INVEGA 6 MG

Israel - English - Ministry of Health

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Active ingredient:
PALIPERIDONE
Available from:
J-C HEALTH CARE LTD
ATC code:
N05AX13
Pharmaceutical form:
TABLETS EXTENDED RELEASE
Composition:
PALIPERIDONE 6 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
JANSSEN CILAG S.P.A., ITALY
Therapeutic group:
PALIPERIDONE
Therapeutic area:
PALIPERIDONE
Therapeutic indications:
Invega is indicated for : - treatment of schizophrenia in adults and adolescents (12-17 years).-acute treatment of schizoaffective disorder as monotherapy-acute treatment of schizoaffective disorder as an adjunct to mood stabilizers and/or antidepressants
Authorization number:
139 16 31640 01
Authorization date:
2013-07-31

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

18-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

01-11-2016

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Paliperidone 3 mg Paliperidone 6 mg

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acetate (398-10);Acetone;Carnauba wax (powder);Ferric oxide

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SH 12/10

PATIENT PACKAGE INSERT IN ACCORDANCE WITH

THEPHARMACISTS'REGULATIONS(PREPARATIONS)-1986

The dispensing of this medicine requires a doctor's prescription

Read this package insert carefully in its entirety

before using this medicine

The format of this leaflet was determined by the Ministry of Health

and its content was checked and approved

INVEGA ® INVEGA ®

3 mg 6 mg

Extended ReleaseTablets Extended ReleaseTablets

Composition:

Each extended release Each extended release

tablet contains: tablet contains:

Paliperidone 3 mg Paliperidone 6 mg

INVEGA ®

9 mg

Extended ReleaseTablets

Composition:

Each extended release

tablet contains:

Paliperidone 9 mg

Sodium chloride - 30 mg.

The white coating ofInvega 3 mgcontains lactose.

Additional inactive ingredients:

Polyethylene oxide, 200K, LEO;Povidone (K29-32);Stearic acid

(powder);Butylated hydroxytoluene;Polyethylene oxide,7000K,

LEO;Hydroxyethyl cellulose;Polyethylene glycol 3350, LEO;Cellulose

acetate (398-10);Acetone;Carnauba wax (powder);Ferric oxide

(red);Ink water-based black;Purified water;Hypromellose;Titanium

dioxide E171;Ferric oxide (yellow) E172

and also:

Invega 3 mg: Lactose monohydrate;Triacetin

Invega 6 mg: Polyethylene glycol 400

Invega 9 mg: Polyethylene glycol 400;Iron oxide black (E172)

Therapeutic activity:

The medicine belongs to the class of second generation antipsychotic

medicines and is used for the treatment of schizophrenia and

schizoaffective disorder.

The characteristic symptoms of these diseases are, for example:

hearing, seeing or sensing things that are not there (hallucinations

or delusions), false beliefs, unusual suspiciousness,becoming

withdrawn, incoherent speech, apathy, difficulty concentrating and

despondency.Patients with schizophrenia may experience

depression, anxiety, guilt, self-neglect or tension.Patients with

schizoaffectivedisorder will also experience symptoms of exaggerated

despondent or elated mood, changes in appetite and sleep

disturbances (depression or mania).

When should the preparation not be used?

Do not breastfeed while you are using this medicine.

Do not use if there is a known sensitivity to the active ingredient

paliperidone or to any other ingredients of the medicine, or if you

are sensitive to risperidone.

Do not take this medicine without consulting a doctor before

starting treatment:

If you are pregnant or may be pregnant.Do not use this medicine

during pregnancy except with the doctor's agreement.

If you are suffering, or havesuffered in the past, from impaired

function of:the heart and/or blood vessels - if you are a heart patient

or are receiving treatment for heart disease that may cause low

blood pressure, the liver, the kidney,from Parkinson's disease or

dementia.

If you havesuffered in the past from neuroleptic malignant syndrome

- the signs for which are high fever and muscle stiffness,or from

delayed movement disorder (tardive dyskinesia) - the signs for which

are abnormal movements of the face or tongue.These conditions

may be caused bytaking antipsychotic medicines.

If you are diabetic or at risk for diabetes.The doctor may instruct

you to haveblood tests to monitor your blood sugar level.

From epilepsy or seizures.

If you havea problem swallowing, a stomach or intestinal disorder

that impairs your ability to swallow or pass foods through your

intestines bynormal intestinal motility or from problems that change

the time for passage of food through the intestine.

If you suffer from a narrowing or blockage of the digestive tract.

If you suffer from an illness that causes diarrhea.

If you suffer from prolonged or painful erection.

If you suffer from a problem of body temperature regulation or from

high fever, pay attention to situations that contribute to raising the

body temperature such as strenuous physical activity, exposure to

sources of heat, medical treatment with other medicines with

anticholinergic activity or exposure to dehydrating conditions.

If you or anyone else in your family suffer/s or suffered in the past

from blood clots, since antipsychotics may havean effect on formation

of blood clots.

Invega 3 mg tablet contains lactose (a type of sugar).If you suffer

from intolerance to certain sugars, consult your doctor before taking

this medicine.There is no problem with taking the other dose

strengths since theydo not contain lactose monohydrate.

There is no information regarding the use ofInvegain elderly people

with dementia.Elderly people suffering from dementia who are

treated with antipsychotics similar toInvegamay be at increased

risk for strokeor death.

If you suffer from congenital QT prolongation (a type of arrhythmia),

if you suffer, or havesuffered in the past, from arrhythmias, slowed

heart rate, a drop in the level of magnesium or potassium.

If you haveany of these conditions, you should consult your doctor

since an adjustment of dosage or surveillance for a certain period

of time may be required.

How will this medicine affect your dailylife?

Use of this medicine may cause dizziness, a decline in readiness

and alertness, and vision disturbances.This should be taken into

consideration in situations requiring full alertness, such as when

driving a car or operating dangerous machinery,until you and

your doctor are convinced that the medicine is not causing these

effects.

Donotdrinkwine or alcoholic beverages while under treatment with

this medicine.

Warnings:

Avoid sudden transition from a lying/sitting position to standing,

especially at the beginning of treatment withInvegaor when the

dosage is raised.It is recommended to takethe first dose while

lying or sitting in viewof the fact that a temporary drop in blood

pressure is possible.Patients with heart diseases and patients being

treated with antihypertensives must be careful when changing

position.

Antipsychotic medicines, includingInvega, are associated with a

temporary reduction in the white blood cell count (leucopenia,

neutropenia).In patients suffering from a low white blood cell count

frequent blood counts should be performed in the first months of

treatment, and discontinuation of treatment should be considered

if a significant reduction in white blood cell count occurs without any

other reason.Agranulocytosis has also been reported.

If you are sensitive to any type of food or medicine, inform your

doctor before commencing treatment with this medicine.

Drug interactions:

If you are taking another drug concomitantly or if you havejust

finished treatment with another medicine, inform the attending

doctor, in order to prevent hazards or lack of efficacy arising from

drug interactions.This is especially important for medicines belonging

to the following groups:

SinceInvegaacts mainly on the brain, there may be an increased

effect of other medicines (or alcohol) that act on the brain.

Since the medicine may lower blood pressure, be careful when

taking it together with other medicines that lower blood pressure.

Invega may reduce the effect of medicines for treatment of Parkinson's

disease or restless leg syndrome (for example,levodopa).

Medicines for the treatment of arrhythmias, such as quinidine and

procainamide, amiodarone and sotalol, certain antipsychotics (for

example, chlorpromazine, thioridazine), antibiotics (for example,

gatifloxacin, moxifloxacin).

Carbamazepine.

Divalproexsodium, valproate.

Side effects:

In addition to the desired effect of the medicine, adverse reactions

may occur during the course of taking this medicine, such as:

The most common side effects (more than 5%): are extrapyramidal

symptoms (that can be manifested byimpaired movement, muscle

tone disorder, extrapyramidal disorder, hypertonia, muscle stiffness,

abnormal eyemovement, parkinsonism, tremor, slowness of

movement, drooling, muscle cramps, abnormal gait, restlessness),

extremities, somnolence, dyspepsia, constipation, weight gain and

nasopharyngitis.

Common side effects (more than 2%):

Arrhythmias, tachycardia.

Fixed gaze for varied amounts of time (oculogyric crisis).

Vomiting, upper abdominal pain, dry mouth, salivary hypersecretion,

upper abdominal discomfort, constipation, nausea, stomach

discomfort.

Fatigue, weakness.

Dizziness, headache, reduced alertness, impaired speech.

Lowblood pressure when changing from sitting to standing.

Nasopharyngitis, upper respiratorytract infection, runny nose.

Increased appetite, decreased appetite.

Back pain, muscle pain.

Sleep disturbances.

Cough, pharyngolaryngeal pain.

Uncommon side effects (less than 2%):

Arrhythmias, slowed heart rate, palpitations.

Excessivesecretion of prolactin.

Clouded vision.

Abdominal pain, flatulence, obstruction of the small intestine,

stomach discomfort.

Edema, peripheral edema.

Anaphylactic reaction.

Infections:urinary tract infection.

Abnormal ECG.

Joint pain, pain of the extremities, muscle spasms,back pain, locked

jaws (trismus), twisted neck - a distortion in the position of the neck

due to contraction of the neck muscles, muscle stiffness, muscle

cramps, musculoskeletal pain.

Stroke,convulsions, postural dizziness, epileptic attacks or seizures,

lethargy, fainting, impaired movement and gait, slowness of

movement, transient ischemic attack, muscle spasms, anxiety,

nightmares, restlessness.

Amenorrhea, discharge from the breasts,breast enlargement,

breast tenderness,breast pain, inability to achieve erection, discharge

of milk from the breasts, breast enlargement in men, irregular

menstruation, retrograde ejaculation.

Nasal congestion, pneumonia due to aspiration of digestive juices.

Itching, rash.

Lowblood pressure.

Side effects that requirespecial attention:

Allergic reaction (fever, swelling of the mouth, face, lips or tongue,

shortness of breath, itching, rash, and occasionally a drop in blood

pressure even up to anaphylactic shock) may occur at a low frequency.

If it does occur, seek medical attention immediately.

Elderly patients with dementia and under treatment with medicines

from the same class asInvegamay suffer from sudden weakness,

numbness of the face, arms or legs, episodes of slurred speech or

blurred vision;these symptoms may indicate a stroke.In case any

of these signs is experienced, even for a short period of time, seek

medical attention immediately.

Pain, pressure or a feeling of compression in the chest, difficulty

breathing, pain or feeling of discomfort in the upper part of the body

(arms, shoulders, neck or back), nausea, sweating, dizziness - seek

medical attention immediately.

Involuntary spasms of the face, tongue, mouth or jaws - refer to the

doctor.

Neuroleptic malignant syndrome (see also section“Do not take this

medicine without consulting the doctor before starting treatment”).

Tardivedyskinesia, abnormal movements of the face or tongue.

Veryrarely, a raised blood sugar level has been reported - contact

your doctor if you experience increased thirst or are passing urine

more frequently.

Confusion, clouded consciousness, high fever and acute muscle

rigidity, may occur in rare cases - stop treatment and contact the

doctor immediately.

Decreased white blood cell count - contact the doctor.

If you took an overdose of the medicine (i.e.if you took more than

the dose prescribed bythe doctor) - contact the doctor immediately.

You may experience sleepiness, tiredness, abnormal body

movements, problems with standing and walking, dizziness due to

low blood pressure and an irregular pulse.

A significant change in body temperature may occur in isolated and

veryrare cases (generally due to a number of factors including

extreme heat or cold) - stop treatment and contact the doctor.

Painful or prolonged erection (more than 4 hours), rare - stop

treatment and contact the doctor.

Since paliperidone (the activeingredient inInvega) is a metabolite

of risperidone, any side effect that may occur after taking risperidone

may also occur after takingInvega.

In the event that you experience side effects not mentioned in this

leaflet, or if there is a change in your general health, consult your

doctor immediately.

Recommended dosageunless otherwise prescribed byyour

doctor:

Dosage is according to the doctor's instructions only.

Do not exceed the recommended dosage.

This medicine is to be taken at specific time intervals as determined

byyour doctor.

Takethe medicine every morning, with or without breakfast, but the

same wayeveryday:do not takethe medicine with breakfast one

day and without breakfast the following day.

If you forget to take a dose, do not take a double dose to makeup

for the one you missed.If you forget one dose, take your next dose

at the regularly scheduled time (i.e.the next day) and continue

treatment without any change.If you forget two or more doses -

contact your doctor.

If you took an overdose bymistake - contact your doctor immediately

(see also section“Side effects that require special attention”).

This medicine is not generally intended for patients under 18

years of age.

Attention!

The active ingredient, paliperidone, is dissolved from the tablet after

taking it.

The tablet shell is eliminated from the body with the stool.

Directions for use:

Swallow the tablet whole.

Do not chew,break, crush or halvethe tablet!

Swallow the tablet with water or some other liquid.

How can you contribute to the success of the treatment?

Even if there is an improvement in your health, do not discontinue

treatment with this medicine without consulting your doctor.

Avoidpoisoning!

This medicine,and all other medicines, must be stored in a safe

place out of the reach of children and/or infants, to avoid poisoning.

If you havetaken an overdose or if a child has accidentally swallowed

the medicine, proceed immediately to a hospital emergency room

and bring the package of the medicine with you.

Donotinducevomiting unless explicitly instructed to do so bya

doctor!

This medicine has been prescribed for you, for the treatment of your

ailment;in another patient it may cause harm.Do not give this

medicine to your relatives, neighbors or acquaintances.

Donottakemedicinesinthedark! Check the label and the dose

eachtime you take your medicine.Wear glasses if you need them.

Storage:

Bottle pack:Do not store above30 o C.Protect from moisture.Store

in the original package.Keep the bottle tightly closed to protect from

moisture.

Blister pack:Do not store above30 o C.Protect from moisture.Store

in the original package.

Keep out of the reach and sight of children.

Even if kept in their original container and stored as recommended,

medicines may be kept for a limited period only.Please note the

expiry date of the medicine! In case of doubt, consult the pharmacist

who dispensed the medicine to you.

Do not store different medications in the same package.

License numbers:

Invega 3 mg: 1391531639

Invega 6 mg: 1391631640

Invega 9 mg: 1391731641

Manufacturer:

Alza Corporation,Vacaville, California, USA.

Registration holder:

J-C Health Care Ltd.,

Kibbutz Shefayim 60990, Israel.

Invega PI Dec 2013 CL

FULL PRESCRIBING INFORMATION

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-

RELATED PSYCHOSIS

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an

increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10

weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in

drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated

patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-

treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.

Although the causes of death were varied, most of the deaths appeared to be either

cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.

Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with

conventional antipsychotic drugs may increase mortality. The extent to which the findings

of increased mortality in observational studies may be attributed to the antipsychotic drug

as opposed to some characteristic(s) of the patients is not clear. INVEGA

®

(paliperidone)

Extended-Release Tablets is not approved for the treatment of patients with dementia-

related psychosis. [see Warnings and Precautions (5.1)]

1

INDICATIONS AND USAGE

1.1

Schizophrenia

INVEGA

(paliperidone)

Extended-Release

Tablets

indicated

treatment

schizophrenia in adults and adolescents (12-17 years)

[see Clinical Studies (14)]

Monotherapy

INVEGA

(paliperidone) Extended-Release Tablets are indicated for the acute treatment of

schizoaffective disorder as monotherapy

Adjunctive Therapy

INVEGA

(paliperidone) Extended-Release Tablets are indicated for the acute treatment of

schizoaffective disorder as an adjunct to mood stabilizers and/or antidepressants.

2

DOSAGE AND ADMINISTRATION

2.1

Schizophrenia

Adults

The recommended dose of INVEGA

(paliperidone) Extended-Release Tablets for the treatment

of schizophrenia in adults is 6 mg once daily, administered in the morning. Initial dose titration is

not required. Although it has not been systematically established that doses above 6 mg have

additional benefit, there was a general trend for greater effects with higher doses. This must be

Invega PI Dec 2013 CL

weighed against the dose-related increase in adverse reactions. Thus, some patients may benefit

from higher doses, up to 12 mg/day, and for some patients, a lower dose of 3 mg/day may be

sufficient. Dose increases above 6 mg/day should be made only after clinical reassessment and

generally should occur at intervals of more than 5 days. When dose increases are indicated,

increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day.

In a longer-term study, INVEGA

has been shown to be effective in delaying time to relapse in

patients with schizophrenia who were stabilized on INVEGA

for 6 weeks

[see Clinical Studies

(14)]

. INVEGA

should be prescribed at the lowest effective dose for maintaining clinical

stability and the physician should periodically reevaluate the long-term usefulness of the drug in

individual patients.

Adolescents (12-17 years of age)

The recommended starting dose of INVEGA® (paliperidone) Extended-Release Tablets for the

treatment of schizophrenia in adolescents 12-17 years of age is 3 mg administered once daily.

Initial dose titration is not required. Dose increases, if considered necessary, should be made

only after clinical reassessment and should occur at increments of 3 mg/day at intervals of more

than 5 days. Prescribers should be mindful that, in the adolescent schizophrenia study, there was

no clear enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than

51 kg and 12 mg for subjects weighing 51 kg or greater, while adverse events were dose-related.

2.2

Schizoaffective Disorder

The recommended dose of INVEGA

(paliperidone) Extended-Release Tablets for the treatment

of schizoaffective disorder is 6 mg administered once daily, administered in the morning. Initial

dose titration is not required. Some patients may benefit from lower or higher doses within the

recommended dose range of 3 to 12 mg once daily. A general trend for greater effects was seen

with higher doses. This trend must be weighed against dose-related increase in adverse reactions.

Dosage adjustment, if indicated, should occur only after clinical reassessment. Dose increases, if

indicated, generally should occur at intervals of more than 4 days. When dose increases are

indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12

mg/day.

2.3

Administration Instructions

INVEGA

can be taken with or without food. Clinical trials establishing the safety and efficacy

of INVEGA® were carried out in patients without regard to food intake.

INVEGA

must be swallowed whole with the aid of liquids. Tablets should not be chewed,

divided, or crushed. The medication is contained within a nonabsorbable shell designed to

release the drug at a controlled rate. The tablet shell, along with insoluble core components, is

Invega PI Dec 2013 CL

eliminated from the body; patients should not be concerned if they occasionally notice in their

stool something that looks like a tablet.

2.4

Use with Risperidone

Concomitant use of INVEGA

with risperidone has not been studied. Since paliperidone is the

major active metabolite of risperidone, consideration should be given to the additive paliperidone

exposure if risperidone is coadministered with INVEGA

2.5

Dosage in Special Populations

Renal Impairment

Dosing must be individualized according to the patient’s renal function status. For patients with

mild renal impairment (creatinine clearance

50 mL/min to < 80 mL/min), the recommended

initial dose of INVEGA

is 3 mg once daily. The dose may then be increased to a maximum of 6

mg once daily based on clinical response and tolerability. For patients with moderate to severe

renal impairment (creatinine clearance

10 mL/min to < 50 mL/min), the recommended initial

dose of INVEGA

is 3 mg once daily. As INVEGA

has not been studied in patients with

creatinine clearance below 10 mL/min, use is not recommended in such patients.

[See Clinical

Pharmacology (12.3)]

Hepatic Impairment

For patients with mild to moderate hepatic impairment, (Child-Pugh Classification A and B), no

dose adjustment is recommended

[see Clinical Pharmacology (12.3)]

. INVEGA

has not been

studied in patients with severe hepatic impairment.

Elderly

Because elderly patients may have diminished renal function, dose adjustments may be required

according to their renal function status. In general, recommended dosing for elderly patients with

normal renal function is the same as for younger adult patients with normal renal function. For

patients

with

moderate

severe

renal

impairment

(creatinine

clearance

mL/min

< 50 mL/min), the maximum recommended dose of INVEGA

is 3 mg once daily

[see Renal

Impairment above]

3

DOSAGE FORMS AND STRENGTHS

INVEGA

Extended-Release Tablets are available in the following strengths and colors: 3 mg

(white), 6 mg (beige), and 9 mg (pink). All tablets are capsule shaped and are imprinted with

either “PAL 3”, “PAL 6”, or “PAL 9”.

