-week Transition Phase (bringing patients to a dose of VIMPAT® 200 mg/day) was required for patients who completed the Maintenance Phase and who chose to enroll in an open-label extension trial of VIMPAT®. The 2- to 3-week Taper Phase (during which dosing was reduced by weekly increments of 200 mg/day) was required for patients who chose not to enroll in the open-label extension trial of VIMPAT® or who did not complete the Titration or Maintenance Phases.1-3 A Baseline seizure frequency of =4 partial-onset seizures per 28 days on average was deemed sufficiently high to detect both decreases and increases in seizure frequency. An 8-week Baseline Phase was considered necessary to adequately assess Baseline seizure frequency due to spontaneous fluctuations of seizure frequency in this subject population. Furthermore, the duration of the Maintenance Phase (12 weeks) was chosen due to regulatory guidance (European Medicines Agency [EMEA]) that suggests a 12-week Maintenance Phase has adequate duration to evaluate efficacy.1-3 Two primary variables were defined in each of these trials. For the US FDA, the primary variable was the change in partial seizure frequency per 28 days from Baseline to the Maintenance Phase. For the EMEA, the primary variable was the proportion of responders, or patients experiencing a =50% reduction in partial seizure frequency from Baseline to the Maintenance Phase.1-3 References: Study 1: Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308-1317. Study 2: Halász P, Kälviäinen R, Mazurkiewicz-Beldzinska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50:443-453. Study 3: Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia. 2010;51:958-967.Key Point: The primary evaluation of VIMPAT® for adjunctive therapy in adults with partial-onset seizures is based on 3 phase II/III clinical trials: Study 1 (Phase II, N=415, conducted in the US and Europe), Study 2 (Phase III, N=477, conducted in Europe and Australia), and Study 3 (Phase III, N=402, conducted in the US). (Note: The total number of patients in each study represents the intent-to-treat population, which is defined as patients who received trial medication and had =1 post-Baseline efficacy assessment.)1-3 All 3 trials were powered to be adequate and well-controlled studies to evaluate the efficacy and safety of the oral formulation of VIMPAT® 200, 400, or 600 mg/day vs placebo in patients with refractory partial-onset seizures taking 1 to 3 AEDs, with or without vagus nerve stimulation (VNS). (Note: The 600-mg/day dose was included in the clinical trial designs shown on this slide in the interest of full disclosure. However, because VIMPAT® 600 mg/day is not an approved dose, the efficacy and safety data for this dosage are not included in this presentation.)1-3 Each of the trials used a fixed-dose, forced-titration design and included an 8-week Baseline Phase to evaluate Baseline seizure frequency, a 4- or 6-week Titration Phase, a 12-week Maintenance Phase, and a 2- to 3-week Taper or Transition Phase into open-label extension trials.1-3 The 3 trials were similar in design; all were multicenter, randomized, double-blind, placebo-controlled trials to assess the efficacy and safety of VIMPAT® as adjunctive therapy in adult subjects with partial-onset seizures.1-3 In Study 1, patients were randomized in a 1:1:1:1 ratio to placebo, VIMPAT® 200 mg/day, VIMPAT® 400 mg/day, or VIMPAT® 600 mg/day, and in Study 2, patients were randomized in a 1:1:1 ratio to placebo, VIMPAT® 200 mg/day or VIMPAT® 400 mg/day.1,2 However, in Study 3, patients were randomized in a 1:2:1 ratio to placebo, VIMPAT® 400 mg/day, or VIMPAT® 600 mg/day.3 The dosage of concomitant AEDs was kept constant for =4 weeks prior to entry into the Baseline Phase and throughout the trial. In each trial, patients were enrolled and entered into an 8-week Baseline Phase. Only patients who reported =4 partial-onset seizures per 28 days on the average, with seizure-free period =21 days during the Baseline Phase, were randomized.1-3 After randomization, the patients began double-blind treatment as follows: a 4- (Study 2) or 6-week (Studies 1 and 3) forced titration up to the respective randomized dose of VIMPAT® (200, 400, or 600 mg/day) or placebo (note: a 1-step, back-titration of VIMPAT® 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the Titration Phase); a 12-week Maintenance Phase on the achieved randomized (or back-titrated) dose; and either a 2-week Transition Phase or a 2- (Study 2) or 3-week (Studies 1 and 3) Taper Phase. The 2-week Transition Phase (bringing patients to a dose of VIMPAT® 200 mg/day) was required for patients who completed the Maintenance Phase and who chose to enroll in an open-label extension trial of VIMPAT®. The 2- to 3-week Taper Phase (during which dosing was reduced by weekly increments of 200 mg/day) was required for patients who chose not to enroll in the open-label extension trial of VIMPAT® or who did not complete the Titration or Maintenance Phases.1-3 A Baseline seizure frequency of =4 partial-onset seizures per 28 days on average was deemed sufficiently high to detect both decreases and increases in seizure frequency. An 8-week Baseline Phase was considered necessary to adequately assess Baseline seizure frequency due to spontaneous fluctuations of seizure frequency in this subject population. Furthermore, the duration of the Maintenance Phase (12 weeks) was chosen due to regulatory guidance (European Medicines Agency [EMEA]) that suggests a 12-week Maintenance Phase has adequate duration to evaluate efficacy.1-3 Two primary variables were defined in each of these trials. For the US FDA, the primary variable was the change in partial seizure frequency per 28 days from Baseline to the Maintenance Phase. For the EMEA, the primary variable was the proportion of responders, or patients experiencing a =50% reduction in partial seizure frequency from Baseline to the Maintenance Phase.1-3 References: Study 1: Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308-1317. Study 2: Halász P, Kälviäinen R, Mazurkiewicz-Beldzinska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50:443-453. Study 3: Chung S, Sperling MR, Biton V, et al. Lacosamide as adjunctive therapy for partial-onset seizures: a randomized controlled trial. Epilepsia. 2010;51:958-967.

