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new formulations of antiepleptic drugs for the management of epilepsy

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					New Formulations of
Antiepileptic Drugs for
the Management of Epilepsy




                             1
Goals of Treatment for Epilepsy
•       Control of seizures
•       Minimal adverse events
•       Good patient compliance




    1. Marks & Garcia, 1998
    2. Chapman & Giles, 1997
    3. Garnett, 2000
                                  2
    AED Response – Established AEDs
    • Earlier studies suggested that many patients
      respond to monotherapy but fewer and fewer
      patients respond to combination therapy.
                                     70%
                                     controlled*
    Monotherapy                                          30% controlled* on
                                                         2 drugs
                                   30% poorly
                                   managed               Combinations of two or
                                                         more drugs provide little
                                                         more benefit
* Controlled was defined as adequately managed but not
necessarily seizure-free

      1. Mattson, 1992
                                                                                     3
   AED Response
   – Newer is Not Always Better
   • 525 untreated patients (470 drug-naïve)


                                    60% controlled*
    1st Monotherapy
                                                                    1% controlled*
    2nd   Monotherapy
                                                      3rd
                                    40%               Monotherapy
                                    difficult to
                                    control                         99% not
                                                                    controlled
*Controlled was defined as seizure-free


   • Only 3% were controlled with two AEDs, and none with
     three.
     1. Brodie & Kwan, 2002                                                      4
Newer AEDs
• Similar effectiveness to established AEDs in the
  treatment of partial seizures
• All AEDs have adverse effects1
• Not appropriate for all seizure types1
• Possible teratogenicity2
• Limited data available for efficacy and safety
• Most used as adjunctive therapy2


 1. Yoon & Jagoda, 2000
 2. Brodie & French, 2000
                                                 5
  CNS AEs with New AEDs
                                  Blurred    Cognitive
                        Ataxia    Vision      Effects    Dizziness   Drowsiness   Fatigue   Headache
  New AEDs

    Felbamate             +                                 +                       +          +

    Gabapentin            +                                 +            +          +          +

    Lamotrigine           +          +                      +            +                     +

    Levetiracetam                                           +            +          +

    Oxcarbazepine         +          +           +          +                       +          +

    Tiagabine                                    +          +                       +          +

    Topiramate            +                      +          +

    Vigabatrin            +                      +                       +          +          +

    Zonisamide            +                      +          +            +          +


                                                                                                   6
Chapman DP, et al. South Med J. 1997;90:L171-L180.
 Other AEs with New AEDs
 • Lamotrigine - not indicated for use in patients
   below the age of 16 years.
       – Rash is reported in 0.3% of adults and in 0.8% of
         children1
 • Topiramate
       – Cases of secondary angle closure glaucoma have
         been reported in pediatric and adult populations. If left
         untreated, serious sequelae, including permanent
         vision loss, may occur. 2
 • Levetiracetam
       – Cognitive and behavioral adverse events3
1.   Lamotrigine presrcibing information
2.   Topiramate prescribing information                          7

3.   Levetiracetam prescribing information
AEDs: Dose versus Tolerability
• Balance efficacy against side effects
• Sub-therapeutic doses may lead to
  breakthrough seizures
• High doses may lead to unwanted adverse
  effects and poor compliance
• Adjust the dose to achieve response for
  individual patients1,2
    – This may provide plasma levels higher or lower than
      normal therapeutic range
• Dosing intervals should be considered
 1. Browne & Holmes, 2001
 2. Marks & Garcia, 1998
                                                            8
Compliance in Epilepsy
• Successful treatment requires patient
  compliance1
• Noncompliance is the primary cause of
  breakthrough seizures
• Identify and address the reasons for
  noncompliance
• Compliance declines as number of daily doses
  increases
• Maximum compliance achieved at once-daily
  dosing1
 1. Garnett, 2000
                                                 9
Benefits of Extended-release AEDs
• Benefits of extended-release formulations
  include:
  – Fewer fluctuations in blood levels and hence
    improved seizure control and tolerability
  – Less frequent dosing
  – Improved compliance