4

CONTRAINDICATIONS

Hypersensitivity

reactions,

including

anaphylactic

reactions

angioedema,

have

been

observed in patients treated with risperidone and paliperidone. INVEGA

(paliperidone) is a

Invega PI Dec 2013 CL

metabolite

risperidone

therefore

contraindicated

patients

with

known

hypersensitivity to either paliperidone or risperidone, or to any of the excipients in INVEGA

5

WARNINGS AND PRECAUTIONS

5.1

Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an

increased risk of death. INVEGA

®

(paliperidone) is not approved for the treatment of

dementia-related psychosis [see Boxed Warning].

5.2

Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients

With Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with

dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular

accidents

transient

ischemic

attacks)

including

fatalities

compared

placebo-treated

subjects. INVEGA

was not marketed at the time these studies were performed. INVEGA

not approved for the treatment of patients with dementia-related psychosis

[see also Boxed

Warning and Warnings and Precautions (5.1)]

5.3

Neuroleptic Malignant Syndrome

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome

(NMS)

been

reported

association

with

antipsychotic

drugs,

including

paliperidone.

Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and

evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis,

cardiac

dysrhythmia).

Additional

signs

include

elevated

creatine

phosphokinase,

myoglobinuria (rhabdomyolysis), and acute renal failure.

The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a

diagnosis, it is important to identify cases in which the clinical presentation includes both serious

medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated

extrapyramidal signs and symptoms (EPS). Other important considerations in the differential

diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central

nervous system pathology.

The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs

and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and

medical monitoring; and (3) treatment of any concomitant serious medical problems for which

specific treatments are available. There is no general agreement about specific pharmacological

treatment regimens for uncomplicated NMS.

patient

appears

require

antipsychotic

drug

treatment

after

recovery

from

NMS,

Invega PI Dec 2013 CL

reintroduction of drug therapy should be closely monitored, since recurrences of NMS have been

reported.

5.4

QT Prolongation

Paliperidone

causes

modest

increase

corrected

(QTc)

interval.

paliperidone should be avoided in combination with other drugs that are known to prolong QTc

including Class 1A

(e.g.,

quinidine,

procainamide) or Class III (e.g., amiodarone,

sotalol)

antiarrhythmic

medications,

antipsychotic

medications

(e.g.,

chlorpromazine,

thioridazine),

antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong

the QTc interval. Paliperidone should also be avoided in patients with congenital long QT

syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or

sudden death in association with the use of drugs that prolong the QTc interval, including

(1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that

prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

The effects of paliperidone on the QT interval were evaluated in a double-blind, active-

controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia

and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose

efficacy trials in adults with schizophrenia.

In the QT study (n = 141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed

a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on

day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg

dose of paliperidone immediate-release was more than twice the exposure observed with the

maximum recommended 12 mg dose of INVEGA

ss = 113 ng/mL and 45 ng/mL,

respectively, when administered with a standard breakfast). In this same study, a 4 mg dose of

the immediate-release oral formulation of paliperidone, for which C

ss = 35 ng/mL, showed

an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours

post-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding

500 msec at any time during this study.

For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram

(ECG) measurements taken at various time points showed only one subject in the INVEGA

mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No

subject receiving INVEGA

had a QTcLD exceeding 500 msec at any time in any of these three

studies.

5.5

Tardive Dyskinesia

Invega PI Dec 2013 CL

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in

patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be

highest among the elderly, especially elderly women, it is impossible to predict which patients

will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause

tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible

appear to increase as the duration of treatment and the total cumulative dose of antipsychotic

drugs administered to the patient increase, but the syndrome can develop after relatively brief

treatment periods at low doses, although this is uncommon.

There is no known treatment for established tardive dyskinesia, although the syndrome may

remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment

itself may suppress (or partially suppress) the signs and symptoms of the syndrome and may thus

mask the underlying process. The effect of symptomatic suppression on the long-term course

of the syndrome is unknown.

Given these considerations, INVEGA

should be prescribed in a manner that is most likely to

minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally

reserved

patients

suffer

from

chronic

illness

that

known

respond

antipsychotic drugs. In patients who do require chronic treatment, the smallest dose and the

shortest duration of treatment producing a satisfactory clinical response should be sought. The

need for continued treatment should be reassessed periodically.

If signs and symptoms of tardive dyskinesia appear in a patient treated with INVEGA

, drug

discontinuation should be considered. However, some patients may require treatment with

INVEGA

despite the presence of the syndrome.

5.6

Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase

cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia,

dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to

produce some metabolic changes, each drug has its own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or

hyperosmolar

coma

death,

been

reported

patients

treated

with

atypical

antipsychotics. These cases were, for the most part, seen in post-marketing clinical use and

Invega PI Dec 2013 CL

epidemiologic studies, not in clinical trials, and there have been few reports of hyperglycemia or

diabetes in trial subjects treated with INVEGA

. Assessment of the relationship between atypical

antipsychotic use and glucose abnormalities is complicated by the possibility of an increased

background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence

of diabetes mellitus in the general population. Given these confounders, the relationship between

atypical

antipsychotic

hyperglycemia-related

adverse

events

completely

understood. However, epidemiological studies suggest an increased risk of treatment-emergent

hyperglycemia-related

adverse

events

patients

treated

with

atypical

antipsychotics.

Because INVEGA

was not marketed at the time these studies were performed, it is not known if

INVEGA

is associated with this increased risk.

Patients

with

established

diagnosis

diabetes

mellitus

started

atypical

antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk

factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment

with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of

treatment and periodically during treatment. Any patient treated with atypical antipsychotics

should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia,

and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical

antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has

resolved when the atypical antipsychotic was discontinued; however, some patients required

continuation of anti-diabetic treatment despite discontinuation of the suspect drug.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with

schizophrenia are presented in Table 1a.

Table 1a. Change in Fasting Glucose from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult

Subjects with Schizophrenia

INVEGA®

Placebo

3 mg/day

6 mg/day

9 mg/day

12 mg/day

Mean change from baseline (mg/dL)

n=322

n=122

n=212

n=234

n=218

Serum Glucose

Change from

baseline

-0.7

Proportion of Patients with Shifts

Serum Glucose

Normal to High

5.1%

3.2%

4.5%

4.8%

3.8%

(<100 mg/dL to

≥126 mg/dL)

(12/236)

(3/93)

(7/156)

(9/187)

(6/157)

In the uncontrolled, longer-term open-label extension studies, INVEGA® was associated with a

mean change in glucose of +3.3 mg/dL at Week 24 (n=570) and +4.6 mg/dL at Week 52

(n=314).

Invega PI Dec 2013 CL

Data from the placebo-controlled 6-week study in adolescent subjects (12-17 years of age) with

schizophrenia are presented in Table 1b.

Table 1b. Change in Fasting Glucose from a Placebo-Controlled, 6-Week study in Adolescent Subjects (12-17

years of age) with Schizophrenia

INVEGA®

Placebo

1.5 mg/day

3 mg/day

6 mg/day

12 mg/day

Mean change from baseline (mg/dL)

n=41

n=44

n=11

n=28

n=32

Serum Glucose

Change from

baseline

-1.4

-1.8

-0.1

Proportion of Patients with Shifts

Serum Glucose

Normal to High

(<100 mg/dL to

≥126 mg/dL)

(1/32)

0/34)

(0/9)

(0/20)

(3/27)

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical

antipsychotics.

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with

schizophrenia are presented in Table 2a.

Table 2a. Change in Fasting Lipids from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult

Subjects with Schizophrenia

INVEGA®

Placebo

3 mg/day

6 mg/day

9 mg/day

12 mg/day

Mean change from baseline (mg/dL)

Cholesterol

n=331

n=120

n=216

n=236

n=231

Change from

baseline

-6.3

-4.4

-2.4

-5.3

-4.0

LDL

n=322

n=116

n=210

n=231

n=225

Change from

baseline

-3.2

-0.8

-3.9

-2.0

HDL

n=331

n=119

n=216

n=234

n=230

Change from

baseline

-0.4

Triglycerides

n=331

n=120

n=216

n=236

n=231

Change from

baseline

-22.3

-18.3

-12.6

-10.6

-15.4

Proportion of Patients with Shifts

Cholesterol

Normal to High

2.6%

2.8%

5.6%

4.1%

3.1%

(<200 mg/dL to

≥240 mg/dL)

(5/194)

(2/71)

(7/125)

(6/147)

(4/130)

LDL

Normal to High

1.9%

0.0%

5.0%

3.7%

0.0%

(<100 mg/dL to

≥160 mg/dL)

(2/105)

(0/44)

(3/60)

(3/81)

(0/69)

HDL

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Normal to Low

22.0%

16.3%

29.1%

23.4%

20.0%

( ≥40 mg/dL to

<40 mg/dL)

(44/200)

(13/80)

(39/134)

(32/137)

(27/135)

Triglycerides

Normal to High

5.3%

11.0%

8.8%

8.7%

4.3%

(<150 mg/dL to

≥200 mg/dL)

(11/208)

(9/82)

(12/136)

(13/150)

(6/139)

In the uncontrolled, longer-term open-label extension studies, INVEGA® was associated with a

mean change in (a) total cholesterol of -1.5 mg/dL at Week 24 (n=573) and -1.5 mg/dL at Week

52 (n=317), (b) triglycerides of -6.4 mg/dL at Week 24 (n=573) and -10.5 mg/dL at Week 52

(n=317); (c) LDL of -1.9 mg/dL at Week 24 (n=557) and -2.7 mg/dL at Week 52 (n=297); and

(d) HDL of +2.2 mg/dL at Week 24 (n=568) and +3.6 mg/dL at Week 52 (n=302).

Data from the placebo-controlled 6-week study in adolescent subjects (12-17 years of age) with

schizophrenia are presented in Table 2b

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Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is

recommended.

Schizophrenia Trials

Data on mean changes in body weight and the proportion of subjects meeting a weight gain

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criterion of ≥ 7% of body weight from the three placebo-controlled, 6-week, fixed-dose studies

in adult subjects are presented in Table 3a.

Table 3a. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight

from Three Placebo-Controlled, 6-Week, Fixed-Dose Studies in Adult Subjects with Schizophrenia

INVEGA®

Placebo

3 mg/day

6 mg/day

9 mg/day

12 mg/day

n=323

n=112

n=215

n=235

n=218

Weight (kg)

Change from baseline

-0.4

Weight Gain

≥ 7% increase from

baseline

In the uncontrolled, longer-term open-label extension studies, INVEGA® was associated with a

mean change in weight of +1.4 kg at Week 24 (n=63) and +2.6 kg at Week 52 (n=302).

Weight gain in adolescent subjects with schizophrenia was assessed in a 6-week, double-blind,

placebo-controlled study and an open-label extension with a median duration of exposure to

INVEGA® of 182 days. Data on mean changes in body weight and the proportion of subjects

meeting a weight gain criterion of ≥ 7% of body weight [see Clinical Studies (14.1)] from the

placebo-controlled 6-week study in adolescent subjects (12-17 years of age) are presented in

Table 3b.

Table 3b. Mean Change in Body Weight (kg) and the Proportion of Subjects with ≥ 7% Gain in Body Weight

from a Placebo-Controlled, 6-Week Study in Adolescent Subjects (12-17 years of age) with Schizophrenia

INVEGA®

Placebo

1.5 mg/day

3 mg/day

6 mg/day

12 mg/day

n=51

n=54

n=16

n=45

n=34

Weight (kg)

Change from baseline

Weight Gain

≥ 7% increase from

baseline

In the open-label long-term study the proportion of total subjects treated with INVEGA® with an

increase in body weight of ≥ 7% from baseline was 33%. When treating adolescent patients with

INVEGA®, weight gain should be assessed against that expected with normal growth. When

taking into consideration the median duration of exposure to INVEGA® in the open-label study

(182 days) along with expected normal growth in this population based on age and gender, an

assessment of standardized scores relative to normative data provides a more clinically relevant

measure of changes in weight. The mean change from open-label baseline to endpoint in

standardized score for weight was 0.1 (4% above the median for normative data). Based on

comparison to the normative data, these changes are not considered to be clinically significant

Invega PI Dec 2013 CL

Schizoaffective Disorder Trials

In the pooled data from the two placebo-controlled, 6-week studies in adult subjects with

schizoaffective

disorder,

higher

percentage

INVEGA®-treated

subjects

(5%)

increase in body weight of ≥7% compared with placebo-treated subjects (1%). In the study that

examined high- and low-dose groups, the increase in body weight of ≥ 7% was 3% in the low-

dose group, 7% in the high-dose group, and 1% in the placebo group.

5.7

Hyperprolactinemia

Like other drugs that antagonize dopamine D

receptors, paliperidone elevates prolactin levels

and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating

effect similar to that seen with risperidone, a drug that is associated with higher levels of

prolactin than other antipsychotic drugs.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in

reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by

impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea,

gynecomastia,

impotence

have

been

reported

patients

receiving

prolactin-elevating

compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to

decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are

prolactin dependent

in vitro

, a factor of potential importance if the prescription of these drugs is

considered in a patient with previously detected breast cancer. An increase in the incidence of

pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas,

pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies

conducted in mice and rats

[see Nonclinical Toxicology (13.1)]

. Neither clinical studies nor

epidemiologic

studies

conducted

date

have

shown

association

between

chronic

administration of this class of drugs and tumorigenesis in humans, but the available evidence is

too limited to be conclusive.

5.8

Potential for Gastrointestinal Obstruction

Because the INVEGA

tablet is non-deformable and does not appreciably change in shape in the

gastrointestinal tract, INVEGA

should ordinarily not be administered to patients with pre-

existing severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal

motility disorders, small bowel inflammatory disease, “short gut” syndrome due to adhesions or

Invega PI Dec 2013 CL

decreased

transit

time,

past

history

peritonitis,

cystic

fibrosis,

chronic

intestinal

pseudoobstruction,

Meckel’s

diverticulum)

patients

with

dysphagia

significant

difficulty in swallowing tablets. There have been rare reports of obstructive symptoms in patients

with known strictures in association with the ingestion of drugs in non-deformable controlled-

release formulations. Because of the controlled-release design of the tablet, INVEGA

should

only

used

patients

able

swallow

tablet

whole

[see

Dosage

and

Administration (2.3) and Patient Counseling Information (17.8)]

decrease

transit

time,

e.g.,

seen

with

diarrhea,

would

expected

decrease

bioavailability and an increase in transit time, e.g., as seen with gastrointestinal neuropathy,

diabetic gastroparesis, or other causes, would be expected to increase bioavailability. These

changes in bioavailability are more likely when the changes in transit time occur in the upper GI

tract.

5.9

Orthostatic Hypotension and Syncope

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its

alpha-blocking activity. In pooled results of the three placebo-controlled, 6-week, fixed-dose

trials in subjects with schizophrenia, syncope was reported in 0.8% (7/850) of subjects treated

with INVEGA

(3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with

placebo.

INVEGA

should be used with caution in patients with known cardiovascular disease

(e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities),

cerebrovascular

disease,

conditions

that

predispose

patient

hypotension

(e.g.,

dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of

orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

5.10 Leukopenia, Neutropenia, and Agranulocytosis

Class Effect:

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia

have

been

reported

temporally

related

antipsychotic

agents,

including

INVEGA

Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count

(WBC)

history

drug-induced

leukopenia/neutropenia.

Patients

with

history

clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their

complete blood count (CBC) monitored frequently during the first few months of therapy and

discontinuation of INVEGA

should be considered at the first sign of a clinically significant

decline in WBC in the absence of other causative factors.

Patients with clinically significant neutropenia should be carefully monitored for fever or other

symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients

Invega PI Dec 2013 CL

with severe neutropenia (absolute neutrophil count <1000/mm

) should discontinue INVEGA

and have their WBC followed until recovery.

5.11 Potential for Cognitive and Motor Impairment

Somnolence was reported in subjects treated with INVEGA

[see Adverse Reactions (6.1, 6.2)]

Antipsychotics, including INVEGA

, have the potential to impair judgment, thinking, or motor

skills. Patients should be cautioned about performing activities requiring mental alertness, such

as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain

that paliperidone therapy does not adversely affect them.

5.12 Seizures

During premarketing clinical trials in subjects with schizophrenia (the three placebo-controlled,

6-week, fixed-dose studies and a study conducted in elderly schizophrenic subjects), seizures

occurred in 0.22% of subjects treated with INVEGA

(3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of

subjects

treated

with

placebo.

Like

other

antipsychotic

drugs,

INVEGA

should

used

cautiously in patients with a history of seizures or other conditions that potentially lower the

seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients

65 years or older.

5.13 Dysphagia

Esophageal

dysmotility

aspiration

have

been

associated

with

antipsychotic

drug

use.

Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced

Alzheimer’s dementia. INVEGA

and other antipsychotic drugs should be used cautiously in

patients at risk for aspiration pneumonia.

5.14 Suicide

The possibility of suicide attempt is inherent in psychotic illnesses, and close supervision of

high-risk patients should accompany drug therapy. Prescriptions for INVEGA

should be written

for the smallest quantity of tablets consistent with good patient management in order to reduce

the risk of overdose.

5.15 Priapism

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism

has been reported with INVEGA

during postmarketing surveillance. Severe priapism may

require surgical intervention.

5.16 Thrombotic Thrombocytopenic Purpura (TTP)

No cases of TTP were observed during clinical studies with paliperidone. Although cases of

TTP have been reported in association with risperidone administration, the relationship to

risperidone therapy is unknown.

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5.17 Body Temperature Regulation

Disruption

body’s

ability

reduce

core

body

temperature

been

attributed

antipsychotic agents. Appropriate care is advised when prescribing INVEGA

to patients who

will be experiencing conditions which may contribute to an elevation in core body temperature,

e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with

anticholinergic activity, or being subject to dehydration.

5.18 Antiemetic Effect

An antiemetic effect was observed in preclinical studies with paliperidone. This effect, if it

occurs in humans, may mask the signs and symptoms of overdosage with certain drugs or of

conditions such as intestinal obstruction, Reye’s syndrome, and brain tumor.

5.19 Use in Patients with Concomitant Illness

Clinical experience with INVEGA

in patients with certain concomitant illnesses is limited

[see

Clinical Pharmacology (12.3)]

Patients with Parkinson’s Disease or Dementia with Lewy Bodies are reported to have an

increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity

include

confusion,

obtundation,

postural

instability

with

frequent

falls,

extrapyramidal

symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

INVEGA

has not been evaluated or used to any appreciable extent in patients with a recent

history of myocardial infarction or unstable heart disease. Patients with these diagnoses were

excluded from premarketing clinical trials. Because of the risk of orthostatic hypotension with

INVEGA

, caution should be observed in patients with known cardiovascular disease

[see

Warnings and Precautions (5.9)]

5.20 Monitoring: Laboratory Tests

No specific laboratory tests are recommended.

5.21 Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products.

Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible

risk factors for VTE should be identified before and during treatment with INVEGA and preventive

measures undertaken.

5.22 Lactose content (pertains only to the 3 mg tablets)

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-

galactose malabsorption should not take this medicine.

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5.23 Intraoperative Floppy Iris Syndrome

Intraoperative floppy iris syndrome (IFIS) has been observed during cataract surgery in patients

treated with medicines with alpha1a

adrenergic antagonist effect, such as INVEGA

IFIS may increase the risk of eye complications during and after the operation. Current or past

use of medicines with alpha1a

adrenergic antagonist effect should be made known to the

ophthalmic surgeon in advance of surgery. The potential benefit of stopping alpha1 blocking

therapy prior to cataract surgery has not been established and must be weighed against the risk of

stopping the antipsychotic therapy.

