Equivalence Among Antiepileptic Drug Generic and Brand Products in People With Epilepsy: Chronic-Dose 4-Period Replicate Design

Qualified subjects will be screened and upon fulfilling inclusion/exclusion criteria and
signing the informed consent will be enrolled into the study and enter the randomization
phase (2-30 days). Subjects will be randomized according to a sealed allocation list that
will be balanced for sequence and provided to each site prior to the first subject
enrollment. Subjects that withdraw prior to completing the second period will be replaced in
a randomized manner. The randomization list will be generated by the study statistical group.
There are four test periods in two sequences for a sequence-randomized study. During two test
periods subjects will receive twice daily dosing of the "low" generic product and during the
other two periods subjects will receive twice daily dosing of the "high" generic product.
Each subject will return at the end of the 14+/-1 day stable dosing period for an in-facility
12-hour pharmacokinetic (PK) session to collect samples to determine Cmax and AUCs (area
under curve). Each in-facility pharmacokinetic testing will be separated by a 14+/-1 day
stable dosing period. A final follow-up phone evaluation will be conducted 12-16 days (target
14 days) after the last dose of study medication. A single make-up period will be permitted
if there are issues during any single period. During the study the subjects will continue
their usual concomitant medications, including AEDs (anti epilepsy drugs), without change.

Investigators will compare the AED levels as measured by Cmax and AUC in each group using
average bioequivalence (ABE) and individual bioequivalence (IBE) criteria. Average
bioequivalence will be established if the 90% confidence intervals of the geometric mean of
Cmax and AUCs for the most disparate generic products compared to each other are entirely
within the 80%-125% range (the FDA criteria for bioequivalence) using the two one-sided
standard analyses. Otherwise the products will be considered to not be bioequivalent.

Study Population: Approximately 36 subjects (30 subjects to completion).

Number of centers: 3 sites enrolling approximately 12 subjects each.

Duration of study: Approximately 1 year.

Inclusion Criteria:

Eligible subjects must satisfy the criteria below at the time of enrollment:

1. 18 years or older.

2. BMI not less than 18.5 and weight not less than 110 pounds.

3. Not donated blood within 56 days of the first pharmacokinetic testing.

4. Agrees not to donate blood at any time during the trial and for 56 days after the
final PK in-facility admission.

5. Has had epilepsy for at least one year based on site PIs assessment.

6. Receiving conventional (not extended release) lamotrigine as an antiepileptic drug in
twice daily dosing at either 100 mg twice per day, 200 mg twice per day, 300 mg twice
per day, or 400 mg twice per day.

7. No changes in AED regimen (lamotrigine or concomitant AED) for at least 28 days prior
to first pharmacokinetic testing.

8. Have the ability to understand the informed consent form and be willing to provide
informed consent.

9. Willing to remain on same AED regimen through entire study. Subjects will be
responsible to supply all of their concomitant medications (except for the study
medication, lamotrigine).

10. Willing to stay approximately 14 hours in the research facility on four separate
occasions for pharmacokinetic testing.

11. Willing to fast overnight and the morning of each of the four pharmacokinetic testing
sessions.

12. Willing to have at least 21 blood samples collected during the pharmacokinetic testing
including the in-facility session and outpatient portion for each period. The
in-facility blood collections will mainly be performed using an inserted catheter. In
the event of difficulty with the catheter or by subject preference, samples may be
drawn by venipuncture. The outpatient portion consists of morning trough levels within
+/-1 hour of the morning scheduled dose time on the 2 days prior to each research
facility PK admission drawn by venipuncture for each of the 4 periods. The total
amount of blood during each PK session will be equal to about 12 teaspoons (58.5
milliliters). The total amount of blood drawn throughout the entire study will be
about 62 teaspoons (309.5 milliliters) or less. For reference, this amount is
approximately two-thirds of the quantity of blood drawn during a standard blood
donation by the Red Cross.

13. Willing to completely abstain from alcohol consumption for at least 72-hours prior to
each PK in-facility admission (that is from 1 day prior to the first outpatient steady
state level) until after the last sample is drawn for each period. Investigators
encourage no or minimal alcohol use throughout the study, but alcohol is not
restricted at other times.

14. Willing to remain on a consistent regimen of concomitant medications including
over-the-counter drugs and herbal drugs, if they are being used and deemed to possibly
affect the metabolism of the study medication.

15. Willing to not eat grapefruit or drink grapefruit juice through the duration of the
study.

16. If a tobacco user, willing to continue with the same pattern of tobacco use except
that no tobacco use is permitted during the PK facility admissions of approximately 14
hours (includes all tobacco products).

17. Willing to complete the subject diary as outlined in the protocol.

18. Willing to adhere to all other protocol requirements as outlined in the informed
consent document.

19. Females must be either of non-childbearing potential (defined as having undergone
surgical sterilization or postmenopausal (greater than 50 years old and amenorrhea for
greater than or equal to 12 months) or must be using at least one acceptable method of
contraception as follows:

1. Double-barrier method (e.g. condom plus spermicide, condom plus diaphragm with
spermicide)

2. Hormonal contraceptive treatment (progesterone only agents - use of any agents
containing estrogen are an exclusion for the lamotrigine testing)

3. Intrauterine Device (IUD)

4. Monogamous relationship with a vasectomized partner

5. Abstinent for 8 weeks prior to and throughout the study.

20. Subject must be at least 28 days from last participation in any other study.

Exclusion Criteria:

- 1. Use of an extended release formulation of LTG within 28 days of study entry. 2.
Subject is receiving LTG at a total daily dose above 800 mg per day within 28 days of
study entry.

3. Progressive CNS disorder that could influence adverse effects or seizure control.

4. Known medication non-adherence. Non-adherence is assessed by the investigator based
on the procedures defined in the manual of procedures.

5. Use of valproate (as divalproex sodium or valproic acid), any form of estrogens,
rifampin, orlistat, felbamate or sertraline within 28 days of study entry.

6. Subject has a history of alcohol or substance abuse within 1 year prior to
screening of study participation, or is currently using alcohol, drugs of abuse, or
any prescribed or over-the-counter medication in a manner, which, in the opinion of
the Investigator, indicates abuse.

7. History of psychogenic seizures within the past 2 years. 8. Any clinically
significant psychiatric illness or psychological or behavioral problem which, in the
opinion of the investigator, could interfere with the subject being able to
participate in the study or comply with the study requirements.

9. Any clinically significant laboratory abnormality or illness which, in the opinion
of the investigator, could interfere with the conduct or interpretation of the study
or put the subject at risk.

10. Pregnant or lactating within 56 days of enrollment. 11. Unstable seizure control
that makes AED changes likely during the course of the study.

12. Use of rescue AEDs (e.g. benzodiazepines) during more than two weeks of the 2
months prior to enrollment.

13. Subject is in the process of quitting smoking within 28 days of study entry or
plans to quit smoking during the period of time the study will be conducted.