An open label study in two parallel groups, each receiving in a randomized, two period, cross-over design two single doses of Risperdal® Consta®, to explore the comparative bioavailability of two different batches of Risperdal® Consta® and the intra subject variability of one Risperdal® Consta® batch after intramuscular administration in healthy volunteers

Teva Pharmachemie is developing a generic version of Risperdal® Consta®. Before
starting pilot and pivotal bioavailability studies with the potential new
formulation, a PK study in healthy volunteers is designed to obtain the
information on the intra-subject variability of the reference formulations
(i.e. Risperdal® Consta®). In addition, this study will compare the
bioavailability of 12.5 mg taken from a EU-sourced Risperdal® Consta® 25 mg
marketed formulation versus 12.5 mg taken from a US-sourced Risperdal® Consta®
12.5 mg marketed formulation, to investigate the feasibility and effect on PK
parameters of preparing a 12.5 mg dose from a EU-sourced Risperdal® Consta® 25
mg marketed formulation.

For registration of the formuliation in Europe, a single dose bioequivalence
study is required in healthy volunteers. This is only possible with a low dose
(12.5 mg). Because this strength is not available on the European market, the
study will have to be conducted by preparing half of the dose strength of the
25 mg formulation, in a dose volume of 2 mL. The current study investigates
whether this dose preparation results in the same bioavailability as a 12.5 mg
dose from a 12.5 mg strength formulation currently available on the US market.

This data will support the design of a pivotal single dose bioequivalence study
in healthy volunteers. Based on regional differences in regulatory requirements
for registration of a generic formulation of Risperdal® Consta®, both EU and
US-sourced reference products will be investigated in this study.

The data of this study will be used to optimize the design of the clinical
studies comparing the test product with the reference product (Risperdal®
Consta®) in order to demonstrate bioequivalence.

Primary objectives:
* To explore the comparative bioavailability between 12.5 mg of Risperdal®
Consta® prepared from a 25 mg dose strength of Risperdal® Consta® EU-sourced,
and 12.5 mg of Risperdal® Consta® prepared from a 12.5 mg dose strength
Risperdal® Consta® US-sourced, after a single-dose administered intramuscularly
in healthy subjects.
* To estimate the intra-subject variability of Risperdal® Consta® US-sourced
pharmacokinetics after twice a single 12.5 mg dose, administered
intramuscularly in healthy subjects.
* To estimate the intra-subject variability of the Risperdal® Consta®
US-sourced pharmacokinetics after a single 12.5 mg dose and the Risperdal®
Consta® EU-sourced pharmacokinetics after a single 12.5 mg dose, administered
intramuscularly in healthy subjects.

Secondary objective:
* To assess the safety and tolerability of different long-acting risperidone
injection products.

This study is an open label, randomized, two-way cross over study with a
washout of at least 10 weeks between subsequent intramuscular (IM)
administrations. These administrations will be preceded by multiple dose
administration of 1 mg risperidone for 3 days to determine individual
tolerability to risperidone (Phase I, extended screening phase), at least two
weeks prior to the first intramuscular administration (Phase II).

This study consists of two phases: during Phase I, which is an extended
screening phase, subjects* tolerability to risperidone is determined;
sufficient subjects (55) will be administered risperidone orally. During Phase
II, two cohorts of 24 subjects each will start their two way cross-over part of
the study and will be administered risperidone intramuscularly.

Phase I, extended screening phase to determine subjects* tolerability to 3 mg
risperidone as an oral administration
Phase I is considered an extended screening phase. Subjects who do not tolerate
this dose are not considered drop outs, rather screen failures.
Subjects will start this phase of the study to assess how well they tolerate
multiple oral doses of 1 mg risperidone (immediate release formulation) once
daily for 3 days. The CYP2D6 genotype will be determined to estimate the
metabolic rate. They will come to the study center on the day before the first
dosing (Day -1) for baseline assessments and to (re*) confirm eligibility. In
the mornings of Day 1, 2 and 3, all subjects will receive an oral dose of 1 mg
risperidone. Adverse events and vital signs will be recorded throughout this
phase of the study. No pharmacokinetic samples will be collected. They will be
discharged from the study center after at least 48 h after the last dosing and
when medically justified.
Only those subjects, who tolerated this dose regimen well according to the
principal investigator, will proceed to the next phase of the study.

Phase II, intramuscular administration of risperidone long-acting (Risperdal®
Consta®)
After a wash-out period of at least two weeks after Phase I, two cohorts of 24
subjects each, will start their two way cross-over part of the study. All
subjects of both cohorts will have the same schedule of assessments. Subjects
will return to the clinic on the day before the first intramuscular dosing of
Risperdal® Consta® (Day -1). After eligibility is (re)confirmed, the
appropriate dose of Risperdal® Consta® (Treatment A or B) is given in the
morning of Day 1 of Period 1. Confinement is scheduled till the morning of Day
3. Another confinement period is scheduled from the afternoon/evening of Day 22
till the morning of Day 35. Ambulatory visits for collecting PK samples and
assessing safety and tolerability are scheduled for the mornings (at the same
time as dosing) of Days 8, 12, 15, 18, 21, 36, 37, 39, 41, 44, 48, 52, 56, 63
and 70. Should safety or tolerability be a concern, subjects can be confined in
the study center any time during this period. Confinement itself will not be
considered a Serious Adverse Event. At least 10 weeks after the first IM
dosing, subjects will receive their second IM dosing with the other Treatment
in Period 2 (= Day 1 of Period 2) for which they follow the same schedule of
assessments as for Period 1. After the last blood sample taken on Day 70 of
Period 2 or at early discontinuation, subjects will be subjected to an End*of*
study examination.