19. Median Percent Seizure Frequency Reduction from Baseline* (Per Protocol Set) Key Point: VIMPAT® significantly reduced median partial-onset seizure frequency per 28 days from baseline compared with placebo in the per protocol set, which is defined as patients who had =1 efficacy measurement during the Maintenance Phase and did not have a major protocol violation during the trial.1-3 The median reduction in seizure frequency was consistent for each dose across the 3 trials, with reductions of 33% and 35% for VIMPAT® 200 mg/day and 46%, 45%, and 40% for VIMPAT® 400 mg/day, all of which were statistically significant compared with placebo.1-3 For the intent-to-treat population of the 3 pivotal studies (Studies 1, 2, and 3, respectively), median percent seizure frequency reduction for patients treated with VIMPAT® 200 mg/day were 26% and 35%; with VIMPAT® 400 mg/day were 39%, 37%, and 36%; vs 10%, 21%, and 21% for those receiving placebo.1-3 Only 2 of the 3 treatment groups in Study 3 are shown on this slide; the clinical trial studied VIMPAT® doses of 400 mg/day and 600 mg/day vs placebo, but for purposes of this discussion, only the placebo and VIMPAT® 400 mg/day data are presented because that is the highest approved VIMPAT® dose in the US.3 Similarly, the VIMPAT® 600 mg/day data from Study 1 have been excluded.1 References: Study 1: Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308-1317. Study 2: Halász P, Kälviäinen R, Mazurkiewicz-Beldzinska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50:443-453. Study 3: Chung S, Sperling M, Biton V, et al. Lacosamide: efficacy and safety as oral adjunctive treatment in adults with partial-onset seizures. Poster presented at: 61st Annual American Epilepsy Society Meeting; November 30-December 4, 2007; Philadelphia, PA. Key Point: VIMPAT® significantly reduced median partial-onset seizure frequency per 28 days from baseline compared with placebo in the per protocol set, which is defined as patients who had =1 efficacy measurement during the Maintenance Phase and did not have a major protocol violation during the trial.1-3 The median reduction in seizure frequency was consistent for each dose across the 3 trials, with reductions of 33% and 35% for VIMPAT® 200 mg/day and 46%, 45%, and 40% for VIMPAT® 400 mg/day, all of which were statistically significant compared with placebo.1-3 For the intent-to-treat population of the 3 pivotal studies (Studies 1, 2, and 3, respectively), median percent seizure frequency reduction for patients treated with VIMPAT® 200 mg/day were 26% and 35%; with VIMPAT® 400 mg/day were 39%, 37%, and 36%; vs 10%, 21%, and 21% for those receiving placebo.1-3 Only 2 of the 3 treatment groups in Study 3 are shown on this slide; the clinical trial studied VIMPAT® doses of 400 mg/day and 600 mg/day vs placebo, but for purposes of this discussion, only the placebo and VIMPAT® 400 mg/day data are presented because that is the highest approved VIMPAT® dose in the US.3 Similarly, the VIMPAT® 600 mg/day data from Study 1 have been excluded.1 References: Study 1: Ben-Menachem E, Biton V, Jatuzis D, et al. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308-1317. Study 2: Halász P, Kälviäinen R, Mazurkiewicz-Beldzinska M, et al. Adjunctive lacosamide for partial-onset seizures: efficacy and safety results from a randomized controlled trial. Epilepsia. 2009;50:443-453. Study 3: Chung S, Sperling M, Biton V, et al. Lacosamide: efficacy and safety as oral adjunctive treatment in adults with partial-onset seizures. Poster presented at: 61st Annual American Epilepsy Society Meeting; November 30-December 4, 2007; Philadelphia, PA.