                                                   10
Managing Patients on ER Formulations
• Extended-release formulations of AEDs improve
  tolerability and enhance compliance
• Flexibility in dosing AEDs simplifies regimens for
  patients
• Initiation is simple
• Switching from traditional formulations to
  extended-release formulations can be done
  overnight
• A slightly higher total daily dose of the extended-
  release formulation is usually necessary in order
  to maintain serum AED levels
                                                    11
Divalproex Sodium ER (extended
release) in Adults
• Approved for epilepsy in December 2002
  – 250 mg tablets
  – 500 mg tablets


• Divalproex sodium ER is indicated for multiple
  seizure types in adults

• Once-daily dosing
  – Broad-spectrum coverage of multiple seizure types

                                                        12
Divalproex Sodium ER Bioavailability in
Adult Epilepsy Patients
•        In a Phase I study of adult epilepsy patients,
         the bioavailability of the ER formulation given at
         8-20% higher dose once daily was the same as
         the bioavailability of the divalproex sodium
         formulation given Q8H




    1. Dutta et al, 2002
                                                         13
Pharmacokinetic Data
                                   Concentration–Time Profiles 875 Delayed release (DR)/ 1000
                                   Extended release (ER)
                             110
                             100
 VPA Concentration (µg/mL)




                              90
                              80
                              70
                              60
                              50
                              40
                              30                                         1000 mg ER (n=35)
                              20                                         825 mg DR (n=35)
                              10
                               0
                                   0   2   4   6   8   10    12    14    16    18   20       22   24
                                                            Time (hrs)
1. Dutta et al, 2002
                                                                                                       14
Divalproex Sodium ER Has Less
Fluctuation in Plasma Concentrations
• The degree of fluctuation in plasma
  concentrations is significantly less for divalproex
  sodium ER compared with divalproex sodium

                  Divalproex   Divalproex
                                            P-value
                   sodium      sodium ER
 Degree
                    0.790        0.641      <0.01
 of fluctuation




                                                      15
Divalproex Sodium ER Efficacy in Adults
•        Patients aged 12 to 65 years with generalized
         epilepsy
•        Patients were switched (equal doses mg for
         mg) from BID or TID divalproex sodium to the
         ER formulation in crossover study
•        All patients maintained seizure freedom for
         6 months
•        There was no statistically significant difference
         between the formulation groups for seizure
         control rate (95% for divalproex and 93% for
         extended-release divalproex).

    1. Thibault et al, 2002
                                                             16
Divalproex to Divalproex ER Conversion:
Impact on Effficacy and Adverse Events
• 20 patients with epilepsy, aged 5 to 75 years
   –   6 generalized tonic clonic
   –   12 complex partial
   –   1 primary generalized
   –   1 secondary partial
• After switching to divalproex sodium ER
   – Seizure control: maintained or improved
   – Tolerability improved
        • Reductions in tremor, nausea, somnolence
        • Subjective reports of less hair loss and less weight gain
        • Patients able to tolerate increased doses
   – Reduced number of daily doses leading to better compliance

                                                                      17
Divalproex to Divalproex ER Conversion:
Impact on Tremor and Weight Gain
• After conversion to
                                 100
  Depakote ER                     90
     – Reduced incidence of       80
       tremor (75-5%)             70
     – No additional weight       60
       gain                       50            Before
                                                After
     – Reduction in reports of    40
                                  30
       lethargy, ataxia and
                                  20
       hair loss
                                  10
     – Improved compliance         0
                                       Tremor

 1. Zielinski et al, 2001
                                                    18
Initiation of Divalproex Sodium ER
• Patients converting from immediate-release
  forms should be given QD dosage 8-20% higher
  than the total daily dose of divalproex sodium

 Initial dose               10-15 mg/kg/day
 Increase dose              5-10 mg/kg/week
 Maximum recommended dose   60 mg/kg/day