6

ADVERSE REACTIONS

6.1 Overall Adverse Reaction Profile

The following adverse reactions are discussed in more detail in other sections of the labeling:

Increased mortality in elderly patients with dementia-related psychosis

[see Boxed Warning

and

Warnings and Precautions (5.1)]

Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related

psychosis

[

Warnings and Precautions (5.2)]

Neuroleptic malignant syndrome

[

Warnings and Precautions (5.3)]

QT prolongation

[see Warnings and Precautions (5.4)]

Tardive dyskinesia

[see Warnings and Precautions (5.5)]

Metabolic changes

[see Warnings and Precautions (5.6)]

Hyperprolactinemia

[see

Warnings and Precautions (5.7)]

Potential for Gastrointestinal Obstruction

[see Warnings and Precautions (5.8)]

Orthostatic hypotension and syncope

[see

Warnings and Precautions (5.9)]

Leukopenia, neutropenia, and agranulocytosis

[see Warnings and Precautions (5.10)]

Potential for cognitive and motor impairment

[

Warnings and Precautions (5.11)]

Seizures

[see Warnings and Precautions (5.12)]

Dysphagia

[see Warnings and Precautions (5.13)]

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Suicide

[see Warnings and Precautions (5.14)]

Priapism

[see Warnings and Precautions (5.15)]

Thrombotic thrombocytopenic purpura (TTP)

[see Warnings and Precautions (5.16)]

Disruption of body temperature regulation

[see Warnings and Precautions (5.17)]

Antiemetic effect

[see Warnings and Precautions (5.18)]

Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy

bodies

[see Warnings and Precautions (5.19)]

Diseases

conditions

that

could

affect

metabolism

hemodynamic

responses

[see

Warnings and Precautions (5.19)]

The most common adverse reactions in clinical trials in adult subjects with schizophrenia

(reported in 5% or more of subjects treated with INVEGA

and at least twice the placebo rate in

any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most

common adverse reactions in clinical trials in adult patients with schizoaffective disorder

(reported in 5% or more of subjects treated with INVEGA

and at least twice the placebo rate)

were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and

nasopharyngitis.

The most common adverse reactions that were associated with discontinuation from clinical

trials in adult subjects with schizophrenia (causing discontinuation in 2% of INVEGA

-treated

subjects)

were

nervous

system

disorders.

most

common

adverse

reactions

that

were

associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder

were gastrointestinal disorders, which resulted in discontinuation in 1% of INVEGA

-treated

subjects.

[See Adverse Reactions (6.4)]

safety

INVEGA

evaluated

1205

adult

subjects

with

schizophrenia

participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects

received INVEGA

at fixed doses ranging from 3 mg to 12 mg once daily. The information

presented in this section was derived from pooled data from these three trials. Additional safety

information from the placebo-controlled phase of the long-term maintenance study, in which

subjects received INVEGA

at daily doses within the range of 3 mg to 15 mg (n=104), is also

included.

Invega PI Dec 2013 CL

The safety of INVEGA® was evaluated in 150 adolescent subjects 12-17 years of age with

schizophrenia who received INVEGA® in the dose range of 1.5 mg to 12 mg/day in a 6-week,

double-blind, placebo-controlled trial.

The safety of INVEGA

was also evaluated in 622 adult subjects with schizoaffective disorder

who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials,

206 subjects were assigned to one of two dose levels of INVEGA

: 6 mg with the option to

reduce to 3 mg (n = 108) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. In the

other study, 214 subjects received flexible doses of INVEGA

(3-12 mg once daily). Both

studies included subjects who received INVEGA

either as monotherapy or as an adjunct to

mood stabilizers and/or antidepressants. Adverse events during exposure to study treatment were

obtained by general inquiry and recorded by clinical investigators using their own terminology.

Consequently, to provide a meaningful estimate of the proportion of individuals experiencing

adverse events, events were grouped in standardized categories using MedDRA terminology.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that

were considered to be reasonably associated with the use of INVEGA

(adverse drug reactions)

based on the comprehensive assessment of the available adverse event information. A causal

association for INVEGA

often cannot be reliably established in individual cases. Further,

because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials

of another drug and may not reflect the rates observed in clinical practice.

6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-

Controlled Clinical Trials – Schizophrenia in Adults and Adolescents

Adult Patients with Schizophrenia

Table

4

enumerates

pooled

incidences

adverse

reactions

reported

three

placebo-controlled, 6-week, fixed-dose studies in adults, listing those that occurred in 2% or

more of subjects treated with INVEGA

in any of the dose groups, and for which the incidence

in INVEGA

-treated subjects in any of the dose groups was greater than the incidence in

subjects treated with placebo.

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Table 4.

Adverse Reactions Reported by

2% of INVEGA

®

-Treated

Adult Subjects with Schizophrenia in Three Short-Term, Fixed-

Dose, Placebo-Controlled Clinical Trials

Percent of Patients

INVEGA

Placebo

3 mg

once

daily

6 mg

once

daily

9 mg

once

daily

12 mg

once daily

Body System or

Organ Class

(N=355)

(N=127)

(N=235)

(N=246)

(N=242)

Dictionary-Derived

Term

Total percentage of

subjects with adverse

reactions

Cardiac disorders

Atrioventricular block

first degree

Bundle branch block

<1

Sinus arrhythmia

<1

Tachycardia

Gastrointestinal

disorders

Abdominal pain upper

Dry mouth

Salivary

hypersecretion

<1

<1

General disorders

Asthenia

<1

Fatigue

Nervous system

disorders

Akathisia

Dizziness

Extrapyramidal

symptoms

Headache

Somnolence

Vascular disorders

Orthostatic

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Percent of Patients

INVEGA

Placebo

3 mg

once

daily

6 mg

once

daily

9 mg

once

daily

12 mg

once daily

Body System or

Organ Class

(N=355)

(N=127)

(N=235)

(N=246)

(N=242)

Dictionary-Derived

Term

hypotension

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Percent of Patients

INVEGA

Placebo

3 mg

once

daily

6 mg

once

daily

9 mg

once

daily

12 mg

once daily

Body System or

Organ Class

(N=355)

(N=127)

(N=235)

(N=246)

(N=242)

Dictionary-Derived

Term

* Table includes adverse reactions that were reported in 2% or more of subjects

in any of the INVEGA

dose groups and which occurred at greater incidence

than in the placebo group. Data are pooled from three studies; one study

included once-daily INVEGA

doses of 3 mg and 9 mg, the second study

included 6 mg, 9 mg, and 12 mg, and the third study included 6 mg and 12 mg

[see Clinical Studies (14)]). Extrapyramidal symptoms includes the terms

dyskinesia, dystonia, extrapyramidal disorder, hypertonia, muscle rigidity,

oculogyration, parkinsonism, and tremor. Somnolence includes the terms

sedation and somnolence. Tachycardia includes the terms tachycardia, sinus

tachycardia, and heart rate increased. Adverse reactions for which the

INVEGA

incidence was equal to or less than placebo are not listed in the

table, but included the following: vomiting.

Adolescent Patients with Schizophrenia

Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled

study in adolescent subjects 12-17 years of age with schizophrenia, listing

those that occurred in 2% or more of subjects treated with INVEGA® in any

of the dose groups, and for which the incidence in INVEGA®-treated subjects

in any of the dose groups was greater than the incidence in subjects treated

with placebo.

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6.3

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-

Controlled Clinical Trials – Schizoaffective Disorder in Adults

Table 6

enumerates the pooled incidences of adverse reactions reported in the two placebo-

controlled 6-week studies in adult subjects, listing those that occurred in 2% or more of subjects

treated with INVEGA

and for which the incidence in INVEGA

-treated subjects was greater

than the incidence in subjects treated with placebo.

Table 6.

Adverse Drug Reactions Reported by

2% of INVEGA

®

-

Treated Adult Subjects with Schizoaffective Disorder in Two

Double-Blind, Placebo-Controlled Clinical Trials

Precentage of patients

Placebo

INVEGA

®

3-6 mg

once-daily

fixed-dose

range

INVEGA

®

9-12 mg

once-daily

fixed-dose

range

INVEGA

®

3-12 mg

once-daily

flexible-

dose

Body System or Organ

Class

(N=202)

(N=108)

(N=98)

(N=214)

Dictionary-Derived Term

Total percentage of

subjects with adverse

reactions

Cardiac disorders

Tachycardia

Gastrointestinal disorders

Abdominal

discomfort/Abdominal pain

upper

Constipation

Dyspepsia

Nausea

Stomach discomfort

General disorders

Asthenia

<1

Infections and

Infestations

Nasopharyngitis

Rhinitis

Upper respiratory tract

infection

Investigations

Invega PI Dec 2013 CL

Placebo

INVEGA

®

3-6 mg

once-daily

fixed-dose

range

INVEGA

®

9-12 mg

once-daily

fixed-dose

range

INVEGA

®

3-12 mg

once-daily

flexible-

dose

Body System or Organ

Class

(N=202)

(N=108)

(N=98)

(N=214)

Dictionary-Derived Term

Weight increased

Metabolism and nutrition

disorders

Decreased appetite

<1

Increased appetite

<1

Musculoskeletal and

connective tissue

disorders

Back pain

Myalgia

<1

Nervous system disorders

Akathisia

Dysarthria

Extrapyramidal symptoms

Somnolence

Psychiatric disorders

Sleep disorder

<1

Respiratory, thoracic and

mediastinal disorders

Cough

Pharyngolaryngeal pain

<1

* Table includes adverse reactions that were reported in 2% or more of subjects

in any of the INVEGA

dose groups and which occurred at greater incidence

than in the placebo group. Data are pooled from two studies. One study included

once-daily INVEGA

doses of 6 mg (with the option to reduce to 3 mg) and 12

mg (with the option to reduce to 9 mg). The second study included flexible

once-daily

doses

Among

subjects

treated

with

INVEGA

, 230 (55%) received INVEGA

as monotherapy and 190 (45%)

received INVEGA

as an adjunct to mood stabilizers and/or antidepressants.

Extrapyramidal

symptoms

includes

terms

bradykinesia,

drooling,

dyskinesia,

dystonia,

hypertonia,

muscle

rigidity,

muscle

twitching,

oculogyration,

parkinsonian

gait,

parkinsonism,

restlessness,

tremor.

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Somnolence includes the terms sedation and somnolence. Tachycardia includes

the terms tachycardia, sinus tachycardia, and heart rate increased.

Monotherapy versus Adjunctive Therapy

The designs of the two placebo-controlled, 6-week, double-blind trials in adult subjects with

schizoaffective disorder included the option for subjects to receive antidepressants (except

monoamine oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine). In

subject

population

evaluated

safety,

(55%)

subjects

received

INVEGA

monotherapy and 190 (45%) subjects received INVEGA

as an adjunct to mood stabilizers

and/or antidepressants. When comparing these 2 subpopulations, only nausea occurred at a

greater frequency (≥ 3% difference) in subjects receiving INVEGA

as monotherapy.

6.4

Discontinuations Due to Adverse Reactions

Schizophrenia Trials

The percentages of subjects who discontinued due to adverse reactions in the three schizophrenia

placebo-controlled, 6-week, fixed-dose studies in adults were 3% and 1% in INVEGA

- and

placebo-treated subjects, respectively. The most common reasons for discontinuation were

nervous system disorders (2% and 0% in INVEGA

- and placebo-treated subjects, respectively).

Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents

with schizophrenia, only dystonia led to discontinuation (<1% of INVEGA®-treated subjects).

Schizoaffective Disorder Trials

The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective

disorder placebo-controlled 6-week studies in adults were 1% and <1% in INVEGA

- and

placebo-treated subjects, respectively. The most common reasons for discontinuation were

gastrointestinal disorders (1% and 0% in INVEGA

- and placebo-treated subjects, respectively).

6.5

Dose-Related Adverse Reactions

Schizophrenia Trials

Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult

subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2%

incidence in the subjects treated with INVEGA

, the incidences of the following adverse

reactions

increased

with

dose:

somnolence,

orthostatic

hypotension,

akathisia,

dystonia,

extrapyramidal disorder, hypertonia, parkinsonism, and salivary hypersecretion. For most of

these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg

dose.

in the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the

adverse reactions that occurred with >2% incidence in the subjects treated with INVEGA®, the

Invega PI Dec 2013 CL

incidences

following

adverse

reactions

increased

with

dose:

tachycardia,

akathisia,

extrapyramidal symptoms, somnolence, and headache.

Schizoaffective Disorder Trials

In a placebo-controlled, 6-week, high- and low-dose study in subjects with schizoaffective

disorder,

akathisia,

dystonia,

dysarthria,

myalgia,

nasopharyngitis,

rhinitis,

cough,

pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects

who received higher doses of INVEGA

compared with subjects who received lower doses.

6.6

Demographic Differences

An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose

studies in adult subjects with schizophrenia and in the two placebo-controlled, 6-week studies in

adult subjects with schizoaffective disorder did not reveal any evidence of clinically relevant

differences in safety on the basis of gender or race alone; there was also no difference on the

basis of age

[see Use in Specific Populations (8.5)]

6.7

Extrapyramidal Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with

schizophrenia provided information regarding treatment-emergent EPS. Several methods were

used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which

broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating

score

(mean

change

from

baseline)

which

evaluates

akathisia,

anticholinergic

medications to treat emergent EPS (

Table

7), and (4) incidence of spontaneous reports of EPS

Table

8). For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic

medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There

was no difference observed between placebo and INVEGA

3 mg and 6 mg doses for any of

these EPS measures.

Invega PI Dec 2013 CL

Table 7

Treatment-Emergent Extrapyramidal Symptoms (EPS)

Assessed by Incidence of Ratings Scales and Use of

Anticholinergic Medication – Schizophrenia Studies in

adults

Percentage of Patients

INVEGA

®

Placebo

3 mg

6 mg

9 mg

12 mg

once

daily

once

daily

once

daily

once

daily

EPS Group

(N=355)

(N=127)

(N=235)

(N=246)

(N=242)

Parkinsonism

Akathisia

Use of

anticholinergic

medications

a: For Parkinsonism, percent of patients with Simpson-Angus global

score > 0.3 (Global score defined as total sum of items score divided

by the number of items)

b: For Akathisia, percent of patients with Barnes Akathisia Rating

Scale global score ≥ 2

c: Percent of patients who received anticholinergic medications to treat

emergent EPS

Invega PI Dec 2013 CL

Table 8

Treatment-Emergent Extrapyramidal Symptoms (EPS)-

Related Adverse Events by MedDRA Preferred Term –

Schizophrenia Studies in adults

Percentage of Patients

INVEGA

®

Placebo

3 mg

6 mg

9 mg

12 mg

once

daily

once

daily

once

daily

once

daily

EPS Group

(N=355)

(N=127)

(N=235)

(N=246)

(N=242)

Overall percentage of 11

patients with EPS-

related AE

Dyskinesia

Dystonia

Hyperkinesia

Parkinsonism

Tremor

Dyskinesia group includes: Dyskinesia, extrapyramidal disorder, muscle

twitching, tardive dyskinesia

Dystonia group includes: Dystonia, muscle spasms, oculogyration, trismus

Hyperkinesia group includes: Akathisia, hyperkinesia

Parkinsonism group includes: Bradykinesia, cogwheel rigidity, drooling,

hypertonia, hypokinesia, muscle rigidity, musculoskeletal stiffness,

parkinsonism

Tremor group includes: Tremor

Compared to data from the studies in adult subjects with schizophrenia, pooled data from the two

placebo-controlled 6-week studies in adult subjects with schizoaffective disorder showed similar

types and frequencies of EPS as measured by rating scales, anticholinergic medication use, and

spontaneous reports of EPS-related adverse events. For subjects with schizoaffective disorder,

there was no dose-related increase in EPS observed for parkinsonism with the Simpson-Angus

scale or akathisia with the Barnes Akathisia Rating Scale. There was a dose-related increase

observed with spontaneous EPS reports of hyperkinesia and dystonia and in the use of

anticholinergic medications.

Table 9 shows the EPS data from the pooled schizoaffective disorder trials.

Invega PI Dec 2013 CL

Table 9.

Treatment-Emergent Extrapyramidal Symptoms (EPS)-

Related Adverse Events by MedDRA Preferred Term –

Schizoaffective Disorder Studies in adults

Percentage of Patients

INVEGA

®

Placebo

3-6 mg

once-daily

fixed-dose

range

9-12 mg

once-daily

fixed-dose

range

3-12 mg

once-daily

flexible dose

EPS Group

(N=202)

(N=108)

(N=98)

(N=214)

Overall percentage of

patients with EPS-

related AE

Dyskinesia

Dystonia

Hyperkinesia

Parkinsonism

Tremor

Invega PI Dec 2013 CL

Dyskinesia group includes: Dyskinesia, muscle twitching

Dystonia group includes: Dystonia, muscle spasms, oculogyration

Hyperkinesia group includes: Akathisia, hyperkinesia, restlessness

Parkinsonism group includes: Bradykinesia, drooling, hypertonia, muscle rigidity, muscle

tightness, musculoskeletal stiffness, parkinsonian gait, parkinsonism

Tremor group includes: Tremor

The incidences of EPS-related adverse events in the adolescent schizophrenia studies

showed a similar dose-related pattern to those in the adult studies. There were notably

higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent

population as compared to the adult studies (Table 10).

Dystonia

Class Effect:

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may

occur in susceptible individuals during the first few days of treatment. Dystonic symptoms

include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing

difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur

at low doses, they occur more frequently and with greater severity with high potency and at

Invega PI Dec 2013 CL

higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is

observed in males and younger age groups.

6.8

Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects

with schizophrenia and from the two placebo-controlled, 6-week studies in adult subjects with

schizoaffective

disorder,

between-group

comparisons

revealed

medically

important

differences

between

INVEGA

placebo

proportions

subjects

experiencing

potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis

parameters.

Similarly,

there

were

differences

between

INVEGA

placebo

incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry,

including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL,

LDL, and total cholesterol measurements. However, INVEGA

was associated with increases in

serum prolactin

[see Warnings and Precautions (5.7)].

6.9

Other Adverse Reactions Observed During Premarketing Evaluation of

INVEGA

®

The following additional adverse reactions occurred in < 2% of INVEGA

-treated subjects in the

above schizophrenia and schizoaffective disorder clinical trial datasets. The following also

includes additional adverse reactions reported at any frequency by INVEGA

-treated subjects

who participated in other clinical studies.

Cardiac disorders:

bradycardia, bundle branch block left, palpitations

Endocrine disorders:

hyperprolactinemia

Eye disorders:

eye movement disorder,

Gastrointestinal disorders:

abdominal pain, flatulence, small intestinal obstruction, Stomach

discomfort

General disorders:

oedema, oedema peripheral

Immune system disorders:

anaphylactic reaction

Infections and infestations:

urinary tract infection, Upper respiratory tract infection, Rhinitis

Investigations:

alanine

aminotransferase

increased,

aspartate

aminotransferase

increased,

Musculoskeletal and connective tissue disorders:

arthralgia, pain in extremity

,

Muscle spasms,

Back pain, Trismus, Torticollis, Muscle rigidity, Muscle twitching, Musculoskeletal pain

Metabolism and Nutritional Disorders:

Decreased appetite

Invega PI Dec 2013 CL

Nervous system disorders:

opisthotonus,

Psychiatric disorders:

agitation, insomnia, nightmare, Sleep disorder, Restlessness

Reproductive system and breast disorders:

amenorrhea, breast discharge, breast engorgement,

breast

tenderness,

breast

pain,

erectile

dysfunction,

galactorrhea,

gynecomastia,

breast

discomfort, menstruation irregular, retrograde ejaculation

Respiratory, thoracic and mediastinal disorders:

nasal congestion, pneumonia aspiration

Pharyngolaryngeal pain, Cough

Skin and subcutaneous tissue disorders:

pruritus, rash, rash popular,

Vascular disorders:

hypotension, ischemia hypertension

The safety of INVEGA® was also evaluated in a long-term trial designed to assess the

maintenance of effect with INVEGA® in adults with schizophrenia

[see Clinical Studies (14)]

In general, adverse reaction types, frequencies, and severities during the initial 14-week open-

label phase of this study were comparable to those observed in the 6-week, placebo-controlled,

fixed-dose studies. Adverse reactions reported during the long-term double-blind phase of this

study were similar in type and severity to those observed in the initial 14-week open-label phase.

