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Medications: New and What’s on the Horizon
Joanne B. Rogin, M.D.
Professional Advisory Board, Epilepsy Foundation of MN
Midwest Center for Seizure DisordersMinneapolis Clinic of NeurologyClinical Professor of Neurology,
University of Minnesota
Anti-Epileptic Drugs
Carbamazepine/Tegretol Phenytoin/Dilantin
PhenobarbitalValproate/Depakote
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)
Why do we need
new drugs?
No seizures
and
no side effects!
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
Asconape JJ. Semin Neurol. 2002;22:27-39; Willmore LJ et al. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2006:735-745; Bourgeois BFD. In: Wyllie E, ed. The Treatment of Epilepsy: Principles and Practice. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2006:655-664.
New and Improved Antiepileptic Drugs
• Lacosamide - Vimpat
• Pregabalin – Lyrica
• Rufinamide – Banzel
• Vigabatrin-Sabril
• KeppraXR
• LamictalXR
Coming Attractions
• Brivaracetam
• Eslicarbazepine
• Ezogabine
Seizures
Seizures vs.
Epilepsy
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%
International Classification of Seizures
• Partial Seizures
• Generalized Seizures
• Unclassified Epileptic Seizures
• Status Epilepticus
Generalized Seizures
• Absence
• Tonic-Clonic
• Clonic-Tonic-Clonic
• Clonic
• Myoclonic
• Atonic (drop attack)
• Tonic
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
Lacosamide / Vimpat
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
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
Study 2 – Phase III (N=477)VIMPAT® 200, 400 mg/day
*600 mg/day is not an approved dose; data on this dosage are not included in the presentation.†Studies 1 and 3: 6-week titration phase. Study 2: 4-week titration phase. One 100-mg dose reduction allowed at end of titration phase.
Titration†Baseline
Study 1 – Phase II (N=415)VIMPAT® 200, 400, 600* mg/day
Study 3 – Phase III (N=402)VIMPAT® 400, 600* mg/day
Maintenance
8 wks 12 wks 2−3 wks
Ratio1:1:1:1
Ratio1:1:1
Transition/taper
Study 1: Ben-Menachem E, et al. Epilepsia. 2007;48:1308-1317. Study 2: Halász P, et al. Epilepsia. 2009;50:443-453.Study 3: Chung S, et al. Epilepsia. 2010;51:958-967.Please see your UCB sales representative for full prescribing information.
Ratio1:2:1
Clinical Trial Designs
Phase II/III Clinical Trials Assessed the Efficacy and Safety of VIMPAT® as
Adjunctive Therapy
0
20
40
60
Study 1 Study 2 Study 3
Current Therapy + Placebo
Current Therapy + VIMPAT 200 mg/day
Current Therapy + VIMPAT 400 mg/day
Median Percent Seizure Frequency Reduction from Baseline*
(Per Protocol Set)
Med
ian
Red
uct
ion
(%
)
12%
22%
33%
46%
†
‡ †
40%35%
†45%
25%
†
For the intent-to-treat population of the 3 pivotal studies (Studies 1, 2, and 3, respectively), median 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 VIMPATpercent seizure frequency reduction for patients treated with VIMPAT®® 200 mg/day were 26% and 35%; 200 mg/day were 26% and 35%; with VIMPATwith VIMPAT®® 400 mg/day were 39%, 37%, and 36%; vs 10%, 21%, and 21% for those receiving placebo 400 mg/day were 39%, 37%, and 36%; vs 10%, 21%, and 21% for those receiving placebo
*Per 28 days from baseline to maintenance; †P<0.05 vs placebo; ‡P<0.01 vs placebo; P values based on log-transformed data from pairwise treatment using ANCOVA models. Per protocol set=patients who had ≥1 efficacy measurement during the Maintenance Phase and did not have a major protocol violation during the trial.
Study 1: Ben-Menachem E, et al. Epilepsia. 2007;48:1308-1317. Study 2: Halász P, et al. Epilepsia. 2009;50:443-453. Study 3: Chung S, et al. Poster presented at: 61st Annual American Epilepsy Society Meeting; November 30-December 4, 2007; Philadelphia, PA.. Please see your UCB sales representative for full prescribing information.
(N=248) (N=339) (N=227)
®
®
Vimpat-Side Effects
• Side Effects• dizziness • headache • nausea • vomiting • double vision • blurred vision • walking difficulty • drowsiness • diarrhea • fall • unintentional rapid eye movement • tremor
Vimpat: most common side effects
• Vomiting, Nausea, Drowsiness, Tremor, Dizziness, Blurred or double vision, Headaches
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.
Vimpat: Dosing
• Oral VIMPAT® is available in 50-mg, 100-mg, 150-mg, and 200-mg tablets
• Therapeutic doses are 200-400 mg/day
Vimpat for injection
.
Pregabalin / Lyrica
Lyrica indications
• Adjunctive therapy for adult patients with partial onset seizures
• Management of fibromyalgia, painful diabetic neuropathy, and postherpetic neuralgia
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.
Pregabalin / Lyrica
• No labs, no levels required
• Low potential for drug interactions
Lyrica- side effects
• Blurred or double vision, Dry mouth, Sleepiness, Difficulty concentrating, Dizziness, Swelling of hands and feet, Weight gain, Drowsiness
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.
Rufinamide/Banzel
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.
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
Banzel -Side Effects
• drowsiness • vomiting • headache • fatigue • loss of appetite • dizziness • irritability • attention difficulty • itchiness • stomach pain
Banzel- most common side effects
• Dizziness, Fatigue, Difficulty concentrating, Vomiting, Irritability, Drowsiness, Appetite loss, Headaches
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).
Vigabatrin/Sabril
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
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.