20. Vimpat-Side Effects Side Effects dizziness headache nausea vomiting double vision blurred vision walking difficulty drowsiness diarrhea fall unintentional rapid eye movement tremor

21. Vimpat: most common side effects Vomiting, Nausea, Drowsiness, Tremor, Dizziness, Blurred or double vision, Headaches

22. How do I take Vimpat? Usually your doctor will tell you to take Vimpat two times a day. Your doctor will start you on low dose of Vimpat and gradually increase your dose. Vimpat can be taken with food or without food. However, try to take in the same manner and at the same time every day.

23. Vimpat: Dosing Oral VIMPAT® is available in 50-mg, 100-mg, 150-mg, and 200-mg tablets Therapeutic doses are 200-400 mg/day Key Point: The initial dose of VIMPAT® should be 50 mg BID (100 mg/day). The dose can be increased at weekly intervals by 100 mg/day, given as 2 divided doses, up to the recommended maintenance dose of 200 to 400 mg/day, based on individual patient response and tolerability. In clinical trials, the 600-mg daily dose was not more effective than the 400-mg daily dose and was associated with a substantially higher rate of adverse reactions. VIMPAT® can be taken with or without food; food does not affect the rate and extent of absorption. No dose adjustment is necessary based on age, gender, or race. Tablets shown on slide are not actual size. Key Point: The initial dose of VIMPAT® should be 50 mg BID (100 mg/day). The dose can be increased at weekly intervals by 100 mg/day, given as 2 divided doses, up to the recommended maintenance dose of 200 to 400 mg/day, based on individual patient response and tolerability. In clinical trials, the 600-mg daily dose was not more effective than the 400-mg daily dose and was associated with a substantially higher rate of adverse reactions. VIMPAT® can be taken with or without food; food does not affect the rate and extent of absorption. No dose adjustment is necessary based on age, gender, or race. Tablets shown on slide are not actual size.

24. Vimpat for injection Key Point: VIMPAT® can be initiated as either oral or intravenous therapy and is easily converted between these 2 formulations. The initial total daily intravenous dosage of VIMPAT® should be equivalent to the total daily dosage and frequency of oral VIMPAT®. At the end of the intravenous treatment period, the patient may be switched to VIMPAT® oral administration at the equivalent daily dosage and frequency of the intravenous administration. After intravenous administration, Cmax is reached at the end of infusion, the rate of which is 30 to 60 minutes. For example, patients prescribed VIMPAT® injection 200 mg BID would receive 20 mL (200 mg) infused over a minimum of 30 minutes twice daily. Although VIMPAT® injection does not require dilution, the following diluents are approved for use with VIMPAT® injection: sodium chloride injection 0.9% (w/v), dextrose injection 5% (w/v), and lactated Ringer's injection. VIMPAT® injection has not been evaluated with any other diluents. Any unused portion of VIMPAT® injection should be discarded. Key Point: VIMPAT® can be initiated as either oral or intravenous therapy and is easily converted between these 2 formulations. The initial total daily intravenous dosage of VIMPAT® should be equivalent to the total daily dosage and frequency of oral VIMPAT®. At the end of the intravenous treatment period, the patient may be switched to VIMPAT® oral administration at the equivalent daily dosage and frequency of the intravenous administration. After intravenous administration, Cmax is reached at the end of infusion, the rate of which is 30 to 60 minutes. For example, patients prescribed VIMPAT® injection 200 mg BID would receive 20 mL (200 mg) infused over a minimum of 30 minutes twice daily. Although VIMPAT® injection does not require dilution, the following diluents are approved for use with VIMPAT® injection: sodium chloride injection 0.9% (w/v), dextrose injection 5% (w/v), and lactated Ringer's injection. VIMPAT® injection has not been evaluated with any other diluents. Any unused portion of VIMPAT® injection should be discarded.

