New Formulations of Antiepileptic Drugs for the Management of Epilepsy

1
New Formulations of Antiepileptic Drugs for the
Management of Epilepsy
2
Goals of Treatment for Epilepsy

• Control of seizures
• Minimal adverse events
• Good patient compliance

• Marks Garcia, 1998
• Chapman Giles, 1997
• Garnett, 2000

3
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

• Mattson, 1992

4
AED Response Newer is Not Always Better

• 525 untreated patients (470 drug-naïve)

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

• Only 3 were controlled with two AEDs, and none
  with three.

• Brodie Kwan, 2002

5
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

• Yoon Jagoda, 2000
• Brodie French, 2000

6
CNS AEs with New AEDs
Chapman DP, et al. South Med J. 199790L171-L180.
7
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

• Lamotrigine presrcibing information
• Topiramate prescribing information
• Levetiracetam prescribing information

8
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

• Browne Holmes, 2001
• Marks Garcia, 1998

9
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

• Garnett, 2000

10
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

11
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

12
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

13
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

• Dutta et al, 2002

14
Pharmacokinetic Data
ConcentrationTime Profiles 875 Delayed release
(DR)/ 1000 Extended release (ER)
110
100
90
80
70
60
VPA Concentration (µg/mL)
50
40
30
1000 mg ER (n35)
20
825 mg DR (n35)
10
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (hrs)

• Dutta et al, 2002

15
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

16
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).

• Thibault et al, 2002

17
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

18
Divalproex to Divalproex ER Conversion Impact on
Tremor and Weight Gain

• After conversion to Depakote ER
• Reduced incidence of tremor (75-5)
• No additional weight gain
• Reduction in reports of lethargy, ataxia and hair
  loss
• Improved compliance

100
90
80
70
60
Before
50
After
40
30
20
10
0
Tremor

• Zielinski et al, 2001

19
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

20
Divalproex Sodium Extended-release Dose
Conversions
21
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

22
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

• Randinitis et al, 1990

23
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

24
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

25
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

• Garnett et al, 1998

26
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

• Mirza et al, 1998

27
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
28
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

29
Special Populations

• Epilepsy in Children

30
Epilepsy in Children

• Epilepsy is a common neurological disorder in
  childhood1
• Prevalence of 36 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

• Cowan et al, 1989
• Eriksson Koivikko, 1997
• Kurtz et al, 1998
• Camfield et al, 1996
• Brorson et al, 1987
• Sander, 2002
• Pellock, 1996

31
Expert Consensus Guidelines for the Treatment of
Epilepsy
1st Monotherapy
2nd Monotherapy
Additional trial of monotherapy
Combination therapy two drugs
?

• Karecski et al, 2001

32
Expert Consensus Guidelines for the Treatment of
Epilepsy IGE

• Karecski et al, 2001

33
Expert Consensus Guidelines for the Treatment of
Epilepsy SGE

• Karecski et al, 2001

34
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

• Genton et al, 2000
• Biraben et al, 2000
• Carrazena Wheeler, 2001
• Panayiotopoulos et al, 1997

35
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)

• Sallee et al, 2002

36
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

• Sallee et al, 2002

37
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

• Thompson et al, 2001
• Yu et al, 2001

38
Special Populations

• Women with Epilepsy

39
Diagnosing PCOS

• PCOS is a metabolic disorder. The NIH diagnostic
  criteria for PCOS are1
• 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

• Duncan, 2001
• Ernst Goldberg, 2002

40
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

• Ernst Goldberg, 2002
• Herzog Schachter, 2001

41
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.
42
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-appearin
  g ovaries (PCAOs) by AED.

• Morrell et al, 2002

43
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

44
Pregnancy in Women With Epilepsy

• 1.1 million women of childbearing age have
  epilepsy in the USA
• Issues with management of women1
• 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

• Yerby, 2000
• Crawford, 1997

45
Effects of AEDs on Oral Contraceptives

• Reduces efficacy
• Barbiturates
• Carbamazepine
• Phenytoin
• Tiagabine
• Topiramate
• Oxcarbazepine

• No effect on efficacy
• Felbamate
• Gabapentin
• Lamotrigine
• Valproate

• Hachad et al, 2002
• Morrell, 1998

46
FDA Use-in-Pregnancy Risk

• Category C
• Zonisamide
• Gabapentin
• Oxcarbazepine
• Felbamate
• Levetiracetam
• Lamotrigine
• Tiagabine

• Category D
• Phenytoin
• Valproic acid
• Carbamazepine
• (moved from Category C in 1998)
• Phenobarbital

• http//www.perinatology.com/exposures/Drugs/FDACat
  egories.htm

47
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

• Lindhout Omtzigt, 1994

48
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