                                               19
Divalproex Sodium Extended-release
Dose Conversions
        Divalproex sodium       Divalproex sodium
                                Extended release
        Total daily dose (mg)
                                      (mg)
             500*-625                 750
             750*-875                 1000
           1000*-1125                 1250
            1250-1375                 1500
            1500-1625                 1750
               1750                   2000
            1875-2000                 2250
            2125-2250                 2500
               2375                   2750
            2500-2750                 3000
               2875                   3250
            3000-3125                 3500
                                                    20
Extended-release Phenytoin
• Dilantin® Kapseals® – 30 mg and 100 mg
• Phenytek™ capsules – 200 and 300 mg
• Indicated for generalized tonic-clonic seizures,
  CPS, prevention and treatment of seizures
  during or following neurosurgery




                                                     21
Extended-release Phenytoin
•        Cmax at 4-12 hours
•        QD dosing after initiation
        – Once seizure control is established with divided
          doses of 3 x 100 mg, patients can be converted to
          300 mg QD extended-release phenytoin
        – 300mg QD formulation bioequivalent to 100 mg TID1




    1. Randinitis et al, 1990
                                                          22
Initiation and Conversion with
Extended-release Phenytoin
• Adults
  – Initiation 1 x 100 mg capsule TID increasing to 1 x
    200 mg capsule TID if necessary
  – Once seizure control is established with divided
    doses of
    3 x 100 mg, patients can then be converted to 300 mg
    Phenytek ER QD

• Children
  – Initiation 5 mg/kg/day in two or three equally divided
    doses, increasing to a maximum of 300 mg/day if
    necessary
                                                             23
Extended-release Carbamazepine
• Tegretol-XR® tablets – 100, 200 and 400 mg
• Carbatrol® capsules – 200 and 300 mg
• Indicated for CPS, generalized tonic-clonic
  seizures, mixed seizure patterns
• BID dosing




                                                24
Extended-release Carbamazepine
•        A study of 24 adult patients with epilepsy1
       – Extended-release formulation (Carbatrol) BID vs
         immediate-release formulation four times daily
       – Carbatrol BID was bioequivalent to immediate-
         release carbamazepine four times daily
       – There was no difference in the frequency of seizures
         between treatment (P = 0.103)
       – The extended release formulation reduces the daily
         fluctuations of plasma carbamazepine
       – Optimal dosage is 800-1200 mg/day


    1. Garnett et al, 1998
                                                            25
Extended-release Carbamazepine
•        An open-label study of 124 patients with CPS stable on
         up to 1600 mg/day carbamazepine for at least one
         month
•        Patients were converted to Carbatrol at same dose as
         pre-study
•        Results1:
       –       91% of patients completed the study and had good seizure
               control on Carbatrol capsules
       –       Most patients did not experience a change in frequency or
               intensity of seizures during the switch
       –       Improvement was noted in quality of life (using QOLIE-10)
       –       Switching patients with CPS from multiple-daily-dose
               carbamazepine to twice-daily Carbatrol is relatively safe

    1. Mirza et al, 1998
                                                                           26
 Extended-release carbamazepine
 • Immediate release and extended release
   formulations are bioequivalent
 • Reduced plasma fluctuations
           – Lower Cmax
 • Marked reduction in CNS side effects in 61
   patients switched from immediate release
   carbamazepine to extended release drug
 • No change in monthly seizure frequency1


1 Miller   et al, 2002                          27
 Initiation and Conversion with
 Extended-release Carbamazepine
• Adults
   – Initiation: 200 mg BID, increasing weekly in increments of up to 200
     mg/day until optimal response
   – Maintenance: Patients are usually maintained on 800-1000 mg/day. Doses
     should not exceed 1000 mg/day in children aged 12-15 years or 1200 mg
     in those aged over 15 years
   – Conversion: Patients converting from immediate-release to extended-
     release drug should be given the same total daily mg dose of
     carbamazepine
• Children under 12
   – Children taking 400 mg/day or more IR carbamazepine can be converted
     to the same total daily dose of Carbatrol ER capsules BID
   – Optimal clinical response is usually seen with 35 mg/kg/day or below
                                                                            28
Special Populations
Epilepsy in Children