25. Pregabalin / Lyrica

26. Lyrica indications Adjunctive therapy for adult patients with partial onset seizures Management of fibromyalgia, painful diabetic neuropathy, and postherpetic neuralgia

27. Pregabalin / Lyrica Generic Name: Pregabalin (pre-GA-ba-lin) Used to Treat: epilepsy Seizure Type: Partial seizures (all types) No labs, no levels required Low potential for drug interactions Forms of the medicine: Pill Dosing: 150 mg. - 600 mg.

28. Pregabalin / Lyrica No labs, no levels required Low potential for drug interactions

30. Lyrica- side effects Blurred or double vision, Dry mouth, Sleepiness, Difficulty concentrating, Dizziness, Swelling of hands and feet, Weight gain, Drowsiness

31. How do I take Lyrica? Lyrica is taken by mouth two to three times a day. It may or may not be taken with food. However, try to take it at the same time and in the same manner every day. Your doctor will probably start you on a low dose of Lyrica and may gradually increase your dose during the first week of treatment.

32. Speaker Points Pregabalin is available in 8 different strengths to maximize dosing flexibility Background Approved total daily dosage ranges: Partial onset seizures: 150 to 600 mg/day in 2 or 3 divided doses Painful DPN: 150 to 300 mg/day in 3 divided doses PHN: 150 to 600 mg/day in 2 or 3 divided doses Speaker Points Pregabalin is available in 8 different strengths to maximize dosing flexibility Background Approved total daily dosage ranges: Partial onset seizures: 150 to 600 mg/day in 2 or 3 divided doses Painful DPN: 150 to 300 mg/day in 3 divided doses PHN: 150 to 600 mg/day in 2 or 3 divided doses

33. Rufinamide/Banzel

34. Rufinamide / Banzel Banzel (BAN-zel) is the brand name for the seizure medicine rufinamide (ru-FIN-a-mide). Banzel is usually used as an add-on treatment to control seizures associated with Lennox-Gastaut syndrome, which is a severe form of epilepsy. Banzel is taken orally and is available in 200mg and 400 mg film-coated tablets.

35. Rufinamide / Banzel Generic Name: Rufinamide ((ru-FIN-a-mide)) Used to Treat: Seizures associated with Lennox-Gastaut syndrome 4 years and older Seizure Type: Myoclonic, Absence Seizures, Drop Attacks, Lennox-Gastaut Syndrome Forms of the medicine: 200mg and 400 mg tablets

36. Banzel -Side Effects drowsiness vomiting headache fatigue loss of appetite dizziness irritability attention difficulty itchiness stomach pain

37. Banzel- most common side effects Dizziness, Fatigue, Difficulty concentrating, Vomiting, Irritability, Drowsiness, Appetite loss, Headaches

38. How do I take Banzel? Usually your doctor will tell you to take Banzel two times a day. Your doctor will start you on low dose of Banzel and gradually increase your dose. To precisely adjust dose, tablet can be taken whole, as half tablets or crushed. Banzel is absorbed better when taken with food so it is usually taken with a meal. Banzel is not for the people who have Familial Short QT syndrome, which is a rare familial disease of abnormal heart rhythm. If you or your family member have a heart rhythm problem, discuss with your doctor before taking Banzel so that your doctor could check your heart rhythm with an electrocardiogram (EKG).

39. Vigabatrin/Sabril

40. Vigabatrin /Sabril Generic Name: Vigabatrin(FOR ADULTS) (vie-GAB-a-trin) Used to Treat: Complex partial seizures, when benefits outweigh risks Seizure Type: Complex partial Forms of the medicine: Tablet Dosing: 1000 mg/day as 500 mg tablets taken twice daily which may be increased by 500 mg increments at weekly intervals depending on response

41. Sabril/ Vigabatrin Sabril® (vigabatrin) was approved by the FDA in August 2009 as add-on therapy for adults with complex partial seizures (CPS) whose seizures remain uncontrolled despite treatment with other therapies and for whom the potential benefits outweigh the risk of vision loss. Sabril is not indicated as a first line agent for adults with CPS. Sabril® (vigabatrin) was approved by the FDA as monotherapy for children one month to two years of age with infantile spasms (IS) where the potential benefits outweigh the risk of vision loss.