Additional adverse events reported in clinical and postmarketing experience:

Infections and infestations :

Common:

bronchitis, , sinusitis, , influenza

Uncommon:

pneumonia, cystitis, ear infection, tonsillitis

Rare:

eye infection, onychomycosis, cellulitis, acarodermatitis

Blood and lymphatic system disorders

Uncommon:

anaemia, haematocrit decreased

Rare:

thrombocytopenia, eosinophil count increased

Immune system disorders

Rare:

hypersensitivity

Endocrine disorders

Rare:

inappropriate antidiuretic hormone secretion

, glucose urine present

Invega PI Dec 2013 CL

Metabolism and nutrition disorders

Common:

weight decreased

Uncommon:

anorexia

Rare:

water intoxication, hypoglycaemia

Not known

: hyperinsulinaemia

Psychiatric disorders

Common:

mania, depression

Uncommon

: confusional state, libido decreased, anorgasmia, nervousness

Rare:

blunted affect

Nervous system disorders

Common:

dyskinesia

Uncommon:

convulsion

, syncope psychomotor hyperactivity, dizziness postural, disturbance

in attention, dysgeusia, hypoaesthesia, paresthaesia

Rare

: cerebrovascular accident, unresponsive to stimuli

, loss of consciousness, depressed level

of consciousness

, balance disorder, coordination abnormal, head titubation

Eye disorders

Common:

vision blurred

Uncommon:

conjunctivitis, dry eye,

Rare:

glaucoma, eye rolling

, photophobia, lacrimation increased, ocular hyperaemia

Not Known: Floppy iris syndrome (intraoperative)

Ear and labyrinth disorders

Uncommon:

vertigo, tinnitus, ear pain

Cardiac disorders

Common:

conduction disorder

Uncommon

: electrocardiogram abnormal

Rare:

atrial fibrillation, tachycardia syndrome

Vascular disorders

Rare:

venous thrombosis, pulmonary embolism, flushing

Respiratory, thoracic and mediastinal disorders

Uncommon:

dyspnoea, wheezing, epistaxis

Rare:

sleep apnoea syndrome, hyperventilation, respiratory tract congestion, dysphonia

Not known:

pulmonary congestion

Invega PI Dec 2013 CL

Gastrointestinal disorders

Common:

Diarrhoea

Uncommon:

Gastroenteritis

Rare:

pancreatitis

, faecal incontinence, faecaloma

, cheilitis

Very Rare:

Ileus

Hepatobiliary disorders

Common:

transaminases increased

Uncommon

: gamma-glutamyltransferase increased

Rare:

jaundice

Skin and subcutaneous tissue disorders

Uncommon

: urticaria, alopecia, acne

Rare:

drug eruption

, hyperkeratosis, eczema, dry skin, erythema, skin

discolouration,seborrhoeic dermatitis, dandruff

Musculoskeletal and connective tissue disorders

Uncommon:

blood creatine phosphokinase increased, joint stiffness, joint swelling, muscular

weakness, neck pain

Rare

: posture abnormal

Renal and urinary disorders

Uncommon:

pollakiuria, dysuria

Reproductive system and breast disorders

Uncommon:

sexual dysfunction

Rare:

vaginal discharge

6.10 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of INVEGA

because these reactions were reported voluntarily from a population of uncertain size, it is not

possible to reliably estimate their frequency: angioedema, priapism, swollen tongue. tardive

dyskinesia, urinary incontinence, urinary retention.

6.11 Adverse Reactions Reported With Risperidone

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with

risperidone can be found in the ADVERSE REACTIONS section of the risperidone package

insert.

Invega PI Dec 2013 CL

7

DRUG INTERACTIONS

7.1 Potential for INVEGA

®

to Affect Other Drugs

Caution is advised when prescribing INVEGA with medicines known to prolong the QT

interval, e.g., class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III

antiarrhythmics (e.g., amiodarone, sotalol), some antihistaminics, some other antipsychotics

and some antimalarials (e.g., mefloquine).

Given the primary CNS effects of paliperidone

[see Adverse Reactions (6.1, 6.2)]

, INVEGA

should be used with caution in combination with other centrally acting drugs

,

e.g., anxiolytics,

most antipsychotics, hypnotics, opiates, etc.

and alcohol. Paliperidone may antagonize the effect

of levodopa and other dopamine agonists.

If this combination is deemed necessary, particularly in end-stage Parkinson’s disease, the lowest

effective dose of each treatment should be prescribed.

Because of its potential for inducing orthostatic hypotension,

an additive effect may be observed

when INVEGA

is administered with other therapeutic agents that have this potential

e.g., other

antipsychotics, tricyclics.

[see Warnings and Precautions (5.9)]

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with

drugs that are metabolized by cytochrome P450 isozymes.

In vitro

studies in human liver

microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs

metabolized

cytochrome

P450

isozymes,

including

CYP1A2,

CYP2A6,

CYP2C8/9/10,

CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit

clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant

manner. Paliperidone is also not expected to have enzyme inducing properties.

Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No

in vivo

data

are available and the clinical relevance is unknown.

Caution is advised if paliperidone is combined with other medicines known to lower the seizure threshold

(i.e., phenothiazines or butyrophenones, clozapine, tricyclics or SSRIs, tramadol, mefloquine, etc.).

Pharmacokinetic interaction between lithium and INVEGA

is unlikely.

In a drug interaction study, co-administration of INVEGA® (12 mg once daily for 5 days) with

divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the

steady-state pharmacokinetics (AUC

and Cmax,ss) of valproate in 13 patients stabilized on

valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate

average plasma concentrations when INVEGA® 3-15 mg/day was added to their existing

valproate treatment.

Invega PI Dec 2013 CL

7.2

Potential for Other Drugs to Affect INVEGA

®

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9 and CYP2C19, so

that an interaction with inhibitors or inducers of these isozymes is unlikely. While

in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in

paliperidone metabolism, in vivo studies do not show decreased elimination by

these isozymes and they contribute to only a small fraction of total body

clearance. In vitro studies have shown that paliperidone is a P-gp substrate.

Co-administration of INVEGA

6 mg once daily with carbamazepine 200 mg twice daily caused

a decrease of approximately 37% in the mean steady-state C

and AUC of paliperidone. This

decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone.

A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was

little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine

co-administration. On initiation of carbamazepine, the dose of INVEGA

should be re-evaluated

and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of

INVEGA

should be re-evaluated and decreased if necessary.

Paliperidone is metabolized to a limited extent by CYP2D6

[see Clinical Pharmacology (12.3)]

In an interaction study in healthy subjects in which a single 3 mg dose of INVEGA

administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor),

paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive

metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is

unknown.

Co-administration of a single dose of INVEGA

12 mg with divalproex sodium extended-release

tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C

paliperidone.

Dosage

reduction

INVEGA

should

considered

when

INVEGA

is co-administered with valproate after clinical assessment.

Pharmacokinetic interaction between lithium and INVEGA

is unlikely.

Medicinal products affecting gastrointestinal transit time may affect the absorption of paliperidone, e.g.,

metoclopramide.

Concomitant use of INVEGA with risperidone

Concomitant use of INVEGA with oral risperidone is not recommended as paliperidone is the active

metabolite of risperidone and the combination of the two may lead to additive paliperidone exposure.

Invega PI Dec 2013 CL

8

USE IN SPECIFIC POPULATIONS

8.1

Pregnancy

Pregnancy Category C.

There are no adequate and well controlled studies of INVEGA

in pregnant women.

Use of first generation antipsychotic drugs during the last trimester of pregnancy has been

associated with extrapyramidal symptoms in the neonate. These symptoms are usually self-

limited. It is not known whether paliperidone, when taken near the end of pregnancy, will lead to

similar neonatal signs and symptoms.

In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats

and rabbits were treated during the period of organogenesis with up to 8 times the maximum

recommended human dose of paliperidone (on a mg/m

basis).

In rat reproduction studies with risperidone, which is extensively converted to paliperidone in

rats and humans, there were increases in pup deaths seen at oral doses which are less than the

maximum recommended human dose of risperidone on a mg/m

basis (see risperidone package

insert).

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for

extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of

agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder

in these neonates. These complications have varied in severity; while in some cases symptoms

have been self-limited, in other cases neonates have required intensive care unit support and

prolonged hospitalization.

INVEGA® should be used during pregnancy only if the potential benefit justifies the potential

risk to the fetus.

8.3 Nursing Mothers

Paliperidone is excreted in human breast milk. The known benefits of breastfeeding should be

weighed against the unknown risks of infant exposure to paliperidone.

Invega PI Dec 2013 CL

8.4

Pediatric Use

Safety and effectiveness of INVEGA® in the treatment of schizophrenia were evaluated in 150

adolescent subjects 12-17 years of age with schizophrenia who received INVEGA® in the dose

range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

Safety and effectiveness of INVEGA® for the treatment of schizophrenia in patients < 12 years

of age have not been established. Safety and effectiveness of INVEGA® for the treatment of

schizoaffective disorder in patients < 18 years of age have not been studied.

In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a

reversible impairment of performance in a test of learning and memory was seen, in females

only, with a no-effect dose of 0.63 mg/kg/day, which produced plasma levels (AUC) of

paliperidone similar to those in adolescents. No other consistent effects on neurobehavioral or

reproductive development were seen up to the highest dose tested (2.5 mg/kg/day), which

produced plasma levels of paliperidone 2-3 times those in adolescents.

Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized

to paliperidone in animals and humans, at doses of 0.31, 1.25, or 5 mg/kg/day. Decreased bone

length and density were seen with a no-effect dose of 0.31 mg/kg/day, which produced plasma

levels (AUC) of risperidone plus paliperidone which were similar to those in children and

adolescents receiving the maximum recommended human dose of risperidone. In addition, a

delay in sexual maturation was seen at all doses in both males and females. The above effects

showed little or no reversibility in females after a 12-week drug-free recovery period.

The long-term effects of INVEGA® on growth and sexual maturation have not been fully

evaluated in children and adolescents.

8.5

Geriatric Use

safety,

tolerability,

efficacy

INVEGA

were

evaluated

6-week

placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older,

of whom 21 were 75 years of age and older). In this study, subjects received flexible doses of

INVEGA

(3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age

and older were included in the 6-week placebo-controlled studies in which adult schizophrenic

subjects received fixed doses of INVEGA

(3 mg to 15 mg once daily)

[see Clinical Studies

(14)]

. There were no subjects ≥ 65 years of age in the schizoaffective disorder studies.

Overall, of the total number of subjects in schizophrenia clinical studies of INVEGA

(n =

1796), including those who received INVEGA

or placebo, 125 (7.0%) were 65 years of age and

older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or

effectiveness were observed between these subjects and younger subjects, and other reported

Invega PI Dec 2013 CL

clinical experience has not identified differences in response between the elderly and younger

patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney and clearance is decreased in

patients with moderate to severe renal impairment

[see Clinical Pharmacology (12.3)]

, who

should be given reduced doses.

Because elderly patients are more likely to have decreased renal

function, care should be taken in dose selection, and it may be useful to monitor renal function

[see Dosage and Administration (2.5)]

8.6

Renal Impairment

Dosing must be individualized according to the patient’s renal function status

[see Dosage and

Administration (2.5)]

8.7

Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment.

INVEGA

has not been studied in patients with severe hepatic impairment.

9

DRUG ABUSE AND DEPENDENCE

9.1

Controlled Substance

INVEGA

(paliperidone) is not a controlled substance.

9.2

Abuse

Paliperidone

has not been systematically studied in animals or humans for its potential for abuse.

It is not possible to predict the extent to which a CNS-active drug will be misused, diverted,

and/or abused once marketed. Consequently, patients should be evaluated carefully for a history

of drug abuse, and such patients should be observed closely for signs of INVEGA

misuse or

abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

9.3

Dependence

Paliperidone has not been systematically studied in animals or humans for its potential for

tolerance or physical dependence.

10

OVERDOSAGE

10.1 Human Experience

While experience with paliperidone overdose is limited, among the few cases of overdose

reported in pre-marketing trials, the highest estimated ingestion of INVEGA

was 405 mg.

Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other

potential signs and symptoms include those resulting from an exaggeration of paliperidone’s

known pharmacological effects, i.e., drowsiness and somnolence, tachycardia and hypotension,

and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a

Invega PI Dec 2013 CL

patient in the setting of overdose.

Paliperidone is the major active metabolite of risperidone. Overdose experience reported with

risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

10.2 Management of Overdosage

There is no specific antidote to paliperidone, therefore, appropriate supportive measures should

be instituted and close medical supervision and monitoring should continue until the patient

recovers. Consideration should be given to the extended-release nature of the product when

assessing treatment needs and recovery. Multiple drug involvement should also be considered.

In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and

ventilation. Gastric lavage (after intubation if patient is unconscious) and administration of

activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following

overdose may create a risk of aspiration with induced emesis.

Cardiovascular

monitoring

should

commence

immediately,

including

continuous

electrocardiographic

monitoring

possible

arrhythmias.

antiarrhythmic

therapy

administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive

QT-prolonging effects when administered in patients with an acute overdose of paliperidone.

Similarly the alpha-blocking properties of bretylium might be additive to those of paliperidone,

resulting in problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures, such as

intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be

used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha

blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be

administered.

Invega PI Dec 2013 CL

11

DESCRIPTION

Paliperidone, the active ingredient in INVEGA

Extended-Release Tablets, is a psychotropic

agent belonging to the chemical class of benzisoxazole derivatives. INVEGA

contains a

racemic mixture of (+)- and (-)- paliperidone. The chemical name is (

)-3-[2-[4-(6-fluoro-1,2-

benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-

pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C

and its molecular weight is

426.49. The structural formula is:

Paliperidone is sparingly soluble in 0.1N HCl and methylene chloride; practically insoluble in

water, 0.1N NaOH, and hexane; and slightly soluble in N,N-dimethylformamide.

INVEGA

(paliperidone) Extended-Release Tablets are available in 3 mg (white), 6 mg (beige),

and 9 mg (pink) strengths. INVEGA

utilizes OROS

osmotic drug-release technology

[see

Description (11.1)]

Inactive ingredients are carnauba wax, cellulose acetate, hydroxyethyl cellulose, propylene

glycol,

polyethylene

glycol,

polyethylene

oxides,

povidone,

sodium

chloride,

stearic

acid,

butylated hydroxytoluene, hypromellose, titanium dioxide, and iron oxides. The 3 mg tablets also

contain lactose monohydrate and triacetin.

11.1 Delivery System Components and Performance

INVEGA

uses osmotic pressure to deliver paliperidone at a controlled rate. The delivery

system, which resembles a capsule-shaped tablet in appearance, consists of an osmotically active

trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is

composed of two drug layers containing the drug and excipients, and a push layer containing

osmotically active components. There are two precision laser-drilled orifices on the drug-layer

dome of the tablet. Each tablet strength has a different colored water-dispersible overcoat and

print

markings.

aqueous

environment,

such

gastrointestinal

tract,

water-

dispersible

color

overcoat

erodes

quickly.

Water

then

enters

tablet

through

semipermeable membrane that controls the rate at which water enters the tablet core, which, in

turn, determines the rate of drug delivery. The hydrophilic polymers of the core hydrate and

swell, creating a gel containing paliperidone that is then pushed out through the tablet orifices.

The biologically inert components of the tablet remain intact during gastrointestinal transit and

Invega PI Dec 2013 CL

are eliminated in the stool as a tablet shell, along with insoluble core components.

12

CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Paliperidone

major

active

metabolite

risperidone.

mechanism

action

paliperidone, as with other drugs having efficacy in schizophrenia, is unknown, but it has been

proposed that the drug's therapeutic activity in schizophrenia is mediated through a combination

of central dopamine Type 2 (D

) and serotonin Type 2 (5HT

) receptor antagonism.

12.2 Pharmacodynamics

Paliperidone is a centrally active dopamine Type 2 (D

) antagonist and with predominant

serotonin Type 2 (5HT

) activity. Paliperidone is also active as an antagonist at

adrenergic receptors and H

histaminergic receptors, which may explain some of the other effects

of the drug. Paliperidone has no affinity for cholinergic muscarinic or

- and

-adrenergic

receptors.

pharmacological

activity

(+)-

(-)-

paliperidone

enantiomers

qualitatively and quantitatively similar

in vitro.

12.3 Pharmacokinetics

Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak

plasma concentration (C

) approximately 24 hours after dosing. The pharmacokinetics of

paliperidone following INVEGA

administration are dose-proportional within the available dose

range. The terminal elimination half-life of paliperidone is approximately 23 hours.

Steady-state

concentrations

paliperidone

attained

within

4-5 days

dosing

with

INVEGA

in most subjects. The mean steady-state peak:trough ratio for an INVEGA

dose of

9 mg was 1.7 with a range of 1.2-3.1.

Following administration of INVEGA

, the (+) and (-) enantiomers of paliperidone interconvert,

reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.

Absorption and Distribution

The absolute oral bioavailability of paliperidone following INVEGA

administration is 28%.

Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects

with a standard high-fat/high-caloric meal gave mean C

and AUC values of paliperidone that

were increased by 60% and 54%, respectively, compared with administration under fasting

conditions. Clinical trials establishing the safety and efficacy of INVEGA

were carried out in

subjects without regard to the timing of meals. While INVEGA

can be taken without regard to

food, the presence of food at the time of INVEGA

administration may increase exposure to

paliperidone

[see Dosage and Administration (2.3)]

Invega PI Dec 2013 CL

Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L. The

plasma protein binding of racemic paliperidone is 74%.

Metabolism and Elimination

Although

in vitro

studies suggested a role for CYP2D6 and CYP3A4 in the metabolism of

paliperidone,

in vivo

results indicate that these isozymes play a limited role in the overall

elimination of paliperidone

[see Drug Interactions (7)]

week

following

administration

single

oral

dose

immediate-release

C-paliperidone to 5 healthy volunteers, 59% (range 51% - 67%) of the dose was excreted

unchanged into urine, 32% (26% - 41%) of the dose was recovered as metabolites, and 6% - 12%

of the dose was not recovered. Approximately 80% of the administered radioactivity was

recovered in urine and 11% in the feces.

Four primary metabolic pathways have been identified

in vivo

, none of which could be shown to account for more than 10% of the dose: dealkylation,

hydroxylation, dehydrogenation, and benzisoxazole scission.

Population

pharmacokinetic

analyses

found

difference

exposure

clearance

paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates.

Special Populations

Renal Impairment

The dose of INVEGA

should be reduced in patients with moderate or severe renal impairment

[see Dosage and Administration (2.5)]

. The disposition of a single dose paliperidone 3 mg

extended-release tablet was studied in adult subjects with varying degrees of renal function.

Elimination of paliperidone decreased with decreasing estimated creatinine clearance. Total

clearance of paliperidone was reduced in subjects with impaired renal function by 32% on

average in mild (CrCl = 50 mL/min to < 80 mL/min), 64% in moderate (CrCl = 30 mL/min to

< 50 mL/min), and 71% in severe (CrCl = 10 mL/min to < 30 mL/min) renal impairment,

corresponding to an average increase in exposure (AUCinf) of 1.5 fold, 2.6 fold, and 4.8 fold,

respectively,

compared

healthy

subjects.

mean

terminal

elimination

half-life

paliperidone was 24 hours, 40 hours, and 51 hours in subjects with mild, moderate, and severe

renal impairment, respectively, compared with 23 hours in subjects with normal renal function

(CrCl ≥ 80 mL/min).

Hepatic Impairment

In a study in adult subjects with moderate hepatic impairment (Child-Pugh class B), the plasma

concentrations of free paliperidone were similar to those of healthy subjects, although total

paliperidone exposure decreased because of a decrease in protein binding. Consequently, no dose

Invega PI Dec 2013 CL

adjustment is required in patients with mild or moderate hepatic impairment. INVEGA

has not

been studied in patients with severe hepatic impairment.

Adolescents (12-17 years of age)

Paliperidone systemic exposure in adolescents weighing ≥ 51 kg (≥ 112 lbs) was similar to that

in adults. In adolescents weighing < 51 kg (< 112 lbs), a 23% higher exposure was observed; this

is considered not to be clinically significant. Age did not influence the paliperidone exposure.

Elderly

No dosage adjustment is recommended based on age alone. However, dose adjustment may be

required because of age-related decreases in creatinine clearance

[see Renal Impairment above

and Dosage and Administration (2.1, 2.5)]

Race

No dosage adjustment is recommended based on race. No differences in pharmacokinetics were

observed in a pharmacokinetic study conducted in Japanese and Caucasians.

Gender

No dosage adjustment is recommended based on gender. No differences in pharmacokinetics

were observed in a pharmacokinetic study conducted in men and women.

Smoking

No dosage adjustment is recommended based on smoking status. Based on in vitro studies

utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should,

therefore, not have an effect on the pharmacokinetics of paliperidone.

13

NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity studies of paliperidone have not been performed.

Carcinogenicity studies of risperidone, which is extensively converted to paliperidone in rats,

mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was

administered in the diet at daily doses of 0.63 mg/kg, 2.5 mg/kg, and 10 mg/kg for 18 months to

mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There

were

statistically

significant

increases

pituitary

gland

adenomas,

endocrine

pancreas

adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less

than or equal to the maximum recommended human dose of risperidone on a mg/m2 basis

(see risperidone package insert). An increase in mammary, pituitary, and endocrine pancreas

neoplasms has been found in rodents after chronic administration of other antipsychotic drugs

Invega PI Dec 2013 CL

considered

mediated

prolonged

dopamine

D2 antagonism

hyperprolactinemia. The relevance of these tumor findings in rodents in terms of human risk is

unknown

[see Warnings and Precautions (5.7)]

Mutagenesis

No evidence of genotoxic potential for paliperidone was found in the Ames reverse mutation

test, the mouse lymphoma assay, or the

in vivo

rat micronucleus test.

