Bio-equivalence Study Between SAPHRIS and Asenapine

Molecule Name Asenapine Country of submission US

PRODUCT DETAILS

Test formulation

Drug name: Asenapine Sublingual Tablet EQ 10mg base Manufactured by: Sun Pharmaceutical
Industries, Ltd.

Reference formulation

Drug name: SAPHRIS® (Asenapine) sublingual tablets Manufactured by: Schering Corporation, a
Subsidiary of Merck & Co., Inc.

STUDY DESIGN

Title An open-label, randomized, two treatment, multi-site, multiple dose, steady state,
three-way, reference-replicated crossover, pharmacokinetic study to determine the in-vivo
bioequivalence between Asenapine 10 mg sublingual tablet and SAPHRIS® (asenapine) 10 mg
sublingual tablet

Study Design Multiple-dose, steady state, three-way reference-replicated crossover study

Type of Study Pharmacokinetic (PK)

Number of subjects 57 randomized to complete 42 subjects

Dosing Test or Reference drug (EQ 10mg) base sublingual tablets are to be taken twice daily,
once in the morning and once in the evening, for a period of 7 days before crossing-over to
receive the next drug assigned for a period of 7 days, followed by a period of 7 days where
the third drug assigned will be received.. There will be a total of three 7-day treatment
periods during which each subject will receive the test product in one period and the
reference product in two other periods.

To ensure optimal absorption, subjects will be instructed to place the tablet under the
tongue and allow it to dissolve completely. The tablet will dissolve in saliva. Tablets will
not be crushed, chewed, or swallowed

Housing Subjects will be housed in the clinic or hospital for a multiple days in each period
during treatment and the collection of pharmacokinetic samples. Housing will be provided
for:

- Day 1 and Day 8 or 15 (12-hour confinement)

- Days 6-7

- Days 13-14

- Days 20-21

Investigators may choose to house subjects during the interim days between specified
in-patient clinic visits, either in the clinic or at an appropriate off-site facility such
as a hotel or motel. Housing offers may be made to each subject population according to the
respective Investigator's judgment as to what is best for his/her patients. Such interim
housing is not to be considered as study visits, but will be offered at the discretion of
the Investigator to all subjects in his/her clinic, at his/her discretion, and simply to
improve subject compliance and attempt to reduce variability.

Subjects will be confined for at least 12 hours after initial dosing of either SAPHRIS®
(Asenapine) or Asenapine sublingual tablets. Subjects will be required to remain supine for
6 hours following the initial dose. Subjects may get up briefly in order to relieve
themselves.

Washout period There will be no washout period

Sampling time points Blood samples will be collected over a dosing interval on day 7,
following preliminary sampling on days 5 and 6 to confirm steady-state conditions. The
sampling time points are as follows:

- Day 5 (1 sample)

- Day 6 (1 sample)

- Day 7 (15 samples) 0.0(pre-dose), 0.25, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 5.0,
6.0, 8.0, 10.0, 12.0

Dietary Plan Subjects will fast for at least 8 hours prior to and 4 hours after the
administration of the morning dose of the test or reference treatment on day 7 of each
period (i.e., the days on which blood samples are to be collected to assess the
concentration-time curve). All meals on day 7 will be standardized during the study. Water
may be allowed, except for 1 hour before and 1 hour after drug administration, when no
liquid will be permitted.

Special requirements

- Subjects will remain in the supine position for the first 6 hours after the first dose,
even if they were previously on a stable dose of asenapine maleate.

- Subjects will be adequately hydrated. This may be achieved by administering 240 mL of
water before the overnight fast, 240 mL of water one hour before dosing, and beginning
no sooner than 1 hour after drug administration, 240 mL of water every 2 hours for 6
hours post-dosing. Subjects will not eat or drink for 10 minutes after drug
administration.

- Subjects must be adequately informed of possible cardiovascular adverse effects in the
consent form.

Safety Parameters

- White blood cell (WBC) counts will be monitored and asenapine maleate sublingual tablet
treatment modified, if necessary, in accordance with the leukopenia, neutropenia and
agranulocytosis warning in the labeling of the reference listed drug product.

- Subjects requiring modification of asenapine maleate sublingual tablet treatment will
be dropped from the study and provided with prompt medical care.

- Blood pressure, heart rate, and body temperature will be monitored during the study and
immediate medical care provided for any significant abnormalities.

- Subject medical histories, physical examination and laboratory reports, and all
incidents of possible adverse reactions will be reported.

Analyte(s) to measure Asenapine in plasma

Pharmacokinetic parameters

Asenapine AUC0-tau, Cmax, Tmax, Cmin and %Fluctuation will be estimated for each subject and
period using WinNonlin version 5.2 or higher. The trough samples collected just prior to the
morning dose on Days 5, 6 and 7 in each period will be evaluated to demonstrate that
steady-state has been achieved by the final morning dose in each period.