42. Sabril- Side effects Black Box Warning Label:   VISION LOSS Sabril causes progressive and permanent bilateral concentric visual field constriction in a high percentage of patients. In some cases, Sabril may also reduce visual acuity. Risk increases with total dose and duration of use, but no exposure to Sabril is known that is free of risk of vision loss. Risk of new and worsening vision loss continues as long as Sabril is used, and possibly after discontinuing Sabril. Periodic vision testing is required for patients on Sabril, but cannot reliably prevent vision damage. Because of the risk of permanent vision loss, Sabril is available only through a special restricted distribution program.

43. New Formulations: Extended Release

44. Lamotrigine Lamictal XR

45. Indication for LAMICTAL XR LAMICTAL XR is indicated as adjunctive therapy for primary generalized tonic-clonic (PGTC) seizures and partial onset seizures with or without secondary generalization in patients =13 years of age. The safety and effectiveness of LAMICTAL XR for use in patients below the age of 13 have not been established. LAMICTAL XR is indicated as adjunctive therapy for primary generalized tonic-clonic seizures and partial onset seizures with or without secondary generalization in patients 13 years of age and older. The safety and effectiveness of LAMICTAL XR for use in patients below the age of 13 have not been established.LAMICTAL XR is indicated as adjunctive therapy for primary generalized tonic-clonic seizures and partial onset seizures with or without secondary generalization in patients 13 years of age and older. The safety and effectiveness of LAMICTAL XR for use in patients below the age of 13 have not been established.

46. Lamotrigine extended release Lamictal XR Lamictal XR (La-MIC-tal) is the brand name for the seizure medicine lamotrigine (la-MO-tri-geen).  Lamotrigine is used in the treatment of partial-onset and generalized tonic-clonic seizures.  XR stands for “extended release,” which means slow release and slow absorption of medicine after someone swallows it.  This feature allows patients to take the medicine less frequently, usually once a day.  Lamictal XR is usually used in combination with other medications.  Lamictal XR is manufactured in the form of tablets which gradually release medication.

47. Lamictal XR The primary endpoint, median percent change from baseline in average weekly partial seizure frequency, was approximately two-fold higher with LAMICTAL XR (47%) than with placebo (25%) throughout the double-blind treatment (Escalation and Maintenance). Reference: Naritoku DK, Warnock CR, Messenheimer JA, et al. Lamotrigine extended-release as adjunctive therapy for partial seizures [published correction appears in Neurology. 2009;72:201]. Neurology. 2007;69:1610–1618.The primary endpoint, median percent change from baseline in average weekly partial seizure frequency, was approximately two-fold higher with LAMICTAL XR (47%) than with placebo (25%) throughout the double-blind treatment (Escalation and Maintenance). Reference: Naritoku DK, Warnock CR, Messenheimer JA, et al. Lamotrigine extended-release as adjunctive therapy for partial seizures [published correction appears in Neurology. 2009;72:201]. Neurology. 2007;69:1610–1618.

48. LAMICTAL XR Significantly Reduced Seizure Frequency vs Placebo in Patients With Uncontrolled Primary Generalized Tonic-Clonic Seizures The primary endpoint, the median percent change from baseline in average weekly primary generalized tonic-clonic seizure frequency during double-blind treatment (Escalation + Maintenance phases), was a 75% reduction in patients treated with LAMICTAL XR and a 32% reduction in patients treated with placebo, a difference that was statistically significant (defined as a 2-sided P value <0.05). References: LAMICTAL XR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010. Data on file, GlaxoSmithKline.The primary endpoint, the median percent change from baseline in average weekly primary generalized tonic-clonic seizure frequency during double-blind treatment (Escalation + Maintenance phases), was a 75% reduction in patients treated with LAMICTAL XR and a 32% reduction in patients treated with placebo, a difference that was statistically significant (defined as a 2-sided P value <0.05). References: LAMICTAL XR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010. Data on file, GlaxoSmithKline.

49. Lamictal XR Generic Name: Extended Release Lamotrigine (lah-moh-tra-jean) Seizure Type: Partial and Generalized Forms of the medicine: pill Dosing: gradual increase

50. Lamictal XR – side effects Ataxia, Blurred or double vision, Sleepiness, Skin rashes, Dizziness, Nausea, Headaches, Clumsiness, Drowsiness, Insomnia, Fatigue, Upset stomach, Vomiting, Difficulty concentrating

51. Rash Factors that may increase the risk of serious rash include: coadministration with valproate exceeding recommended initial dose of Lamictal XR exceeding recommended dose escalation of Lamictal XR

52. How do I take Lamictal XR? Since Lamictal XR tablets are specially coated for slow absorption, they should be swallowed whole.  Do not chew, break, or crush tablets.  Lamictal XR is usually taken once a day.  It may or may not be taken with food. Your doctor will start you on low dose of lamotrigine and gradually increase your dose, not more than once every 1-2 weeks. .