                       29
Epilepsy in Children
•        Epilepsy is a common neurological disorder in
         childhood1
•        Prevalence of 3–6 cases per 10002,3
•        Incidence decreases with age3,4
•        Childhood epilepsy may remit, but can continue into
         adult life5
•        Around 30% of children will be resistant to AED
         therapy6,7

    1.   Cowan et al, 1989
    2.   Eriksson & Koivikko, 1997
    3.   Kurtz et al, 1998
    4.   Camfield et al, 1996
    5.   Brorson et al, 1987
    6.   Sander, 2002
    7.   Pellock, 1996
                                                               30
Expert Consensus Guidelines for the
Treatment of Epilepsy

                          1st Monotherapy




                          2nd Monotherapy




    Additional trial                        Combination
    of monotherapy                          therapy – two
                                            drugs


1. Karecski et al, 2001
                                ?
                                                            31
Expert Consensus Guidelines for the
Treatment of Epilepsy: IGE
Seizure type               Treatment of   Alternate
                           choice         choice
All seizure types          Valproate

Generalized tonic- Valproate              Lamotrigine,
clonic                                    topiramate
Absence                    Valproate,     Lamotrigine
                           Ethosuximide
Myoclonic                  Valproate      Lamotrigine

 1. Karecski et al, 2001
                                                         32
Expert Consensus Guidelines for the
Treatment of Epilepsy: SGE
Seizure type               Treatment of   Alternate
                           choice         choice
Generalized tonic- Valproate              Lamotrigine,
clonic                                    topiramate
Absence                    Valproate      Lamotrigine

Myoclonic                  Valproate      Lamotrigine

Atypical absence           Valproate      Lamotrigine

 1. Karecski et al, 2001
                                                         33
Aggravation of Epilepsy by AEDs
•        There is evidence that some AEDs can
         aggravate epilepsy:
       – Carbamazepine appears to have the strongest
         aggravating potential in patients with juvenile
         myoclonic epilepsy, whereas the aggravating effect
         of phenytoin is less prominent1
       – Lamotrigine aggravated JME in 7 patients2
       – 4/24 patients with JME had aggravation of condition,
         two dramatically3
       – Vigabatrin aggravates absence seizures4
    1. Genton et al, 2000
    2. Biraben et al, 2000
    3. Carrazena & Wheeler, 2001
    4. Panayiotopoulos et al, 1997
                                                            34
Divalproex Sodium Extended-release
Pharmacokinetic Profile in Children
•        Study design
        – Phase I pharmacokinetic study to assess the
          pharmacokinetic profile and safety of divalproex
          sodium ER
        – Patients were already taking divalproex sodium DR
          or ER
        – Two age groups: 8-11 years (children) and 12-17
          years (adolescents)




    1. Sallee et al, 2002
                                                              35
Divalproex Sodium Extended Release in
Children
•        VPA plasma concentration-time profiles of
         divalproex sodium ER formulation similar
         among children, adolescents and adults1
•        Dose per unit body weight was different for
         children compared with adults
•        Higher rate of clearance in children




    1. Sallee et al, 2002
                                                       36
Divalproex Sodium Extended Release in
Children
•       20 children aged 12-17 years switched from
        divalproex sodium DR to the ER formulation1
•       All patients seizure free 3 months after
        converting to divalproex sodium ER
•       More likely to take once-daily medication
•       Improved tolerability
•       IV formulation of divalproex sodium also found
        to be effective in pediatric emergencies2


    1. Thompson et al, 2001
    2. Yu et al, 2001
                                                         37
Special Populations
Women with Epilepsy




                      38
Diagnosing PCOS
•      PCOS is a metabolic disorder. The NIH diagnostic
       criteria for PCOS are:1
       – ovulatory dysfunction
       – hyperandrogenism
       – exclusion of other endocrinopathies
•      PCOS should not be confused with polycystic ovaries
       (PCO), which is the presence of multiple ovarian cysts
       2-8mm in diameter and increased ovarian stroma and is
       not intrinsically2
•      PCOS occurs in 12% of the general premenopausal
       population, while PCO occurs in 22% of women
    1. Duncan, 2001
    2. Ernst & Goldberg, 2002
                                                            39
Epilepsy as a Cause of PCOS
•       Epileptic discharges may affect the secretion of
        GnRH
•       Seizures can cause hyperprolactinemia, which
        can elevate LH levels and support
        androgenization
•       Epilepsy and PCOS may be caused by a
        common factor, such as a dysfunction in
        neurotransmission or genetic vulnerability