Impairment of Fertility

In a study of fertility, the percentage of treated female rats that became pregnant was not affected

at oral doses of paliperidone of up to 2.5 mg/kg/day. However, pre- and post-implantation loss

was increased, and the number of live embryos was slightly decreased, at 2.5 mg/kg, a dose that

also caused slight maternal toxicity. These parameters were not affected at a dose of 0.63 mg/kg,

which is half of the maximum recommended human dose on a mg/m

basis.

The fertility of male rats was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day,

although sperm count and sperm viability studies were not conducted with paliperidone. In a

subchronic study in Beagle dogs with risperidone, which is extensively converted to paliperidone

in dogs and humans, all doses tested (0.31 mg/kg - 5.0 mg/kg) resulted in decreases in serum

testosterone and in sperm motility and concentration. Serum testosterone and sperm parameters

partially recovered, but remained decreased after the last observation (two months after treatment

was discontinued).

14

CLINICAL STUDIES

14.1 Schizophrenia

Adults

The acute efficacy of INVEGA

(3 mg to 15 mg once daily) was established in three placebo-

controlled and active-controlled (olanzapine), 6-week, fixed-dose trials in non-elderly adult

subjects (mean age of 37) who met DSM-IV criteria for schizophrenia. Studies were carried out

in North America, Eastern Europe, Western Europe, and Asia. The doses studied among these

three trials included 3 mg/day, 6 mg/day, 9 mg/day, 12 mg/day, and 15 mg/day. Dosing was in

the morning without regard to meals.

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated

multi-item

inventory

composed

five

factors

evaluate

positive

symptoms,

negative

symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression.

Efficacy was also evaluated using the Personal and Social Performance (PSP) scale. The PSP is a

validated clinician-rated scale that measures personal and social functioning in the domains of

socially useful activities (e.g., work and study), personal and social relationships, self-care, and

Invega PI Dec 2013 CL

disturbing and aggressive behaviors.

In all 3 studies (n = 1665), INVEGA

was superior to placebo on the PANSS at all doses. Mean

effects at all doses were fairly similar, although the higher doses in all studies were numerically

superior. INVEGA

was also superior to placebo on the PSP in these trials.

examination

population

subgroups

reveal

evidence

differential

responsiveness on the basis of gender, age (there were few patients over 65), or geographic

region. There were insufficient data to explore differential effects based on race.

In a longer-term trial, adult outpatients meeting DSM-IV criteria for schizophrenia who had

clinically responded (defined as PANSS score

70 or

4 on pre-defined PANSS subscales, as

well as having been on a stable fixed dose of INVEGA

for the last two weeks of an 8-week run-

in phase) were entered into a 6-week open-label stabilization phase where they received

INVEGA

(doses ranging from 3 mg to 15 mg once daily). After the stabilization phase,

patients were randomized in a double-blind manner to either continue on INVEGA

at their

achieved stable dose, or to placebo, until they experienced a relapse of schizophrenia symptoms.

Relapse was pre-defined as significant increase in PANSS (or pre-defined PANSS subscales),

hospitalization, clinically significant suicidal or homicidal ideation, or deliberate injury to self or

others. An interim analysis of the data showed a significantly longer time to relapse in patients

treated

with

INVEGA

compared

placebo,

trial

stopped

early

because

maintenance of efficacy was demonstrated.

Adolescents

The efficacy of INVEGA® in adolescent subjects with schizophrenia was established in a

randomized, double-blind, parallel-group, placebo-controlled, 6-week study using a fixed-dose

weight-based treatment group design over the dose range of 1.5 to 12 mg/day. The study was

carried out in the US, India, Romania, Russia, and Ukraine, and involved subjects 12-17 years of

age meeting DSM-IV criteria for schizophrenia, with diagnosis confirmation using the Kiddie

Schedule

Affective

Disorders

Schizophrenia-Present

Lifetime

Version

SADS-PL).

Eligible subjects were randomly assigned to 1 of 4 treatment groups: a placebo group or

INVEGA® Low, Medium, or High dose groups. Doses were administered based on body weight

to minimize the risk of exposing lower-weight adolescents to high doses of INVEGA®. Subjects

weighing between 29 kg and less than 51 kg at the baseline visit were randomly assigned to

receive placebo or 1.5 mg (Low dose), 3 mg (Medium dose), or 6 mg (High dose) of INVEGA®

daily, and subjects weighing at least 51 kg at the baseline visit were randomly assigned to

Invega PI Dec 2013 CL

receive placebo or 1.5 mg (Low dose), 6 mg (Medium dose), or 12 mg (High dose) of

INVEGA® daily. Dosing was in the morning without regard to meals.

Efficacy

evaluated

using

PANSS.

Overall,

this

study

demonstrated

efficacy

INVEGA® in adolescents with schizophrenia in the dose range of 3 to 12 mg/day. Doses within

this broad range were shown to be effective, however, there was no clear enhancement to

efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for

subjects weighing 51 kg or greater. Although paliperidone was adequately tolerated within the

dose range of 3 to 12 mg/day, adverse events were dose related.

14.2 Schizoaffective Disorder

Adults

The acute efficacy of INVEGA

(3 mg to 12 mg once daily) in the treatment of schizoaffective

disorder was established in two placebo-controlled, 6-week trials in non-elderly adult subjects.

Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed by the

Structured Clinical Interview for DSM-IV Disorders, 2) had a Positive and Negative Syndrome

Scale (PANSS) total score of at least 60, and 3) had prominent mood symptoms as confirmed by

a score of at least 16 on the Young Mania Rating Scale and/or Hamilton Rating Scale for

Depression. The population included subjects with schizoaffective bipolar and depressive types.

In one of these trials, efficacy was assessed in 211 subjects who received flexible doses of

INVEGA

(3-12 mg once daily). In the other study, efficacy was assessed in 203 subjects who

were assigned to one of two dose levels of INVEGA

: 6 mg with the option to reduce to 3 mg (n

= 105) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. Both studies included

subjects

received

INVEGA

either

monotherapy

mood

stabilizers

and/or

antidepressants (55%)] or as an adjunct to mood stabilizers and/or antidepressants (45%). The

most commonly used mood stabilizers were valproate and lithium. The most commonly used

antidepressants were SSRIs and SNRIs. INVEGA

was dosed in the morning without regard to

meals. Studies were carried out in the United States, Eastern Europe, Russia, and Asia.

Efficacy was evaluated using the PANSS, a validated multi-item inventory composed of five

factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled

hostility/excitement, and anxiety/depression. As secondary outcomes, mood symptoms were

evaluated using the Hamilton Depression Rating Scale (HAM-D-21) and the Young Mania

Rating Scale (YMRS).

The INVEGA

group in the flexible-dose study (dosed between 3 and 12 mg/day, mean modal

dose of 8.6 mg/day) and the higher dose group of INVEGA

in the 2 dose-level study (12

mg/day with option to reduce to 9 mg/day) were each superior to placebo in the PANSS.

Invega PI Dec 2013 CL

Numerical improvements in mood symptoms were also observed, as measured by the HAM-D-

21 and YMRS. In the lower dose group of the 2 dose-level study (6 mg/day with option to reduce

to 3 mg/day), INVEGA

was not significantly different from placebo as measured by the

PANSS.

Taking the results of both studies together, INVEGA

improved the symptoms of schizoaffective

disorder at endpoint relative to placebo when administered either as monotherapy or as an

adjunct to mood stabilizers and/or antidepressants. An examination of population subgroups did

not reveal any evidence of differential responsiveness on the basis of gender, age, or geographic

region. There were insufficient data to explore differential effects based on race.

16

HOW SUPPLIED/STORAGE AND HANDLING

INVEGA

(paliperidone) Extended-Release Tablets are available in the following strengths and

packages. All tablets are capsule-shaped.

3 mg tablets are white and imprinted with “PAL 3”, and are available in bottles of 30

6 mg tablets are beige and imprinted with “PAL 6”, and are available in bottles of 30

9 mg tablets are pink and imprinted with “PAL 9”, and are available in bottles of 30

Storage and Handling

Blister

: Do not store above 30°C

Keep out of reach of children.

17

PATIENT COUNSELING INFORMATION

Physicians are advised to discuss the following issues with patients for whom they prescribe

INVEGA

17.1 Orthostatic Hypotension

Patients should be advised that there is risk of orthostatic hypotension, particularly at the time of

initiating

treatment,

re-initiating

treatment,

increasing

dose

[see

Warnings

and

Precautions (5.9)]

17.2 Interference with Cognitive and Motor Performance

As INVEGA

has the potential to impair judgment, thinking, or motor skills, patients should be

cautioned about operating hazardous machinery, including automobiles, until they are reasonably

certain that INVEGA

therapy does not affect them adversely

[see

Warnings and Precautions

(5.11)]

17.3 Pregnancy

Invega PI Dec 2013 CL

Patients should be advised to notify their physician if they become pregnant or intend to become

pregnant during treatment with INVEGA

[see Use in Specific Populations (8.1)]

17.4 Nursing

Caution should be exercised when INVEGA

is administered to a nursing woman. The known

benefits of breastfeeding should be weighed against the unknown risks of infant exposure to

paliperidone.

[See

Use in Specific Populations (8.3)]

17.5 Concomitant Medication

Patients should be advised to inform their physicians if they are taking, or plan to take, any

prescription

over-the-counter

drugs,

there

potential

interactions

[see

Drug

Interactions (7)]

17.6 Alcohol

Patients should be advised to avoid alcohol while taking INVEGA

[see

Drug Interactions

(7.1)]

17.7 Heat Exposure and Dehydration

Patients should be advised regarding appropriate care in avoiding overheating and dehydration

[see Warnings and Precautions (5.17)]

17.8 Administration

Patients should be informed that INVEGA

should be swallowed whole with the aid of liquids.

Tablets should not be chewed, divided, or crushed. The medication is contained within a

nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with

insoluble core components, is eliminated from the body; patients should not be concerned if they

occasionally

notice

something

that

looks

like

tablet

their

stool

[see

Dosage

and

Administration (2.3)]

INVEGA

(paliperidone) Extended-Release Tablets

Manufactuer:

Janssen Cilag S.p.A., Via C. Janssen 04100, Borgo S. Michele, Latina, Italy

Registration holder: J-C Health Care Ltd., Kibbutz Shefayim 6099000, Israel

Page

1

48

להונ

תשגהל

תושקב

יוניש ,םושירל

שודיחו

םירישכת

םייאופר

הקלחמל

םושירל

םירישכת רבוטקוא

2013

חפסנ

םיספט

תשגהל

תורמחה

םינולעב העדוה

לע

הרמחה

עדימ(

ןולעב)תוחיטב

ןכרצל

ןכדועמ(

05.2013

ןדועמ

898989

:ךיראת

dec 2013

םש

רישכת

תילגנאב

רפסמו :םושירה

INVEGA EXTENDED RELEASE TABLETS 3, 6, 9 MG

(31639, 31640, 31641)

םש

לעב

:םושירה מ"עב רק 'תלה יס י'ג !דבלב תורמחהה טורפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

1

.

תדעוימ המל ?הפורתה תופורתה תצובקל תכייתשמ הפורתה לופיטל תשמשמו ינשה רודהמ תויטוכיספיטנאה הינרפוזיכסב

תיביטקפאוזיכס הערפהבו

םיינייפואה )םינימסת( םימוטפמיסה

תולחמל הלא

םירבד תשגרה וא הייאר ,העימש :ןוגכ םה תובשחמ ,)תויזולד וא תויצניצולה( םימייק אלש ,לבלובמ רוביד ,תורגתסה ,הגירח תונדשח ,אווש תושידא

זוכירב םיישק םילוח .ךודכדו ,הדרח ,ןואכיד שוחל םילולע הינרפוזיכסב שא תשוחת תימצע החנזה ,המ .חתמ וא םג ושוחי תיביטקפאוזיכס הערפהב םילוח םימוטפמיסב

חור בצמ לש

ןפואב םמורמ וא דורי םזגומ הנישב תוערפהו ןובאתב םייוניש , ןואכיד( תויטוכיספיטנאה תופורתה תצובקל תכייתשמ הפורתה רודהמ ינשה הינרפוזיכסב לופיטל תשמשמו

םירגבתמבו םירגובמב

יאליגב

ךליאו םינש

תיביטקפאוזיכס הערפהבו

םירגובמב

םיינייפואה )םינימסת( םימוטפמיסה

הינרפוזיכסל

הלא תולחמל םה ןוגכ םימייק אלש םירבד תשגרה וא הייאר ,העימש : ,הגירח תונדשח ,אווש תובשחמ ,)תויזולד וא תויצניצולה( תושידא ,לבלובמ רוביד ,תורגתסה

זוכירב םיישק .ךודכדו תשוחת ,הדרח ,ןואכיד שוחל םילולע הינרפוזיכסב םילוח שא ,המ תימצע החנזה .חתמ וא ושוחי תיביטקפאוזיכס הערפהב םילוח םג

םימוטפמיסב םינימסתב ףסונבו )הלעמ טרופמכ( הינרפוזיכס לש םינימסתב לש תוערפה חור בצמ

חור בצמ( םזגומ ןפואב םמורמ וא דורי

ןדבא ,תונטפטפ ,הניש רסוח ,תעד תחסה ,תונבצע תשוחת ץוביק

םייפש

0060990

:ןופלט

09-9591111

:סקפ

09-9583636

Kibbutz Shefayim 6099000, Tel: +972-9-9591111, Fax: +972-9-9583636

Page

2

48

וא

.)הינאמ יינע

תליכא ,הניש רסוח וא תמזגומ הניש ,תימוי םוי תוליעפב )תונשנ תוינדבוא תובשחמו הליכא רסוח וא רתי ןובאתב םייוניש הנישב תוערפהו .)הינאמ וא ןואכיד(

רוזחל םהמ עונמלו הלחמה ינימסת לקהל הלוכי הפורתה תועגונה תודחוימ תורהזא הפורתב שומישל

( הריאממ תיטפלוריונ תנומסתמ רבעב תלבס

Neuroleptic Malignant Syndrome

הינמיסש םוח םה

הובג

םירירש תושקונו

תערפהמ וא ( תרחואמ העונת

Tardive dyskinesia

רשא ) .ןושלה וא םינפה לש תוגירח תועונת םה הינמיס תופורת תליטנמ םרגיהל םילולע ולא םיבצמ תויטוכיספיטנא

תולחל ןוכיסב ךנהש וא תרכוסב הלוח ךנה םא .הב רוטינל םד תוקידב לע הרוי אפורהו ןכתי םדב רכוסה תמר בל הלוח ךנה םא .םדה ילכ וא/ו בלה

לבקמ וא .ךומנ םד ץחלל םורגל לולעש בל תלחמל לופיט

.....

ןמז תכראהממ לבוס ךניה -

לש גוס( תדלומ רבעב תלבס וא לבוס ךנה םא ,)בצק תערפה הדירי ,בלה בצקב הטאה ,בלה בצקב תוערפהמ .ןגלשאה וא םויזנגמה תמרב

( הריאממ תיטפלוריונ תנומסתמ רבעב תלבס

Neuroleptic

Malignant Syndrome

םה הינמיסש

........

-

.תונבל םד תוירודכ לש הכומנ הריפסמ רבעב תלבס )תורחא תופורתמ המרגנ אל וא המרגנש(

.םדה ילכ וא/ו בלה בל הלוח ךנה םא

תלחמל לופיט לבקמ וא .ךומנ םד ץחלל םורגל לולעש בל

........

ןומרוהה לש הניקת אל הרוצב תוהובג תומרמ לבוס ךניה ןיטקלורפ יולת לודיג ךל שיש וא םדב ןיטקלורפ

ןמז תכראהממ לבוס ךניה -

,)בצק תערפה לש גוס( תדלומ הטאה ,בלה בצקב תוערפהמ רבעב תלבס וא לבוס ךנה םא בלה בצקב .ןגלשאה וא םויזנגמה תמרב הדירי ,

םישישקב הגווניאב שומישה יבגל עדימ ןיא היצנמדמ םילבוסה םישישק .היצנמדמ םילבוסה םימוד םייטוכיספיטנא םירישכתב םילפוטמה וא ץבשל רבגומ ןוכיסב תויהל םילולע הגווניאל .תוומ הפורתב םילפוטמה תיביטקפאוזיכס הערפה םע םילפוטמ- ינימסתמ ירשפא רבעמל בטיה םירטונמ תויהל םיכירצ ,תאז ואכיד ינימסתל )םזגומ ןפואב םמורמ חור בצמ( הינמ

םילבוסה םישישקב הגווניאב שומישה יבגל עדימ ןיא היצנמדמ םילבוסה םישישק .היצנמדמ

םירישכתב םילפוטמה רבגומ ןוכיסב תויהל םילולע הגווניאל םימוד םייטוכיספיטנא .תוומ וא ץבשל תיתועמשמ הילע .לקשמב היילעל םורגל הלולע הגווניא רחא בוקעי אפורה ןכלו ךתואירב לע עיפשהל הלולע לקשמב .לופיטה ךלהמב ךלקשמ םילטונה םילפוטמב ופצנ תמייק תרכס לש הרמחה וא תרכס תוהובג רכוס תומר לש םינמיס קודבל אפורה לע ןכלו הגווניא םדב רכוס תומר רוטינ ,תמייק תרכס שי םהב םילפוטמב .םדב ץוביק

םייפש

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.עובק סיסב לע עצבתהל ךירצ וגיעה( ןיע ןושיאו ןכתיי , טקרטק חותינ ךלהמב

זכרמב רוחשה קלחה( ןיעה תיתשקו ןכתיי ,ןכ ומכ .יוצרה לדוגל לדגי אל )ןיעה םורגל לולע הזו חותינה ךלהמב הייופרל ךופהת )ןיעב ינועבצה .ןיעל קזנל לטונ ךניה יכ ךאפורל רומא ,ןיעב חותינ רובעל ןנכתמ ךניה םא .וז הפורת

...........

ןכתית ,חומב רקיעב תלעופ הגווניאש ןוויכמ וא( תורחא תופורת לש העפשהה תרבגה .חומה לע תולעופה )לוהוכלא

,םדה ץחל תא דירוהל הלולע הפורתהש ןוויכמ תופורתל ליבקמב תחקלנ איה רשאכ רהזיהל שי תורחא

.םדה ץחל תא תודירומה

תופורתה תעפשה תא תיחפהל הלולע הגווניא תורסח םילגרה תנומסתב וא ןוסניקרפב לופיטל החונמה

restless leg syndrome

אמגודל( ) .)הפודובל ןוגכ בלה בצקב תוערפהב לופיטל תופורת תופורת ,לולטוסו ןורדוימא דימאניאקורפו ןידיניוק ,ןיזמורפרולכ אמגודל( תומיוסמ תויטוכיספ יטנא אמגודל( תוקיטויביטנא ,)ןיזאדירוית )ןיצסקולפיסקומ ,ןיצסקולפיטאג

ןיפזמברק

טאורפלאוו ,םוידוס סקאורפלאויד ,תוינימטסיהיטנא תופורת ,בל בצק תוערפהב לופיטל תופורת תויטוכיספ יטנא תופורת וא הירלמה תלחמב לופיטל תופורת תורחא

רשאכ ופצנ בלה לש הניקת תילמשח הכלוהב תויעב הלעמ תוניוצמה תופורתהמ תחאו הגווניא ולטנ םילפוטמ

העפשהה תרבגה ןכתית ,חומב רקיעב תלעופ הגווניאש ןוויכמ .חומה לע תולעופה )לוהוכלא וא( תורחא תופורת לש

רהזיהל שי ,םדה ץחל תא דירוהל הלולע הפורתהש ןוויכמ תורחא תופורתל ליבקמב תחקלנ איה רשאכ

.םדה ץחל תא תודירומה

לופיטל תופורתה תעפשה תא תיחפהל הלולע הגווניא החונמה תורסח םילגרה תנומסתב וא ןוסניקרפב

restless leg

syndrome

.)הפודובל אמגודל( )

תופורת חקול התא םא תונתשהל הלולע הגווניא תעפשה :תמגודכ( םייעמה תויתעונת תוריהמ לע תועיפשמה תופסונ )דימארפולקוטמ

טאורפלו םע ליבקמ ןתמב הגווניא לש ןונימ תדרוה לוקשל שי

הגווניאב לופיטל ליבקמב הפה ךרד ןודירפסיר לוטל ץלמומ אל תורבגומ יאוול תועפותל ליבוהל לולע בולישהש םושמ ןידיניוק ןוגכ בלה בצקב תוערפהב לופיטל תופורת תויטוכיספ יטנא תופורת ,לולטוסו ןורדוימא דימאניאקורפו תוקיטויביטנא ,)ןיזאדירוית ,ןיזמורפרולכ אמגודל( תומיוסמ )ןיצסקולפיסקומ ,ןיצסקולפיטאג אמגודל(

ןיפזמברק

ןתמב הגווניא לש ןונימ תאלעה שרדתו ןכתי ןיפזמברקל ליבקמ

טאורפלאוו ,םוידוס סקאורפלאויד

םידליב שומיש םירגבתמבו הינרפוזיכסב לופיטל

םילפוטמל תדעוימ הניא הפורתה ליגל תחתמ

םינש תויביטקפאוזיכס תוערפהב לופיטל

תדעוימ הניא הפורתה ץוביק

םייפש

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48

ליגל תחתמ םילפוטמל

םינש הפורתב שמתשת דציכ ןונימ תמאתה עצבי אפורהו ןכתיי-תוילכב תויעב םע םילפוטמ תוילכה דוקפתל םאתהב דוקפתו הדימב ןונימה תא דירוי אפורהו ןכתי-םירגובמ םילפוטמ דורי תוילכה םירגבתמבו םידליב לופיט

אפורה תויחנה יפ לע

יאוול תועפות

.......