53. LAMICTAL XR (lamotrigine) Modified-release eroding formulation as core Clear enteric coat and aperture drilled through coat on both faces of tablet (DiffCORE™) Results in controlled release of drug in acidic environment of stomach Dissolution rate over approximately 12 to 15 hours, leading to gradual increase in serum lamotrigine levels LAMICTAL XR Extended-release Tablets contain a modified-release eroding formulation as the core. The tablets are coated with a clear enteric coat and have an aperture drilled through the coat on both faces of the tablet (DiffCORE™) to enable controlled release of the drug in the acidic environment of the stomach. The combination of this and the modified-release core are designed to control the dissolution rate of lamotrigine over a period of approximately 12 to 15 hours, leading to a gradual increase in serum lamotrigine levels.LAMICTAL XR Extended-release Tablets contain a modified-release eroding formulation as the core. The tablets are coated with a clear enteric coat and have an aperture drilled through the coat on both faces of the tablet (DiffCORE™) to enable controlled release of the drug in the acidic environment of the stomach. The combination of this and the modified-release core are designed to control the dissolution rate of lamotrigine over a period of approximately 12 to 15 hours, leading to a gradual increase in serum lamotrigine levels.

54. Conversion from LAMICTAL to LAMICTAL XR: LAMICTAL XR Reduces Peak-Trough Variability According to the results of the pharmacokinetic analyses, the Neutral group showed less fluctuation in serum lamotrigine after administration of LAMICTAL XR than after administration of LAMICTAL. Reference: Tompson DJ, Ali I, Oliver-Willwong R, et al. Steady-state pharmacokinetics of lamotrigine when converting from a twice-daily immediate-release to a once-daily extended-release formulation in subjects with epilepsy (The COMPASS Study). Epilepsia. 2008;49:410–417.According to the results of the pharmacokinetic analyses, the Neutral group showed less fluctuation in serum lamotrigine after administration of LAMICTAL XR than after administration of LAMICTAL. Reference: Tompson DJ, Ali I, Oliver-Willwong R, et al. Steady-state pharmacokinetics of lamotrigine when converting from a twice-daily immediate-release to a once-daily extended-release formulation in subjects with epilepsy (The COMPASS Study). Epilepsia. 2008;49:410–417.

55. A new 50-mg strength is available for LAMICTAL XR. To reduce the potential for medication errors, each LAMICTAL XR tablet has a distinct color and white center, and is printed with “LAMICTAL XR” and the tablet strength.A new 50-mg strength is available for LAMICTAL XR. To reduce the potential for medication errors, each LAMICTAL XR tablet has a distinct color and white center, and is printed with “LAMICTAL XR” and the tablet strength.

56. Lamictal XR (lamotrigine): LAMICTAL XR offers convenience for patients who are new to LAMICTAL or for patients converting from LAMICTAL. For patients looking to add LAMICTAL XR to their treatment regimen, LAMICTAL XR can be initiated using the same 5-week titration schedule as LAMICTAL Tablets. Free 5-week Patient Titration Kits make titration simple to follow. For patients looking to convert, there is a simple 1:1 conversion from LAMICTAL Tablets to new LAMICTAL XR. LAMICTAL XR will continue to maintain trough serum concentrations (Cmin) of lamotrigine following conversion to LAMICTAL XR. Following conversion to LAMICTAL XR, all patients (but especially those on an enzyme-inducing AED) should be closely monitored for seizure control. LAMICTAL XR offers convenience for patients who are new to LAMICTAL or for patients converting from LAMICTAL. For patients looking to add LAMICTAL XR to their treatment regimen, LAMICTAL XR can be initiated using the same 5-week titration schedule as LAMICTAL Tablets. Free 5-week Patient Titration Kits make titration simple to follow. For patients looking to convert, there is a simple 1:1 conversion from LAMICTAL Tablets to new LAMICTAL XR. LAMICTAL XR will continue to maintain trough serum concentrations (Cmin) of lamotrigine following conversion to LAMICTAL XR. Following conversion to LAMICTAL XR, all patients (but especially those on an enzyme-inducing AED) should be closely monitored for seizure control.