Sabril- Side effects
•Black Box Warning Label: VISION LOSS
• Sabril causes progressive and permanent bilateral concentric visual field constriction in ahigh 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 thatis free of risk of vision loss.
• Risk of new and worsening vision loss continues as long as Sabril is used, and possiblyafter discontinuing Sabril.
• Periodic vision testing is required for patients on Sabril, but cannot reliably prevent visiondamage.
• Because of the risk of permanent vision loss, Sabril is available only through a specialrestricted distribution program.
New Formulations:Extended Release
Lamotrigine Lamictal XR
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.
45
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.
Lamictal XRLamictal XR
P =0.0001
Naritoku DK et al. [published correction appears in Neurology. 2009;72:201]. Neurology. 2007;69:1610–1618.
n = 116 n = 120
Significant decrease in frequency of partial seizuresM
edia
n %
Red
uct
ion
F
rom
Bas
elin
e
47%
25%
0
20
40
60
Escalation +Maintenance
LAMICTAL XR
Placebo
LAMICTAL XR Significantly Reduced Seizure Frequency vs Placebo in Patients With Uncontrolled Primary Generalized Tonic-Clonic Seizures
*2-sided P value.
75%
32%
0
20
40
60
80
100
Double-Blind Treatment Period (Escalation + Maintenance)
Med
ian
Perc
ent
Redu
ction
From
Bas
elin
e
LAMICTAL XR
Placebo
P < 0.05*
n = 69 n = 72
48LAMICTAL XR [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2010.Data on file, GlaxoSmithKline.
(Primary Endpoint)
Lamictal XR
• Generic Name: Extended Release Lamotrigine (lah-moh-tra-jean)
• Seizure Type: Partial and Generalized
• Forms of the medicine: pill
• Dosing: gradual increase
Lamictal XR – side effects
• Ataxia, Blurred or double vision, Sleepiness, Skin rashes, Dizziness, Nausea, Headaches, Clumsiness, Drowsiness, Insomnia, Fatigue, Upset stomach, Vomiting, Difficulty concentrating
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
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.
• .
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
Aperture
Enteric coating
Subcoat
Vertical Cross Section
Modified-release core
Conversion from LAMICTAL to LAMICTAL XR:Conversion from LAMICTAL to LAMICTAL XR:LAMICTAL XRLAMICTAL XR Reduces Peak-Trough Variability Reduces Peak-Trough Variability
0
1
2
3
4
5
6
7
8
9
0 2 4 6 8 10 12 14 16 18 20 22 24
Time postdose (h)
LAMICTAL (BID)
LAMICTAL XR (QD)
La
mo
trig
ine
se
rum
c
on
ce
ntr
ati
on
(μ
g/m
L)
Group 1 (Neutral): Median serum lamotrigine concentration-time profiles for steady-state LAMICTAL and LAMICTAL XR*
Tompson DJ et al. Epilepsia. 2008;49:410–417.
*Clinical significance of these data is unknown. The relationship between these results and efficacy has not been evaluated.
Dosage Strengths: LAMICTAL® XR™ (lamotrigine) Extended-
Release Tablets
25 mg 100 mg 200 mg
There is no AB-rated generic for LAMICTAL XR1
1. US Department of Health and Human Services. Food and Drug Administration. Electronic Orange Book. http://www.fda.gov/cder/ob/default.htm. Accessed June 2, 2009.
Please consult complete Prescribing Information including Boxed Warning for LAMICTAL XR.
50 mg
Lamictal XR (lamotrigine):
.
Levetiracetam Keppra XR
Keppra XR™ Indication
• Adjunctive therapy in the treatment of partial onset seizures in patients ≥16 years of age with epilepsy
Keppra XR™ (levetiracetam) extended-release tablets [prescribing information]. Smyrna, GA: UCB, Inc., September 2008.
Levetiracetam/ Keppra
• Approved in 1999
• Multiple additional indications since 2003
• IV formulation approved in 2006
• Extended release formulation approved in 2008
1 Lynch et al, PNAS 2004; 101:9861–6. 2. Wolters Kluwers Health retail Pharmacy Database, Dec 2006
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
33%
46%
0
10
20
30
40
50
Keppra XR Placebo
Me
dia
n r
ed
uc
tio
n (
%)
Partial Onset Seizure Frequency
™
Median Reduction in Partial Onset Seizure FrequencyOver the 12-week Treatment Period*
*Intention-to-treat (ITT) population; P<0.05 vs placebo.Peltola J, et al. Epilepsia. In Press.
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
Pharmacokinetics
Cmax ~ 4 hrs vs 1 hr with IR
PK parameters Cmax, AUC within bioequivalence limits
Mean LEV Plasma Concentrations: Single Dose
Time (Hours)
LEV immediate release 500 mg BID (fasting)
LEV extended-release 2 x 500 mg QD (fasting)
LEV
Pla
sma
Con
cent
ratio
n (µ
g/m
L)
0 6 12 18 24 30 36 42 480
25
20
15
10
5
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.
• .
• 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”
Dosing
Keppra XR: Side Effects
• Vomiting, Sleepiness, Weakness, Fatigue, Appetite loss, Poor coordination, Headaches, Dizziness
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
.
On the Horizon….
• Brivaracetam
• Eslicarbazepine
• Ezogabine (retigabine)
Brivaracetam
Eslicarbazepine
Ezogabine
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)
Medications: New and What’s on the Horizon
Joanne B. Rogin, M.D.Midwest Center for Seizure Disorders
Minneapolis Clinic of NeurologyClinical Professor of Neurology,
University of Minnesota
Factors in selecting AEDs
• Age• Sex• Efficacy/Effectiveness• Tolerability/Side Effects• Cost/Formulary Access• Generic• Comorbidities