יישק ,הזחב הסיחד תשוחת וא ץחל ,םיבאכ לש ןוילעה קלחב תוחונ רסוח וא םיבאכ ,המישנ ,ףוגה ,העזה ,הליחב ,)בג וא ראווצ ,םייפתכ ,םידי( תרוחרחס

.תיאופר הרזעל דימ תונפל שי

( הריאממ תיטפלוריונ תנומסת

Neuroleptic Malignant Syndrome

ןוישקו הובג םוח ,הרכה לופרע ,לובלב ,ףירח םירירש שחרתהל םילולע םירקמב רידנ םי

הפב ,ןושלב ,םינפב תויניצר אל תותיווע תותסלב וא

אפורל הנפ

הפקז ( תכשוממ וא תבאוכ עבראמ רתוי תועש

י/הנפו לופיטה י/קספה ,רידנ אפורל

תיגרלא הבוגת

,הפב תוחיפנ ,םוח רצוק ,ןושלב וא םייתפשב ,םינפב םיתיעלו החירפ ,דוריג ,המישנ

החינצ )יטקליפאנא קוש ידכל דע םדה ץחלב .הכומנ תוחיכשב שחרתהל הלולע דימ תונפל שי ,תשחרתמו הדימב .תיאופר הרזעל םינימסתה( םיילגרה ידירוב דחוימב ,םידירוב םד ישירק- רובעל םילולעה ,)םיילגרב תוימומדאו באכ ,תוחיפנ :םיללוכ .המישנב ישוקו הזחב באכל םורגלו תואירל עיגהלו םדה ילכב תיאופר הרזעל הנפ אנא הלא םימוטפמיס הווח התאו הדימב תידיימ וא םיבאכ ,המישנ יישק ,הזחב הסיחד תשוחת וא ץחל ,םיבאכ וא ראווצ ,םייפתכ ,םידי(,ףוגה לש ןוילעה קלחב תוחונ רסוח תרוחרחס ,העזה ,הליחב ,)בג

.תיאופר הרזעל דימ תונפל שי

( הריאממ תיטפלוריונ תנומסת

Neuroleptic

Malignant Syndrome

םה הינמיסש תושקונ ,םוח .הרכהה תמרב הדירי וא העזה ,םירירש

היהיו ןכתיי ידיימ יאופר לופיטב ךרוצ ,ףירח םירירש ןוישקו הובג םוח ,הרכה לופרע ,לובלב םירקמב שחרתהל םילולע רידנ םי

תותסלב וא הפב ,ןושלב ,םינפב תויניצר אל תותיווע

אפורל הנפ

רדיתו ןכתי

הגווניאב לופיט תקספה

תיגרלא הבוגת

הרומח

אטבתהל הלוכיה

,םוח ,המישנ רצוק ,ןושלב וא םייתפשב ,םינפב ,הפב תוחיפנ םיתיעלו החירפ ,דוריג

קוש ידכל דע םדה ץחלב החינצ הדימב .הכומנ תוחיכשב שחרתהל הלולע )יטקליפאנא .תיאופר הרזעל דימ תונפל שי ,תשחרתמו

הפיצר הנישב וא תומדרהב ישוק

הדורי תונרע וא תוינונשי תשוחת

שאר באכ ךותמ דחאמ רתויב( דאמ תוחיכש יאוול תועפות

10

)םילפוטמ

הטאהו תוערפהב אטבתמה בצמ ,םזינוסניקרפ םימרוגה( םירירש ץוויכו ןוישיק לש השוחת ,העונתב ויתיווע תועונתל

"העונת תאפקה" לש השוחת ףאו ) ץוביק

םייפש

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דער ,העבה תורסח םינפ ,שדחמ התלחתה ןכמ רחאלו .תיטיא הכילהו םילגר תרירג ,רתי רויר ,החונמב

החונמ רסוח

ןתשה יכרדב םימוהיז

הדירי ,ןובאית תרבגה ,לקשמב הילע ןובאתב

תוצווכתהב אטבתמה בצמ ,הינוטסיד הינוטסיד כ"דב .םירירש לש תינוצר אל תמרוגו םינפה ירירש לע העיפשמ ייניעה לש הליגר אל העונתל

,הפה , .תותסלה וא ןושלה

תרוחרחס

תותיוועב אטבתמה בצמ ,היזניקסיד .תוינוצר אל תורזוח םירירש

הייאר שוטשט

ריהמ בל בצק

הבישי/הביכשמ רבעמב ךומנ םד ץחל

ףאב שדוג ,לועיש ,ןורג באכ

,תואקה ,ןטבב תוחונ יא וא ןטבב באכ שבוי ,לוכיע יישק ,תוריצע ,תוליחב ,הפב

החירפ ,דרג

בג יבאכ םירירש יבאכ

תסוו רדעה

השלוח ךותמ דחאמ תוחפב( תוחיכש יאוול תועפות

10

:)םילפוטמ

,תוררקתה לש םינימסת ,)סיטיכנורב( הזחב םוהיז ,םינוניסב םוהיז ןתשה יכרדב םימוהיז ייומד םינימסת , תעפש

ןובאית תרבגה ,לקשמב הילע ,לקשמ ןדבוא , הדירי ןובאתב

,תונבצע ,)הינאמ( םזגומ ןפואב םמורמ חור בצמ ואכיד

הדרח ,

לש תינוצר אל תוצווכתהב אטבתמה בצמ ,הינוטסיד םינפה ירירש לע העיפשמ הינוטסיד כ"דב .םירירש ייניעה לש הליגר אל העונתל תמרוגו

וא ןושלה ,הפה , .תותסלה

תרוחרחס

תורזוח םירירש תותיוועב אטבתמה בצמ ,היזניקסיד תוינוצר אל

דער

הייאר שוטשט

חוורמ תכראה ,בלה לש תילמשחה הכלוהב העיגפ

,יטיא בל בצק , ריהמ בל בצק

הבישי/הביכשמ רבעמב ךומנ םד ץחל לוכיה הדימעל ,תרוחרחסו ןופלעל םורגל

הובג םד ץחל

ףאב שדוג ,לועיש ,ןורג באכ

תוריצע ,תוליחב ,תואקה ,ןטבב תוחונ יא וא ןטבב באכ ,לושלש , הפב שבוי ,לוכיע יישק םייניש יבאכ ,

םדב )זאנימאסנרט( דבכ ימיזנא תומרב היילע

החירפ ,דרג

םירירש יבאכ ,תומצע וא בג יבאכ םיקרפ יבאכ ,

תסוו רדעה

,םוח השלוח תופייע ,

המישנה יכרד לש םוהיז

הניש תוערפה

טלשנ יתלב ךרוצ ,ןופלע ,םיסוכרפ םירחא ףוג יקלחו םייפגה תא זיזהל הערפה ,הדימעל רבעמב תרוחרחס ךותמ דחאב רתויה לכל( תוחיכש אל יאוול תועפות

100

:)םילפוטמ

וא תואיר תקלד המישנה יכרד לש םוהיז םוהיז םידקשב וא םיינזואב וא ןתשה תיחופלשב

תומודא םד תוירודכ תריפסב הדירי ,הימנא ץוביק

םייפש

0060990

:ןופלט

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:סקפ

09-9583636

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48

רובידב

קלחה ןיב תילמשחה הכלוהב העיגפ קפוד ,בלה לש ןותחתה קלחהו ןוילעה .ק.א( ילמשחה םושירב יוניש ,ליגר אל תוקזח בל תוקיפד ,בלה תוליעפ לש ).ג )תויצטיפלפ(

ךומנ םד ץחל

לוכיעה תכרעמב םירבגומ םיזג

ויוצווכתה

םירירש

הפקזב םיישק

,םיידשהמ בלח תפילד רוזחמ ןדבא דשב תוחונ יא ,דשב באכ

רכוס לש תוהובג תומר ,תרכס לש הרמחה וא תרכס תדיריו הנוזתב העיגפ ויתובקעבו ןובאית דוביא ,םדב םדב םינמושב הילע ,לקשמ

הניש תוערפה רסוח ,ינימה קשחב הדירי ,לובלב , םיטויס ,תונבצע ,המזגרואל עיגהל תלוכי

םייפגה תא זיזהל טלשנ יתלב ךרוצ ,ןופלע ,םיסוכרפ תרוחרחס ,םירחא ףוג יקלחו

הדימעל רבעמב

,זוכירב תוערפה הערפה

,רובידב העיגפ וא ןדבוא ,באכ וא עגמ שוחל רועה תלוכיב הדירי ,םעטה שוחב רועב השוחת ןדבוא וא תוריקד ,ץוצקע תשוחת

םייניע תקלד ,תושבי םייניע ,תומודא םייניע

באכ ,םיינזואב םילוצלצ ,)וגיטרו( רורחס תשוחת םיינזוא

ןוילעה קלחה ןיב תילמשחה הכלוהב העיגפ

קלחהו םושירב יוניש ,ליגר אל קפוד ,בלה לש ןותחתה תוקזח בל תוקיפד ,בלה תוליעפ לש ).ג.ק.א( ילמשחה )תויצטיפלפ(

ךומנ םד ץחל

.ףאהמ םומיד ,םיפוצפצ ,המישנ רצוק

העילבב ישוק ,לוכיעה תכרעמב םוהיז ,ןושלב תוחיפנ

לוכיעה תכרעמב םירבגומ םיזג

( םדב דבכ ימיזנא לש תוהובג תומר

רעיש ןדבא ,הנקא ,)רועב תיגרלא הבוגת( תדפרס

םיזנאה תמרב היילע

ררחתשמה םיזנא( , םדב םירירשב העיגפ שישכ םיתיעל

,םירירש תשלוח ויוצווכתה

,םירירש תושקונ ,םיקרפמב תוחיפנ ראווצב םיבאכ ,םיקרפמב

,תרבגומ תורידתב הנתשה ,ןתש ןתמב הטילש רסוח ןתש תתל תלוכי יא ,ןתש ןתמ תעב םיבאכ

הפקזב םיישק הכיפשב םיישק ,

רוזחמ ןדבא ,רוזחמב תורידס יא וא בלח תפילד םיידשהמ ,ינימה דוקפתב העיגפ , תוחונ יא ,דשב באכ דשב

תוחיפנ ,םייתפשב וא םייניעב ,הפב ,םינפב תוחיפנ םייפגב וא ףוגב

ףוגה םוחב היילע ,תרומרמצ

הכילהה תרוצב יוניש

ואמיצ תשוחת

הבוט אל תיללכ השוחת ,הזחב באכ

הליפנ

תנייפואמה הרומח תיגרלא הבוגת

ץוביק

םייפש

0060990

:ןופלט

09-9591111

:סקפ

09-9583636

Kibbutz Shefayim 6099000, Tel: +972-9-9591111, Fax: +972-9-9583636

Page

7

48

וא םייתפש ,םינפ ,הפב תוחיפנ ,םוחב רועב החירפ ,דוריג ,המישנ רצוק ,ןושל םד ץחלב הדירי םיתיעלו

תמרב הילעל םורגל לוכי הגווניא איבהל הלולעה םדב ןיטקלורפ םיידשב תוחיפנ :ןוגכ יאוול תועפותל הלולע םישנב ,הפקזב םיישק ,םירבגב תושיגרל איבהל ההובג ןיטקלורפ תמר יא ,םיידשהמ בלח תפילד ,םיידשב רוזחמב תורחא תערפה וא תורידס .ישדוחה

( הריאממ תיטפלוריונ תנומסת

Neuroleptic Malignant Syndrome

םה הינמיסש תמרב הדירי ,לובלב ,הרכה דוביא וא הרכהה םוח

הובג םירירש תושקונו

תרחואמ העונת תערפה

Tardive

dyskinesia

םינפה לש תוגירח תועונת ןושלה וא .םירחא ףוג יקלח וא תפיאשמ האצותכ תואיר תקלד ,)יחומ ץבש( םייעמ תמיסח ,ןוזמ

,םירירש באכו

PRIAPISM

תכשוממ הפקז םירבגב דש תמקר לש תוחתפתה

השרפה תמקר לש הלדגה ,רוזחמב בוכיע ,דשהמ דשה ךותמ דחאב רתויה לכל( תורידנ יאוול תועפות

1000

)םילפוטמ

,רועב םוהיז ,םיינרופיצב יתיירטפ םוהיז ,םייניע תקלד תידרק י"ע תמרגנה רועב תקלד

םיוסמ גוסמ תונבל תוירודכ רפסמב תנכוסמ הדירי ,םדב )םיטיצובמורט( תויסטה רפסמב הדירי ,םדב )םינבל םד יאת לש םיוסמ גוס( םיליפוניזואאב היילע םדב

,םוחב תנייפואמה הרומח תיגרלא הבוגת

תוחיפנ ,דוריג ,המישנ רצוק ,ןושל וא םייתפש ,םינפ ,הפב םד ץחלב הדירי םיתיעלו רועב החירפ

ןתשב רכוס תואצמה

םדב ןיטקלורפ תמרב הילעל םורגל לוכי הגווניא םיידשב תוחיפנ :ןוגכ יאוול תועפותל איבהל הלולעה ,הפקזב םיישק ,םירבגב .ינימה דוקפתב תורחא תויעבו תושיגרל איבהל ההובג ןיטקלורפ תמר הלולע םישנב תערפה וא תורידס יא ,םיידשהמ בלח תפילד ,םיידשב ישדוחה רוזחמב תורחא

ןתשה חפנ לע יארחאה ןומרוה לש הניקת אל השרפה

תנזואמ אל תרכס לש םייח ינכסמ םיכוביס

תמר ,םייח תנכסמ המרב םילזונ לש תמזגומ הייתש םדב לורטסלוכב היילע ,םדב הכומנ רכוס

שגר רדעה

( הריאממ תיטפלוריונ תנומסת

Neuroleptic

Malignant Syndrome

םה הינמיסש הדירי ,לובלב ,הרכה דוביא וא הרכהה תמרב םוח

הובג

תושקונו םירירש

תרחואמ העונת תערפה

Tardive dyskinesia

ןושלה וא םינפה לש תוגירח תועונת ףוג יקלח וא .םירחא

תמרב הדירי ,)יחומ ץבש( חומל םדה תקפסאב העיגפ תויעבו לקשמ יוושב תויעב ,הרכה ןדבוא ,הרכהה היצנידרואוקב

הניאש תרכס ללכב תמדרת ,חומב םד ילכב תויעב דער ,הכומנ הרכה תמר ,יוריגל הבוגת רסוח ,תנזואמ שארה לש

לש רתי תושיגר ,)רבגומ יניע ךות ץחל( המוקואלג ,םייניעב תוימומדא ,תורבגומ תועמד ,רואל םייניעה םייניע לוגלג ,םייניעה תזזהב היעב

ריהמ בל בצק ,)ןיקת אל בל בצק( םירודזורפ רופרפ ץוביק

םייפש

0060990

:ןופלט

09-9591111

:סקפ

09-9583636

Kibbutz Shefayim 6099000, Tel: +972-9-9591111, Fax: +972-9-9583636

Page

8

48

הדימע תעב

םיילגרה ידירוב דחוימב ,םידירוב םד ישירק תוימומדאו באכ ,תוחיפנ :םיללוכ םינימסתה( תואירל עיגהלו םדה ילכב רובעל םילולעה ,)םיילגרב הווח התאו הדימב .המישנב ישוקו הזחב באכל םורגלו תידיימ תיאופר הרזעל הנפ אנא הלא םימוטפמיס

תמירזב העיגפ בקע תומקרב ןצמחה תמרב הדירי הקמסה ,םדה

תיחטש המישנ ,הניש ידכ ךות המישנב תוערפה הריהמו

,ןוזמ תפיאשמ האצותכ תואיר תקלד יכרדב שדוג לוקב תויעב ,המישנ

םייעמ תמיסח השק האוצ ,םירגוסב הטילש יא , רדעיה , המיסחל תמרוגה לוכיעה תכרעמב םירירש תויתעונת

םייניעהו רועה לש הבהצה

בלבלב תקלד

הפירח תיגרלא הבוגתמ האצותכ ןורגב תוחיפנ המישנ יישקל איבהל הלולעה

,רועב תוימומדא ,רועב שבוי ,המזקא ,רועה תובעתה תשקשק ,דרגמו יתיתפ רוע ,רועה עבצב םייוניש

רירש יביס לש תוקרפתה םירירש באכו אל הביצי , הניקת

PRIAPISM

תכשוממ הפקז שורדל הלולעה תיחותינ תוברעתה

םירבגב דש תמקר לש תוחתפתה תוטולבב תוחיפנ , ,דשב דשהמ השרפה תילניגו השרפה ,

דשה תמקר לש הלדגה ,רוזחמב בוכיע

הזחב תוחונ יא

ףוגה םוחב הדירי ,ךומנ דאמ ףוג םוח

הלימג לש תועפות העודי אל ןתוחיכשש יאוול תועפות

תואירב שדוג

לע יארחאה ןומרוה( םדב ןילוסניא לש תוהובג תומר )םדב רכוסה תומר תרקב

חותינ ךלהמב .טקרטק חותינ ךהמב םייניע תויעב לש בצמ שחרתהל לולע ,טקרטק

intraoperative

floppy iris syndrome )IFIS(

לטונ ךניהו הדימב ץוביק

םייפש

0060990

:ןופלט

09-9591111

:סקפ

09-9583636

Kibbutz Shefayim 6099000, Tel: +972-9-9591111, Fax: +972-9-9583636

Page

9

48

רומא ,טקרטק חותינ רובעל ךירצ ךניה םא .הגווניא .הגוויא לטונ ךניה יכ ךאפורל

)הגווניאב ליעפה רמוחה( ןודירפילאפו רחאמ רצות וניה תרזגנ יאוול תעפות לכ ,ןודירפסיר לש ןודירפסיר תליטנ רחאל שחרתהל הלולעש הגווניא תליטנ רחאל םג שחרתהל הלולע

רצות וניה )הגווניאב ליעפה רמוחה( ןודירפילאפו רחאמ תרזגנ תליטנ רחאל שחרתהל הלולעש יאוול תעפות לכ ,ןודירפסיר לש הגווניא תליטנ רחאל םג שחרתהל הלולע ןודירפסיר ,ןודירפסיר ולטנש םילפוטמב ופצנ תואבה יאוולה תועפות הלא יאוול תועפותש תורשפא תמייק ןכל ,הגווניאל המודה םיציפנ תולוקו חומב םד ילכב תויעב :הגווניאב לופיטב ולבקתי תואירהמ :יאוול תועפות לעמ( תוצופנ יאוול תועפות