Statistical Analysis

The primary pharmacokinetic parameters (Cmax, AUC0-tau,) and Cmin will be natural
log-transformed (ln) prior to statistical analyses. Any ln-transformed parameter where the
observed intra-subject CV for the reference product is at least 30% (swr ≥ 0.294) will be
evaluated using the scaled average bioequivalence (SABE) method. The GLM procedure of SAS
will be used to conduct the SABE analyses, as well as to estimate the intra-subject CV for
the reference product. The statistical model for the GLM procedure will contain only a term
for Sequence*Site. The linearized Scaled Average Bioequivalence statistic and the upper 95%
Confidence Bound on the statistic will be estimated. The ratio of geometric means (T/R)
will also be calculated.

Plasma concentrations at each time point, Tmax, %Fluctuation, and any ln-transformed
pharmacokinetic parameter where the observed intra-subject CV of the reference product is
less than 30% (swr < 0.294), will be evaluated using the average (unscaled) bioequivalence
(ABE) approach will be used. The MIXED procedure of SAS will be used in this case with a
statistical model that includes terms for Sequence, Site, Sequence*Site, Subject nested
within Sequence*Site, Period nested within Site, Treatment, and if necessary,
Treatment*Site. A separate statistical analysis will be done to determine if the
Treatment*Site term is statistically significant (p<0.05) and needs to be retained in the
model. If this term is not significant, it will be dropped from the statistical model for
the definitive statistical evaluation. The ratio of geometric means (T/R) and 90% confidence
intervals for the ratio, based on least-squares means from the analysis of the
log-transformed PK Parameter, will be calculated.

Bioequivalence criteria Bioequivalence will be concluded for those primary parameters
evaluated by SABE if:

- The geometric mean Test-to-Reference ratio falls within the range of 0.800 to 1.250.

- The 95% upper confidence bound on the linearized SABE statistic.

Bioequivalence will be concluded for those primary parameters evaluated by ABE if:

The 90% confidence interval on the geometric mean Test-to Reference ratio is contained
within the interval 0.800 to 1.250.

Fluctuation for the test product will be evaluated for comparability with the fluctuation of
the reference product.

Report format eCTD

Inclusion Criteria:

1. Male and/or non-pregnant female subjects aged 18 to 80 years of age

2. For females of child-bearing potential, the subject must be willing to practice a
clinically accepted method of birth control

3. Receiving a stable twice daily dose of Asenapine Maleate EQ 10 mg base sublingual
tablets for at least 3 months prior to randomization

4. Subjects will be otherwise healthy as determined by the investigator in reference to
physical examination, medical history and routine hematologic and biochemical tests

5. Able to obtain written informed consent for the study by the subject or Subject's
Legally Acceptable Representative (LAR). If the subject or his/her LAR is unable to
read/write, and impartial witness will be present during the entire consenting
process who must append his/her signatures to the consent form

Exclusion Criteria:

1. A history of any clinically significant allergic or adverse reactions to asenapine
maleate or any comparable or similar product

2. QTc > 450 msec in male subject or QTc > 470 msec in female subjects at screening

3. Heart rate at screening less than 50 bts/min

4. Hypokalemia (defined as serum or plasma potassium less than 3.5 mM or mEq/L) and/or
Hypomagnesaemia (defined as serum magnesium less than 0.7 mEq/L) at screening.

5. A history of severe hepatic impairment, drug induced leukopenia/neutropenia,
congenital prolongation of the QT interval, cardiac arrhythmias, myocardial
infarction or unstable heart disease

6. Concurrent primary psychiatric or neurological diagnosis, including organic mental
disorder, severe tardive dyskinesia, or idiopathic Parkinson's disease

7. A total white blood cell count below 4000/mL, or an absolute neutrophil count below
2000/mL

8. A history of granulocytopenia or myeloproliferative disorders (drug-induced or
idiopathic)

9. Significant orthostatic hypotension (i.e., a drop in systolic blood pressure of 30 mm
Hg or more and/or a drop in diastolic blood pressure of 20 mm Hg or more on standing)

10. Concurrent use of antihypertensive medication or any medication that can predispose
to orthostatic hypotension, unless receiving stable dose of those medications for at
least 3 months prior to randomization.

11. A medical or surgical condition that might interfere with the absorption, metabolism,
or excretion of Asenapine

12. A history of epilepsy or risk for seizures

13. Concurrent use of other drugs known to suppress bone marrow function

14. Expected changes in concomitant medications during the period of study

15. Positive tests for drug or alcohol abuse at screening or baseline

16. A history of alcohol or drug dependence by Diagnostic and Statistical Manual of
Mental Disorders IV (DSM-IV) criteria during the 6-month period immediately prior to
study entry

17. Has participated in another clinical research study within 30 days prior to
randomization

18. Compliance with outpatient medication schedule not expected

19. History of multiple syncopal episodes

20. Any other clinically significant condition that the investigator thinks puts the
subject at risk