    1. Ernst & Goldberg, 2002
    2. Herzog & Schachter, 2001
                                                       40
 Prevalence of PCOS in Various
 Populations of Women

   Reproductive age (4% to 12%)*

                  With oligomenorrhea1
                        With amenorrhea2

                     Untreated epilepsy3

  Idiopathic generalized epilepsy3
Unilateral temporolimbic epilepsy4

        Valproate-treated epilepsy3

Carbamazepine-treated epilepsy3

                                                   0         15         30     45    60        75   90
                                                                      Prevalence of PCOS (%)


 1Dunaif A   et al, 2001; 2Franks, 1995; 3Duncan, 2001; 4Herzog et al, 2001.                         41
Association of Epilepsy Type, AED, and
Ovulatory Function
•        Morrell et al studied the association of epilepsy
         syndrome category and AED (carbamazepine,
         phenytoin, phenobarbital, valproate,
         lamotrigine, or gabapentin) on ovulatory failure
•        There was no association between current
         AED use and anovulatory cycles
•        Valproate does not affect ovulatory function; no
         difference in the frequency of polycystic-
         appearing ovaries (PCAOs) by AED.

    1. Morrell et al, 2002
                                                         42
PCOS Conclusions
• PCOS is a serious reproductive endocrine
  disorder with an increased incidence in women
  with epilepsy. It is characterized by ovulatory
  dysfunction and hyperandrogenism
• It is important to distinguish PCOS from PCO
• There are no reliable data showing a greater
  prevalence of PCOS in women treated with
  valproate or any other AEDs
• Treatment choices for epilepsy should be based
  on the most effective agent for seizure control

                                                43
Pregnancy in Women With Epilepsy
•      1.1 million women of childbearing age have epilepsy in the USA
•      Issues with management of women:1
       –    Cosmetic consequences of some AEDs
       –    Catamenial epilepsy
       –    Effectiveness of hormonal contraceptives may be reduced by some
            AEDs
       –    Pregnancy has a greater risk for complications
       –    Difficulties during labor and adverse outcomes are more likely
       –    The practitioner must choose a course that both prevents seizures and
            minimizes fetal exposure to AEDs
•      With careful management the majority of women with epilepsy will
       have a better than 90% chance of a normal baby2

    1. Yerby, 2000
    2. Crawford, 1997
                                                                                44
Effects of AEDs on Oral Contraceptives
Reduces efficacy            No effect on efficacy
•     Barbiturates          •   Felbamate
•     Carbamazepine         •   Gabapentin
•     Phenytoin             •   Lamotrigine
•     Tiagabine             •   Valproate
•     Topiramate
•     Oxcarbazepine




    1. Hachad et al, 2002
    2. Morrell, 1998
                                                    45
FDA Use-in-Pregnancy Risk
Category C                                                 Category D
•     Zonisamide                                           • Phenytoin
•     Gabapentin                                           • Valproic acid
•     Oxcarbazepine                                        • Carbamazepine
•     Felbamate                                            (moved from Category C in 1998)
•     Levetiracetam                                        • Phenobarbital
•     Lamotrigine
•     Tiagabine



    1. http://www.perinatology.com/exposures/Drugs/FDACategories.htm
                                                                                         46
Teratogenic Effects of AEDs
• Adverse pregnancy outcomes are associated
  with AEDs
• Specific cognitive defects may be causally
  related to AED exposure
• Reduce risks with monotherapy at lowest
  possible dose
• Use divided doses or ER formulations to even
  out fluctuations


 1. Lindhout & Omtzigt, 1994
                                                 47
Summary
• Balance efficacy against side effects
• Extended-release AEDs offer improved
  tolerability, improved compliance and improved
  seizure control
• The benefits may be especially relevant in
  special populations such as children and women
  with epilepsy



                                               48

				
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