( םינתשמ ןמז יקרפל טבמה עוביק

Oculogyr

ic crisis

,קור לש תרבגומ השרפה

.תלזנ ,עולבו ףאב תקלד מ תוחפ( הכומנ תוחיכשב יאוול תועפות

.תיפקיה תקצב ,תקצב

תותסל תתיבצ ,םייפג יבאכ ,םיקרפמ יבאכ.

trismus

ראווצ לותיפ ,)

ראווצה תחונתב תוויע דלשה ירירשב באכ ,ראווצה ירירש ץוויכ בקע ,םיטויס ,ףלוח יחומ עוריא

.תיחופלשל ערזה לזונ תרזח ,

ףוגה םוחב יתועמשמ יוניש שחרתהל לולע רתויב םירידנו םידדוב םירקמב עבונ ללכ ךרדב( )םיינוציק רוק וא םוח ללוכ םימרוג רפסממ אפורל י/הנפו לופיטה י/קספה :יאוול תועפות לעמ( תוצופנ יאוול תועפות

( םינתשמ ןמז יקרפל טבמה עוביק

Oculogyric crisis

קור לש תרבגומ השרפה

.תלזנ ,עולבו ףאב תקלד מ תוחפ( הכומנ תוחיכשב יאוול תועפות

תיפקיה תקצב ,תקצב

( תותסל תתיבצ ,םייפג יבאכ ,םיקרפמ יבאכ

trismus

ראווצ לותיפ

,ראווצה ירירש ץוויכ בקע ראווצה תחונתב תוויע דלשה ירירשב באכ ,םיטויס ,ףלוח יחומ עוריא

.תיחופלשל ערזה לזונ תרזח

ףוגה םוחב יתועמשמ יוניש םידדוב םירקמב שחרתהל לולע רתויב םירידנו וא םוח ללוכ םימרוג רפסממ עבונ ללכ ךרדב( אפורל י/הנפו לופיטה י/קספה )םיינוציק רוק להונ

תשגהל

תושקב

יוניש ,םושירל

שודיחו

םירישכת

םייאופר

הקלחמל

םושירל

םירישכת רבוטקוא

2013

העדוה

לע

הרמחה

עדימ(

ןולעב )תוחיטב

אפורל

ןכדועמ(

05.2013

:ךיראת

23.12.2013

ץוביק

םייפש

0060990

:ןופלט

09-9591111

:סקפ

09-9583636

Kibbutz Shefayim 6099000, Tel: +972-9-9591111, Fax: +972-9-9583636

Page

10

48

םש

רישכת

תילגנאב

רפסמו :םושירה

INVEGA EXTENDED RELEASE TABLETS 3, 6, 9 MG

(31639, 31640, 31641)

םש

לעב

:םושירה מ"עב רק 'תלה יס י'ג !דבלב תורמחהה טורפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

Indications and Usage

Schizophrenia - Adolescents (ages 12-17)

The efficacy of invega in schizophrenia in adolescents

was established in one 6-week trial

Dosage and

Administration

Schizophrenia

recommended

dose

INVEGA

(paliperidone) Extended-Release Tablets for the

treatment of schizophrenia is 6 mg once daily,

administered in the morning. Initial dose titration

is not required

Schizophrenia

Adults

The recommended dose of INVEGA

(paliperidone)

Extended-Release

Tablets

treatment

schizophrenia in adults is 6 mg once daily, administered

in the morning. Initial dose titration is not required

Adolescents (12-17 years of age)

recommended

starting

dose

INVEGA®

(paliperidone)

Extended-Release

Tablets

treatment of schizophrenia in adolescents 12-17 years of

age is 3 mg administered once daily. Initial dose

titration is not required. Dose increases, if considered

necessary,

should

made

only

after

clinical

reassessment and should occur at increments of 3

mg/day at intervals of more than 5 days. Prescribers

ץוביק

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Page

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48

should be mindful that, in the adolescent schizophrenia

study, there was no clear enhancement to efficacy at the

higher doses, i.e., 6 mg for subjects weighing less than

51 kg and 12 mg for subjects weighing 51 kg or greater,

while adverse events were dose-related

Schizoaffective Disorder

The recommended dose of INVEGA

(paliperidone)

Extended-Release Tablets for the treatment of

schizoaffective disorder is 6 mg once daily,

administered in the morning. Initial dose titration is

not required

Schizoaffective Disorder

The recommended dose of INVEGA

(paliperidone)

Extended-Release Tablets for the treatment of schizoaffective

disorder is 6 mg administered once daily, administered in the

morning. Initial dose titration is not required

Administration Instructions

INVEGA

can be taken with or without food.

Clinical trials establishing the safety and efficacy

of INVEGA

were carried out in patients without

regard to food intake

Administration Instructions

INVEGA

can be taken with or without food. Clinical

trials establishing the safety and efficacy of INVEGA

were carried out in patients without regard to food

intake

ץוביק

םייפש

0060990

:ןופלט

09-9591111

:סקפ

09-9583636

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Page

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48

Dosage in Special

Populations

Renal Impairment

Dosing must be ……… the recommended initial

dose of INVEGA

is 3 mg once daily

Renal Impairment

Dosing must be …….., the recommended initial dose of

INVEGA

is 3 mg once daily after clinical reassessment

Metabolic Changes

Hyperglycemia, in some cases extreme and

associated with ketoacidosis or hyperosmolar coma

or death, has been reported in patients treated with all

atypical antipsychotics

Atypical antipsychotic drugs have been associated with

metabolic changes that may increase

cardiovascular/cerebrovascular risk. These metabolic

changes include hyperglycemia, dyslipidemia, and body

weight gain. While all of the drugs in the class have been

shown to produce some metabolic changes, each drug has its

own specific risk profile.

Hyperglycemia and Diabetes Mellitus

Hyperglycemia and diabetes mellitus, in some cases extreme

and associated with ketoacidosis or hyperosmolar coma or

death, has been reported in patients treated with all atypical

antipsychotics

.………

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0060990

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09-9591111

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Page

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48

ץוביק

םייפש

0060990

:ןופלט

09-9591111

:סקפ

09-9583636

Kibbutz Shefayim 6099000, Tel: +972-9-9591111, Fax: +972-9-9583636

Page

14

48

ץוביק

םייפש

0060990

:ןופלט

09-9591111

:סקפ

09-9583636

Kibbutz Shefayim 6099000, Tel: +972-9-9591111, Fax: +972-9-9583636

Page

15

48

ץוביק

םייפש

0060990

:ןופלט

09-9591111

:סקפ

09-9583636

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Page

16

48

Schizoaffective Disorder Trials

In the pooled data from the two placebo-controlled, 6-

week studies in adult subjects with schizoaffective

disorder, a higher percentage of INVEGA®-treated

subjects (5%) had an increase in body weight of ≥7%

compared with placebo-treated subjects (1%). In the

study that examined high- and low-dose groups, the

increase in body weight of ≥ 7% was 3% in the low-

dose group, 7% in the high-dose group, and 1% in the

placebo group

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48

Monitoring:

Laboratory Tests

No specific laboratory tests are recommended

No specific laboratory tests are recommended

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with

antipsychotic medicinal products. Since patients treated with

antipsychotics often present with acquired risk factors for VTE, all

possible risk factors for VTE should be identified before and during

treatment with INVEGA and preventive measures undertaken

Lactose content

(pertains only to the 3 mg tablets)

Patients with rare hereditary problems of galactose intolerance, the

Lapp lactase deficiency or glucose-galactose malabsorption should

not take this medicine

Intraoperative Floppy Iris Syndrome

Intraoperative floppy iris syndrome (IFIS) has been observed

during cataract surgery in patients treated with medicines with

alpha1a

adrenergic antagonist effect, including TRADENAME (see

Section 4.8)

IFIS may increase the risk of eye complications during and after the

operation. Current or past use of medicines with alpha1a

adrenergic

antagonist effect should be made known to the ophthalmic surgeon

in advance of surgery. The potential benefit of stopping alpha1

blocking therapy prior to cataract surgery has not been established

and must be weighed against the risk of stopping the antipsychotic

therapy

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48

Adverse reactions

The following are discussed in more detail in

other sections of the labeling

Increased mortality in elderly patients with

dementia-related

psychosis

[see

Boxed

Warning

and

Warnings and Precautions

(5.1)]

Cerebrovascular adverse, including stroke, in

elderly

patients

with

dementia-related

psychosis [see Warnings and Precautions

(5.2)]

Neuroleptic

malignant

syndrome

[see

Warnings and Precautions (5.3)]

prolongation

[see

Warnings

and

Precautions (5.4)]

Tardive

dyskinesia

[see

Warnings

and

Precautions (5.5)]

Hyperglycemia and diabetes mellitus [see

Warnings and Precautions (5.6)]

………

The most common adverse reactions in clinical

trials in subjects with schizophrenia (reported in

5% or more of subjects treated with INVEGA

and at least twice the placebo rate in any of the

dose groups) were extrapyramidal symptoms,

tachycardia, and akathisia. The most common

adverse reactions in clinical trials in patients

6.1

Overall Adverse Reaction Profile

The following adverse reactions are discussed in more

detail in other sections of the labeling

Increased

mortality

elderly

patients

with

dementia-related psychosis [see Boxed Warning and

Warnings and Precautions (5.1)]

Cerebrovascular adverse reactions, including stroke, in

elderly patients with dementia-related psychosis [see

Warnings and Precautions (5.2)]

Neuroleptic malignant syndrome [see Warnings and

Precautions (5.3)]

QT prolongation [see Warnings and Precautions (5.4)]

Tardive dyskinesia [see Warnings and Precautions (5.5)]

Metabolic changes [see Warnings and Precautions (5.6)]

Hyperglycemia and diabetes mellitus [see Warnings

and Precautions (5.6)]

.……

The most common adverse reactions in clinical trials in

adult subjects with schizophrenia (reported in 5% or

more of subjects treated with INVEGA

and at least

twice the placebo rate in any of the dose groups) were

extrapyramidal symptoms, tachycardia, and akathisia.

The most common adverse reactions in clinical trials in

adult patients with schizoaffective disorder (reported in

5% or more of subjects treated with INVEGA

and at

least twice the placebo rate) were extrapyramidal

symptoms, somnolence, dyspepsia, constipation, weight

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with schizoaffective disorder (reported in 5% or

more of subjects treated with INVEGA

and at

least twice the placebo rate) were extrapyramidal

symptoms, somnolence, dyspepsia, constipation,

weight increased, and nasopharyngitis

The most common adverse reactions that were

associated with discontinuation from clinical

trials in subjects with schizophrenia (causing

discontinuation in 2% of INVEGA

-treated

subjects) were nervous system disorders. The

most common adverse reactions that were

associated with discontinuation from clinical

trials in subjects with schizoaffective disorder

were gastrointestinal disorders, which resulted in

discontinuation in 1% of INVEGA

-treated

subjects. [See Adverse Reactions (6.4)]

..……

increased, and nasopharyngitis

most

common

adverse

reactions

that

were

associated with discontinuation from clinical trials in

adult

subjects

with

schizophrenia

(causing

discontinuation in 2% of INVEGA

-treated subjects)

were nervous system disorders. The most common

adverse

reactions

that

were

associated

with

discontinuation from clinical trials in adult subjects with

schizoaffective disorder were gastrointestinal disorders,

which resulted in discontinuation in 1% of INVEGA

treated subjects. [See Adverse Reactions (6.4)]

..……

The safety of INVEGA® was evaluated in 150 adolescent

subjects 12-17 years of age with schizophrenia who received

INVEGA® in the dose range of 1.5 mg to 12 mg/day in a 6-

week, double-blind, placebo-controlled trial

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6.2 Commonly-Observed

Adverse Reactions in

Double-Blind, Placebo-

Controlled Clinical Trials –

Schizophrenia in Adults

and Adolescents

Table enumerates the pooled incidences of adverse

reactions reported in the three placebo-controlled, 6-

week, fixed-dose studies, listing those that occurred

in 2% or more of subjects treated with INVEGA

any of the dose groups, and for which the incidence

in INVEGA

-treated subjects in any of the dose

groups was greater than the incidence in subjects

treated with placebo

Adult Patients with Schizophrenia

Table 4

enumerates the pooled incidences of adverse

reactions reported in the three placebo-controlled, 6-week,

fixed-dose studies in adults, listing those that occurred in 2%

or more of subjects treated with INVEGA

in any of the dose

groups, and for which the incidence in INVEGA

-treated

subjects in any of the dose groups was greater than the

incidence in subjects treated with placebo

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Adolescent Patients with Schizophrenia

Table 5 lists the adverse reactions reported in a fixed-

dose, placebo-controlled study in adolescent subjects

12-17 years of age with schizophrenia, listing those

that occurred in 2% or more of subjects treated with

INVEGA® in any of the dose groups, and for which

the incidence in INVEGA®-treated subjects in any of

the dose groups was greater than the incidence in

subjects treated with placebo

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Monotherapy versus

Adjunctive Therapy

The designs of the two placebo-controlled, 6-week,

double-blind trials in subjects with schizoaffective

disorder included the option for subjects to receive

antidepressants (except monoamine oxidase

inhibitors) and/or mood stabilizers (lithium,

valproate, or lamotrigine)

The designs of the two placebo-controlled, 6-week, double-

blind trials in adult subjects with schizoaffective disorder

included the option for subjects to receive antidepressants

(except

monoamine

oxidase

inhibitors)

and/or

mood

stabilizers (lithium, valproate, or lamotrigine)

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Discontinuations Due

to Adverse Reactions

Schizophrenia Trials

The percentages of subjects who discontinued due to

adverse reactions in the three schizophrenia

placebo-controlled, 6-week, fixed-dose studies were

3% and 1% in INVEGA

- and placebo-treated

subjects, respectively. The most common reasons for

discontinuation were nervous system disorders (2%

and 0% in INVEGA

- and placebo-treated subjects,

respectively)

Schizoaffective Disorder Trials

The percentages of subjects who discontinued due to

adverse reactions in the two schizoaffective disorder

placebo-controlled 6-week studies were 1% and <1%

in INVEGA

- and placebo-treated subjects,

respectively. The most common reasons for

discontinuation were gastrointestinal disorders (1%

and 0% in INVEGA

- and placebo-treated subjects,

respectively)

Schizophrenia Trials

The percentages of subjects who discontinued due to adverse

reactions in the three schizophrenia placebo-controlled, 6-

week, fixed-dose studies in adults were 3% and 1% in

INVEGA

- and placebo-treated subjects, respectively. The

most common reasons for discontinuation were nervous

system disorders (2% and 0% in INVEGA

- and placebo-

treated subjects, respectively)

Among the adverse reactions in the 6-week, fixed-dose,

placebo-controlled

study

adolescents

with

schizophrenia, only dystonia led to discontinuation

(<1% of INVEGA®-treated subjects)

Schizoaffective Disorder Trials

The percentages of subjects who discontinued due to adverse

reactions in the two schizoaffective disorder

placebo-controlled 6-week studies in adults were 1% and

<1% in INVEGA

- and placebo-treated subjects,

respectively. The most common reasons for discontinuation

were gastrointestinal disorders (1% and 0% in INVEGA

and placebo-treated subjects, respectively)

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Dose-Related Adverse

Reactions

Schizophrenia Trials

Based on the pooled data from the three placebo-

controlled, 6-week, fixed-dose studies in subjects

with schizophrenia, among the adverse reactions that

occurred with a greater than 2% incidence in the

subjects treated with INVEGA

, the incidences of the

following adverse reactions increased with dose:

somnolence, orthostatic hypotension, akathisia,

dystonia, extrapyramidal disorder, hypertonia,

parkinsonism, and salivary hypersecretion

Schizophrenia Trials

Based on the pooled data from the three placebo-controlled,

6-week, fixed-dose studies in adult subjects with

schizophrenia, among the adverse reactions that occurred

with a greater than 2% incidence in the subjects treated with

INVEGA

, the incidences of the following adverse reactions

increased with dose: somnolence, orthostatic hypotension,

akathisia, dystonia, extrapyramidal disorder, hypertonia,

parkinsonism, and salivary hypersecretion

in the 6-week, fixed-dose, placebo-controlled study in

adolescents with schizophrenia, among the adverse

reactions that occurred with >2% incidence in the

subjects treated with INVEGA®, the incidences of the

following

adverse reactions increased with

dose:

tachycardia,

akathisia,

extrapyramidal

symptoms,

somnolence, and headache

Demographic

Differences

An examination of population subgroups in the three

placebo-controlled, 6-week, fixed-dose studies

subjects with schizophrenia and in the two placebo-

controlled,

6-week

studies

subjects

with

schizoaffective disorder did not reveal any evidence

of clinically relevant differences in safety on the

basis of gender or race alone; there was also no

difference on the basis of age [see Use in Specific

Populations (8.5)]

An examination of population subgroups in the three

placebo-controlled, 6-week, fixed-dose studies

in adult

subjects with schizophrenia and in the two placebo-

controlled,

6-week

studies

adult

subjects

with

schizoaffective disorder did not reveal any evidence of

clinically relevant differences in safety on the basis of gender

or race alone; there was also no difference on the basis of age

[see Use in Specific Populations (8.5)]

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Extrapyramidal

Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-

week,

fixed-dose

studies

subjects

with

schizophrenia

provided

information

regarding

treatment-emergent EPS

Pooled data from the three placebo-controlled, 6-week, fixed-

dose studies in adult subjects with schizophrenia provided

information regarding treatment-emergent EPS

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Compared to data from the studies in schizophrenia,

pooled data from the two placebo-controlled 6-week

studies in subjects with schizoaffective disorder

showed similar types and frequencies of EPS as

measured by rating scales, anticholinergic medication

use, and spontaneous reports of EPS-related adverse

events

Compared to data from the studies in adult subjects with

schizophrenia, pooled data from the two placebo-controlled

6-week studies in adult subjects with schizoaffective disorder

showed similar types and frequencies of EPS as measured by

rating

scales,

anticholinergic

medication

use,

spontaneous reports of EPS-related adverse events

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The incidences of EPS-related adverse events in the

adolescent schizophrenia studies showed a similar

dose-related pattern to those in the adult studies. There

were notably higher incidences of dystonia,

hyperkinesia, tremor, and parkinsonism in the

adolescent population as compared to the adult studies

(Table 10)

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Laboratory Test

Abnormalities

In the pooled data from the three placebo-

controlled,

6-week,

fixed-dose

studies

subjects with schizophrenia and from the two

placebo-controlled, 6-week studies in ……….,

insulin, c-peptide, triglyceride, HDL, LDL, and

total

cholesterol

measurements.

However,

INVEGA

was associated with increases in

serum prolactin [see Warnings and Precautions

(5.7)]

.

In the pooled data from the three placebo-controlled, 6-

week,

fixed-dose

studies

adult

subjects

with

schizophrenia and from the two placebo-controlled, 6-

week

studies

adult

……..insulin,

c-peptide,

triglyceride,

HDL,

LDL,

total

cholesterol

measurements. However, INVEGA

was associated with

increases in serum prolactin [see Warnings and

Precautions (5.7)]

.