The study will start with phase 1, an extended screening phase to determine
subjects' tolerance to multiple oral doses of 1 mg risperidone (immediate
release formulation) once daily for 3 days. During the screening phase standard
medical assessments including safety laboratory tests (blood draw, urine
collection), an alcohol breath test, urine drug screen, a physical examination,
ECG, vital signs, orthostatic challenge test, a questionnaire assessing
suicidal ideation and suicidal behaviour, an assessment of drug-induced
movement disorders by using the Extrapyramidal Symptom Rating Scale (ESRS) and
a psychiatric measurement will be performed. Also a cognitive function
questionnaire will be done (MMSE).
After the subject passes all above mentioned tests and the subject tolerates
the multiple oral doses of 1 mg risperidone once daily for 3 days, the subject
will be enrolled in phase 2 (intramuscular administration of risperidone
long-acting formulation). During study, the subjects will enter the clinic and
will receive Risperdal® Consta® during 2 periods. They will be asked on a
regular basis for possible side effects, blood will be drawn for safety,
prolactin measurements and PK measurements. ECG and vital signs will be checked
regularly during the confinement periods and C-SSRS and ESRS will be filled out
at regular intervals.
Finally an end of study visit will be performed. During this visit standard
medical assessments including safety laboratory tests (blood draw, urine
collection), blood draw for prolactin measurements, an alcohol breath test,
urine drug screen, a physical examination, ECG, vital signs, and C-SSRS and
ESRS will be performed.

Compounds that contain risperidone (oral and intramuscular formulations) have
been previously tested in humans and were generally well tolerated. A number of
side-effects, possibly linked to use of the study drug, were reported. The most
common side-effects of Risperdal® tablets included insomnia, a disturbance in
the movement patter similar to Parkinson*s disease, sleepiness, headache,
pneumonia, infection of the chest (bronchitis), common cold, infection of the
nasal cavity and sinuses, urine tract infection, ear infection, flu-like
symptoms, swelling of the breasts, erection problems, decreased sexual desire
or other sexual dysfunction, breast discomfort, leaking of milk from the
breasts, missed period or other problems with the menstrual cycle or fertility
problems, weight increase, increased appetite, decreased appetite,
irritability, depression, anxiety, restlessness, involuntary muscle movements
(dystonia and dyskinesia), dizziness, shaking, blurred vision, eye infection,
conjunctivitis, rapid pulse, increased blood pressure, dyspnea, sore throat,
coughing, nose bleeding, nasal congestion, stomach pain, stomach discomfort,
vomiting, nausea, obstipation, diarrhea, digestion problems, dry mouth, tooth
ache, rash, red skin, muscle cramps, musculoskeletal pain, back pain, joint
pain, urine incontinentia, swollen body, puffy arms or legs, fever, chest pain,
weakness, fatigue, pain, and falling down.

The most common side-effects of Risperdal® Consta® injections included common
cold, insomnia, depression, anxiety, a disturbance in the movement patter
similar to Parkinson*s disease, headache, pneumonia, infection of the chest
(bronchitis), infection of the nasal cavity and sinuses, urine tract infection,
flu-like symptoms, anemia, erection problems, decreased sexual desire or other
sexual dysfunction, breast discomfort, leaking of milk from the breasts, missed
period or other problems with the menstrual cycle or fertility problems, high
sugar levels in the blood, weight increase, weight decrease, increased
appetite, decreased appetite, sleepiness, involuntary muscle movements
(dystonia and dyskinesia), dizziness, shaking, blurred vision, rapid pulse,
decreased blood pressure, chestpain, stomach pain, stomach discomfort,
vomiting, nausea, stomach or intestinal infection, dry mouth, tooth pain, rash,
muscle cramps, musculoskeletal pain, back pain, joint pain, urine
incontinentia, swollen body, puffy arms or legs, fever, weakness, fatigue,
injection site reaction, and falling down.

Side-effects of Risperdal® Consta® can occur later on, because this drug acts
after a *pause* of 3 weeks.

The dose levels are selected on the basis of research results in animals and
humans. The risk to health at these dose levels is limited but the subjects
mmay experience one of the above mentioned side-effects or other symptoms not
previously reported. Their health will be closely monitored during the trial to
minimize these risks. Volunteers will be kept in-house for medical monitoring
during oral tolerance determination (phase 1), several days after the
intramuscular injections and a fairly long period of time around the expected
Tmax.

The blood collection procedure is not dangerous, but may cause discomfort or
bruising. Occasionally, fainting, bleeding or an infection at the blood
sampling site can occur.

The injection side can be sensitive the first couple of days and may be red or
swollen and feel somewhat hard.