57. Levetiracetam Keppra XR

58. Keppra XR™ Indication Adjunctive therapy in the treatment of partial onset seizures in patients =16 years of age with epilepsy Key Point: Keppra XR™ is indicated as adjunctive therapy in the treatment of partial onset seizures in patients =16 years of age with epilepsy. Reference: Keppra XR™ (levetiracetam) extended-release tablets [prescribing information]. Smyrna, GA: UCB, Inc., September 2008. Key Point: Keppra XR™ is indicated as adjunctive therapy in the treatment of partial onset seizures in patients =16 years of age with epilepsy. Reference: Keppra XR™ (levetiracetam) extended-release tablets [prescribing information]. Smyrna, GA: UCB, Inc., September 2008.

59. Levetiracetam/ Keppra Approved in 1999 Multiple additional indications since 2003 IV formulation approved in 2006 Extended release formulation approved in 2008

60. Keppra XR Generic Name: Extended Release Levetiracetam (lev-eh-turr-RASS-ih-tam) Used to Treat: epilepsy Seizure Type: Generalized seizures (all types) Forms of the medicine: pill Dosing: 1000 mg - 3000 mg

61. Partial Onset Seizure Frequency Key Point: The median percentage reductions in partial onset seizure frequency per week over the treatment period from baseline in the ITT population were 46.1% in the Keppra XR™ group vs 33.4% in the placebo group. In the Keppra XR™ arm, partial onset seizure frequency per week decreased from 1.80 at baseline to 0.99 at the end of the 12-week treatment period, whereas in the placebo arm, the same measure decreased from 2.11 at baseline to 1.36 at the end of the treatment period. In the ITT population, more than 10% of the subjects in the placebo group and in the Keppra XR™ group had major protocol deviations. Deviations in the intake/number of concomitant AEDs taken were the most frequent deviations observed. As a result, efficacy analyses were conducted on both the ITT and PP populations. The primary efficacy analysis on the ITT population, conducted using log transformed data, indicated that the relative reduction in partial onset seizure frequency per week over the treatment period from baseline was 14.4% in a comparison of Keppra XR™ with placebo (P=0.038). The efficacy analysis on the PP population confirmed that the percent reduction of 18.6% in partial onset seizure frequency per week over the treatment period from baseline with Keppra XR™ over placebo is statistically significant (P=0.003). Reference: Peltola J, Coetzee C, Jiménez F, et al. Once-daily extended-release levetiracetam as adjunctive treatment of partial-onset seizures in patients with epilepsy: a double-blind, randomized, placebo-controlled trial. Epilepsia. In Press. Key Point: The median percentage reductions in partial onset seizure frequency per week over the treatment period from baseline in the ITT population were 46.1% in the Keppra XR™ group vs 33.4% in the placebo group. In the Keppra XR™ arm, partial onset seizure frequency per week decreased from 1.80 at baseline to 0.99 at the end of the 12-week treatment period, whereas in the placebo arm, the same measure decreased from 2.11 at baseline to 1.36 at the end of the treatment period. In the ITT population, more than 10% of the subjects in the placebo group and in the Keppra XR™ group had major protocol deviations. Deviations in the intake/number of concomitant AEDs taken were the most frequent deviations observed. As a result, efficacy analyses were conducted on both the ITT and PP populations. The primary efficacy analysis on the ITT population, conducted using log transformed data, indicated that the relative reduction in partial onset seizure frequency per week over the treatment period from baseline was 14.4% in a comparison of Keppra XR™ with placebo (P=0.038). The efficacy analysis on the PP population confirmed that the percent reduction of 18.6% in partial onset seizure frequency per week over the treatment period from baseline with Keppra XR™ over placebo is statistically significant (P=0.003). Reference: Peltola J, Coetzee C, Jiménez F, et al. Once-daily extended-release levetiracetam as adjunctive treatment of partial-onset seizures in patients with epilepsy: a double-blind, randomized, placebo-controlled trial. Epilepsia. In Press.