Other Adverse

Reactions Observed

During Premarketing

Evaluation of

INVEGA

®

Cardiac disorders:

bradycardia, bundle branch

block left, palpitations

Endocrine disorders: hyperprolactinemia

..…

Psychiatric disorders:

agitation, nightmare,

Sleep disorder, Restlessness

Cardiac disorders: bradycardia, bundle branch block left,

palpitations

Endocrine disorders: hyperprolactinemia

Eye disorders: eye movement disorder

..……

Investigations:

alanine

aminotransferase

increased,

aspartate aminotransferase increased

..……

Nervous system disorders: opisthotonus

Psychiatric disorders: agitation, insomnia, nightmare,

Sleep disorder, Restlessness

Vascular

disorders:

hypotension,

ischemia

hypertension

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The safety of INVEGA® was also evaluated in a long-

term trial designed to assess the maintenance of effect

with INVEGA® in adults with schizophrenia [see

Clinical Studies (14)]. In general, adverse reaction

types, frequencies, and severities during the initial 14-

week open-label phase of this study were comparable to

those observed in the 6-week, placebo-controlled, fixed-

dose studies. Adverse reactions reported during the

long-term double-blind phase of this study were similar

in type and severity to those observed in the initial 14-

week open-label phase

Additional adverse events reported in clinical and

postmarketing experience

Infections and infestations :

Common: bronchitis, , sinusitis, , influenza

Uncommon: pneumonia, cystitis, ear infection, tonsillitis

Rare: eye infection, onychomycosis, cellulitis,

acarodermatitis

Blood and lymphatic system disorders

Uncommon: anaemia, haematocrit decreased

Rare: thrombocytopenia, eosinophil count increased

Immune system disorders

Rare: hypersensitivity

Endocrine disorders

Rare: inappropriate antidiuretic hormone secretion

glucose urine present

Metabolism and nutrition disorders

Common: weight decreased

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Uncommon: anorexia

Rare: water intoxication, hypoglycaemia

Not known: hyperinsulinaemia

Psychiatric disorders

Common: mania, depression

Uncommon: confusional state, libido decreased,

anorgasmia, nervousness

Rare: blunted affect

Nervous system disorders

Uncommon: convulsion

, psychomotor hyperactivity.

disturbance in attention, dysgeusia, hypoaesthesia,

paresthaesia

Rare: unresponsive to stimuli

, loss of consciousness,

depressed level of consciousness

, balance disorder,

coordination abnormal, head titubation

Eye disorders

Uncommon: conjunctivitis, dry eye

Rare: glaucoma, eye rolling

, photophobia, lacrimation

increased, ocular hyperaemia

Not Known: Floppy iris syndrome (intraoperative)

Ear and labyrinth disorders

Uncommon: vertigo, tinnitus, ear pain

Cardiac disorders

Common: conduction disorder

Rare: atrial fibrillation, tachycardia syndrome

Vascular disorders

Rare: venous thrombosis, pulmonary embolism,

flushing

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea, wheezing, epistaxis

Rare: sleep apnoea syndrome, hyperventilation,

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respiratory tract congestion, dysphonia

Not known: pulmonary congestion

Gastrointestinal disorders

Common: Diarrhoea

Uncommon: Gastroenteritis

Rare: pancreatitis

, faecal incontinence, faecaloma

cheilitis

Very Rare:

Ileus

Hepatobiliary disorders

Common: transaminases increased

Uncommon: gamma-glutamyltransferase increased

Rare: jaundice

Skin and subcutaneous tissue disorders

Uncommon: urticaria, alopecia, acne

Rare: drug eruption

, hyperkeratosis, eczema, dry skin,

erythema, skin discolouration,seborrhoeic dermatitis,

dandruff

Musculoskeletal and connective tissue disorders

Uncommon: blood creatine phosphokinase increased,

joint stiffness, joint swelling, muscular weakness, neck

pain

Rare: posture abnormal

Renal and urinary disorders

Uncommon: pollakiuria, dysuria

Reproductive system and breast disorders

Uncommon: sexual dysfunction

Rare: vaginal discharge

Weight Gain

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Weight Gain

Schizophrenia Trials

In the pooled data from the three placebo-

controlled,

6-week,

fixed-dose

studies

subjects with schizophrenia, the proportions of

subjects meeting a weight gain criterion of

of body weight were compared, revealing a

similar incidence of weight gain for INVEGA

mg and 6 mg (7% and 6%, respectively)

compared with placebo (5%), and a higher

incidence of weight gain for INVEGA

9 mg

and 12 mg (9% and 9%, respectively)

Schizoaffective Disorder Trials

In the pooled data from the two placebo-

controlled, 6-week studies in subjects with

schizoaffective disorder, a higher percentage of

INVEGA

-treated subjects (5%) had an increase

in body weight of

7% compared with placebo-

treated subjects (1%). In the study that examined

high- and low-dose groups, the increase in body

weight of

7% was 3% in the low-dose group,

7% in the high-dose group, and 1% in the

placebo group

Other Findings Observed During

Clinical Trials

The safety of INVEGA

was also evaluated in a

long-term

trial

designed

assess

maintenance of effect with INVEGA

in adults

with schizophrenia [see Clinical Studies (14)].

In general, adverse reaction types, frequencies,

Schizophrenia Trials

In the pooled data from the three placebo-controlled, 6-

week, fixed-dose studies in subjects with schizophrenia,

the proportions of subjects meeting a weight gain

criterion of

7% of body weight were compared,

revealing a similar incidence of weight gain for

INVEGA

3 mg and 6 mg (7% and 6%, respectively)

compared with placebo (5%), and a higher incidence of

weight gain for INVEGA

9 mg and 12 mg (9% and

9%, respectively)

Schizoaffective

Disorder Trials

In the pooled data from the two placebo-controlled, 6-week

studies in subjects with schizoaffective disorder, a higher

percentage of INVEGA

-treated subjects (5%) had an

increase in body weight of

7% compared with placebo-

treated subjects (1%). In the study that examined high- and

low-dose groups, the increase in body weight of

7% was

3% in the low-dose group, 7% in the high-dose group, and

1% in the placebo group

Other Findings Observed During Clinical Trials

The safety of INVEGA

was also evaluated in a long-term

trial designed to assess the maintenance of effect with

INVEGA

in adults with schizophrenia [see Clinical Studies

(14)]. In general, adverse reaction types, frequencies, and

severities during the initial 14-week open-label phase of this

study were comparable to those observed in the 6-week,

placebo-controlled, fixed-dose studies. Adverse reactions

reported during the long-term double-blind phase of this

study were similar in type and severity to those observed in

the initial 14-week open-label phase

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and severities during the initial 14-week open-

label phase of this study were comparable to

those

observed

6-week,

placebo-

controlled, fixed-dose studies. Adverse reactions

reported during the long-term double-blind

phase of this study were similar in type and

severity to those observed in the initial 14-week

open-label phase

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Drug Interactions

Potential for INVEGA

®

to Affect

Other Drugs

Given the primary CNS effects of paliperidone [see

Adverse Reactions (6.1, 6.2)], INVEGA

should be

used with caution in combination with other centrally

acting drugs

,

and alcohol.

Paliperidone may

antagonize

effect

levodopa

other

dopamine agonists

Because of its potential for inducing orthostatic

hypotension,

an additive effect may be observed

when INVEGA

is administered with other

therapeutic agents that have this potential [see

Warnings and Precautions (5.9)].

Paliperidone is not expected to cause clinically

important pharmacokinetic interactions with drugs

that are metabolized by cytochrome P450 isozymes.

In vitro studies in human liver microsomes showed

that paliperidone does not substantially inhibit the

metabolism of drugs metabolized by cytochrome

P450

isozymes,

including

CYP1A2,

CYP2A6,

CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and

CYP3A5. Therefore, paliperidone is not expected to

inhibit clearance of drugs that are metabolized by

these

metabolic pathways in a clinically relevant

manner. Paliperidone is also not expected to

have enzyme inducing properties

Paliperidone is a weak inhibitor of P-

glycoprotein (P-gp) at high concentrations. No

Potential for INVEGA

®

to Affect Other

Drugs

Caution is advised when prescribing INVEGA with

medicines known to prolong the QT interval, e.g.,

class IA antiarrhythmics (e.g., quinidine,

disopyramide) and class III antiarrhythmics (e.g.,

amiodarone, sotalol), some antihistaminics, some

other antipsychotics and some antimalarials (e.g.,

mefloquine).

Given the primary CNS effects of paliperidone [see

Adverse Reactions (6.1, 6.2)], INVEGA

should be used

with caution in combination with other centrally acting

drugs , e.g., anxiolytics, most antipsychotics, hypnotics,

opiates, etc. and alcohol. Paliperidone may antagonize

the effect of levodopa and other dopamine agonists

If this combination is deemed necessary, particularly in end-

stage Parkinson’s disease, the lowest effective dose of each

treatment should be prescribed.

Because of its potential for inducing orthostatic hypotension,

an additive effect may be observed when INVEGA

administered with other therapeutic agents that have this

potential e.g., other antipsychotics, tricyclics. [see Warnings

and Precautions (5.9)].

Paliperidone

expected

cause

clinically

important pharmacokinetic interactions with drugs that

metabolized

cytochrome

P450

isozymes.

In vitro studies in human liver microsomes showed that

paliperidone

does

substantially

inhibit

metabolism of drugs metabolized by cytochrome P450

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in vivo data are available and the clinical

relevance is unknown

In a clinical study, subjects on a stable dose of

valproate showed comparable valproate average

plasma

concentrations

when

3-15

INVEGA

was added to their existing valproate

treatment

isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10,

CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore,

paliperidone is not expected to inhibit clearance of drugs

that are metabolized by these metabolic pathways in a

clinically relevant manner. Paliperidone is also not

expected to have enzyme inducing properties

Paliperidone is a weak inhibitor of P-glycoprotein (P-

gp) at high concentrations. No in vivo data are available

and the clinical relevance is unknown

Caution is advised if paliperidone is combined with other

medicines known to lower the seizure threshold (i.e.,

phenothiazines or butyrophenones, clozapine, tricyclics or

SSRIs, tramadol, mefloquine, etc.)

Pharmacokinetic

interaction

between

lithium

INVEGA

is unlikely

In a drug interaction study, co-administration of

INVEGA® (12 mg once daily for 5 days) with

divalproex sodium extended-release tablets (500 mg to

2000 mg once daily) did not affect the steady-state

pharmacokinetics (AUC

and Cmax,ss) of valproate in

13 patients stabilized on valproate. In a clinical study,

subjects on stable doses of valproate had comparable

valproate

average

plasma

concentrations

when

INVEGA® 3-15 mg/day was added to their existing

valproate treatment

In a clinical study, subjects on a stable dose of valproate

showed

comparable

valproate

average

plasma

concentrations when 3-15 mg of INVEGA

was added

to their existing valproate treatment

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Potential for Other

Drugs to Affect

INVEGA

®

Paliperidone is not a substrate of CYP1A2,

CYP2A6, CYP2C9 CYP2C19 and CYP3A5, so

that an interaction with inhibitors or inducers of

these isozymes is unlikely. While in vitro studies

indicate that CYP2D6 and CYP3A4 may be

minimally involved in paliperidone metabolism,

in

vivo

studies

show

decreased

elimination

these

isozymes

they

contribute to only a small fraction of total body

clearance.

In vitro

studies have shown that

paliperidone is a P-gp substrate

..……

Paliperidone is not a substrate of CYP1A2, CYP2A6,

CYP2C9,and

CYP2C19 and CYP3A5, so that an

interaction with inhibitors or inducers of these isozymes

is unlikely. While in vitro studies indicate that CYP2D6

CYP3A4

minimally

involved

paliperidone metabolism, in vivo studies do not show

decreased elimination by these isozymes and they

contribute to only a small fraction of total body

clearance. In vitro studies have shown that paliperidone

is a P-gp substrate

..……

Medicinal products affecting gastrointestinal transit time may

affect the absorption of paliperidone, e.g., metoclopramide

Concomitant use of INVEGA with risperidone

Concomitant use of INVEGA with oral risperidone is not

recommended as paliperidone is the active metabolite of

risperidone and the combination of the two may lead to

additive paliperidone exposure

Use in Specific

Populations

Pregnancy Category C

There are no adequate and well controlled studies of

INVEGA

in pregnant women. INVEGA

should be

used during pregnancy only if the potential benefit

justifies the potential risk to the fetus

.……

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs during the

third trimester of pregnancy are at risk for

extrapyramidal and/or withdrawal symptoms

following delivery. There have been reports of

Pregnancy Category C

There are no adequate and well controlled studies of

INVEGA

in pregnant women. INVEGA

should be used

during pregnancy only if the potential benefit justifies the

potential risk to the fetus

.……

Non-teratogenic Effects

Neonates exposed to antipsychotic drugs during the third

trimester of pregnancy are at risk for extrapyramidal and/or

withdrawal symptoms following delivery. There have been

reports of agitation, hypertonia, hypotonia, tremor,

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agitation, hypertonia, hypotonia, tremor, somnolence,

respiratory distress, and feeding disorder in these

neonates. These complications have varied in

severity; while in some cases symptoms have been

self-limited, in other cases neonates have required

intensive care unit support and prolonged

hospitalization.

INVEGA® should be used during pregnancy

only if the potential benefit justifies the potential

risk to the fetus

somnolence, respiratory distress, and feeding disorder in

these neonates. These complications have varied in severity;

while in some cases symptoms have been self-limited, in

other cases neonates have required intensive care unit support

and prolonged hospitalization.

INVEGA® should be used during pregnancy only if the

potential benefit justifies the potential risk to the fetus

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8.3 Nursing Mothers

Paliperidone is 9-hydroxyrisperidone, the active

metabolite of risperidone.

In animal studies,

risperidone

9-hydroxyrisperidone

were

excreted

milk.

Risperidone

9-hydroxyrisperidone are also excreted in human

breast milk. Caution should be exercised when

INVEGA

is administered to a nursing woman.

The known benefits of breastfeeding should be

weighed against the unknown risks of infant

exposure to paliperidone

Paliperidone

excreted

human

breast

milk.

Paliperidone

9-hydroxyrisperidone,

active

metabolite of risperidone. In animal studies, risperidone

and 9-hydroxyrisperidone were excreted in milk.

Risperidone and 9-hydroxyrisperidone are also excreted

in human breast milk. Caution should be exercised when

INVEGA

is administered to a nursing woman. The

known benefits of breastfeeding should be weighed

against the unknown risks of infant exposure to

paliperidone

8.4 Pediatric Use

Safety and effectiveness of INVEGA

in patients

< 18 years of age have not been established

Safety and effectiveness of INVEGA® in the treatment

of schizophrenia were evaluated in 150 adolescent

subjects 12-17 years of age with schizophrenia who

received INVEGA® in the dose range of 1.5 mg to 12

mg/day in a 6-week, double-blind, placebo-controlled

trial

Safety and effectiveness of INVEGA® for the

treatment of schizophrenia in patients < 12 years of age

have not been established. Safety and effectiveness of

INVEGA® for the treatment of schizoaffective disorder

in patients < 18 years of age have not been studied

In a study in which juvenile rats were treated with oral

paliperidone from days 24 to 73 of age, a reversible

impairment of performance in a test of learning and

memory was seen, in females only, with a no-effect dose

of 0.63 mg/kg/day, which produced plasma levels

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(AUC) of paliperidone similar to those in adolescents.

No other consistent effects on neurobehavioral or

reproductive development were seen up to the highest

dose tested (2.5 mg/kg/day), which produced plasma

levels of paliperidone 2-3 times those in adolescents

Juvenile dogs were treated for 40 weeks with oral

risperidone,

which

extensively

metabolized

paliperidone in animals and humans, at doses of 0.31,

1.25, or 5 mg/kg/day. Decreased bone length and

density were seen with a no-effect dose of 0.31

mg/kg/day, which produced plasma levels (AUC) of

risperidone plus paliperidone which were similar to

those

children

adolescents

receiving

maximum recommended human dose of risperidone. In

addition, a delay in sexual maturation was seen at all

doses in both males and females. The above effects

showed little or no reversibility in females after a 12-

week drug-free recovery period

The long-term effects of INVEGA® on growth and

sexual maturation have not been fully evaluated in

children and adolescents

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Special Populations

Renal Impairment

The dose of INVEGA

should be reduced in

patients

with

moderate

severe

renal

impairment

[see Dosage and Administration

(2.5)].

disposition

single

dose

paliperidone. ……….impairment, corresponding

to an average increase in exposure (AUCinf) of

1.5 fold, 2.6 fold, and 4.8 fold, respectively,

…….. (CrCl ≥ 80 mL/min)

Hepatic Impairment

In a study in subjects with moderate hepatic

impairment (Child-Pugh class B), the plasma

concentrations of free paliperidone were similar

to those of healthy subjects, although total

………... INVEGA

has not been studied in

patients with severe hepatic impairment

Renal Impairment

The dose of INVEGA

should be reduced in patients

with moderate or severe renal impairment [see Dosage

and Administration (2.5)]. The disposition of a single

dose paliperidone 3 mg extended-release tablet was

studied in adult subjects with varying degrees of renal

function. Elimination of ……………., impairment,

respectively, compared with 23 hours in subjects with

normal renal function (CrCl ≥ 80 mL/min)

Hepatic Impairment

In a study in adult

subjects with moderate hepatic

impairment

(Child-Pugh

class

plasma

concentrations of free paliperidone were similar to those

of healthy subjects, although total ……….. INVEGA

has not been studied in patients with severe hepatic

impairment

Adolescents (12-17 years of age)

Paliperidone systemic exposure in adolescents weighing

≥ 51 kg (≥ 112 lbs) was similar to that in adults. In

adolescents weighing < 51 kg (< 112 lbs), a 23% higher

exposure was observed; this is considered not to be

clinically significant.

Age did not influence the

paliperidone exposure

CLINICAL STUDIES

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Schizophrenia

The acute efficacy of INVEGA

(3 mg to 15 mg

once daily) was established in three placebo-

controlled and active-controlled (olanzapine)

..……

Schizoaffective Disorder

The acute efficacy of INVEGA

(3 mg to 12 mg

once daily) in the treatment of schizoaffective

disorder

established

placebo-

controlled, 6-week trials in non-elderly adult

subjects. Enrolled subjects 1) met DSM-IV

criteria for schizoaffective disorder

Schizophrenia

Adults

The acute efficacy of INVEGA

(3 mg to 15 mg once

daily) was established in three placebo-controlled and

active-controlled (olanzapine)

Adolescents

The efficacy of INVEGA® in adolescent subjects with

schizophrenia was established in a randomized, double-

blind, parallel-group, placebo-controlled, 6-week study

using a fixed-dose weight-based treatment group design

over the dose range of 1.5 to 12 mg/day. The study was

carried out in the US, India, Romania, Russia, and

Ukraine, and involved subjects 12-17 years of age

meeting DSM-IV criteria for schizophrenia,

with

diagnosis confirmation using the Kiddie Schedule for

Affective Disorders and Schizophrenia-Present and

Lifetime Version (K-SADSPL)

Eligible subjects were randomly assigned to 1 of 4

treatment groups: a placebo group or INVEGA® Low,

Medium, or High dose groups. Doses were administered

based on body weight to minimize the risk of exposing

lower-weight adolescents to high doses of INVEGA®.

Subjects weighing between 29 kg and less than 51 kg at

the baseline visit were randomly assigned to receive

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placebo or 1.5 mg (Low dose), 3 mg (Medium dose), or

6 mg (High dose) of INVEGA® daily, and subjects

weighing at least 51 kg at the baseline visit were

randomly assigned to receive placebo or 1.5 mg (Low

dose), 6 mg (Medium dose), or 12 mg (High dose) of

INVEGA® daily. Dosing was in the morning without

regard to meals

Efficacy was evaluated using PANSS. Overall, this

study demonstrated the efficacy of INVEGA® in

adolescents with schizophrenia in the dose range of 3 to

12 mg/day. Doses within this broad range were shown

effective,

however,

there

clear

enhancement to efficacy at the higher doses, i.e., 6 mg

for subjects weighing less than 51 kg and 12 mg for

subjects weighing 51 kg or greater.

Although

paliperidone was adequately tolerated within the dose

range of 3 to 12 mg/day, adverse events were dose

related

Schizoaffective Disorder

Adults

The acute efficacy of INVEGA

(3 mg to 12 mg once

daily) in the treatment of schizoaffective disorder was

established in two placebo-controlled, 6-week trials in

non-elderly adult subjects. Enrolled subjects 1) met

DSM-IV criteria for schizoaffective disorder

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Storage and Handling

Blister: Do not store above 30°C, Protect from

moisture. Store in the original package

Bottle: Do not store above 30°C, Protect from

moisture. Store in the original package. Keep the

bottle tightly closed to protect from moisture

Store up to 25ºC (77ºF); excursions permitted to

15 - 30ºC (59 - 86ºF) [see USP Controlled Room

Temperature]. Protect from moisture

INVEGA

(paliperidone) Extended-Release

Tablets

Manufactuer ALZA Corporation, Vacaville, CA

95688

Janssen Cilag S.p.A., Via C. Janssen 04100,

Borgo S. Michele, Latina, Italy

Registration holder: J-C Health Care Ltd.,

Kibbutz Shefayim 60990, Israel

Blister:

Do not store above 30°C, Protect from

moisture. Store in the original package

Bottle: Do not store above 30°C, Protect from moisture.

Store in the original package. Keep the bottle tightly

closed to protect from moisture

Store up to 25ºC (77ºF); excursions permitted to 15 -

30ºC

86ºF)

[see

Controlled

Room

Temperature]. Protect from moisture

INVEGA

(paliperidone) Extended-Release Tablets

Manufactuer: ALZA Corporation, Vacaville, CA 95688

Janssen Cilag S.p.A., Via C. Janssen 04100, Borgo S.

Michele, Latina, Italy

Registration holder: J-C Health Care Ltd., Kibbutz

Shefayim 6099000, Israel

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