62. Matrix technology Levetiracetam extended-release 500-mg tablet for oral administration Matrix technology White, oblong, film-coated, non-scored tablet Tablet Size: XR 500, XR 750 mg The tablet shown is actual size if the slide is printed (the image is 1:1 scale and has not been resized). Inactive ingredients are: Colloidal anhydrous silica Hypromellose Magnesium stearate Polyethylene glycol 6000 Polyvinyl alcohol – partially hydrolyzed Titanium dioxide Macrogol/PEG3350 TalcThe tablet shown is actual size if the slide is printed (the image is 1:1 scale and has not been resized). Inactive ingredients are: Colloidal anhydrous silica Hypromellose Magnesium stearate Polyethylene glycol 6000 Polyvinyl alcohol – partially hydrolyzed Titanium dioxide Macrogol/PEG3350 Talc

63. Pharmacokinetics

64. How do I take Keppra XR? Since Keppra XR tablets are specially coated for slow absorption, it should be swallowed whole.  Do not chew, break, or crush tablets.  Keppra XR is usually taken once a day.  It may or may not be taken with food.  However, try to take Keppra XR at the same time and manner every day.  .

65. In the clinical study of Levetiracetam extended-release tablets Initial dose: 1000 mg QD No titration Dose administered at same time daily “Do not break, crush or chew”

66. Keppra XR: Side Effects Vomiting, Sleepiness, Weakness, Fatigue, Appetite loss, Poor coordination, Headaches, Dizziness

67. Dosage and Administration Flexible dosing Can be taken during the day or at night, with or without food Should be taken at the same time every day or night Key Point: The effective starting dose of Keppra XR™ is 1000 mg once daily (2 x 500-mg tablets), without titration. If needed, the daily dosage of Keppra XR™ may be increased by 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg. (The 2-week timeframe is based on immediate-release Keppra® data; there was no titration in the Keppra XR™ study.) If a dose is missed, the next dose should not be doubled to make up for the missed dose. If only a few hours have passed since the missed dose, patients should take Keppra XR™ as soon as remembered and then return to their regular dosing schedule. If it is almost time for the next dose, patients should skip the missed dose and resume their regular schedule. Keppra XR™ employs a proprietary matrix design to delay the exit of the active molecule from the tablet to achieve an extended release of the medication. Tablets should not be chewed, broken, or crushed. Keppra XR™ can be taken with or without food, and it can be taken either during the day or at night; patients should be encouraged to take Keppra XR™ at the same time every day or night. Reference: Keppra XR™ (levetiracetam) extended-release tablets [prescribing information]. Smyrna, GA: UCB, Inc., September 2008. Key Point: The effective starting dose of Keppra XR™ is 1000 mg once daily (2 x 500-mg tablets), without titration. If needed, the daily dosage of Keppra XR™ may be increased by 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg. (The 2-week timeframe is based on immediate-release Keppra® data; there was no titration in the Keppra XR™ study.) If a dose is missed, the next dose should not be doubled to make up for the missed dose. If only a few hours have passed since the missed dose, patients should take Keppra XR™ as soon as remembered and then return to their regular dosing schedule. If it is almost time for the next dose, patients should skip the missed dose and resume their regular schedule. Keppra XR™ employs a proprietary matrix design to delay the exit of the active molecule from the tablet to achieve an extended release of the medication. Tablets should not be chewed, broken, or crushed. Keppra XR™ can be taken with or without food, and it can be taken either during the day or at night; patients should be encouraged to take Keppra XR™ at the same time every day or night. Reference: Keppra XR™ (levetiracetam) extended-release tablets [prescribing information]. Smyrna, GA: UCB, Inc., September 2008.

68. On the Horizon…. Brivaracetam Eslicarbazepine Ezogabine (retigabine)

69. Brivaracetam

70. Eslicarbazepine

71. Ezogabine

72. www.efa.org ; www.efmn.org

73. ANTI-EPILEPTIC DRUGS Carbamazepine (Tegretol, Carbatrol) Phenytoin (Dilantin) Valproate (Depakote) Phenobarbital Felbamate (Felbatol) Gabapentin (Neurontin) Lacosamide (Vimpat) Lamotrigine (Lamictal,LamictalXR Levetiracetam (Keppra,KeppraXR) Oxcarbazepine (Trileptal) Pregabalin (Lyrica) Rufinamide (Banzel) Tiagabine (Gabatril) Topiramate (Topamax) Vigabatrin (Sabril) Zonisamide (Zonegran)

74. Medications: New and What’s on the Horizon

75. Factors in selecting AEDs Age Sex Efficacy/Effectiveness Tolerability/Side Effects Cost/Formulary Access Generic Comorbidities

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